Lipid Based Matrices as Colonic Drug Delivery System for Diflunisal (In-vitro, In-vivo study)
Presented by Dr. AHMED ATEF DONIA, PH. D., Lecturer of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Egypt.
Colon drug delivery system The oral aspect is considered to be the most convenient for administration of drugs to patients. Normally the drug dissolves in stomach fluid and intestinal fluid to be absorbed from these regions of GIT. It is a serious drawback in conditions when localized delivery of drugs into the colon is required as drugs needs to be protected from the hostile environment of upper GIT
Colon Drug Delivery System Preventing chemical & enzymatic degradation Local treatment of colonic diseases Rational for CDDS Increasing the drug bioavailability Polar drugs Chronotherapy
Colon Drug Delivery System Selection criteria of CDDS drugs Drug candidate Drug carrier Drugs which show poor absorption from the stomach and the intestine The choice of drug carrier depends on the functional groups of the drug molecule.
Approaches for colonic drug delivery systems Covalent linkage of drug with carrier Like azo bond. Approaches to deliver intact molecule to colon Like embedding in ph dependant polymer. Novel pharmaceutical approaches Like nanoparticles.
Diflunisal It is a long-acting non-steroidal antiinflammatory drug most commonly used to treat acute postoperative pain or chronic joint pain from osteoarthritis and rheumatoid arthritis.
The aim of work Development of a suitable analytical technique for quantification of the drug. Preparation of solid dispersions using different types of waxy bases. In-vitro evaluation of the preparations regarding drug content, release pattern and spectroscopic analysis. In-vivo evaluation of selected formulation to assess colonic targeting. Performing comparative study between the in vitro characteristics of the chosen formula and the commercial product.
Part I Preparation, in vitro evaluation and characterization of diflunisal solid dispersion using certain waxy matrices as a colon drug delivery system.
Diflunisal solid dispersions with the waxy matrices were prepared by the fusion method at the following ratios. 1:1 Diflunisal BW SA GMS 1:3 1:5 1:1 1:3 1:5 1:1 1:3 1:5
Determination of the drug content of the solid dispersion prepared. Drug content Wax 1:1 1:3 1:5 BW 99.58 ±4.21 101.428± 1.52 100.00±2.35 SA 99.32 ±2.36 98.911±4.07 98.345 ± 0.58 GMS 98.17 ±1.93 97.534± 3.16 99.379 ± 0.69
Dissolution studies
Dissolution studies of diflunisal solid dispersion with BW at different ph (A) ph 1.2 (B) ph 6.8 (C ) ph 7.4
Dissolution studies of diflunisal solid dispersion with SA at different ph (A) ph 1.2 (B) ph 6.8 (C ) ph 7.4
Dissolution studies of diflunisal solid dispersion with GMS at different ph (A) ph 1.2 (B) ph 6.8 (C ) ph 7.4
Release studies notes It can be noticed that the amount of drug released from its solid dispersion in different waxy matrices with different ratios (1:1, 1:3 and 1:5) was decreased significantly (p value < 0.5) than the free drug in the same ph. Also the percentage of the drug released from the ratio of 1:5 >1:3 >1:1 drug-waxy matrices. This abnormal behavior is to be explained by carrying out some instrumental analysis for some selected solid dispersions (FTIR and XRD).
FTIR studies IR scan of diflunisal in KBr disc
FTIR spectra of a SD containing 1:1 dif : BW FTIR spectra of a SD containing 1:1 dif to SA FTIR spectra of a SD containing 1:1 dif to GMS FTIR spectra of a SD containing 1: 3 dif:bw FTIR spectra of a SD containing 1:3 dif to SA FTIR spectra of a SD containing 1:3 dif to GMS FTIR spectra of a SD containing 1:5 dif:bw FTIR spectra of a SD containing 1:5 dif : SA FTIR spectra of a SD containing 1:5 dif to GMS The drug reported peaks was found in the solid dispersions products of the drug in different waxy matrices indicating no structural chemical change of the drug has been occured
FTIR Studies Notes Diflunisal is a polymorphic drug. It exists in three non-solvated crystal forms designated as I (stable form above 98 o C), II (stable form at ambient conditions) and III (unstable). Since form II is thermo stable, it is the preferred common crystal form of the drug. IR spectrum can be used to determine the content of form II in the bulk drug from the ratio of the peak heights at 1210 cm -1 and 1225 cm -1.
FTIR Studies Notes The ratio between the peaks at 1210 and 1225 cm -1 can be used for the determination of polymorph II content in the bulk drug. It was found that it is 1.314 which corresponds to 81.87% of form II. In the same way the amount of polymorph II was calculated in each product prepared with the same or different wax. The results are represented in the following table.
Determination of crystal form content (forms II) of diflunisal by IR absorption at 1210 cm-1 and 1225 cm-1.
The summary of the calculated polymorph II percent Polymer Ratio (drug=1) Ratio Polymorph ratio BW 1:1 0.968 51.25% BW 1:3 0.968 51.25% BW 1:5 0.968 51.25% SA 1:1 0.962 50% SA 1:3 0.986 51.875% SA 1:5 0.985 51.875% GMS 1:1 1.000 54.375% GMS 1:3 1.058 58.75% GMS 1:5 1.018 54.69%
XRD studies The X-ray diffractogram of pure diflunisal exhibits its characteristic diffraction peaks within 100-300 at 2 theta values. In case of diflunisal solid dispersion with BW, SA and GMS, a reduction in peaks intensity can be noticed. That is may be due to change in the crystallinity of the drug.
XRD of a SD containing 1:5 dif to BW. XRD of a SD containing 1:3 dif to SA. XRD of a SD containing 1:3 dif to GMS The order of XRD intensity was BW>SA>GMS. These results are in agreement with what is reported before about the high percent of the polymorph change in the solid dispersion of GMS than SA.
XRD studies Many authors suggested that the drug-polymer ratio plays an important role in the crystallization of Diflunisal. Diflunisal crystallizes in form I at high concentrations of the drug in the solidified melt dispersions; however, polymorph III is mainly obtained as the polymer content increases. The dispersion of the drug in the used waxy matrices with different ratios using fusion method led to change the drug polymorph from form II to forms either I or III or both.
XRD studies These changes depend on the drug-waxy matrices used ratio. The instrumental analysis of the drug solid dispersion products proved that, as a result of a base and technique used there is a change of the drug from stable less dissolution polymorph II to the unstable highly dissolute polymorph III. Accordingly it can be concluded that, this unstable highly dissolute polymorph is responsible for the abnormal drug release phenomena found before.
Kinetic studies
Kinetic studies in ph 1.2 Formula Zero order (r2) K0 First order (r2) K1 Higuchi (r2) KH 1:1 B.W. 0.945 0.010 0.963 0.010 0.967 0.112 1:1 St. a. 0.995 0.018 0.995 0.001 0.966 0.194 1:1 G.M.S. 0.991 0.023 0.991 0.000 0.953 0.247 1:3 B.W. 0.909 0.016 0.909 0.000 0.766 0.183 1:3 St. a. 0.992 0.018 0.992 0.000 0.908 0.213 1:3 G.M.S. 0.987 0.023 0.987 0.000 0.891 0.270 1:5 B.W. 0.962 0.017 0.962 0.000 0.915 0.198 1:5 St. a. 0.958 0.020 0.983 0.011 0.969 0.242 1:5 G.M.S. 0.980 0.032 0.980 0.000 0.911 0.371
Kinetic studies in ph 6.8 Formula Zero order (r2) K0 First order (r2) K1 Higuchi (r2) KH 1:1 B.W. 0.978 0.031 0.976 0.000 0.952 0.913 1:1 St. a. 0.979 0.526 0.986 0.003 0.982 9.530 1:1 G.M.S. 0.884 0.838 0.990 0.011 0.971 15.478 1:3 B.W. 0.999 0.071 0.998 0.000 0.984 1.821 1:3 St. a. 0.976 0.731 0.986 0.003 0.966 13.377 1:3 G.M.S. 0.929 0.654 0.994 0.009 0.993 11.571 1:5 B.W. 0.946 0.112 0.981 0.006 0.975 2.895 1:5 St. a. 0.912 0.840 0.959 0.007 0.950 16.851 1:5 G.M.S. 0.884 0.838 0.990 0.011 0.971 15.478
Kinetic studies in ph 7.4 Formula Zero order (r2) K0 First order (r2) K1 Higuchi (r2) KH 1:1 B.W. 0.658 0.274 0.974 0.037 0.763 6.986 1:1 St. a. 0.994 1.078 0.999 0.002 0.997 24.752 1:1 G.M.S. 0.988 1.116 0.988 0.000 0.957 25.240 1:3 B.W. 0.946 0.523 0.966 0.005 0.974 10.559 1:3 St. a. 0.997 1.978 0.997 0.000 0.978 32.339 1:3 G.M.S. 0.995 1.117 0.995 0.000 0.977 26.447 1:5 B.W. 0.923 0.850 0.972 0.008 0.978 16.904 1:5 St. a. 0.999 1.324 0.999 0.001 0.997 33.620 1:5 G.M.S. 0.983 0.942 0.992 0.003 0.993 27.580
Part II In- Vivo Evaluation Of Colon Specific Drug Delivery System In Rats.
In vivo studies The formula with the best dissolution characters prepared with waxy matrices was loaded with barium sulfate and given to the rats for studying the in vivo performance.
x-ray film of a rat after two hours from taking the dose.
x-ray film of a rat after four hours from taking the dose.
x-ray film of a rat after six hours from taking the dose
x-ray film of a rat after eight hours from taking the dose.
Part III Comparative study between the best formula and the commercial product.
عنوان Time (min) Dissolution studies ph Cumulative drug release % Dolozal Best formula 15 1.2 0.628 0.09 30 1.2 1.473 0.164 60 1.2 2.241 0.25 90 1.2 3.639 0.426 120 1.2 4.312 0.584 135 6.8 42.724 4.13 150 6.8 99.263 8.078 180 6.8 100 16.184 210 6.8 100 21.492 240 6.8 100 24.598 300 7.4 100 29.052 360 7.4 100 34.956 375 7.4 100 40.994 390 7.4 100 45.76 420 7.4 100 51.56 450 7.4 100 59.638 480 7.4 100 63.028 540 7.4 100 76.904 600 7.4 100 93.112
Conclusion The commercial formula failed to reach the colon as confirmed from the release study where nearly 100% drug release was appeared in small intestine Colon targeting of diflunisal can take place by application of different waxy matrices at different ratios using solid dispersion technique