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ISSN: 2329-6887
Journal of Pharmacovigilance
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Design and Evaluation of a Controlled Release Drug Delivery System for Management of Rheumatism

Santhosh Kumar, Anusha G*, Rajyalaxmi, Srinivas and Manoj

Department of Pharmacy, Vaageswari College of Pharmacy, Karimnagar, India

*Corresponding Author:
Anusha G
Assistant Professor, Vaageswari College of Pharmacy
Karimnagar, India
Tel: +91 95025 88612
E-mail: [email protected]

Received date: July 29, 2017; Accepted date: August 29, 2017; Published date: September 05, 2017

Citation: Kumar S, Anusha G, Rajyalaxmi, Srinivas, Manoj (2017) Design and Evaluation of a Controlled Release Drug Delivery System for Management of Rheumatism. J Pharmacovigil 5:234. doi: 10.4172/2329-6887.1000234

Copyright: © 2017 Kumar S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

The present research was aimed to design, formulate and evaluate Mucoadhesive colon targeted microspheres of Ketoprofen for many advantages especially increased bioavailability and reduction in dosing frequency etc. Ketoprofen is a NSAID, like other drugs in this group reduces pain, inflammation and stiffness in rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. In this study an attempt was made to prepare mucoadhesive microspheres of Ketoprofen using the natural polymers designed for oral controlled release.

Ketoprofen microspheres were prepared following 32 full factorial designs with varying concentrations of the polymers using sodium alginate and natural polymer such guar gum, xanthan gum by orifice-ionic gelation method. The prepared ketoprofen microspheres were evaluated for surface morphology and particle shape, rheological studies. Micro encapsulation efficiency, swelling index and in vitro drug release studies were done, and compatibility studies. The microspheres were found discrete, spherical and free flowing.

The percentage yield ranged from 88% to 96% and encapsulation efficiency was from 86.23% to 94.46%. The particle size was found to be between 400-550 μm. From the in vitro drug release studies the (KPN5) showed 92.12% drug release in 12 hrs and showed better control of drug release. The in vitro release data was treated with mathematical equations, and was concluded that ketoprofen followed zero order release from the microspheres and Peppas model with non-Fickian diffusion Super Case II transport. The results indicate that Enteric coated mucoadhesive colon targeted microspheres of ketoprofen containing xanthan gum; guar gum provides a better option for controlled release action and improved bioavailability.

Keywords

Microencapsulation; Mucoadhesion; Colon targeted; Enteric coating; Natural gums; Factorial design; Controlled release

Introduction

To address the short comings of the molecules and thereby alter the pharmacokinetic and pharmacodynamic properties, release of the drug from polymers are being of immense importance, Polymeric materials provide the most important avenues for delivery technology, primarily because of their ease of processing and the ability of researchers to readily control their chemical and physical properties via molecular synthesis. Basically, two broad categories of polymer systems, both known as “Microspheres” because of their size and shape, have been studied: reservoir devices and matrix devices. The former involves the encapsulation of a pharmaceutical product within a polymer shell, whereas the latter describes a system in which a drug is physically entrapped within a polymer network.

Microencapsulation is a useful method for prolonging drug release from dosage forms and reducing adverse effects recently, dosage forms that can precisely control the release rates and target drugs to a specific body site have made an enormous impact in the formulation and development of novel drug delivery systems. Microspheres and microspheres (having a core of the drug) of 1–1000 μm in diameter and consisting either entirely of a bioadhesive polymer or having an outer coating of it, respectively. Bioadhesive/non bioadhesive microspheres have advantages such as efficient absorption and enhanced bioavailability of drugs owing to their high surface to volume ratio, a much more intimate contact with the mucus layer, and specific targeting of drugs to the absorption site [1-7].

Rheumatic diseases and conditions primarily affect joints, tendons, ligaments, bones, and muscles. Rheumatic diseases are characterized by the signs of inflammation-redness, heat, swelling, and pain [7-12].

Among 30% of ill elderly people are suffering from rheumatism in which medication should be used for prolonged period, which may extend up to some months also. While therapy if medicine as conventional dosage form is given twice or thrice in a day, that elevates lot of inconvenience and fluctuations in therapy with some adverse effects also. To overcome demerits of a conventional dosage form a suitable controlled drug delivery system should be developed. Microencapsulation is a technique to deliver the medicament at controlled rate with more advantages over conventional formulations.

The Present aim of the study is to Design and Evaluation of a controlled release drug delivery system for management of Rheumatism, Development of dosage form as colon targeted mucoadhesive microspheres with natural gums (Gum Xanthan & Gum Guar) as mucoadhesive polymers followed by enteric coating and to evaluate various parameters for the prepared microspheres (Figures 1-5).

pharmacovigilance-drug-release-plots

Figure 1: In vitro drug release plots of formulations KPN1-KPN3.

pharmacovigilance-Zero-order-release

Figure 2: Zero order release of plots of KCM1 & KCM3 formulations.

pharmacovigilance-First-order-release

Figure 3: First order release of plots of KCM1 & KCM3 formulations.

pharmacovigilance-Higuchi-release-plots

Figure 4: Higuchi release of plots of KCM1 & KCM3 formulations.

pharmacovigilance-Peppas-release-plots

Figure 5: Peppas release of plots of KCM1 & KCM3 formulations.

Materials and Methods

Preformulation studies

Preformulation activities range from supporting discovery’s identification of new active agents to characterizing physical properties necessary for the design of dosage form. Critical information provided during Preformulation can enhance the rapid and successful introduction of new therapeutics entities for humans. The overall objective of preformulation testing is to generate information useful [13-22] in developing the formulation which is stable and enhancing bioavailability. Further the use of preformulation parameters maximizes the chances in formulating an acceptable, safe, efficacious and stable product. The physicochemical properties of the bulk drug like physical appearance, solubility, bulk density, tapped density, compressibility index, angle repose, sieve analysis were studied (Tables 1-3).

n Mechanism
0.5 Fickian diffusion (Higuchi Matrix)
0.5<n<1 Non-Fickian diffusion
1 Case II transport

Table 1: Different release mechanisms.

S. No. Microspheres code Number of microspheres adhering to tissue at hour
Phosphate buffer pH 7.4
1 2 4 6 8
1 KCM1 30 ± 1 30 ± 1 28 ± 1 20 ± 1 15 ± 1
2 KCM2 30 ± 2 25 ± 2 22 ± 3 18 ± 3 15 ± 2
3 KCM3 30 ± 1 24 ± 2 21 ± 2 18 ± 2 16 ± 3
4 KCM4 30 ± 2 22 ± 3 20 ± 3 17 ± 2 15 ± 2
5 KCM5 30 ± 3 23 ± 3 18 ± 2 14 ± 3 10 ± 3
6 KCM6 30 ± 2 22 ± 3 20 ± 2 15 ± 2 15 ± 2
:7 KCM7 30 ± 2 23 ± 4 21 ± 3 16 ± 4 15 ± 3
8 KCM8 30 ± 2 23 ± 2 20 ± 3 18 ± 5 15 ± 4
9 KCM9 30 ± 2 27 ± 2 25 ± 2 23 ± 3 21 ± 2

Table 2: Mucoadhesion test results by using in vitro wash off test.

S. No. Formulation Code Angle of Repose Bulk Density (g/cm3) Carr’s Index Hausner’s ratio True density (g/cm3) Average particle size
1 KCM1 24.4 ± 0.61 0.66 ± 0.03 96.46 ± 0.31 0.04 0.90 ± 0.2 490 ± 10
2 KCM2 27.3 ± 0.72 0.63 ± 0.04 96.35 ± 0.46 0.04 0.96 ± 0.4 510 ± 5
3 KCM3 26.5 ± 0.81 0.56 ± 0.05 96.68 ± 0.56 0.03 0.92 ± 0.5 530 ± 8
4 KCM4 24.3 ± 0.73 0.64 ± 0.06 96.28 ± 0.51 0.04 0.94 ± 0.3 528 ± 5
5 KCM5 24.6 ± 0.91 0.60 ± 0.03 96.63 ± 0.49 0.03 0.83 ± 0.5 510 ± 10
6 KCM6 26.2 ± 0.63 0.55 ± 0.02 96.39 ± 0.59 0.04 0.91 ± 0.2 525 ± 5
7 KCM7 25.8 ± 0.74 0.57 ± 0.09 96.25 ± 0.41 0.04 0.93 ± 0.3 528 ± 8
8 KCM8 24.3 ± 0.91 0.62 ± 0.06 96.34 ± 0.51 0.03 0.89 ± 0.1 531 ± 6
9 KCM9 27.7 ± .0.84 0.61 ± 0.04 96.93 ± 0.41 0.04 0.79 ± 0.4 500 ± 10

Table 3: Physical properties of ketoprofen microspheres formulations KCM1-KCM9.

Formulation and preparation of ketoprofen microspheres with different polymers and different ratios:

Formulation and preparing microspheres of ketoprofen using polymers Guar gum, Xanthan by using ionotropic gelation technique

Preparation of ketoprofen microspheres: Ketoprofen microspheres were prepared by Ionic orifice gelation technique by using different concentrations of polymers (1:1:0.25, 1:1:0.5, 1:1:0.75, 1:1:1) according to the formula generated by 32 full factorial design, and the pure drug and sodium alginate were mixed thoroughly in a de-mineralized water in order to prepare a clear solution. To this the required quantity of the polymer was added by adding the required amount of de-mineralized water until it [23-32] found free flowing & with out stringing in nature. Drop wisely this solution was poured in to 15% CaCl2 solution by using 22# needle stirring it continuously at 500 rpm over a magnetic stirrer. The microspheres thus formed are allowed for curing for 30 min then decanted and air dried.

Drug entrapment efficiency and % drug content

Accurately weighed 50 mg of drug-loaded microspheres were suspended in 100 ml of simulated intestinal fluid of pH 7.4 PB. The resulting solution was kept for 24 hrs. Next day it was stirred for 5 min and filtered. After suitable dilution, ketoprofen content in the filtrate was analyzed spectrophotometrically at 259 nm using a UV-Vis spectrophotometer. The drug entrapment efficiency was determined using following formula.

% DEE=Actual drug content/Theoritical drug content×100     (1)

FT-IR spectra

Fourier Transform Infrared Analysis (FT-IR) measurements of pure drug, carrier and drug-loaded microspheres formulations were obtained using a Perkin-Elmer system 200 FT-IR spectrophotometer. The pellets were prepared on KBr-press under hydraulic pressure of 150 kg/cm2; the spectra were scanned over the wave number range of 4000 to 400 cm-1 at the ambient temperature (Tables 4-8).

Time log T SQRT Abs Con DF ADR CDR %CDR %CDRM L%CDR L%CDRM
0 #NUM! 0 0 0 0 0 0 0 100 #NUM! 2
0.5 -0.301 0.7071 0.248 3.0244 1 2.721951 2.721951 2.721951 97.27805 0.43488 1.988015
1 0 1 0.272 3.3171 2 5.970732 5.985854 5.985854 94.01415 0.777126 1.973193
2 0.301 1.4142 0.51 6.2195 2 11.19512 11.22683 11.22683 88.77317 1.050257 1.948282
3 0.4771 1.7321 0.891 10.866 2 19.55854 19.62134 19.62134 80.37866 1.292729 1.905141
4 0.6021 2 0.692 8.439 3 22.78537 22.8904 22.8904 77.1096 1.359653 1.887108
5 0.699 2.2361 0.732 8.9268 4 32.13659 32.29591 32.29591 67.70409 1.509148 1.830615
6 0.7782 2.4495 0.784 9.561 4 34.41951 34.57884 34.57884 65.42116 1.53881 1.815718
7 0.8451 2.6458 0.652 7.9512 5 35.78049 36.00116 36.00116 63.99884 1.556316 1.806172
8 0.9031 2.8284 0.697 8.5 5 38.25 38.54152 38.54152 61.45848 1.585929 1.788582
9 0.9542 3 0.732 8.9268 6 48.20488 48.5389 48.5389 51.4611 1.68609 1.711479
10 1 3.1623 0.787 9.5976 6 51.82683 52.20549 52.20549 47.79451 1.717716 1.679378
11 1.0414 3.3166 0.831 10.134 7 63.84512 64.27177 64.27177 35.72823 1.80802 1.553012
12 1.0792 3.4641 0.986 12.024 8 86.57561 87.05293 87.05293 12.94707 1.939783 1.112172

Table 4: In vitro drug release data of formulation KCM1.

Time Log T SQRT Abs Con DF ADR CDR %CDR %CDRM L%CDR L%CDRM
0 #NUM! 0 0 0 0 0 0 0 100 #NUM! 2
0.5 -0.30103 0.707107 0.265 3.231707 1 2.908537 2.908537 2.908537 97.09146 0.463675 1.987181
1 0 1 0.449 5.47561 1 4.928049 4.944207 4.949207 95.05079 0.694536 1.977956
2 0.30103 1.414214 0.467 5.695122 2 10.25122 10.29476 10.30476 89.69524 1.013038 1.952769
3 0.477121 1.732051 0.501 6.109756 2 10.99756 11.06957 11.08957 88.91043 1.044915 1.948953
4 0.60206 2 0.582 7.097561 3 19.16341 19.26598 19.29598 80.70402 1.285467 1.906895
5 0.69897 2.236068 0.597 7.280488 4 26.20976 26.3478 26.3928 73.6072 1.421486 1.86692
6 0.778151 2.44949 0.623 7.597561 4 27.35122 27.52567 27.59067 72.40933 1.440762 1.859795
7 0.845098 2.645751 0.71 8.658537 4 31.17073 31.38317 31.46817 68.53183 1.497871 1.835892
8 0.90309 2.828427 0.696 8.487805 5 38.19512 38.45085 38.55585 61.44415 1.58609 1.788481
9 0.954243 3 0.738 9 6 48.6 48.89817 49.02817 50.97183 1.690446 1.70733
10 1 3.162278 0.803 9.792683 7 61.6939 62.04378 62.23378 37.76622 1.794026 1.577104
11 1.041393 3.316625 0.921 11.23171 7 70.75976 71.15189 71.34689 28.65311 1.853375 1.457172
12 1.079181 3.464102 0.989 12.06098 7 75.98415 76.43244 76.66244 23.33756 1.884583 1.368055

Table 5: In vitro drug release data of formulation KCM2.

TIME Log T SQRT Abs Con DF ADR CDR %CDR %CDRM L%CDR L%CDRM
0 #NUM! 0 0 0 0 0 0 0 100 #NUM! 2
0.5 -0.30103 0.707107 0.286 3.487805 1 3.139024 3.139024 3.139024 96.86098 0.496795 1.986149
1 0 1 0.432 5.268293 1 4.741463 4.758902 4.763902 95.2361 0.677963 1.978802
2 0.30103 1.414214 0.506 6.170732 1 5.553659 5.597439 5.607439 94.39256 0.748765 1.974938
3 0.477121 1.732051 0.539 6.573171 2 11.83171 11.90634 11.92134 88.07866 1.076325 1.944871
4 0.60206 2 0.652 7.95122 2 14.3122 14.4197 14.4447 85.5553 1.159708 1.932247
5 0.69897 2.236068 0.709 8.646341 2 15.56341 15.71067 15.74567 84.25433 1.197161 1.925592
6 0.778151 2.44949 0.739 9.012195 3 24.33293 24.52341 24.56841 75.43159 1.390377 1.877553
7 0.845098 2.645751 0.803 9.792683 4 35.25366 35.48921 35.54921 64.45079 1.55083 1.809228
8 0.90309 2.828427 0.829 10.10976 4 36.39512 36.67963 36.75963 63.24037 1.565371 1.800994
9 0.954243 3 0.869 10.59756 5 47.68902 48.02409 48.12409 51.87591 1.682362 1.714966
10 1 3.162278 0.901 10.9878 5 49.44512 49.83317 49.95817 50.04183 1.698607 1.699333
11 1.041393 3.316625 0.939 11.45122 6 61.83659 62.27957 62.42957 37.57043 1.698607 1.574846
12 1.079181 3.464102 0.976 11.90244 7 74.98537 75.48561 75.66561 24.33439 1.878899 1.38622

Table 6: In vitro drug release data of formulation KCM3.

Time Log T SQRT Abs Con DF ADR CDR %CDR %CDRM L%CDR L%CDRM
0 #NUM! 0 0 0 0 0 0 0 100 #NUM! 2
0.5 -0.30103 0.707107 0.389 4.743902 1 4.269512 4.269512 4.269512 95.73049 0.630378 1.98105
1 0 1 0.409 4.987805 1 4.489024 4.512744 4.517744 95.48226 0.654922 1.979923
2 0.30103 1.414214 0.45 5.487805 2 9.878049 9.926707 9.936707 90.06329 0.997242 1.954548
3 0.477121 1.732051 0.506 6.170732 3 16.66098 16.73707 16.75707 83.24293 1.224198 1.920347
4 0.60206 2 0.573 6.987805 4 25.1561 25.26305 25.29805 74.70195 1.403087 1.873332
5 0.69897 2.236068 0.657 8.012195 5 36.05488 36.19677 36.25177 63.74823 1.559329 1.804468
6 0.778151 2.44949 0.712 8.682927 5 39.07317 39.25512 39.33512 60.66488 1.594781 1.782937
7 0.845098 2.645751 0.769 9.378049 5 42.20122 42.42659 42.53159 57.46841 1.628712 1.759429
8 0.90309 2.828427 0.811 9.890244 5 44.5061 44.77835 44.90835 55.09165 1.652327 1.741086
9 0.954243 3 0.892 10.87805 5 48.95122 49.27293 49.42793 50.57207 1.693972 1.703911
10 1 3.162278 0.899 10.96341 6 59.20244 59.57854 59.75854 40.24146 1.7764 1.604674
11 1.041393 3.316625 0.945 11.52439 7 72.60366 73.03457 73.24457 26.75543 1.7764 1.427412
12 1.079181 3.464102 0.993 12.10976 8 87.19024 87.67878 87.92378 12.07622 1.944106 1.081931

Table 7: In vitro drug release data of formulation KCM4.

Time Log T SQRT Abs Con DF ADR CDR %CDR %CDRM L%CDR L%CDRM
0 #NUM! 0 0 0 0 0 0 0 100 #NUM! 2
0.5 -0.30103 0.707107 0.443 5.402439 1 4.862195 4.862195 4.862195 95.1378 0.686832 1.978353
1 0 1 0.576 7.02439 1 6.321951 6.348963 6.353963 93.64604 0.803045 1.971489
2 0.30103 1.414214 0.675 8.231707 2 14.81707 14.87921 14.88921 85.11079 1.172872 1.929985
3 0.477121 1.732051 0.727 8.865854 2 15.95854 16.06183 16.08183 83.91817 1.206335 1.923856
4 0.60206 2 0.779 9.5 3 25.65 25.79762 25.82762 74.17238 1.412084 1.870242
5 0.69897 2.236068 0.811 9.890244 3 26.70366 26.89878 26.94378 73.05622 1.430459 1.863657
6 0.778151 2.44949 0.834 10.17073 4 36.61463 36.85921 36.91921 63.08079 1.567252 1.799897
7 0.845098 2.645751 0.957 11.67073 4 42.01463 42.31006 42.39006 57.60994 1.627264 1.760497
8 0.90309 2.828427 0.984 12 5 54 54.35378 54.45378 45.54622 1.736028 1.658452
9 0.954243 3 0.997 12.15854 5 54.71341 55.1272 55.2522 44.7478 1.74235 1.650772
10 1 3.162278 0.836 10.19512 7 64.22927 64.70384 64.85384 35.14616 1.811936 1.545878
11 1.041393 3.316625 0.779 9.5 8 68.4 68.92555 69.11055 30.88945 1.811936 1.48981
12 1.079181 3.464102 0.933 11.37805 9 92.1622 92.73524 92.96024 7.039756 1.968297 0.847558

Table 8: In vitro drug release data of formulation KCM5.

In vitro drug release studies

Release of ketoprofen form microspheres was studied phosphate buffer of pH 7.4 (900 ml) using USP XXIV six-station Dissolution Rate Test Apparatus with a basket stirrer at 50 rpm. A sample of microspheres equivalent to 100 mg of ketoprofen was used in each test. The rotational speed of the basket was set at 100 rpm at 37 ± 0.5°C. 5 ml of aliquots was withdrawn at predetermined time intervals by replacing a fresh sample of dissolution medium. The absorbance of the collected samples measured using UV-spectrophotometer at λmax 259 nm in phosphate buffer of pH 7.4 (Figures 5-9).

pharmacovigilance-In-vitro-drug

Figure 6: In vitro drug release of graphs of KCM4-KCM6 formulations.

pharmacovigilance-Zero-order-release

Figure 7: Zero order release plots of KCM4-KCM6 formulations.

pharmacovigilance-order-release-plots

Figure 8: First order release plots of KCM4-KCM6 formulations.

pharmacovigilance-Higuchi-release-plots

Figure 9: Higuchi release plots of KCM4-KCM6 formulations.

In vitro wash-off test for mucoadhesive property of microspheres

The mucoadhesive property of the microspheres was evaluated by an in vitro adhesion testing method known as wash-off method. A piece of intestinal mucous (2 × 2 cm) was mounted on to glass slides of (3 × 1 inch) with Cyanoacrylate glue. Two glass slides were connected with a suitable support. About 50 microspheres were spread on to each wet tissue specimen and there after the support was hung on to the arm of a USP tablet disintegrating test machine. The disintegration machine containing tissue specimen was adjusted at slow, regular up and down moment in a test fluid at 37°C taken in a beaker. At the end of 30 min, 1 hr and later at hourly intervals up to 8 hrs, the machine was stopped and the number of microspheres still adhering on to the tissue was counted. The test was performed in phosphate buffer of pH 7.4.

Determination of release kinetic data

First Order Kinetics: A first order release would be predicated by the following equation:

Equation       (2)

where C=Amount of drug remained at time ‘t’.

Co=Initial amount of drug.

K=First order rate constant (Hr-1).

When, the data was plotted as log cumulative percent drug remaining versus time yields a straight line, indicating that the release follows first order kinetics. The constant ‘K’ can be obtained by multiplying 2.303 with slope values.

Higuchi’s model: Drug released from the matrix devices by diffusion has been described by Higuchi’s classical diffusion equation:

Equation       (3)

where Q=Amount of drug release at time ‘t’.

D=Diffusion coefficient of the drug in the matrix.

A=Total amount of drug in unit volume of matrix.

Cs=the solubility of the drug in the matrix.

∈=Porosity of the matrix.

τ= Tortuosity.

t=Time (hours).

The above equation may be simplified, if one assumes that D, ∈, τ, Cs and A are constant. Then the equation 15 becomes:

Q = KT1/2

When the data is plotted, according to Higuchi’s equation 16 (Q=KT1/2), cumulative drug release versus square root of time yields a straight line, indicating that the drug was released by diffusion mechanism. The slope is equal to ‘K’.

Peppas release model: The release rate data were fitted to the following equation 17, Mt /M∝=K.tn.

Equation       (4)

Where Mt /M∝ is the fraction of drug released, ‘K’ is the release constant,‘t’ is the release time. ‘n’ is diffusion exponent, if n is equal to 0.89, the release is zero order. If n is equal to 0.45 the release is best explained by Fickian diffusion, and if 0.45<n<0.89 then the release is through anomalous diffusion or nonfickian diffusion (Swellable & Cylindrical Matrix). In this model, a plot of log (Mt/M∝) versus log (time) is linear.

Mucoadhesive colon targeted microspheres were prepared and [33-38] evaluated for their use as colon targeting drug delivery systems to increase its local action and bioavailability.

In the present work total nine formulations were prepared and complete composition of all batches shown in Table 9. The microspheres were then characterized for various physico-chemical parameters.

Time Log T SQRT Abs Con DF ADR CDR %CDR %CDRM L%CDR L%CDRM
0 #NUM! 0 0 0 0 0 0 0 100 #NUM! 2
0.5 -0.30103 0.707107 0.303 3.695122 1 3.32561 3.32561 3.32561 96.67439 0.521871 1.985311
1 0 1 0.371 4.52439 1 4.071951 4.090427 4.095427 95.90457 0.612299 1.981839
2 0.30103 1.414214 0.41 5 2 9 9.041098 9.051098 90.9489 0.956701 1.958797
3 0.477121 1.732051 0.563 6.865854 2 12.35854 12.42463 12.44463 87.55537 1.094982 1.942283
4 0.60206 2 0.615 7.5 3 20.25 20.35043 20.38043 79.61957 1.309213 1.90102
5 0.69897 2.236068 0.733 8.939024 3 24.13537 24.27329 24.31829 75.68171 1.385933 1.878991
6 0.778151 2.44949 0.834 10.17073 4 36.61463 36.79726 36.85726 63.14274 1.566523 1.800323
7 0.845098 2.645751 0.889 10.84146 4 39.02927 39.26274 39.34274 60.65726 1.594865 1.782883
8 0.90309 2.828427 0.959 11.69512 4 42.10244 42.39012 42.49012 57.50988 1.628288 1.759742
9 0.954243 3 0.867 10.57317 6 57.09512 57.44128 57.56128 42.43872 1.76013 1.627762
10 1 3.162278 0.989 12.06098 6 65.12927 65.52829 65.67829 34.32171 1.817422 1.535569
11 1.041393 3.316625 0.929 11.32927 8 81.57073 82.03006 82.21006 17.78994 1.817422 1.250174
12 1.079181 3.464102 0.957 11.67073 8 84.02927 84.54524 84.76524 15.23476 1.928218 1.182836

Table 9: In vitro drug release data of formulation KCM6.

Standard calibration curve

Standard calibration curve of ketoprofen was drawn by plotting absorbance vs. concentration. The λmax of ketoprofen in 7.4 pH phosphate buffer was determined to be 259 nm.

Compatibility study

Drug excipients compatibility status was determined by IR (infrared) spectroscopy where the spectra of pure drug were clearly matched with the spectra of formulations. The desired peaks of functional groups which were identified in pure drug are also found in formulation spectra without changing. The extra peaks which are found in formulations indicate the presence of polymers and other excipients.

In IR spectra of ketoprofen pure drug the peaks were found prominently at different wave numbers indicating the presence of functional groups and substituents like peaks at 1655 cm-1, 1598 cm-1, 1457 cm-1 wave number due to C=C stretching inside the benzyl ring. Prominent peaks at 1697 cm-1 due to C=O stretching, and at 1228 cm-1 due to C-O stretching in carboxylic group. Prominent peaks appeared at 2978 cm-1 wave number are due to C-H asymmetric and symmetric stretching, in methyl group indicates the presence of methyl groups in the structure, peak 717 cm-1, 703 cm-1 wave number are due to C-H bending indicates the benzene ring. Peaks observed in between 1420 cm-1 wave number is due to C-O-H stretching in plane which clearly indicates the presence of carboxylic group and peak at 3076 cm-1 and 3455 cm-1 wave numbers indicates the presence of Aromatic -H stretching and O-H stretching out plane. And all these peaks were appeared unchanged in IR spectra of combinations of ketoprofen with natural polymers. The data [39-44] clearly states that there is no interaction between the pure drug ketoprofen and other excipients. The peaks obtained in the spectra of each formulation correlates with the peaks of drug spectrum. The spectrum for pure drug was is compatible with the formulation components (Tables 10-12).

Time Log T SQRT Abs Con DF ADR CDR %CDR %CDRM L%CDR L%CDRM
0 #NUM! 0 0 0 0 0 0 0 100 #NUM! 2
0.5 -0.30103 0.707107 0.248 3.02439 1 2.721951 2.721951 2.721951 97.27805 0.43488 1.988015
1 0 1 0.277 3.378049 1 3.040244 3.055366 3.060366 96.93963 0.485773 1.986501
2 0.30103 1.414214 0.51 6.219512 1 5.597561 5.629573 5.639573 94.36043 0.751246 1.97479
3 0.477121 1.732051 0.891 10.86585 1 9.779268 9.842378 9.857378 90.14262 0.993761 1.95493
4 0.60206 2 0.684 8.341463 2 15.01463 15.13207 15.15207 84.84793 1.180472 1.928641
5 0.69897 2.236068 0.692 8.439024 2 15.19024 15.34939 15.37939 84.62061 1.186939 1.927476
6 0.778151 2.44949 0.652 7.95122 3 21.46829 21.66963 21.70963 78.29037 1.336653 1.893708
7 0.845098 2.645751 0.697 8.5 3 22.95 23.1911 23.2461 76.7539 1.36635 1.8851
8 0.90309 2.828427 0.932 11.36585 3 30.6878 30.9714 31.0414 68.9586 1.491941 1.838588
9 0.954243 3 0.787 9.597561 4 34.55122 34.89165 34.97665 65.02335 1.543778 1.813069
10 1 3.162278 0.831 10.13415 5 45.60366 45.99207 46.09707 53.90293 1.663673 1.731612
11 1.041393 3.316625 0.986 12.02439 5 54.10976 54.54884 54.67884 45.32116 1.663673 1.656301
12 1.079181 3.464102 0.997 12.15854 7 76.59878 77.09799 77.25299 22.74701 1.887915 1.356924

Table 10: In vitro drug release data of formulation KCM7.

Time Log T SQRT Abs Con DF ADR CDR %CDR %CDRM L%CDR L%CDRM
0 #NUM! 0 0 0 0 0 0 0 100 #NUM! 2
0.5 -0.30103 0.707107 0.253 3.085366 1 2.776829 2.776829 2.776829 97.22317 0.443549 1.98777
1 0 1 0.301 3.670732 1 3.303659 3.319085 3.324085 96.67591 0.521672 1.985318
2 0.30103 1.414214 0.432 5.268293 2 9.482927 9.516707 9.526707 90.47329 0.978943 1.95652
3 0.477121 1.732051 0.489 5.963415 2 10.73415 10.79427 10.81427 89.18573 1.033997 1.950295
4 0.60206 2 0.523 6.378049 2 11.48049 11.57043 11.60043 88.39957 1.064474 1.94645
5 0.69897 2.236068 0.567 6.914634 3 18.66951 18.79134 18.83134 81.16866 1.274881 1.909388
6 0.778151 2.44949 0.598 7.292683 3 19.69024 19.84665 19.90165 80.09835 1.298889 1.903624
7 0.845098 2.645751 0.645 7.865854 4 28.31707 28.50994 28.57994 71.42006 1.456061 1.85382
8 0.90309 2.828427 0.702 8.560976 4 30.81951 31.05171 31.14171 68.85829 1.493342 1.837956
9 0.954243 3 0.789 9.621951 5 43.29878 43.57378 43.68378 56.31622 1.64032 1.750633
10 1 3.162278 0.843 10.28049 5 46.2622 46.5853 46.7203 53.2797 1.669506 1.726562
11 1.041393 3.316625 0.879 10.71951 6 57.88537 58.25988 58.41988 41.58012 1.669506 1.618886
12 1.079181 3.464102 0.977 11.91463 8 85.78537 86.21348 86.40348 13.59652 1.936531 1.133428

Table 11: In vitro drug release data of formulation KCM8.

Time Log T SQRT Abs Con DF ADR CDR %CDR %CDRM L%CDR L%CDRM
0 #NUM! 0 0 0 0 0 0 0 100 #NUM! 2
0.5 -0.30103 0.707107 0.112 1.365854 1 1.229268 1.229268 1.229268 98.77073 0.089647 1.994628
1 0 1 0.198 2.414634 1 2.173171 2.18 2.185 97.815 0.339451 1.990405
2 0.30103 1.414214 0.254 3.097561 1 2.787805 2.806707 2.816707 97.18329 0.449742 1.987592
3 0.477121 1.732051 0.299 3.646341 1 3.281707 3.316098 3.331098 96.6689 0.522587 1.985287
4 0.60206 2 0.334 4.073171 2 7.331707 7.384329 7.404329 92.59567 0.869486 1.966591
5 0.69897 2.236068 0.412 5.02439 2 9.043902 9.11689 9.14689 90.85311 0.961273 1.95834
6 0.778151 2.44949 0.489 5.963415 2 10.73415 10.83226 10.87226 89.12774 1.03632 1.950013
7 0.845098 2.645751 0.532 6.487805 3 17.51707 17.645 17.695 82.305 1.247851 1.915426
8 0.90309 2.828427 0.591 7.207317 3 19.45976 19.62012 19.68512 80.31488 1.294138 1.904796
9 0.954243 3 0.667 8.134146 4 29.28293 29.47933 29.55933 70.44067 1.470695 1.847823
10 1 3.162278 0.721 8.792683 5 39.56707 39.80415 39.90415 60.09585 1.601018 1.778845
11 1.041393 3.316625 0.823 10.03659 5 45.16463 45.44567 45.57067 54.42933 1.601018 1.735833
12 1.079181 3.464102 0.875 10.67073 7 67.22561 67.55683 67.70683 32.29317 1.830632 1.509111

Table 12: In vitro drug release data of formulation KCM9.

Evaluation Results of Mucoadhesive Colon Targeted Microspheres Formulations

Particle size

The prepared microspheres were analyzed by sieve analysis and the particle size range between 490-540 μm and the data depicted in Table 13. And low particle size (490 ± 10 μm) was found in KP and high particle size (530 ± 8 μm) was found in KPN8. This data depicted in Scanning Electron Microscopy (SEM) analysis was done and the pictograms revealed spherical and uniform shaped microspheres (Figure 10).

Formulation Zero order First order Higuchi Peppas
R2 R2 R2 R2 n (Slope)
KCM1 0.944 0.725 0.842 0.880 1.1798
KCM2 0.966 0.873 0.854 0.894 1.1993
KCM3 0.960 0.855 0.831 0.883 1.1667
KCM4 0.961 0.804 0.880 0.863 1.1755
KCM5 0.968 0.73 0.887 0.899 1.1269
KCM6 0.974 0.830 0.860 0.835 1.2397
KCM7 0.880 0.729 0.753 0.905 1.1773
KCM8 0.810 0.741 0.738 0.892 1.1714
KCM9 0.828 0.659 0.667 0.917 1.2842

Table 13: Curve fitting data for formulations KCM1-KCM9.

pharmacovigilance-Peppas-release-plots

Figure 10: Peppas release plots of KCM4-KCM6 formulations.

Flow property

The flow property of the prepared formulations was checked by the method, angle of repose. The values obtained for angle of repose for all the formulations are tabulated in Table 13. The values were found to be in the range from 24.3 to 27.7. This indicates good flow property of the microspheres.

Hausner’s ratio of microspheres was found in the range of 0.03- 0.04 and Carr’s index of microspheres was found in the range of 96.25 ± 0.41 to 96.93 ± 0.41 and data shown in the Table 13.

Mucoadhesion test by using in vitro wash of test

The results of Mucoadhesive microspheres are presented in Table 12 and showed fairly good Mucoadhesive property of microspheres in all the cases. The best mucoadhesive property was observed in KPN9 formulation and least mucoadhesion property was observed in KPN5.

In vitro dissolution studies

The dissolution rate studies were performed by using USP-XXIV dissolution apparatus employing rotating Basket at a speed of 50 rpm in the dissolution medium of 7.4 pH Buffer study was continued up to 12 hrs at suitable time intervals, samples of 5 ml were withdrawn by means of pipette and it was immediately replaced with fresh dissolution medium. The withdrawn samples were analyzed for the drug content after appropriate dilutions by measuring the absorbance at 259 nm (7.4 pH buffer) with UV spectrophotometer.

The in vitro drug release profiles of microspheres from each batch (KPN1 to KPN9) were carried in 7.4 pH buffer for 12 hrs by using ring mesh device and the values are shown in Tables 14-20. The plot of % Cumulative drug release vs. time (hr) was plotted and depicted (Figures 11-14).

Response 1 % DR 5 hrs Transform None  
 Sequential Model Sum of Squares [Type I]
Source Sum of Squares df Mean Square F Value p-value Prob>F  
Mean vs Total 4050.898 1 4050.898  -  -  -
Linear vs Mean 348.2115 2 174.1058 6.461529 0.0319 Suggested
2FI vs Linear 20.5209 1 20.5209 0.726923 0.4328  -
Quadratic vs 2FI 20.79584 2 10.39792 0.259185 0.7874  -
Cubic vs Quadratic 58.31127 2 29.15563 0.469935 0.718 Aliased
Residual 62.04188 1 62.04188  -  -  -
Total 4560.78 9 506.7533  -  -  -
 I+"Sequential Model Sum of Squares [Type I]"0+: Select the highest order polynomial where the additional terms are significant and the model is not aliased
 Model Summary Statistics        
  Std.   Adjusted Predicted    
Source Dev. R-Squared R-Squared R-Squared PRESS  
Linear 5.190856 0.682926 0.577235 0.32319 345.093 Suggested
2FI 5.313172 0.723173 0.557077 0.112447 452.5469  
Quadratic 6.333855 0.763959 0.370556 -1.29937 1172.407  
Cubic 7.876667 0.878321 0.026568 -21.176 11307.13 Aliased

Table 14: Factorial analysis data of response % Drug release at time 5 hrs.

Response 1 %DR 5 hr        
  ANOVA for Response Surface Quadratic Model  
Analysis of variance table [Partial sum of squares-Type III]
  Sum of   Mean F p-value Not significant
Source Squares Df Square Value Prob>F
Model 389.5283 5 77.90566 1.941927 0.3103
A-A 3.776267 1 3.776267 0.09413 0.7791
B-B 344.4353 1 344.4353 8.585615 0.0610
AB 20.5209 1 20.5209 0.511517 0.5261
A^2 5.962756 1 5.962756 0.148631 0.7256
B^2 14.83309 1 14.83309 0.369739 0.5861
Residual 120.3531 3 40.11771      
Cor Total 509.8814 8        
The "Model F-value" of 1.94 implies the model is not significant relative to the noise. There is a
31.03 % chance that a "Model F-value" this large could occur due to noise
Values of "Prob>F" less than 0.0500 indicate model terms are significant.
In this case there are no significant model terms
Values greater than 0.1000 indicate the model terms are not significant
If there are many insignificant model terms (not counting those required to support hierarchy),
model reduction may improve your model
Std. Dev. 6.333855   R-Squared 0.763959    
Mean 21.21556   Adj R-Squared 0.370556    
C.V. % 29.85477   Pred R-Squared -1.29937    
PRESS 1172.407   Adeq Precision 3.855373    
A negative "Pred R-Squared" implies that the overall mean is a better predictor of your
response than the current model.
"Adeq Precision" measures the signal to noise ratio. A ratio of 3.86 indicates an inadequate
signal and we should not use this model to navigate the design space
  Coefficient Standard 95% CI 95% CI VIF
Factor Estimate Df Error Low High
Intercept 20.55111 1 4.720977 5.526844 35.57538  
A-A -0.79333 1 2.585785 -9.02246 7.435797 1
B-B -7.57667 1 2.585785 -15.8058 0.652464 1
AB -2.265 1 3.166927 -12.3436 7.813585 1
A^2 -1.72667 1 4.478712 -15.9799 12.52661 1
B^2 2.723333 1 4.478712 -11.5299 16.97661 1

Table 15: Factorial analysis data of response % Drug release at time 5 hrs.

Response 1 %DR 10hr Transform None
 Sequential Model Sum of Squares [Type I]
Source Sum of
Squares
df Mean
Square
F Value p-value
Prob>F
 
Mean vs. Total 26136.11 1 26136.11     Suggested
Linear vs. Mean 327.6617 2 163.8308 2.81281 0.1375 Suggested
2FI vs. Linear 26.5225 1 26.5225 0.410635 0.5499  
Quadratic vs. 2FI 32.26944 2 16.13472 0.166523 0.8539  
Cubic vs. Quadratic 244.2083 2 122.1042 2.627764 0.3998 Aliased
Residual 46.46694 1 46.46694      
Total 26813.24 9 2979.249      
 I+"Sequential Model Sum of Squares [Type I]"0+: Select the highest order polynomial where the
additional terms are significant and the model is not aliased
 Model Summary Statistics
Source Std.
Dev.
R-Squared Adjusted
R-squared
Predicted
R-squared
Press  
Linear 7.631811 0.483899 0.311865 -0.13842 770.8554 Suggested
2FI 8.036725 0.523068 0.236908 -0.93354 1309.254 -
Quadratic 9.843361 0.570724 -0.14474 -3.90731 3322.881 -
Cubic 6.816667 0.931377 0.451012 -11.5066 8468.601 Aliased

Table 16: Factorial analysis data of response % Drug release at time 10 hrs.

Response 1 %DR 10 hr  
  ANOVA for response surface quadratic model
Analysis of variance table [Partial sum of squares-Type III] Not significant
  Sum of   Mean F p-value
Source Squares Df Square Value Prob>F
Model 386.4536 5 77.29072 0.797702 0.6161
A-A 3.526667 1 3.526667 0.036398 0.8609
B-B 324.135 1 324.135 3.345331 0.1648
AB 26.5225 1 26.5225 0.273733 0.6370
A^2 20.90889 1 20.90889 0.215796 0.6739
B^2 11.36056 1 11.36056 0.11725 0.7546
Residual 290.6753 3 96.89176    
Cor Total 677.1289 8      
           
The "Model F-value" of 0.80 implies the model is not significant relative to the noise. There is a
61.61 % chance that a "Model F-value" this large could occur due to noise.
Values of "Prob>F" less than 0.0500 indicate model terms are significant
In this case there are no significant model terms
Values greater than 0.1000 indicate the model terms are not significant
If there are many insignificant model terms (not counting those required to support hierarchy),
model reduction may improve your model
Std. Dev. 9.843361   R-Squared 0.570724    
Mean 53.88889   Adj R-Squared -0.14474    
C.V. % 18.26603   Pred R-Squared -3.90731    
PRESS 3322.881   Adeq Precision 2.647109    
A negative "Pred R-Squared" implies that the overall mean is a better predictor of your
response than the current model
"Adeq Precision" measures the signal to noise ratio. A ratio of 2.65 indicates an inadequate
signal and we should not use this model to navigate the design space
Coefficient Standard 95% CI 95% CI  
Factor
Intercept
Estimate Df Error Low High VIF
50.14444 1 7.336808 26.79543 73.49346 -
A-A 0.766667 1 4.018535 -12.0221 13.55545 1
B-B -7.35 1 4.018535 -20.1388 5.438784 1
AB -2.575 1 4.921681 -18.238 13.088 1
A^2 3.233333 1 6.960307 -18.9175 25.38416 1
B^2 2.383333 1 6.960307 -19.7675 24.53416 1

Table 17: Factorial analysis data of response % Drug release at time 10 hrs.

Response 1 Diffusion exponent Transform None    
 *** WARNING: The Cubic Model is Aliased! ***    
 Sequential Model Sum of Squares [Type I]      
Source Sum of
Squares
Df Mean
Square
F
Value
p-value
Prob>F
 
Mean vs. Total 328.0554 1 328.0554     Suggested
Linear vs. Mean 3.246755 2 1.623377 1.60855 0.2758 Suggested
2FI vs. Linear 0.099856 1 0.099856 0.083836 0.7838  
Quadratic vs. 2FI 0.645859 2 0.32293 0.18246 0.8418  
Cubic vs. Quadratic 3.436251 2 1.718126 0.917146 0.5940 Aliased
Residual 1.87334 1 1.87334      
Total 337.3575 9 37.48416      
 I+"Sequential Model Sum of Squares [Type I]"0+: Select the highest order polynomial where the additional terms are significant and the model is not aliased
 Model Summary Statistics
Source Std.
Dev.
R-squared Adjusted
R-squared
Predicted
R-squared
Press  
Linear 1.004598 0.349036 0.132048 -0.29168 12.01526 Suggested
2FI 1.091371 0.359771 -0.02437 -1.17692 20.24984  
Quadratic 1.330362 0.429203 -0.52213 -5.00166 55.82781  
Cubic 1.3687 0.79861 -0.61112 -35.7033 341.4162 Aliased

Table 18: Factorial analysis data of response final diffusion exponent.

Response 1 Diffusion exponent    
  ANOVA for Response Surface Mean Model  
Analysis of variance table [Partial sum of squares-Type III]
Source Sum of
Squares
df Mean
Square
F
Value
p-value
Prob>F
Model 0 0 - - -
Residual 9.302061 8 1.162758 - -
Cor Total 9.302061 8 - - -
Values of "Prob>F" less than 0.0500 indicate model terms are significant.
In this case there are no significant model terms.
Values greater than 0.1000 indicate the model terms are not significant.
If there are many insignificant model terms (not counting those required to support hierarchy),
model reduction may improve your model.
Std. Dev. 1.078312   R-Squared 0  
Mean 6.037433   Adj R-Squared 0  
C.V. % 17.86044   Pred R-Squared -0.26563  
PRESS 11.77292   Adeq Precision    
A negative "Pred R-Squared" implies that the overall mean is a better predictor of your
response than the current model.    
  Coefficient Standard 95% CI 95% CI
Factor Estimate df Error Low High
Intercept 6.037433 1 0.359437 5.208569 6.866298
 Final Equation in Terms of Coded Factors
Diffusion exponent=6.037433
Final Equation in Terms of Actual Factors
Diffusion exponent=6.037433

Table 19: Factorial analysis data of response diffusion exponent.

Factor Name Level Low Level High Level Std. Dev. Coding  
A A 5.88 5 15 0 Actual  
B B 14.69 5 15 0 Actual  
Response Prediction SE Mean 95% CI low 95% CI high SE Pred 95% PI low 95% PI high
%DR 5hr 14.80589 3.783439 2.765286 26.84649 7.377813 -8.67363 38.2854
%DR 10hr 48.90098 7.253834 25.81602 71.98593 12.22742 9.987826 87.81413
Diffusion exponent 6.037433 0.359437 5.208569 6.866298 1.136641 3.416334 8.658532

Table 20: Factorial prediction data for responses % DR 5 hr, %DR 10 hr, diffusion exponent.

pharmacovigilance-drug-release-graphs

Figure 11: In vitro drug release of graphs of KCM7-KCM9 formulations.

pharmacovigilance-Zero-order-release

Figure 12: Zero order release plots of KCM7-KCM9 formulations.

pharmacovigilance-order-release-plots

Figure 13: First order release plots of KCM7-KCM9 formulations.

pharmacovigilance-Higuchi-release-plots

Figure 14: Higuchi release plots of KCM7-KCM9 formulations.

Curve fitting analysis

The results of dissolution data fitted to various drug release kinetic equations. Peppas model was found to be the best fitted in all dissolution profile having higher correlation coefficient (r-value) followed by Higuchi model and First order release equation. Korsemeyer-Peppas model indicates that release mechanism is not well known or more than one type of release phenomena could be involved. The ‘n’ value could be used to characterize different release mechanisms as:

The results are reported in Table 20 and in the present study ‘n’ values of all the formulations was found to be greater than 1(n>1) so, it can be concluded that all the formulations followed super case II transport.

Maximum regression was found in zero order release from the kinetic data from the data it can be concluded that KPN5 is the best formulation that showed a release of 92.23% in 12 hrs with guar gum and xanthan gum polymers in the ratio of 5% and 5% (Figures 15-20).

pharmacovigilance-Peppas-release-plots

Figure 15: Peppas release plots of KCM7-KCM9 formulations.

pharmacovigilance-SEM-pictograms-depicting

Figure 16: SEM pictograms depicting the size and shape of microspheres.

pharmacovigilance-pure-drug-Ketoprofen

Figure 17: IR Spectra of pure drug Ketoprofen.

pharmacovigilance-ketoprofen-formulation

Figure 18: IR spectra of ketoprofen formulation.

pharmacovigilance-Contour-graph

Figure 19: Contour graph of std. error of design (32 factorial).

pharmacovigilance-Response-surface-plot

Figure 20: Response surface plot for influence of polymers on % drug release at time 5 hrs.

Discussion

The prepared ketoprofen formulations were found with desirable physical properties and, release parameters are also found in acceptable range where the release followed zero order case II super transport. Data of statistical analysis stated that the formulations with much percentage of polymer retarded and even the mucoadhesive property was also found more, that to with Xanthan gum (Figures 21-24).

pharmacovigilance-Surface-plot-influence

Figure 21: Response Surface plot for influence of polymers on % drug release at time 10 hrs.

pharmacovigilance-final-diffusion-coefficient

Figure 22: Response surface plot for influence of polymers on final diffusion coefficient.

pharmacovigilance-mucoadhesive-test-results

Figure 23: In vitro mucoadhesive test results of formulations KCM1-KCM9.

pharmacovigilance-Average-particle-size

Figure 24: Average particle size for formulations KCM1-KCM9.

The ANOVA analysis for %CDR 5 hrs revealed that in linear vs. mean the coefficient was found to be suggested with an F value of 6.46159 (p<0.0319), in model [45-50] found not significant F value 1.941927 (p=0.03103) and % CDR 10 hrs revealed a suggested F value of 2.81281 (p<0.1375), in model F value 0.797702 (p<0.6161) was found not significant. Positive effect was also observed in release rate constant with increase in Xanthan gum and guar gum and showed linear vs. mean coefficient was d with an suggested F value of 1.60855 (p<0.0.2758) and in model F value 9.0162 (p>0.050) found to aliased and insignificant

Conclusion

In the present investigation Mucoadhesive colon targeted microspheres were prepared with guar gum and Xanthan gum. Ketoprofen may cause gastric irritation so this was developed as mucoadhesive colon targeted system hence these systems are useful in the improving the absorption and bioavailability of the drug. From the findings obtained, it can be concluded that:

Mucoadhesive colon targeted microspheres of ketoprofen could be formulated as an approach to improve its bioavailability.

• The flow properties of the polymers and drug were determined and found acceptable.

• Formulated microspheres gave satisfactory results for various physicochemical evaluations for flow property, bulk density and tapped density, in vitro wash off test found in acceptable range.

• FT-IR studies revealed that there was no chemical interaction between ketoprofen and the polymers used in the study.

• The dissolution profiles for ketoprofen made with guar gum, xanthan gum, showed that the use of these polymers permit efficient control of the release of the drug.

• The microspheres made with lower polymer content have faster dissolution rates, thus increasing the dissolution of drug.

• The formulation KPN5 showed 92.23% in 12 hrs. So from the in vitro dissolution profile it can be concluded that KPN5 is best formulation.

• From the kinetic data maximum regression was observed in zero order.

• In Peppas release ‘n’ is greater than >1 so, it can be concluded that the mechanism followed is super case II transport.

• The ANOVA analysis for %CDR 5 hrs revealed that in linear vs. mean the coefficient was found to be suggested with an F value of 6.46159 (p<0.0319), in model found not significant F value 1.941927 (p=0.03103) and % CDR 10 hrs revealed a suggested F value of 2.81281 (p<0.1375), in model F value 0.797702 (p<0.6161) was found not significant.

Positive effect was also observed in release rate constant with increase in Xanthan gum and guar gum and showed linear vs. mean coefficient was d with an suggested F value of 1.60855 (p<0.0.2758) and in model F value 9.0162 (p>0.050) found to aliased and insignificant.

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