Controlled Release Nateglinide Tablets Using Na-CMC and HPC Hydrophilic Polymer

 

Suhas Nalle *, Rupali Sarpate, Mallikarjuna Setty, Inayat Pathan and Anand Deshmukh

Smt. Sharadchandrika Suresh Patil College of Pharmacy, Chopda-425 107, Dist-Jalgaon, India.

*Corresponding Author E-mail: suhasnalle@yahoo.com

ABSTRACT:

Nateglinide, a novel anti-diabetic drug used for management of type II (noninsulin-dependent) diabetes mellitus (NIDDM) was formulated into matrix tablet using hydrophilic polymers such as HPMC, HPC, and Na CMC as release retardants. In present study, the hydrophilic matrixes prepared were containing a blend of one or more gel forming polymer and then the binary mixture was finally prepared having different concentrations. The concentration of nateglinide was kept constant and MCC was used as filler. The tablets were evaluated for hardness, friability, thickness, drug content, invitro release. In the present study, the effect of polymer concentration, binary polymer mixture and direct compression methods on drug release profiles was studied. It was observed that the type of polymer and its concentration influences the drug release from matrix tablets. Matrix tablets that contained a blend of Na CMC and cellulose ethers, successfully sustained the release of nateglinide for a period of 12 hrs. Nateglinide was predominantly released by non-fickian (anomalous) mechanism that is diffusion through the honeycomb network and polymer relaxation.

 

 

 

INTRODUCTION:

The drug nateglinide [N- (trans-4-isopropyl cyclohexylcarbonyl)-D-phenylalanine] is having  rapid onset and short duration action and is used in type II diabetes mellitus (insulinotropic action)^1,2. Nateglinide is having short half life (1.5to 2 hr) and dose is 180mg in TDS/day. For the purpose of maintaining the plasma concentration for long time and to reduce the dose administration interval, the hydrophilic matrices tablets were prepared. Hydrophilic swellable polymers are widely used to control the release of drugs from matrix formulations ^{3, 4}. Cellulose ethers such as Hydroxy  Propyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and sodium carboxy methyl cellulose (NaCMC) have gained popularity in the formulation of oral hydrophilic matrices due to their swelling properties. Additionally, cellulose ethers have good compression characteristics such that they can be directly compressed to form sustained release swellable matrices⁵. The key element of drug release from swellable polymers is the use of polymers that will undergo transition from the glassy to the rubbery state, which is characterized by a gel like layer. This transition should occur fairly rapidly so that the drug for the release has to pass through the viscous gel³.

 

The present work is focused on the preparation of hydrophilic matrices of nateglinide (water-insoluble drug) containing a blend of one or more gel forming polymers. The concentration of nateglinide was kept constant at 120mg. MCC was used as filler. The formulations were prepared as combination of HPMC with other polymers selected. The total amount of polymer content in the tablet was varied from 30 to 45% of the total tablet weight, while the percentage of the two polymers used in formulations was varied from 15 to 30%. Within the formulations, the concentration of the polymers was varied such that four levels were obtained (total 8 formulations were prepared). Study was carried to optimize the hydrophilic matrices for nateglinide which contained a blend of one or more gel forming polymers and further the formulations were evaluated with respect to various physical parameters (hardness, friability, Hausner’s ratio, Carr’s index) and release mechanism of nateglinide from various formulations. The work is also exaggerated on to the evaluation of the tablets with respect to content uniformity and in-vitro dissolution rate studies.

 

MATERIALS AND METHODS:

Materials:

Nateglinide was a kind donation from Glenmark Pvt.Ltd (Mumbai). The microcrystalline cellulose (Avicel PH 101, MCC), Hydroxypropyl methylcellulose (Methocel, K4M Premium, and HPMC), Sodium carboxymethylcellulose (Na CMC), Hydroxy propyl cellulose (HPC) (200-400 cps) and magnesium stearate were purchased from S.D. Fine Chemicals Pvt. limited, Mumbai.

Table 1: Composition of formulations prepared for tablet matrices containing a constant amount of Nateglinide (120 mg) (all ingredients in mg)

Formulation	Nateglinide	HPC	Na CMC	HPMC	MCC	Mg. Stearate
F1	120	80	-	80	237	3
F2	120	120	-	120	157	3
F3	120	160	-	80	157	3
F4	120	80	-	160	157	3
F5	120	-	80	80	237	3
F6	120	-	120	120	157	3
F7	120	-	160	80	157	3
F8	120	-	80	160	157	3

 

Table 2: Pre-compressional parameters of all formulations

Formulation	Angle of repose (±SD), n=3(θ)	Bulk density (g/cm­­­­3) (±SD), n=3	Tapped density (g/cm3) (±SD), n=3	%Compressibility (±SD), n=3	Hausner’s ratio (±SD), n=3
F 1	22.52± 0.97	0.87± 0.046	1.08 ± 0.025	19.44 ± 0.51	1.24± 0.18
F 2	22.03 ± 1.1	0.82 ± 0.009	1.06 ±0.031	22.62 ± 0.41	1.29± 0.21
F 3	22.15 ± 0.94	0.81 ± 0.010	1.04 ± 0.021	15.28 ± 0.46	1.18± 0.19
F 4	22.11 ± 0.91	0.84 ± 0.022	1.05 ± 0.35	20.00 ± 0.64	1.24±0.18
F 5	22.03 ± 0.81	0.83 ± 0.020	1.12 ± 0.030	23.86 ± 0.84	1.34± 0.01
F 6	20.40 ± 0.84	0.86 ± 0.016	1.09 ± 0.021	23.65 ± 0.42	1.26± 0.01
F 7	23.02 ± 0.84	0.82 ± 0.21	1.12 ± 0.015	16.78 ± 0.51	1.36± 0.10
F 8	21.80 ± 0.95	0.85 ± 0.039	1.04 ± 0.019	23.86 ± 0.42	1.22± 0.14

Data Mean ± SD; n=3

 

Table 3: Post-compressional parameters of formulations (F1-F8)

Formulation	Hardness Test (Kg/cm2) (±SD), n=3	Friability (%) (±SD), n=10	Thickness (mm) (±SD), n=3	Drug content(%), (±SD), n=3
F 1	5.1 ± 0.14	0.45 ± 0.045	5.27 ±0.06	99.93 ± 0.12
F 2	5.0 ± 0.15	0.69 ± 0.64	5.26 ±0.04	99.96 ± 0.13
F 3	5.1 ± 0.20	0.75 ± 0.034	5.27 ±0.03	99.97 ± 0.16
F 4	5.2 ± 0.21	0.84 ± 0.042	5.28±0.04	99.98 ± 0.18
F 5	5.3 ± 0.19	0.74 ± 0.045	5.32 ±0.03	99.98 ± 0.15
F 6	5.2 ± 0.12	0.62 ± 0.023	5.34 ±0.02	99.82 ± 0.16
F 7	5.0 ± 0.29	0.84 ± 0.042	5.29 ±0.04	99.89 ± 0.17
F 8	4.9 ± 0.19	0.62 ± 0.35	5.28 ±0.05	99.97 ± 0.11

Data Mean ± SD; n=3

 

 

Methods:

Preparation of calibration curve:

Weighed quantity of nateglinide (20mg) was dissolved in 2 ml methanol and volume made up to 100 ml with phosphate buffer (pH 6.8) to make up the concentration of 200 mcg/ml. From this stock solution 0.5, 1, 1.5, 2, 2.5ml solution were transferred to 25ml volumetric flask and diluted up to 25 ml to make 4, 8, 12, 16, and 20-mcg/ml concentrations respectively. The absorbances of these solutions were determined in UV spectrophotometer at 210 nm, and calibration curve was plotted⁶.

 

Preparation of tablet by direct compression:

The tablet was prepared, containing the active ingredient i.e. Nateglinide and the mixture of polymer (HPMC with Na CMC, HPMC with HPC), filler (MCC), lubricant (magnesium stearate) and this was blended together by dry mixing in a laboratory mixer (poly bag) for 10 mins. In all formulations the amount of nateglinide is 120 mg. Total tablet weight is kept at 520 mg. The mixture was then compressed using 12mm standard concave punch and die set (Rimek Mini Press 1) at compression force 6 ton. The formulations of the tablets with their codes are listed in Table 1.

 

Evaluation of Characteristics of tablets:

Micromeritic properties:

Angle of repose:

Angle of repose was determined using funnel method^7,8. A funnel was fixed at a particular height on a burette stand. A graph paper was placed below the funnel on the table. The powder mixture was allowed to fall through the funnel. The radius (r) of the pile was noted. Maximum pile height (h) was also noted. Angle of repose of the powder mixture was calculated using the expression.

Angle of repose (q) = tan^-1 (h/r)

 

Carr’s consolidation index:

1. Apparent bulk density:

The bulk density, a measure used to describe packing of materials or granules, was determined by transferring the accurately weighed sample of powder mixture to a graduated cylinder with the aid of a funnel.  The initial volume was noted. Ratio of weight of the sample to the volume it occupied was calculated^{7, 8}.

 

2. Tapped density and Carr’s index:

Weighed sample of powder mixture was transferred to a graduated cylinder and was tapped for a fixed time or for a fixed number of taps (100). The tapped density was determined by using the following formula: 

Density = Mass / Volume

Based on the apparent bulk density and the tapped density, the percentage compressibility of the powder mixture was determined by the following formula^7,8.

 

                         Tapped density- Bulk density

Carr’s index =                                                      X   100

                                   Tapped density

 

3. Hausner’s ratio:

Hausner ratio^{7, 8} is an indirect index of ease of measuring the powder flow. It is calculated by the following formula

 

                                Tapped density

Hausner’s ratio =

                                Bulk density

 

Lower Hausner ratio (<1.25) indicates better flow properties than higher ones (>1.25).

 

Fig 1: Dissolution profiles of formulations containing HPC/HPMC

 

EVALUATION OF TABLETS:

1. Hardness:

Monsanto hardness tester was used for the determination of the hardness. The tablet was placed in contact between the plungers and the handle was pressed, the force of the fracture was recorded. For each formulation the hardness of 6 tablets was evaluated⁹.

 

2. Uniformity of thickness:

The crown-to-crown thicknesses of ten tablets from each batch were determined using Vernier Calliper⁹.

 

Fig 2: Dissolution profiles of formulations containing NaCMC/HPMC

 

3. Friability:

Friability of the tablets was determined using Roche friabilator⁹ (Electrolab, Mumbai). This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inches in each revolution. Preweighed sample of tablets was placed in the friabilator and were subjected to 100 revolutions. Tablets were dedusted using a soft muslin cloth and reweighed. The friability (F) is given by the formula

 

                                F = (1- W₀ / W) × 100

 

Where, W₀ is the weight of the tablets before the test and W is the weight of the tablet after the test.

 

 

Fig 3: Swelling studies of different Polymer blend

4. Uniformity of drug content:

For determination of drug content at least three tablets from each formulation were weighed individually, pulverized, and diluted to 250ml with sufficient amount of phosphate buffer pH 6.8. After that an aliquot of the filtrate was diluted and analyzed spectrophotometrically at 210 nm.

 

Dissolution Studies:

Dissolution studies were performed in 900 ml of phosphate buffer, using the basket method (USP 25), at 50 rpm and 37± 0.5 ⁰C. Withdrawing 5 ml samples at various time intervals and replacing them with equal amounts of dissolution medium, determined the amount of nateglinide released. The concentration of nateglinide was obtained by measuring its absorbance at 210 nm in Shimadzu, UV-1700 spectrophotometer, Japan⁶.

 

Swelling Index:

Representative formulations (F1 and F5) were analyzed for its swelling behavior. The matrix tablets were weighed and placed in tared metallic baskets. These baskets were then immersed in 900 ml of Phosphate buffer pH 6.8, at 50 rpm and 37±0.5 °C (USP 25 basket method). At specified time intervals, the baskets containing the matrix tablets were removed, lightly blotted with tissue paper so as to remove excess water and weighed again. They were then placed back in the dissolution vessel as quickly as possible. The percent degree of swelling was calculated by using the formula

Percent degree of swelling= [(Ws−W_d)/W_d] ×100

Where, Ws is the weight of the swollen matrix at time t and W_d is the weight of the dry matrix. The swelling study was done in triplicate for all samples tested¹⁰.

 

 

Table 4: Kinetic parameters of dissolution data described by Korsmeyer-Pappas equation.

 

Formulation	n	Transport mechanism	r2
F 1	0.5830	Non Fickian diffusion	0.9780
F 2	0.5860	Non Fickian diffusion	0.9720
F 3	0.4565	Fickian diffusion	0.8880
F 4	0.4890	Non Fickian diffusion	0.9450
F 5	0.8130	Non Fickian diffusion	0.9815
F 6	0.5470	Non Fickian diffusion	0.9600
F 7	0.7090	Non Fickian diffusion	0.9940
F 8	0.4870	Non Fickian diffusion	0.9780

 

FTIR Studies:

IR spectra of the formulated tablets (F7) was recorded in a Fourier transform infrared (FTIR) spectrophotometer (Shimadzu 8400, Japan) with KBr pellets; cm^-1.

 

 

RESULTS AND DISCUSSION:

Evaluation of characteristics of tablets:

The characteristics properties of all formulations used are given in Table 2 which dealt up with the precompressional parameters i.e. Bulk density (0.81 to 0.87), tapped density (1.04 to 1.12), angle of repose (20.40 to 22.52), % compressibility (15.28 to 23.86), Hausner’s ratios (1.18 to1.36). The results indicate that powder mixtures are having good flow property and suitable for direct compression. The evaluated postcompresionnal parameters of tablets of all the formulations used are given in Table 3. Precompressional parameters indicated that powder blend used for preparing tablets was showing free flowing property. Postcompresionnal parameter i.e. hardness (4.9 to 5.3), friability (0.45 to 0.84), thickness (5.26 to 5.34) and drug content (99.93 to 99.98) was within the acceptable limit.

 

All the tablet matrices that were tested in the study indicated that increased concentration of the gelling polymer HPMC in the matrix sustained the drug release. In general, the release data from swellable systems can be analyzed according to the following Power law expression:

 

                                M _t / M _¥ = ktⁿ

 

Where,  M _t / M _¥ is the fraction of drug released at time t, k is the proportionality constant which accounts for the structural and geometrical properties of the matrix, and n is the diffusional exponent indicative of the mechanism of drug release. According to the criteria for release kinetics from swellable systems, a value of release exponent, n = 0.45, 0.45<n<0.89 and 0.89<n<1.0 indicates Fickian (case I) diffusion, non-Fickian (anomalous) diffusion and zero-order (case II) transport, respectively¹¹. The values of release parameters n and k, were determined after plotting the % drug released as a function of time according to equation by subjecting the data points to least square linear regression method. All the formulations except F3 prepared as combination, showed the release of drug which followed non-Fickian transport. Formulation F3 followed Fickian release as shown in table 4. It progressively thickens the gel layer, and slower the erosion as on time progress. This lead to increase the diffusion path length, decrease the release rate with time. The value of diffusion coefficient (n) for HPC/HPMC matrices was 0.4890-0.5860, which indicates non-Fickian (anomalous) behavior and that the drug partially diffuses through the swollen polymer matrix and also partly through gradually expanding the hydrating matrix with increasing diffusional path length. The diffusional data for the HPC/HPMC matrices showed linearity over the entire dissolution period. Lower hydrophilicity and lower water uptake capability of HPC combined with gel viscosity of HPMC lead to slowest release of nateglinide from all matrices made from HPC/HPMC combination^{12, 13, 14}. In the formulation F3, increase in concentration of HPC leads to retard the release of drug due to its lower hydrophilicity. The linear release of nateglinide is noticed in the matrices prepared with combination of HPMC and NaCMC. Formulation (F5) contained lowest concentration of each polymer, i.e. 15% each, failed to control the release and disintegrated prematurely. Total drug is released within 8.5hrs. The control release upto 12hrs was seen with formulation F7 and is shown in the Fig 2. The slower release from this combination was due to interaction between NaCMC chain, ionic polymer and HPMC chain, non ionic polymer^15-17. The capacity of NaCMC to form hydrogen bonds with the hydroxyl group of HPMC leads to a synergistic effect on gel viscosity that explains the better control of these combined polymers on the release of nateglinide.

 

Swelling Studies:

The rate of swelling for matrix tablets that contain equal proportion of the two polymers is shown in the Fig 3. Formulation F1and F5 was used for the swelling analysis. Swelling of the matrix, indicated by the transition of the polymer from the glassy to the rubbery state, is an important parameter in the determination of the release characteristics of the system. Fig 3 showed that matrices that contained NaCMC/HPMC tablets achieved the highest degree of hydration which ultimately indicates that the ionic interactions between the cellulose ethers increased the water uptake capacity to a greater extent. On the other hand, HPC is less hydrophilic and was hydrated to a much lower extent when combined with HPMC. For matrices containing a combination of ionic and non-ionic polymer, swelling was higher and more control over the release of nateglinide was observed.

 

FTIR Study:

FTIR spectra of the formulation containing drug and polymer indicate that there is no shifting of position of characteristics band of the drug and polymer. When compared with IR spectra of individual component clearly indicating that the drug and polymer have maintained their individual identity and there is no interaction of the drug with the polymer.

 

CONCLUSION:

Matrices tablets that contained a blend of Na CMC and HPMC (F7) successfully controlled the release of nateglinide for a period of 10-12hr. The controlled release from NaCMC/HPMC combination was due to interaction between NaCMC chain (ionic polymer) and HPMC chain (non-ionic polymer) which resulted in favorable increase in the water uptake capacity and gel viscosity due to the formation of the gel layer leading to a better control over the release of nateglinide. Thus the formulation (F7) showed the controlled release of nateglinide as desired and predominantly release by non-fickian (anomalous) mechanism.

 

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Received on 22.06.2009          Modified on 20.08.2009

Accepted on 21.09.2009         © RJPT All right reserved