Formulation development and Evaluation of immediate and sustained release Bilayer Tablets Containing Amitriptyline HCl and Pregabalin for the treatment of Neuropathic Pain

 

P. Purushothaman*, A. Umar Faruk Sha, T. Vetrichelvan.

Department of Pharmaceutics, Adhiparasakthi College of Pharmacy, melmaruvathur, kanchipuram district, Tamilnadu -603 319, India.

*Corresponding Author E-mail: purushoth17293@gmail.com

 

ABSTRACT:

The objective of proposed study was to prepare Bilayer tablet comprising Amitriptyline HCl (AMT) and pregabalin (PGB) for effective treatment of neuropathic pain. AMT was formulated as immediate release (IR) layer using disintegrants such as starch whereas PGB was formulated as sustained release (SR) layer using polymers hydroxypropyl methyl cellulose (HPMC) K100M for increasing with a view to deliver the drug at sustained manner in gastrointestinal tract and consequently into systemic circulation. Tablet blends were evaluated through various pre-compression tests, compressed by wet granulation method and evaluated. As disintegrant, starch at 14.70% concentration produced excellent results by immediately releasing AMT to exert its anti-depression and other additional beneficial effects. K100M grade of HPMC produced excellent SR efficiency at 1:1 drug-polymer ratio whereas extended of the dosage form for long-lasting effect of the therapeutic agent. Final formulation released 98.92% drug in 45 min and 97.27% drug in 12 h, in vitro from respective layers. Pre-compression and post-compression parameters of optimized IR layer comprising AMT and SR layer comprising PGB exhibit satisfactory results. Bilayer tablet of AMT and PGB may prove to be very effective as a combination therapy for the treatment of neuropathic pain by sequential release of the drug.

 

KEY WORDS: Bilayer Tablets,  Amitriptyline HCl, Pregabalin

 

 


1. INTRODUCTION:

The goal of any drug delivery system is to provide a therapeutic amount of the drug to the proper site in the body to achieve promptly and then maintain the desired drug concentration. In recent years, a growing interest has been developed in designing drug delivery systems that include an immediate release (IR) component to sustained release (SR) dosages.

 

The bilayered tablet is innovative drug delivery system comprising two layers, i.e. IR and SR were the choice of the dosage form to control the delivery the rate of either single or two different API’s and to administer fixed dose combinations of different drugs. The term bilayered tablets refer to tablet containing subunits that may be either same or different and are preferred when the release profiles of the drugs are different from one another. Bilayered tablets allow for designing and modulating the dissolution and release characteristics and they are prepared with one layer of drug for IR while the second layer designed to release drug latter, either as the second dose or sustained or controlled release manner to reduce the frequency of the dosing and to increase the effectiveness of drug by reducing the dose required; providing uniform drug delivery, avoiding chemical incompatibility.

This is novel type of smart and advanced drug delivery system in the form of bilayer tablet used for oral administration of Amitriptyline HCl (AMT) as IR and Pregabalin (PGB) as SR for effective treatment of neuropathy by combination therapy. Neuropathy a disease of nerve is the common cause of pain in many patients. Chronic neuropathic pain is the most disturbing symptom of lesions in the peripheral nervous system that can be of many forms and due to various reasons. Combination therapy using low dosage of two different agents seems to be very effective and beneficial over mono therapy in such situations as problems of dose-dependent side effects was minimized. A low dose combination of two different agents reduces the dose related risk; that occur with maximal dosage of individual component of the combined tablet, and thus dosage of the single component can be reduced. The addition of one agent may improve the effects of the other.

 

Amitriptyline is a tricyclic antidepressant (TCA). 3(10,11dihydro 5H dibenzo (a,b) cyclohetene-5-cylidene)-N,N-dimethylpropan-1-amine. It is the most widely used TCA and has at least equal efficacy against depression as the newer class of selective serotonin reuptake inhibitor (SSRI) according to a study from early 2001. As well as reducing depressive symptoms, these types of tricyclics also ease migraines, tension headaches, anxiety attacks and some schizophrenic symptoms. It is also known to reduce aggression and violent behaviour.

 

PGB an antiepileptic, (S)-3-(amino methyl)-5-methylhexanoic acid, binds to the alpha-2-delta subunit site of neuronal voltage-gated calcium channel, resulting in reduced depolarization induced calcium influx at nerve terminals with a consequential reduction in the release of excitatory neurotransmitters. In addition to epilepsy, it has demonstrated excellent efficacy for the treatment of neuropathic pain and generalized anxiety disorder.

 

2. MATERIALS AND METHODS:

AMT and PGB were obtained as a gift sample from sunglow Pharmaceutical Pvt Ltd, Pondycherry. Hydroxypropyl methylcellulose (HPMC) K100M, microcrystalline cellulose, lactose, poly vinyl pyrrolidone K30 (PVP K30), isopropyl alcohol, magnesium stearate, talc was purchased from local authorized dealer. All other reagents and chemicals used were of analytical reagent grade.

 

2.1 Powder characterization:

2.1.1 Angle of repose:

The angle of repose, the maximum slope or angle, measured in degrees from the horizontal, at which loose solid material will remain in place without sliding, was determined using fixed funnel method. The accurately weighed drug powder or its physical mixture was used. The height of the funnel was adjusted in such a way that the tip of the funnel just touches the apex of the heap of the drug powder. The powder was allowed to flow through the funnel freely onto surface. The height (h) and radius (r) of the powder cone was measured, and angle of repose was calculated by following formula.

<< 

2.1.2 Density:

Loose bulk density (LBD): Apparent bulk density was determined by placing the drug excipients blend after sieving into a graduated cylinder and measuring the volume and weight as it is. LBD was determined using following formula.

 

ρb = M/ Vb

 

Tapped bulk density (TBD): 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) using a digital tap density apparatus (Electro lab Ltd, India). The tapped density was determined by using the following formula.

ρt = M / Vt

 

2.1.3 Compressibility index:

Based on the bulk density and the tapped density, the percentage compressibility Carr’s compressibility index (%) of the powder mixture was determined by the following formula.

                             CI   =    ρt –ρb X 100

                                                     ρt

 

2.1.4 Hausner ratio:

Hausner’s ratio is an indirect index of ease of powder flow. It is calculated by the following formula.

 

HR = ρt / ρb

 

2.2 Drug–excipient interaction study:

The compatibility of drug and polymer under the experimental conditions is an important pre-requisite and it is, therefore, necessary to confirm that the drug does not react with excipients. The studies were carried out using Fourier transform infrared (FT-IR) spectroscopy.

 

2.1.1 FT-IR spectroscopy:

To investigate any possible interaction between the AMT, PGB and the polymer under investigation, FT-IR spectrophotometer method was used. Samples of pure drug AMT, PGB and IR layer and SR layer were differently crushed with KBr to make KBr pallets for the IR spectra using Shimadzu IR Affinity-1S FTIR spectrometer (Shimadzu, Japan).

 

2.3 Preparation of IR tablets of AMT:

IR granules containing AMT and starch were mixed with other excipient for 15 min in porcelain mortar except talk and magnesium stearate, and the mass was prepared using iso propyl alcohol as a granulating fluid. The wet mass was passed through 10 # sieve, and granules were allowed to dry in oven at 50°C for 30 min. dried granules were screened through 14 # sieve, 10% fine was added into it and mixed with talk and magnesium stearate for 5 min and processed for compression using 10 mm round flat-faced punches of single punch tablet machine. The composition of all batches was represented in Table 1. Before the compression; granules were evaluated for several precompression parameters.


 

Table 1: Formula for IR tablets of Amitriptyline HCl

S.No.

INGREDIENTS

A1 (mg)

A2 (mg)

A3 (mg)

A4 (mg)

A5 (mg)

1.

Amitriptyline HCl

10

10

10

10

10

2.

MCC 102

40

40

40

40

40

3.

Lactose

89.5

84.5

79.5

74.5

69.5

4.

Starch

5

10

15

20

25

5.

Dicalcium phosphate

15

15

15

15

15

6.

Tartrazine

0.5

0.5

0.5

0.5

0.5

7.

PVP K 30

5

5

5

5

5

8.

Iso propyl alcohol

qs

qs

qs

qs

Qs

9.

Talc

3

3

3

3

3

10.

Magnesium stearate

2

2

2

2

2

 


2.3.1 Precompression parameter evaluation of AMT blends:

The AMT blends (granules) of all batches were evaluated for angle of repose, density, compressibility index and Hausner’s ratio as per the reported methods described above.

 

2.3.2 Evalution of AMT tablets:

Tablets were evaluated for weight variation, friability, hardness and thickness performed according to the Indian pharmacopoeia 2007.

 

Drug content:

20 tablets were weighed and powdered and 200 mg equivalent weight of AMT was accurately weighed, transferred into a 100ml volumetric flask and dissolved in 0.1N HCl volume was made up to the mark. The solution in volumetric flask was filtered, and suitable dilutions were made and analyzed at 239 nm on UV-visible spectrophotometer (Shimadzu UV-1601). Maximum absorbance (λ max) for AMT was determined UV spectrophotometrically by scanning dilute AMT solution in 0.1N HCl at 200-400. The drug content of each sample was estimated using standard calibration curve of AMT in 0.1N HCl. During dissolution studies, AMT exhibited good absorption at 239 nm using 0.1N HCl as a dissolution media.

 

Disintegration test:

Randomly six tablets were selected from each batch for disintegration test. Disintegration test was performed without disc in simulated gastric fluid at 37°C ± 0.5°C temperature using the United States Pharmacopeia (USP) disintegration test apparatus. The mean ± standard deviation (SD) of six tablets was calculated.

 

Dissolution test:

Dissolution test of AMT tablet was performed in simulated gastric fluid as dissolution medium using USP dissolution test apparatus II at 50 rpm and 37°C ± 0.5°C temperature. Test sample (5 ml) was withdrawn at a specific time interval (15, 30 and 45 min) and replaced with fresh dissolution media maintained at 37°C ± 0.5°C. The test sample was filtered and the concentration of dissolved drug was determined using ultraviolet (UV) spectrophotometer at λ max 239 nm. This test was performed on six tablets and mean ± SD calculated.

 

2.4 Preparation of SR tablets of PGB:

The SR granules were prepared by wet granulation technique. Required quantity of PGB and polymers (HPMC K100M) was weighed and passed through sieve #40 and were mixed homogeneously in a poly bag for about 5-10 min and was taken in a mortar. To the mortar 5% PVP K30 in isopropyl alcohol was added as granulating agent. The wet mass was passed through sieve #10 and dried in hot air oven at 50°C for 30 min; dried granules were screened through sieve #14.


Table 2: Formula for SR tablets of Pregabalin

S.No.

Ingredients

P1 (mg)

P2 (mg)

P3 (mg)

P4 (mg)

P5 (mg)

1.

Pregabalin

75

75

75

75

75

2.

MCC 102

80

80

80

80

80

3.

Mannitol

42.75

32.75

22.75

12.75

02.75

4.

HPMC K 100

10

20

30

40

50

5.

PVP K 30

10

10

10

10

10

6.

IPA

Qs

     qs

qs

qs

qs

7.

Talc

0.75

0.75

0.75

0.75

0.75

8.

Magnesium Stearate

0.75

0.75

0.75

0.75

0.75

9.

Colloidal silicon dioxide

0.75

0.75

0.75

0.75

0.75

 


Finally, 10% fine was added to well form granules and was lubricated with magnesium stearate and talc for 5 min. The granules were processed for compression using 10 mm round flat faced punches of single punch tablet machine. Formulation compositions of all batches are given in Table 2. Before the compression; granules were evaluated for several precompression parameters.

 

2.4.1 Precompression parameters - evaluation of PGB blend:

The PGB blends (Granules) of all batches were evaluated for angle of repose, bulk density (TBD, LBD), compressibility index, and Hausner’s ratio as per the reported methods described above.

 

2.4.2 Evaluation of PGB (SR) tablets:

Tablet hardness, weight variation, thickness, and friability were measured using the USP methods. It has been reported that PGB can be detected UV spectrophotometrically at 210 nm.

 

Drug content:

Twenty tablets were weighed triturated to powder and 150 mg accurately weighed equivalent weight of PGB was transferred into a 100ml volumetric flask, dissolved in phosphate buffer pH 6.8; volume was made up to the mark. The solution in the volumetric flask was filtered and suitable dilutions were made and analyzed at 210 nm on UV-visible spectrophotometer (Shimadzu UV-1601). The drug content of each sample was estimated using standard calibration curve of PGB in phosphate buffer pH 6.8. During dissolution studies, PGB exhibited good absorption at 210 nm using phosphate buffer pH 6.8 as a dissolution media. All results were represented as a mean ± SD.

 

Dissolution studies:

The in vitro dissolution studies were carried out in two phases using USP type II apparatus at 50 rpm. The dissolution medium (900 ml) comprising simulated gastric fluid (pH 1.2 HCl buffer) was used for the first 45min in gastric phase and then replaced with phosphate buffer pH 6.8 for 1-12 h (900 ml) for intestinal phase, maintained at 37°C ± 0.5°C. The drug release at different time interval was measured by UV-visible spectrophotometer at 210 nm. The release studies were conducted on six tablets in each batch; results were represented as a mean ± SD.

 

2.5 Bilayer tablets of AMT and PGB:

Development of Bilayer tablets was carried in two different stages, blends of IR layer of AMT and SR layer of PGB were prepared separately and after optimization of individual layer the bilayer tablets were prepared using selected formulas. Optimized batch of AMT (A5) and PGB (P5) was selected for formulation of bilayer tablet and was compressed using 12 mm round flat faced punch of the single punch CADMAC, Ahmedabad India; tablet compression machine. First, the granules of SR layer were poured in the die cavity and compressed with moderate force. Then, the upper punch was lifted and the IR granules were poured in the die cavity, containing initially compressed SR layer and compressed with full force to form bilayer tablet with hardness of 5-8 kg / cm2. The hardness was kept constant for all tablets and was measured using Pfizer hardness tester.


 

Table 3: Formula for Bilayer tablets

Amitriptyline HCl IR Layer

Pregabalin SR Layer

S.No.

Ingrediants

A5 (mg)

S.No.

Ingrediants

P5 (mg)

1.

Amitriptyline HCl

10

1.

Pregabalin

75

2.

MCC 102

40

2.

MCC 102

80

3.

Lactose

69.5

3.

Mannitol

02.75

4.

Starch

25

4.

HPMC K 100

50

5.

Dicalcium phosphate

15

5.

PVP K 30

10

6.

Tartrazine

0.5

6.

IPA

Qs

7.

PVP K 30

5

7.

Talc

0.75

8.

Talc

3

8.

Magnesium Stearate

0.75

9.

Magnesium stearate

2

9.

Colloidal silicon dioxide

0.75

Total weight (mg)

170

Total weight (mg)

220

 


2.5.1 Evaluation of Bilayer tablets of IB and PGB:

Bilayer floating tablets were evaluated for weight variation, friability, hardness, thickness as per the procedure previously mentioned. Content uniformity of both drugs in bilayer tablet was measured by separating both layer of bilayer tablet and measured individually.

 

Dissolution test:

The in vitro dissolution studies were carried out in two phases using USP type II apparatus at 50 rpm. The dissolution medium (900mL) consisted of simulated gastric fluid (pH 1.2 HCl buffer) was used for the first 45min in gastric phase and then replaced with phosphate buffer pH 6.8 for 1-12 h (900mL) for intestinal phase, maintained at 37°C ± 0.5°C. The drug release at different time intervals was measured by UV-visible spectro photometer at 239 and 210 nm for AMT and PGB, respectively. The release studies were conducted on six tablets, and the mean values were plotted versus time with SD. To study the in-vitro release kinetics of the optimized BFT, data obtained from dissolution study were plotted in various kinetics models.

2.6 Drug release kinetics:

1. Zero order equation:

The zero-order release can be obtained by plotting cumulative % percentage drug released vs. time in hours. It is ideal for the formulation to have release profile of zero order to achieve pharmacological prolonged action.

C=K0t

Where,

K0= Zero order constant

               t= Time in hours

 

2. First order equation:

The graph was plotted as log % cumulative drug remaining Vs time in hours.

Log C= log C0- Kt/2.303

Where,

C0= Initial concentration of drug

K= First order

t= Time in hours

 

3. Higuchi kinetics:

The graph was plotted with % cumulative drug released vs. square root of time

Q = Kt½

Where,

K= constant reflecting design variable system (differential rate constant)

t= Time in hours

The drug release rate is inversely proportional to the square root of time

 

4. Hixon and Crowell erosion equation:

To evaluate the drug release with changes in the surface area and the diameter of particles, the data were plotted using the Hixon and Crowell rate equation. The graph was plotted by cube root of % drug remaining vs. time in hours.

Q01/3 – Qt1/3 = KHCXt

Where,

Qt= amount of drug released in time t.

Q0= Initial Amount of drug

KHC= Rate constant for Hixon Crowell equation

 

5. Korsmeyer-Peppas equation:

To evaluate the mechanism of drug release, it was further plotted in Peppas

Equation as log cumulative % of drug released Vs log time.

Mt/Mα = Ktn

Where

Mt/Mα = Fraction of drug released at time t

t = Release time

K= Kinetics constant (Incorporating structural and geometric characteristics of the formulation)

N= Diffusional exponent indicative of the mechanism of drug release.

 

3. RESULTS:

3.1 Drug-excipients interaction study:

FT-IR spectroscopy investigation spectra for AMT, PGB and the polymer mix was exhibited relevant characteristic prominent peaks for respective drugs shows no interaction indicating overall compatibility of drugs with the excipients

.


 

FTIR spectroscopy of Amitriptyline HCl and Pregabalin

 

Fig 1: FTIR of Amitriptyline HCl

 

Fig 2: FTIR of Pregabalin

 

Fig 3: FTIR Spectroscopy of Amitriptyline HCl and Starch

 

Fig 4: FTIR Spectroscopy of Pregabalin with HPMC K100

 


The spectra indicated that there was no drug–excipient interaction as the peaks of the drug and the other excipients were seen in the drug excipient mixture. The study implies that the active ingredients and the excipients are chemically compatible with each other as there was no change in the IR spectral peaks.

 


 

 

3.2 Evaluation of AMT Blend:

Table 4 : Flow property studies of powder blend IR tablets of Amitriptyline HCl

Formulation

Bulk density*

g/cm3

Tapped density*

g/cm3

Carr’s Index (%)

Hausner’s

ratio*

Angle of repose*

(degree)

A1

0.714±0.021

0.833±0.013

09.49±0.011

1.16±0.018

27.29±1.32

A2

0.681±0.026

0.810±0.017

11.91±0.032

1.18±0.025

25.81±0.22

A3

0.731±0.011

0.810±0.017

11.97±0.035

1.10±0.004

27.29±0.57

A4

0.714±0.023

0.810±0.017

11.97±0.035

1.13±0.034

26.56±0.46

A5

0.731±0.032

0.833±0.013

14.29±0.024

1.13±0.034

25.81±0.24

*All the values are expressed as mean ± SD n=3.

 


The bulk density of IR Blends ranged from 0.6818 to 0.7317 g/cm3 and tapped density ranged from 0.8108 to 0.8333g/cm3. The compressibility index of the IR blends ranged from 09.76 to 14.29% and Hausner’s ratio ranged from1.10 to1.18. The angle of repose of IR blends ranged from 25.81 to 27.29. The formulated IR blends with the addition of lubricant showed good flow property.


 

3.4 Evaluation of AMT Tablet:

Table 5: Flow property studies of powder blend IR tablets of Amitriptyline HCl

 Formulation

Weight variation

Thickness

Hardness

Friability

Disintegration time

Drug content

A1

2.15 ± 0.324

3.63 ± 0.0214

 3.30 ± 0.278

0.14 ± 0.030

2min 21sec

97.54 ±0.204

A2

2.21 ± 0.345

3.63 ± 0.0237

3.32 ± 0.210

0.17 ± 0.021

2min57 sec

98.07 ±0.346

A3

2.45 ± 0.311

3.65 ± 0.0227

3.50 ± 0.244

0.20 ± 0.024

2min35 sec

97.26 ±0.082

A4

2.40 ± 0.299

3.61 ± 0.0215

3.33 ± 0.213

0.20 ± 0.024

2min50 sec

97.50 ±0.047

A5

2.52 ± 0.237

3.62 ± 0.0218

3.35 ± 0.215

0.23 ± 0.034

2min29 sec

98.62 ±0.045

*All the values are expressed as mean ± SD n=3.

 


Tablet properties such as weight variation, thickness, hardness, friability, disintegration time, and drug content were represented in Table 4. All batches pass the weight variation 100% ± 5% within range, friability <1%, drug content 90-110% within limit, thickness variation within 5% limit.


 

3.4.1 Dissolution study:

Table 6: In-vitro dissolution studies of IR formulations of Amitriptyline HCl

Time in Minutes

Cumulative % drug release*

A1

A2

A3

A4

A5

0

0

0

0

0

0

15

25.96±0.256

26.90±0.237

27.90±0.476

27.92±0.456

27.96±0.484

30

49.68±0.273

52.72±0.569

52.66±0.582

53.52±0.543

53.67±0.439

45

89.28±0.468

89.24±0.594

92.69±0.457

96.67±0.564

98.92±0.417

*All the values are expressed as mean ± SD n=3.

 


In vitro drug release at 15, 30 and 45 min for all the batches was expressed by a graph cumulative % drug released versus time were represented as cumulative % of drug released at 15, 30 and 45 min to establish positive correlation between the maximal water uptake and the cumulative % of drug dissolved. Fastest dissolution found for batch A5 and hence, it was suitable as an IR layer for bilayer tablet.


 

3.5 Evaluation of PGB blend:

Table 7 : Flow property studies of powder blend SR tablets of Pregabalin.

Formulations

Bulk density*

g/cm3

Tapped density*

g/cm3

Compressibility

index*(%)

Hausner’s

ratio*

Angle of repose*

(degree)

P1

0.731±0.023

0.833±0.016

12.19±0.019

1.13±0.028

27.29±0.37

P2

0.714±0.037

0.810±0.026

11.91±0.031

1.13±0.028

26.56±1.27

P3

0.750±0.015

0.789±0.030

10.24±0.038

1.05±0.041

28.73±0.59

P4

0.714±0.011

0.833±0.024

11.91±0.019

1.16±0.053

28.73±0.59

P5

0.714±0.011

0.810±0.010

11.89±0.386

1.13±0.028

27.29±0.37

*All the values are expressed as mean ± SD n=3.

 


The bulk density of SR blend ranged from 0.7142 to 0.7500 g/cm3and tapped density ranged from 0.7894 to 0.8333 g/cm3. The compressibility index of the SR blend ranged from 10.24 to 12.19 % and Hausner’s ratio ranged from1.05 to1.16. The angle of repose of SR blend ranged from 26.56 to 28.73. The formulated SR blend showed fair to good flow property.


 

3.6 Evaluation of PGB tablet:

Table 8: Flow property studies of powder blend SR tablets of Pregabalin

Formulation

Weight variation

Thickness

Hardness

Friability

Drug content

P1

2.07 ± 0.017

3.13 ± 0.02

5.1 ± 0.22

0.13 ± 0.0095

97.65 ±0.012

P2

2.45 ± 0.011

3.12 ± 0.01

5.3 ± 0.20

0.20 ± 0.0057

98.80 ±0.011

P3

2.29 ± 0.023

3.13 ± 0.02

5.3 ± 0.20

0.09 ± 0.0046

98.20 ±0.015

P4

2.25 ± 0.019

3.12 ± 0.01

5.1 ± 0.22

0.13 ± 0.0098

96.70 ±0.010

P5

2.04 ± 0.024

3.13 ± 0.02

5.3 ± 0.20

0.11 ± 0.0078

98.49 ±0.014

*All the values are expressed as mean ± SD n=3.

 


Tablet properties such as weight variation, thickness, hardness, friability, and drug content of each batch were represented in Table 8. All batches pass the weight variation test and found to be within range (100% ± 5%). Friability of all batches was found <1%, indicates that tablet surfaces are strong enough to withstand mechanical shock and attrition during transportation or storage until they are used. The hardness of tablet increase as polymer concentration increases and friability also decreases as polymer amount increases. Drug content of all batches was found within limit (90-110%). Thickness variation of tablets <5% was also found within the limit.

 

3.6.1 Dissolution study:

PGB is freely soluble in water and both basic and acidic aqueous solutions, posses dissociation constant values (pka1 = 4.2 and pka2 =10.6); therefore, the release of drug from the tablets was only dependent on the nature of matrix structure formed by the polymer. As polymer concentration increases forming dense network structure that retards the drug release from the tablet. Above all studied parameters indicate batch P5 was suitable as a SR layer for bilayer tablet.


 

Table 9: In-vitro dissolution study of Pregabalin SR tablets

TIME

(Hours)

CUMULATIVE % DRUG RELEASE*

P1

P2

P3

P4

P5

0

0

0

0

0

0

1

11.41±0.435

10.92±0.267

10.23±0.532

10.35±0.324

10.43±0.239

2

22.67±0.378

22.49±0.274

21.69±0.431

23.98±0.321

21.08±0.317

3

34.96±0.362

36.32±0.311

34.34±0.342

35.56±0.434

34.52±0.226

4

41.32±0.526

44.10±0.299

43.23±0.562

41.44±0.473

44.31±0.329

5

53.91±0.376

52.18±0.319

50.01±0.235

51.52±0.390

54.02±0.230

6

64.87±0.372

61.42±0.328

63.51±0.417

63.86±0.271

63.83±0.381

7

70.35±0.328

69.32±0.372

69.40±0.271

71.86±0.288

71.98±0.228

8

77.39±0.436

76.95±0.271

77.33±0.228

78.59±0.319

79.65±0.390

9

82.36±0.382

83.52±0.232

81.68±0.342

84.62±0.276

85.25±0.410

10

87.20±0.387

88.65±0.378

88.53±0.378

87.19±0.437

90.43±0.210

11

92.12±0.298

92.75±0.543

92.08±0.422

94.65±0.328

95.64±0.426

12

95.65±0.328

94.54±0.543

94.98±0.279

96.65±0.211

97.87±0.435

*All the values are expressed as mean ± SD n=3.

 


3.7 Mechanism of drug release:

The plot of log cumulative percent drug release versus log time for the Korsmeyer–Peppas equation exhibited linearity with R2 = 0.997 and the release exponent “n” was found to be 0.5334 indicating the Fickian diffusion type of drug release [Figure 5].

 

Fig 5: Korsemeyer peppas kinetics

 

Determination of drug release mechanism of Bilayer tablets:

The co-efficient of determination (R2) was taken as criteria for the conclusion of kinetic modelling. The R2 values of various kinetic models are given in the table 10.

 

Table 10: R2 values of various kinetic models

Kinetic model

co-efficient of determination(R2)

Zero order

0.992

First order

0.9042

Higuchi

0.9951

Hixon- Crowell

0.9871

Korsmeyer and Peppas

0.997

 

The results showed that the best fit kinetic model is Korsmeyer Peppas. The R2 value of Korsmeyer Peppas equation was found to be 0.997, from that it was concluded that the release followed Fickian transport.

 

 

3.8 Evaluation of bilayer tablet of AMT and PGB:

Properties of bilayer tablets such as weight variation, thickness, hardness and friability were determined. The average weight of bilayer tablet was found (390mg) and weight variation (5%) within limit. Friability of bilayer tablet was found (0.40%) <1%. Hardness was found 8 kg/cm2 and thickness variation was found less than 5%. Content uniformity of AMT and PGB in bilayer tablet was found 101.8 ± 0.84 and 100.3 ± 0.37, respectively.

 

Table 11: Post compression study of bilayer tablets

PARAMETERS

BILAYER TABLETS

Uniformity of weight (mg)*

400.06 ± 0.109

Thickness (mm)*

4.2 ± 0.00

Diameter (mm)*

11.00 ± 0.00

Hardness (kg/cm2)*

8.36 ± 0.210

Friability (%)*

0.14±0.0056

Dissolution for amitriptyline HCl*

98.92±0.492

Dissolution for Pregabalin*

97.27±0.591

% Drug content

Amitriptyline HCl

98.61%

Pregabalin

97.28%

*All the values are expressed as mean ± SD n=3.

 

3.8.1 Dissolution study:

In vitro drug release study for bilayer tablet, AMT layer was indicated 98.92% drug release within 45 min where as PGB layer exhibited slow sustained drug release, during 12 h dissolution study 97.27% drug was released. In vitro drug release profile cumulative % drug release versus time plot for AMT and PGB represented in Figures 6, respectively.

 

Fig 6: In-vitro drug release study of bilayer tablets

 

3.9 DISCUSSION:

The Bilayer tablet consisting of AMT as IR was formulated using disintegrant starch in different concentrations. Among these 20% concentration of starch produced excellent results by immediately releasing AMT to exert its anti-depression and other additional beneficial effects. PGB as SR were prepared using polymers different ratio K100M grade of HPMC produced excellent SR efficiency at drug-polymer ratio where as the dosage form for long-lasting effect of the therapeutic agent.

Neuropathy, a disease of the nerve, is the common cause of pain in the modern world. Chronic neuropathic pain is the most disturbing symptom of lesions in the peripheral nervous system. Painful neuropathy is difficult to treat since patients may experience severe pain, various therapies and procedures may be utilized to help ease the signs and symptoms of peripheral neuropathy. Therefore, combination therapy using low dosage of two different agents seems to be very effective and beneficial over mono therapy; proposed novel type of smart advanced drug delivery system in the form of bilayered tablet will prove to be very effective in management of neuropathic pain.

 

Table 12: In-vitro dissolution study of Bilayer tablets

TIME

(Hours)

CUMULATIVE % DRUG RELEASE

Amitriptyline HCl

Pregabalin

0

0

-

0.15

25.90 ± 0.327

-

0.30

52.51 ± 0.470

-

0.45

98.92 ± 0.492

-

1

-

11.30 ± 0.357

2

-

20.90 ± 0.277

3

-

32.09 ± 0.372

4

-

41.97 ± 0.421

5

-

54.62 ± 0.378

6

-

65.12 ± 0.320

7

-

72.90 ± 0.419

8

-

79.16 ± 0.522

9

-

86.92 ± 0.270

10

-

90.16 ± 0.537

11

-

95.09 ± 0.352

12

-

97.27 ± 0.591

*All the values are expressed as mean ± SD n=3.

 

4. CONCLUSION:

Pre-compression and post compression parameters of optimized IR layer comprising AMT and SR layer comprising PGB exhibit satisfactory results. Bilayer tablet of AMT and PGB may prove to be very effective as a combination therapy for treatment of neuropathic pain by sequential release of the drug.

 

5. ACKNOWLEDGMENTS:

Authors specially acknowledge sunglow pharmaceutical Pvt. Ltd, pondycherry for providing gift sample of AMT and PGB respectively for valuable support and the also like to thank my guide and principle providing research facilities their laboratories to carry out this work.

 

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Received on 17.04.2017       Accepted on 30.08.2017     

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2017; 7 (3): 127-136.

DOI: 10.5958/2231-5713.2017.00021.6