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

Rational for CDDS

Local treatment of colonic diseases

Increasing the drug

bioavailability

Chronotherapy Polar drugs

Preventing chemical & enzymatic

degradation

Selection criteria of CDDS drugs

Drug candidate

Drugs which show poor absorption from the stomach

and the intestine

Drug carrier

The choice of drug carrier depends on the functional

groups of the drug molecule.

Colon Drug Delivery System

Approaches for colonic drug delivery

systems

• Like azo bond.

Covalent linkage of drug with carrier

• Like embedding in pH dependant polymer.

Approaches to deliver intact molecule to colon

• Like nanoparticles.

Novel pharmaceutical approaches

Diflunisal

• It is a long-acting non-steroidal anti-

inflammatory 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.

Diflunisal

BW

1:1

1:3

1:5

SA 1:1

1:3

1:5

GMS

1:1

1:3

1:5

Determination of the drug content of the

solid dispersion prepared.

Wax

Drug content

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

(A) pH 1.2 (B) pH 6.8 (C ) pH 7.4

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

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

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 spectra of a SD containing 1:1 dif : BW

FTIR spectra of a SD containing 1: 3 dif:BW

FTIR spectra of a SD containing 1:5 dif:BW

FTIR spectra of a SD containing 1:1 dif to SA

FTIR spectra of a SD containing 1:3 dif to SA

FTIR spectra of a SD containing 1:5 dif : SA

FTIR spectra of a SD containing 1:1 dif to GMS

FTIR spectra of a SD containing 1:3 dif to GMS

FTIR spectra of a SD containing 1:5 dif to GMS

FTIR Studies Notes

• Diflunisal is a polymorphic drug. It exists in three non-solvated crystal forms designated as I (stable form above 98oC), 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.

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 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

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 .

عنوانTime (min) 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

Dissolution studies

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