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Formulation and in Vitro Evaluation of Sustained Release Matrix Tablets of Lornoxicam

 

Clinical courses

About Author: G. Anand Rao*, V. Venu, R. Senthil Selvi, P. Perumal,
Department of Pharmaceutics,
J. K. K. Nattraja College of Pharmacy,
Komarapalayam - 638 183, Namakkal (D.T),
Tamil Nadu, India

Abstract
The main objective of the present work was to develop sustained release matrix tablets of Lornoxicam using Hydrophilic polymers viz. Hydroxy propyl methyl cellulose (HPMC K4M, HPMC K10M, HPMC K15M) was developed using wet granulation technique at varying ratios of drug and polymer like 1:1, 1:2 and 1:3 were selected for the study. Micro crystalline cellulose and Lactose was added in this formulation as a function of binder and diluent. Prior to compression, the prepared granules were evaluated for flow and compression characteristics. After evaluation of physical properties of tablet, the in vitro release study was performed in 0.1 N Hcl, pH 1.2 for 2 hrs and in phosphate buffer pH 6.8 up to 12 hrs. The effect of polymer concentration and polymer blend concentration were studied. Dissolution data was analyzed by Korsmeyer- Peppas law expression. It was observed that matrix tablets contained polymer HPMC K10M was successfully sustained the release of drug up to 12 hrs. Among all the formulations, formulation F9 which contains 1:3 ratios of drug and polymer release the drug which follows Zero order kinetics via, swelling, diffusion and erosion. Stability studies (40±2oc/75±5%RH) for three months indicated that Lornoxicam was stable in the matrix tablets. The FTIR study revealed that there was no chemical interaction between drug and excipients.

Reference ID: PHARMATUTOR-ART-1123

Introduction
Lornoxicam is a non-steroidal anti-inflammatory drug (NSAID) with potent analgesic and anti-inflammatory activity and belongs to the class of oxicams. In common with other NSAIDs, the analgesic and anti-inflammatory activity of Lornoxicam is related to its inhibitory action on prostaglandin synthesis, via inhibition of cyclo-oxygenase (COX) activity. Lornoxicam inhibits both isoforms in the same concentration range, that is, the ratio of COX-1inhibition to COX-2inhibition. It readily penetrates into the synovial fluid.Unlike some NSAIDs, however, Lornoxicam does not inhibit 5-lipoxygenase activity and thus does not inhibit leukotriene synthesis or shunt arachidonic acid to the 5-lipoxygenase pathway. Activation of the opioid neuropeptides system may be a component of the analgesic effect of Lornoxicam.

Lornoxicam is a non-steroidal anti-inflammatory drug of the oxicam class, with analgesic, anti-inflammatory and antipyretic properties. It is used for inflammatory disease of the joints, osteoarthritis, pain surgery as well as pain in the lower back and hip which travels down the back of the thigh into the leg. The mean elimination half life is 4 hrs and requires dosing every 4 hours in order to maintain optimal relief of chronic pain. Consequently, once daily sustained release tablets have been formulated. Long term treatment with sustained release lornoxicam once daily is generally safe in patients with osteoarthritis or rheumatoid arthritis and is well tolerated. Non steroidal anti-inflammatory drugs (NSAIDs) are widely used for patients suffering from LBP. A quick release formulation of lornoxicam (LNX), a potent NSAID from the chemical class of oxicams, provides a faster onset of pain relief (PAR) compared to the standard tablet formulation. The aim of the study was to assess analgesic efficacy and safety of lornoxicam quick release formulation versus diclofenac potassium (DP) in acute LBP. LNX administered as quick release formulation was proven to be as effective as the equivalent DP formulation in terms of onset of PAR and more effective on most of the major standard efficacy outcomes.

Lornoxicam is a potent balanced COX-1/ COX-2 inhibitors whose short half life of 3- 4 hours may beneficially influence safety and tolerability. Lornoxicam was associated with a significantly lower risk of adverse events compared with comparator analgesics and carried no increase risk of adverse events verses placebo. Pain control after dental surgery lornoxicam 8, 16 and 20 mg was superior to placebo and at least as effective as morphine 20 mg in controlling moderate to severe pain. Painrelief: Adult: 8-16 mg daily. Max: 24 mg daily. Osteoarthritisand rheumatoid arthritis: Adult: 12 mg daily in 2-3 divided doses. Lornoxicam is absorbed rapidly and almost completely from the GIT following oral administration, no first pass was observed. Oral bioavailability is 90%, Plasma binding 99% and Peak plasma concentration 270µg/L.

These biopharmaceutical and physicochemical properties reveal that Lornoxicam is an ideal candidate to develop into a sustained release matrix tablet. To maintain oral bioavailability for longer period of time with the relative lack of peak plasma concentration Lornoxicam is formulated as sustained release matrix tablet.

The most common controlled delivery system have been the matrix type such as the tablets and granules where the drug is uniformly dissolved or dispersed thoroughly out the polymer, because of its effectiveness, low cost, ease of manufacturing and prolongation delivery time period. Hydrophilic polymers are becoming more popular in formulating oral controlled release tablets, it is well documented that the dissolution curve of drug release from a hydrophilic matrix shows a typical time dependent profile. The release of a dissolved drug inherently follows near first order diffusion either an initially high release rate, due to the dissolution of the drug present at the surface of the matrix followed by a rapid declining drug release rate.

The enhanced release rate observed at the beginning for the short time of release process is known as ‘burst effect’ and is many a time undesirable since it may, have negative therapeutic consequences. After this burst, hydration and consequent swelling and /or erosion of related polymer occur. These phenomenon control the release process but with time, the diffusion path length increase and saturation effect is attained, resulting in a progressively slow release rate during the end of dissolution span.

The main objective of the present work was to develop sustained release matrix tablet of lornoxicam using different polymers viz. Hydroxy propyl methyl cellulose (HPMC K4M, HPMC K10M, HPMC K15M) was developed using wet granulation techniqueat varying ratios of drug and polymer like 1:1, 1:2 and 1:3 were selected for the study. Micro crystalline cellulose and Lactose was added in this formulation as a function of binder and diluent. Before go for formulation find evaluation characterization of granules then go for compression. The matrix tablets were prepared and evaluated for different physiochemical parameters such as appearance, weight variation, thickness, hardness, friability, drug content and in vitro release.

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2. MATERIALS AND METHODS
2.1 Materials:

Lornoxicam was procured as gift sample from Hetero drugs. HPMC K4M, HPMC K10M, HPMC K15M were obtained as gift samples from Vivimed Pharma Ltd.Lactose, Micro crystalline cellulose and PVPK- 30 were obtained as gift sample from Ray’s health care Pvt. Ltd. All other solvents and reagent were of analytical grade.

2.2 Methods
2.2.1 Fourier Transform IR spectroscopy
Drug and excipient were analysed by IR spectral studies by using KBr pellet technique. In     this method, the drug and KBr were mixed at the ratio of 1:100. Then these mixtures were pressed in to a pellet. The FTIR spectra were recorded using KBr pellet method in the region of 400-2000 cm-1. Spectra were recorded for pure drug, pure excipients and drug with excipients.

2.2.2 Formulation of matrix tablets
Matrix tablet containing 12mg of Lornoxicam were prepared by wet granulation technique. The composition of each tablet is shown in table 1. All the components were screened and then thoroughly mixed for a period of 15 mins. The powder mix was granulated with alcoholic solution of Povidone. The wet mass was passed through # 16 and the granules were dried at 50oc for 2 hrs in a hot air oven. The dried granules were passed through # 20 and lubricated with magnesium stearate by further blending for 3 mins and finally talc was added to the blend. Compression was done on 16 station Cadmach tablet compression machine using 8mm deep concave punches.

Table No 1
Formulation of Lornoxicam sustained release matrix tablet.

Ingredients

Quantity (mg)

F1

F2

F3

F4

F5

F6

F7

F8

F9

Lornoxicam

12

12

12

12

12

12

12

12

12

HPMC K 4 M

12

24

36

-

-

-

-

-

-

HPMC K 15 M

-

-

-

12

24

36

-

-

-

HPMC K 10 M

-

-

-

-

-

-

12

24

36

MCC

40

40

40

40

40

40

40

40

40

Lactose

71

59

47

71

59

47

71

59

47

IPA

qs.

qs.

qs.

qs.

qs.

qs.

qs.

qs.

qs.

PVP K 30

10

10

10

10

10

10

10

10

10

Talc

3

3

3

3

3

3

3

3

3

Magnesium stearate

2

2

2

2

2

2

2

2

2

Total tablet weight

150

150

150

150

150

150

150

150

150

2.2.3 Evaluation of Tablets
The prepared tablets were evaluated for weight variation, hardness, thickness, friability, drug content, and stability studies. Pfizer hardness tester was used for the determination of the hardness. In weight variation test twenty tablets were selected at a random and average weight was calculated. Then individual tablets were weighed and the weight was compared with an average weight. The tablet was placed in contact between the plungers and the handle was pressed, the force of the fracture was recorded. In this work, for each formulation the hardness of 6 tablets was evaluated. The crown-to-crown thicknesses of ten tablets from each batch were determined using Vernier calipers. The Friability of the tablets was determined using Roche friabilator (Electro lab). 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. For determination of drug content at least three tablets from each formulation were weighed individually, pulverized, and diluted with phosphate buffer pH 6.8. After that an aliquot of the filtrate was analyzed spectrophotometrically at 378 nm. In vitrodrug release studies for the prepared matrix tablets were conducted for a period of 12 hrs using a 8 station USP II (Lab India) apparatus at 37 ± 0.5oC and at 50 rpm speed, the in vitro release study was performed in 0.1N HCL pH 1.2 for 2 hrs and in phosphate buffer pH 6.8 up to 12 hrs. At every interval 5 ml of sample was withdrawn from the dissolution medium and replaced with fresh medium to maintain the volume constant. After filtration and appropriate dilution, the sample solutions were analyzed at 378 nm for Lornoxicam by a UV-Visible spectrophotometer. The amount of drug present in the samples was calculated.

2.2.4 Stability Studies
The stability study of the optimized tablets was carried out according to ICH guidelines at 40±2oC/75±5% RH for three months by storing the samples in stability chamber.

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3. Result and discussion
Precompressional parameters of granules shows Table 2, angle of repose (27.98 to 30.64), %compressibility (10.11 to 14.95), and Hausner’s ratio (1.11 to 1.17) are in the range given in official standards. Table 3 shows postcompressional parameters i.e. hardness (4.7 to 5.3 kg/cm2), friability (0.28 to 0.55%), and thickness (3.47 to 3.52mm). Drug content was (97.64 to 99.73%) within the acceptable official limits.
Dissolution study of all the formulations was carried out using 0.1N Hcl pH 1.2 for 2 hrs and in phosphate buffer pH 6.8 up to 12 hrs. The values are shown in table 4 and plotted cumulative % drug release Vs time was shown in Fig 4. From the in vitro dissolution data, it was found that the drug release study from formulations containing HPMC K4M in that F1 shows 100.07% drug release after 8 hrs, F2 shows 99.88% drug release after 9 hrs, F3 shows 99.69% drug release after 10 hrs respectively. Formulation containing HPMC K15M (F4-F6) showed 69.92%, 65.02%, 57.67% drug release after 12 hrs respectively. Formulation containing HPMC K10M (F7-F9) showed 99.13%, 98.56%, 98.19% drug release after 12 hrs respectively.
The comparative release of all formulations showed the improvement in sustaining property of drug release increasing the HPMC K10M concentration in formulation F9 shows more sustained action  and optimum release than remaining all, which indicates that the concentration of polymer control the drug release.

Table No 2
Blend characteristics of Lornoxicam granules

Formulation

Angle of repose ± S.D

Bulk density

(gm/ml) ±S.D

Tapped density

(gm/ml)±S.D

Compressibility index (%)

± S.D

Hausner’s ratio

± S.D

F1

30.01o ± 0.12

0.436 ± 0.01

0.501 ± 0.02

12.94 ± 0.36

1.14 ± 0.04

F2

29.98o ± 0.15

0.457 ± 0.03

0.517 ± 0.02

11.53 ± 0.19

1.13 ± 0.01

F3

30.12o ± 0.08

0.456 ± 0.02

0.532 ± 0.01

14.23 ± 0.29

1.16 ± 0.02

F4

29.78o ± 0.23

0.457 ± 0.02

0.527 ± 0.02

13.17 ± 0.13

1.15 ± 0.03

F5

28.19o ± 0.33

0.454 ± 0.03

0.512 ± 0.02

11.35 ± 0.10

1.12 ± 0.04

F6

30.64o ± 0.27

0.469 ± 0.01

0.532 ± 0.02

11.81 ± 0.15

1.13 ± 0.02

F7

29.41o ± 0.31

0.462 ± 0.02

0.527 ± 0.03

12.38 ± 0.09

1.14 ± 0.04

F8

29.35o ± 0.17

0.445 ± 0.02

0.523 ± 0.02

14.95 ± 0.18

1.17 ± 0.03

F9

27.98o ± 0.19

0.450 ± 0.01

0.501 ± 0.02

10.11 ± 0.16

1.11 ± 0.01

(n=3, ± S.D) (S.D= Standard deviation)

Table no 3
Physical Characteristics of Lornoxicam sustained release Tablet

Formulation

Weight variation in mg ± S.D

Thickness in mm

± S.D

Diameter in mm ± S.D

Hardness in Kg/cm2

± S.D

Friability (%)

Drug content (%)

± S.D

F1

148.4 ± 0.61

3.48 ± 0.02

8.01± 0.014

4.7 ± 0.16

0.55

98.36  ± 0.04

F2

148.8 ± 0.74

3.51 ± 0.01

8.02 ± 0.027

4.8 ± 0.13

0.28

99.81

± 0.03

F3

150.6 ± 0.54

3.48 ± 0.01

8.00 ± 0.015

4.9 ± 0.12

0.46

97.64

± 0.01

F4

151.5 ± 0.63

3.50 ± 0.01

8.01± 0.015

4.9 ± 0.12

0.28

97.85

± 0.03

F5

150.6 ± 0.53

3.51 ± 0.02

8.02 ± 0.018

5.2 ± 0.15

0.39

98.63

± 0.02

F6

151.2 ± 0.34

3.52 ± 0.01

8.02 ± 0.016

5.3 ± 0.10

0.35

98.24

± 0.02

F7

151.1 ± 0.61

3.47 ± 0.02

8.02 ± 0.008

4.9 ± 0.14

0.38

98.75

± 0.04

F8

148.6 ± 0.56

3.48 ± 0.03

8.01± 0.011

5.0 ± 0.13

0.41

99.73

± 0.02

F9

149.8 ± 0.42

3.49 ± 0.02

8.00 ± 0.019

5.2 ± 0.14

0.31

99.78

± 0.01

(n=3, ± S.D) (S.D= Standard deviation)

Table No 4
In-Vitro drug release data for formulation F1-F9

Time in hours

Formulation code

F1

F2

F3

F4

F5

F6

F7

F8

F9

0

0

0

0

0

0

0

0

0

0

1

40.13

38.81

36.18

19.22

14.32

10.36

34.86

30.33

24.30

2

43.72

42.59

40.14

21.10

17.71

13.56

39.20

35.43

29.58

3

52.76

48.43

47.30

25.44

22.42

19.97

46.17

44.28

39.38

4

65.39

59.36

52.95

28.45

25.82

21.48

50.69

47.49

46.36

5

73.87

66.33

59.93

31.66

30.53

25.44

58.61

57.10

52.39

6

86.31

75.19

69.54

35.05

34.11

29.40

65.20

64.26

60.87

7

96.68

85.18

77.64

41.83

39.39

35.24

71.42

70.67

67.28

8

100.07

94.42

87.25

47.68

43.16

40.33

77.83

77.08

75.57

9

 

99.88

96.30

53.71

48.81

46.36

84.62

82.17

81.41

10

 

 

99.69

61.25

54.28

49.19

89.33

87.82

86.31

11

 

 

 

66.15

60.87

54.84

95.36

93.10

92.53

12

 

 

 

69.92

65.02

57.67

99.13

98.56

98.19

3.1 Kinetics and mechanism of drug release
Kinetics results shown in table 5 and in fig no 5 to 8 reveals that the F9 formulation follows zero order kinetics as correlation coefficient (r2) values are higher than that of first- order release kinetics. In order to understand the complex mechanism of drug release from the matrix system, the in vitro release rate were fitted to Korsmeyer-peppas model and interpretation of release exponent value (n) enlighten in understanding the release mechanism from the dosage form. The release exponent value (n) obtained thus obtained was 0.598. The F9 formulation exhibited anomalous (non Fickian) diffusion mechanism. The drug release was diffusion controlled as plot of higuchi’s model was found to be linear. Kinetic studies shows that the amount of drug from the matrix system were by both diffusion and erosion.

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Table No 5
Kinetic values obtained from F9 plot formulation of Lornoxicam

Formulation

Zero order R2

First order R2

Higuchi

R2

Korsmeyer

-Peppas R2

n

Mechanism Of drug release

F9

0.996

-0.833

0.985

0.983

0.598

Zero order non Fickian diffusion

3.2 Selection of optimized batch
The F9 of sustained release matrix tablet was chosen as optimized formulation because it showed more linearity between the cumulative percentage Lornoxicam verses time, as indicated by the highest value of the correlation coefficient in all selected models, among all sustained release matrix tablets  and best fitted for both Korsmeyer-peppas (0.983) and zero order (0.996) model.

3.3 Accelerated stability studies
The selected formulation was evaluated for accelerated stability studies. The formulation were stored at 40o C at 75% RH for 3 months and analyzed for their physical parameters, drug content and in vitro dissolution studies at every one month interval. The data were shown in the table no 6 and 7. After storage the formulation subjected to drug content, hardness, friability and in vitro dissolution studies showed no significant change.

Table No 6
Stability Characteristics of optimized F9 Formulation

 

Drug content (%)

Hardness (Kg/cm2)

Friability (%)

After one month

99.68 ± 0.07

5.20 ± 0.14

0.31

After two months

99.59 ± 0.12

5.20 ± 0.15

0.31

After three months

99.45 ± 0.08

5.19 ± 0.13

0.32

Table No 7
In vitro dissolution studies

Time in hours

Cumulative % drug release

 

 

1st Month

2nd Month

3rd Month

0

0.00

0.00

0.00

1

24.02

23.85

23.63

2

29.37

29.45

28.96

3

39.10

38.96

38.55

4

46.25

45.84

45.03

5

52.45

52.07

51.55

6

60.64

60.51

60.38

7

67.05

66.83

66.51

8

75.24

75.15

74.87

9

81.07

80.84

80.55

10

85.93

85.66

85.54

11

92.25

91.78

91.41

12

97.94

97.56

97.35

4. Conclusion
The study was undertaken with the aim to design, development and evaluation of sustained release matrix tablet of Lornoxicam tablet using different HPMC grades of polymer as retarding agent. Preformulation studies were done initially and result directed for further course of formulation. Based on the preformulation different batches of Lornoxicam are prepared using selected excipients and the granules were evaluated for tests of angle of repose, bulk density, tapped density, compressibility index and Hausner ratio before punched as tablet which were found within the limits. Tablets were tested for weight variation, hardness, thickness, friability and in vitro drug release as per pharmacopoeial procedure, which are within limits. Kinetic studies were observed as zero order plot and Korsmeyer-peppas is highest value of correlation coefficient all selected models. FTIR spectra revels, that there is no significant interaction between drug and polymer.
From the above result and discussion, it may be concluded that the formulation of sustained release tablet of Lornoxicam containing HPMC K10M (1:3) is an ideal and optimized formulation of sustained release tablet for 12 hours release as it fulfills all the requirement of sustained release tablet and study long term stability study on this formulation. However, further in vivo studies are needed to access the utility of this system.

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