ELSEVIER Journal of Controlled Release 32 ( 1994) 259-268

The fo~ulation-pe~o~auc~ relationship of multiply emulsions and ocular activity

S.M. Safwat*, M.A. Kassem, M.A. Attia, M. El-Mahdy Department uf Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt

Received 18 May 1993; accepted in revised form 3 May 1994

Abstract

Multiple emulsions containing prednisolone were prepared using a two step emulsification technique. The effect of various concentrations of hydrophilic and lipophilic emulsifiers (Tween-20 and Span-60) in multiple emulsions based on liquid paraffin on the drug bioavailabiiity and duration of action as a controlled release formulation was studied following instillation in the rabbit’s eye. The parameter of ocular activity such as area under the intraocular pressum/time curve (AUC); time for maximum response (TMR) and haIf value duration (HVD) were assessed for the o/w/o and w/o/w multiple emulsions. It was found that the hydrophilic emulsifier reduced the bioavailability but increased the concentration of lipophilic emulsifier to bring about the reverse effect. Therefore the bioavaiiability of the drug can be controlled by the proper choice and concentm~on of the emulsifier in the preparation of emulsions. The hydrophile-lipophile balance (HLB) values calculated for a surfactant mixture in a multiple emulsion was found to be highly negatively correlated to the values of the parameters of ocular activity. Decreasing the HLB value of the surfactant mixture in a w/o/w emulsion favours the bioavailability; the intensity and duration of drug action.

Keywords: Ocular activity; Multiple emulsions; Drug defivery systems

1. Induction

Multiple emulsions are receiving increasing atten- tion as potential drug delivery systems, Multiple emul- sions may be prepared by using pairs of surfactants, one of which will stabilize a w/o emulsion (lipophilic) and the other capable of stabilizing an o/w emulsion (hydrophilic) and this forms the basis for the prepa- ration of multiple systems [ 11.

Brodin et al. [ 21 formulated multiple emulsions by dispersing the suspension or solution of naltrexone base in the oily phase into water containing Tween-20 with the aid of sonication. Fukushima et al. f3] prepared w/o/w emulsions stable for a long time, by 2 a two- step emulsification procedure.

The nature of the oil phase in the prep~ation of multiple emulsions can markedly affect the behaviour of the system [ 11. Soliman [ 41 demonstrated that mul- tiple emulsions of w/o/w type prepared with (mineral oil) liquid paraffin gave a higher yield than that of vegetable oils (Cotton seed and Corn oils emulsions). Omotosho et al. [ 51 studied the effect of the nature of the oil phase on the size of multiple drops and the release of sodium chloride and Sfluorouracil from w/ o/w emulsions.

By photomicrographic observations of w/o/w emulsions, they found that both the internal aqueous droplets and multiple oil drops varied in size according to the nature of the oil used. Also, the rates of release differed with different oils. Ionic or non-ionic surfac-

0168-3659/94/$07.00 0 1994 Elsevier Science B.V. All rights reserved NXO168-3659(94)00051-U

260 S.M. Sajivat et al. /Journal of Controlled Release 32 (1994) 259-268

tants may be used although the type selected would depend on the use of the multiple emulsion.

The optimum surfactant to emulsify a given oil can be determined by the use of the hydrophilic-lipophilic

balance (HLB) system [ 61. Pateanu and co-workers [ 71 found that the release of tetracycline from ointment bases is dependent on HLB values of Tweens and

Spans. Also, Waggoner and Fincher [ 81 found that the release rate of ephedrine from emulsified liquid paraffin systems increases as the HLB values of surfactant increase. The structure of w/o/w multiple globules is dependent on the nature of secondary surfactant. Mag-

dassi et al. [ 91 studied the effect of emulsifier type on the preparation and stability of multiple emulsions. Abd Elbary et al. [ lo] reported that formation of a multiple

emulsion is a function of the emulsifying system used. There will be an optimal concentration of surfactant required to stabilize the system. The general range of

concentration is between 1% and lo%, but Matsumoto et al. [ 111 suggested that concentrations greater than 30% by weight of Span-80 in the oil phase are required to obtain yields of more than 90% of multiple drops. Matsumoto et al. [ 111 considered that the ratio of con- centration of primary to secondary surfactant was sig- nificant, and they suggested that more than lo-times as much Span-80 as Tween-20 was required to obtain 90%

or higher yields of w/o/w emulsion. Mohamed et al. [ 121 found that increasing the con-

centration of lipophilic surfactant (Span-80) was accompanied by an increase in the yield of w/o/w emulsion; while the yield was reduced, when Tween-

20 concentration was increased. Eros et al. [ 131 found that the efficiency of emulsification of w/o/w emul- sions increased with the concentration of the lipophilic

emulsifier, but an increase in the amount of the hydro- philic emulsifier sharply reduced the efficiency. They also found that the HLB value of the hydrophilic emul- sifier influences the emulsification of w/o/w emulsions with increasing volume of the w/o emulsion. In vivo studies on multiple emulsion systems are sporadic and

almost limited to some specific aspects and cases in oral and parenteral application.

Span-40, -60 and -65 at concentration of 30%, Span- 85 at lOO%, Tween-21, -60, -80 and -81 at 100% and Tween-61 at 60% were all non-irritating in the rabbit eye. These results hold whether the eyes were washed or unwashed after instillation of the non-ionics [ 14,161. Similar results on some of the Span, Tween,

and Myrj products have been obtained by Draize and Kelly [ 141 and by Hazleton [ 151, showing high tol- erance of the eye to these materials. The non-irritancy of these esters is illustrated by their frequent usage, particularly polysorbate 80 (Tween-80) in ophthalmic preparations [ 161.

A physiological property of surfactants is their local analgesic effect [ 171 when applied topically to the cornea of rabbits. In general, long straight-chain sur- factants are less irritating than short-chain and

branched-chain products, and those that contain 12 carbon atoms exert greatest irritation. From the toxi- cological point of view the use of surfactants seems eminently safe in low concentrations and acute oral toxicities of sorbitan esters of fatty acids and their poly- oxyethylene derivatives are very low in animals, e.g.

Tween-60 [ 181. The hydrophile-lipophile balance (HLB) is an

expression of the relative simultaneous attraction of an

emulsifier for water and for oil. A strongly lipophilic emulsifier has a low HLB number, usually less than 10; a highly hydrophilic emulsifier has a high HLB number,

over 10 [ 191. Corboy [ 201 investigated whether topically admin-

istered ophthalmic corticosteroids (e.g. prednisolone) are effective in reducing postoperative ocular inflam- matory lesions. Prednisolone was selected for this study

on the basis of its moderate potency as anti-inflamma- tory drug and binding to glucocorticoid receptors. The

potency of ophthalmic steroids may be influenced by drug formulation, route of administration and the experimental design for clinical system evaluated. However, the increased anti-inflammatory potency of these agents appeared to be prone to a rise in the intra-

ocular pressure (IOP). Possibly for this reason, these steroids became the standard drugs employed in the topical testing protocols [ 21 I.

The main objective of this study is the formulation and evaluation of the in-vivo performance of multiple emulsion delivery systems for ophthalmic applications.

2. Materials and methods

Prednisolone (Sigma, MO, USA), Corn oil (Amphora phelex Machan, France), light liquid par- affin, castor oil (pure grades), Tween-20 and Span-60 (Atlas, Chem., Wilmington, USA), isotonic phosphate

S.M. Sajivat et al. /Journal of Controlled Release 32 (1994) 25%268 261

Fig. 1. Photomicrograph of multiple w /o/w emulsion based on liquid Fig. 2. Photomicrograph of o/w/o multiple emulsion based on liquid

paraffin (Jnv/o/w, 0.5; o/w/o, 0.5; Span-60,2.5% and Tween-20, paraffin (I&J/W/O, 0.5; o/o/w, 0.5; Tween-20, 1% and Span-60,

1%). 2.5%).

buffer (pH 6.8) [ 121, propylene glycol (ROTH), iso-

tonic xylocaine solution (2%), chloramphenicol eye drops (MISR Co., Egypt). Experimental animals were

albino rabbits 1.8-2.8 kg receiving green fodder. Appa- ratus consisted of a homogenizer (Braun), a polarizing microscope (Carl Ziess, Jena, Germany), a Shiotz tonometer (Riester, Germany), and a transmitted light

microscope (Litz, Laborlux 5 12795/04 1654, Ger- many).

2.1. Preparation of multiple emulsions

Multiple emulsions (w/o/w) based on liquid par- affin were prepared by a two-step emulsification pro- cedure [ 11. In the first step, the oily solution of the lipophilic emulsifier (2.5%; 5.0%; 7.5% Span-60) was placed in the cup of the homogenizer to which the required amount of water was added (0.5) and the

mixture was homogenized at 7000 rpm for 15 min to

Table 1 Effect of surfactant concentrations on the mean change in IOP in mmHg post-instillation of prednisolone in multiple emulsions based on liquid

paraffin

Type of Concentration

emulsion of surfactants

Time (h)

0 1 2 3 4 5 6 7 8 9 10

w/o/w

o/w/o

Standard*

2% Tween-20

4% Tween-20

5% Span-60

7.5% Span-60

Standard* *

2% Tween-20

5% Span-60

18.83

18.79

18.57

18.48

18.32

18.27

18.73

18.50

20.41 20.71 20.85 20.09 19.44 18.88

(0.71) (1.19) (0.76) (0.94) (0.26) (0.42)

20.73 21.07 21.22 20.82 19.79 19.28

(0.59) (0.69) ( 1.94) (1.17) (1.16) (0.95)

20.14 20.95 20.66 20.04 19.33 18.74

(1.55) (0.67) (0.87) (1.39) (0.97) (0.59)

20.09 21.04 21.28 20.78 20.18 19.59

(0.79) (1.05) (1.34) (1.03) (0.52) (0.63)

20.21 20.68 21.22 20.94 20.33 19.69

(0.57) (0.91) (1.55) ( 1.35) (0.58) (0.52)

20.14 20.72 21.28 20.78 20.07 19.30

(1.02) (1.21) (0.85) ( 1.74) (1.51) (0.65)

20.31 21.41 21.57 21.08 20.33 19.95

(0.53) (0.92) (1.17) (0.97) (0.62) (0.51)

20.17 20.92 21.63 21.41 20.71 20.28

(1.43) (1.48) (0.96) (2.49) (0.87) (1.04)

18.51

(0.74)

18.92

(0.48)

18.57

18.99 18.73 18.48

(0.59) (0.74)

19.20 18.83 18.32

(0.55) (0.75)

18.81 18.44 18.27

(0.75) (0.60)

19.36 18.88 18.73

(0.55) (0.45)

19.56 19.04 18.73 18.50 (0.31) (0.37) (0.57)

18.38

18.79

*Standard w/o/w ($w/o/w/ 0.5; *w/o 0.5; Span-60,2.5% and Tween-20.1% w/w). **Standard w/o/w (I/JO/W/O 0.5; $01~ 0.5; Tween-20, 1% and Span-60,2.5% w/w).

262

6-

&U. Sajivat et al. /Journal of Controlled Release 32 (1994) 25%268

o------O 1 % tween 20

k+- .d 2% tween 20

O---d 4% tween 20

1 2 3 4 5 6 7 8

Time (hr)

Fig. 3. Effect of the concentration of hydrophilic emulsifier (Tween-20) on the percent mean change in IOP of rabbit’s eye post-instillation of prednisolone in w/o/w emulsions based on liquid paraffin.

provide the w/o emulsion. The surfactant or surfactant mixture used to prepare primary emulsion is termed the primary emulsifier and the volume fraction of water in the w/o emulsion (I,/? w/o) becomes the internal aque- ous volume of the w/o/w emulsion. In the second emulsification step, the aqueous solution of the required volume and concentration of the hydrophilic emulsifier ( 1%; 2%; 4% Tween-20) was then added and the mix- ture was homogenized at 7000 rpm for 1 min at ambient temperature.

To prepare multiple o/w/o emulsions, the first step in the emulsification provides the o/w emulsion. The hydrophilic emulsifying agent was dissolved in the aqueous phase and the solution was placed in the cup of the homogenizer. The oil was then added and the mixture was homogenized. In the second emulsifica- tion step, the freshly prepared o/w emulsion was mixed with a definite volume of oil phase that contains the

lipophilic emulsifying agent and the mixture was homogenized. Homogenization was performed under the same conditions followed for preparation of w/o/ w emulsion. Prednisolone 0.1% (w/v) was incorpo- rated in the aqueous phase of the simple emulsions by adding five drops of propylene glycol (the inner aque- ous phase of the multiple w/o/w emulsions) to increase its aqueous solubility or in the oily phase of the emulsions (the inner oily phase of the o/w/o mul- tiple emulsions).

2.2. Evaluation of emulsions

2.1. Microscopical examination Immediately after preparation of the multiple emul-

sion, microscopical examination was performed using a polarizing microscope. Other examinations were

8-

6-

SM. &jivat et ai. /Journal o~controlled Release 32 f1994) 259-268 263

0-0 2.5 % Span 60

P-----P 5% Span 60

O---O 7.5% span 60

4 5 6 7 8 9 IO

Time (hr)

Fig. 4. Effect of the concentration of lipophilic emulsifier (Span-60) on the percent mean change in IOP of rabbit’s eye post-instillation of prednisolone in w/o/w emulsions based on Iiqnid paraffin.

made after diluting the emulsions. Photomi~ro~aphs of emulsions were taken using a transmitting light microscope.

Figs. 1 and 2 show photomicrographs of multiple emulsions of WI o/w and o/w/o based on liquid par- affin, prepared with Span-60 (2.5%) and Tween-20 ( 1%) as emulsifying agents, the phase volume ratios of the internal phase as well as the external phase were 0.5. It is clear from these figures that the multiple drops contain vast numbers of internal droplets. This obser- vation is in agreement with Whitehill and Florence [ 221 who claimed that three types of multiple emul- sions could be identified as type A which was composed of small multiple drops containing few relatively large internal droplets; type B, in which the emulsion con- sisted of few larger multiple drops containing smaller internal droplets; and type C, more complex, where vast numbers of internal droplets are seen. According to Figs. 1 and 2, type C systems are more pr~omin~t in multiple emulsions based on liquid paraffin.

2.2, ~~-viva perjhmunce of rn~lt~p~e emulsions in eye of rabbits

The experimental animals were kept in place to allow the rabbit to be easily positioned for the measurement of IOP. Isotonic xylocaine solution (2% w/v) was dropped into rabbit’s eyes to anaesthetize the cornea, Doses of 10 ~1 of ophthalmic solution were dropped in the lower conjunctival sac. Non-medicated formula- tions were applied to the opposite eye which served as control. Each fo~ulation was tested in each of six rabbits and was applied to the right eye while the con- trol was applied to the left eye. The intraocular pressure of both eyes was measured before and after application of both control and test formulations by using Schiotz tonometer at certain time intervals. The instrument was placed gently in a vertical position directly over the cornea and the plunger was allowed to exert its full weights. Three readings were taken for IOP using the weights 5.5, 7.5 and 10 g and the average IOP was calculated.

264

Table 2

S.M. Sajival et al. /Journal of Controlled Release 32 (1994) 259-268

Effect of surfactant concentrations (and HLB) on the parameters of activity of the mean change in IOP of rabbit’s eye post-instillation of

prednisolone in multiple emulsions based on liquid paraffin

Emulsion Concentration Parameters of activity

type of

surfactants AUC MR TMR HVD

(mmHg/h) (mmHg) (h)

Vd c.v.%e V C.V.8 V C.V.8 V C.V.%

w/o/w

o/w/o

Standarda 10.85

[8.13]’ (0.74)

2% Tween 10.17

[ IO.031 (0.72)

4% Tween 8.42

[ 12.081 (0.77)

5% span 12.83

[ 6.701 (0.47)

7.5% span 14.50

[6.11] (0.41)

Standardb 13.28

[8.13] (0.62)

2% Tween 13.01

[ 10.03) (0.71)

5% span 15.94

[ 6.701 (0.37)

3.29 16.70

3.09 17.29

3.58 22.47

1.32 8.94

1.01 6.91

2.32 11.47

3.04 13.39

0.82 5.68

2.75

(0.24)

2.68

(0.30)

2.43

(0.14)

3.11

(0.13)

3.30

(0.07)

3.38

(0.18)

3.04

(0.17)

3.81

(0.04)

0.34

0.53

0.11

0.09

0.03

0.19

0.16

0.01

21.40

27.21

13.68

9.46

5.27

12.83

13.31

2.67

2.50

(0.22)

2.33

(0.33)

2.00

(0.26)

2.67

(0.21)

3.00

(0.26)

3.00

(0.26)

3.00

(0.26)

3.33

(0.33)

0.30

0.67

0.40

0.27

0.40

0.40

0.40

0.67

21.90

35.00

31.62

19.36

21.08

21.08

21.08

24.49

3.86

(0.14)

3.75

(0.14)

3.38

(0.22)

4.28

(0.20)

4.55

(0.13)

4.23

(0.24)

4.14

(0.14)

4.85

(0.13)

0.11 8.60

0.12 9.12

0.29 16.03

0.04 4.70

0.11 7.12

0.34 13.92

0.12 8.45

0.10 6.65

‘w/o/w (&v/o, 0.5; @v/o/w, 0.5, Span-60,2.5% and Tween-20,1% w/w).

ho/w/o (N/w, 0.5; @/w/o, 0.5, Tween-20, 1% w/w and Span-60,2.5% w/w).

‘Values represent HLB of surfactants mixtures.

WIIklIlCe.

“C.V.%, coefficient of variation percent.

2.3. Statistical analysis of the in-vivo data 3.1. W/O/W emulsions The in-vivo data of the intra-ocular pressure were

subjected to statistical analysis according to the Stu- dent-t-test [ 231.

To provide for a quantitative measure for the indi- vidual variations both the variance and the coefficient of variation percent (C.V.%) were computed, the latter

is given by the following equation [ 241

C.V.% = Standard Deviation/Mean X 100

Table 1 and Figs. 3 and 4 show the time course of the intraocular pressure (IOP) after instillation of pred-

nisolone in w/o/w delivery system both for the stan- dard emulsion ( 1% Tween-20+ 2.5% Span-60) and for emulsions in which the percentage of Tween-20 and

Span-60 was increased up to 4% and 7.5%, respec- tively. From Table 2, which shows the parameters of activity of prednisolone in these emulsion systems, it is obvious that increasing the concentration of Tween- 20 reduces the bioavailability (AUC) , the maximum response, the time of maximum response, and the half value duration. However, the effect of the concentra- tion of Tween-20 becomes statistically significant only when the concentration reaches 4% below this level, the effect is insignificant (Table 3).

3. Results and discussion

The effect of the concentration of the surfactant was studied both for the more hydrophilic component (Tween-20) and the more hydrophobic one (Span- 60), each being varied at one time. The effect was studied for prednisolone in multiple emulsions of the w/o/w and o/w/o types based on liquid paraffin.

On the other hand, increasing the concentration of Span-60 is found to bring about the reverse effect of that observed for Tween-20 (Table 2, Fig. 5). Here,

SM. Safwat et al. /Journal of Controlled Release 32 (1994) 25%268 265

Table 3 Significance level (value of P) of differences in the values of the parameters of activity for prednisolone in multiple emulsions

Type of emulsion

Pairs of comparison Parameters of activity

AUC (mmHg/h)

MR (mmHg)

TMR

(h) HVD (h)

w/o/w

o/w/o

Standard with 2% Tween Standard with 4% Tween Standard with 5% Span Standard with 7.5%

Span 2% Tween with 4% Tween 5% Tween with 4% Span 2% Tween with 5% Span 2% Tween with 7.5%

Span 4% Tween with 5%

Span 4% Tween with 7.5%

Span Standard with 2% Tween Standard with 5%

Span 2% Tween with 5% Span

0.1

0.05

0.05

0.01

0.1

0.05

0.05

0.001

0.001

0.001

0.01

0.01

0.01

0.1

0.1

0.1

0.05

0.1

0.1

0.1

0.1

0.01

0.001

0.1

0.05

0.01

0.1

0.1

0.1

0.1

0.1

0.1

0.1

0.1

0.1

0.05

0.1

0.1

0.1

0.1

0.1

0.05

0.01

0.1

0.1

0.01

0.01

0.01

0.001

0.1

0.05

0.01

M e a n

C h a n 9 e

+ Standard ( “LB -8.13)

+I+ P%Tween 2O(Hm -10.03)

-x-- B%Spen cot nre-6.7)

--.*

Time6 8 10

(hr)

-I

12

Fig. 5. Effect of the concentration of surfactant and HLB on the percent mean change 1OP of rabbit’s eye induced by prednisolone in o/w/o emulsion based on liquid paraffin.

266 S.M. Safwat et al. /Journal of Controlled Release 32 (1994) 259-268

Table 4

Correlation coefficient (r) for the parameters of activity of pmdnisolone and HLB of the surfactant mixture (one and the same pair of surfactants

with different concentrations) in multiple emulsions based on liquid paraffin

Type of emulsion Parameters of activity

AUC

(mmHg/h)

MR

(mml-fg)

TMR

(h)

HVD

(h)

w/0/w 0.960 - 0.955 - 0.967 - 0.964 o/w/o -0.867 - 0.989 - 0.823 - 0.883

0 3 6 9 12 15

HLE

1

0 3 6 9 12 15

HLB

Fig. 6. Correlation between AUC and MR for prednisolone and the

HLB of the surfactant mixture in w/o/w emulsion based on liquid

paraffin.

0 3 6 9 12 15

HLB

5

4

-3 L A

9 = 2

1

0 I I I I I 0 3 6 9 12 15

HLB

Fig. 7. Correlation between TMR and HVD of prednisolone and

HLB of surfactant mixture in w/o/w emulsions based on liquid

paraffin as oily phase.

S.M. Sajivat et al. /Journal of Controlled Release 32 (1994) 25%268 26-l

the bioavailability, the maximum response and the half value duration increase with increasing lipophilic sur-

factant concentration. The increase is more marked in the lower level of concentration, viz., 2.5-5%.

Table 3 shows that the difference between systems containing 2.5% and 5% Span are generally statistically significant. Differences between systems containing

5% and 7.5% Span-60, on the other hand, are almost insignificant except for the parameter AUC where a significant difference is observed.

Calculation of the HLB values for the surfactant mixtures [ 251 and the correlation coefficient between these values and the value of the parameters of activity

was studied for the different systems. Table 4 reveals fairly high correlation coefficients, indicating the high dependency of the in vivo performance of prednisolone

on the HLB value of the surfactant mixture in multiple emulsions.

The correlation is negative, i.e., the bioavailability, the maximum response, the time of maximum response and the half value duration of the drug increase with

decreasing HLB of the surfactant mixture. Figs. 6 and 7 present the linear relationship between

the HLB and the parameters of activity. It has to be stated that, in spite of the fact that the different systems contain different concentrations of the surfactant mix- ture, (varying between 3.5% and 8.55%), yet the par- ameters of activity are governed in the first place by the HLB of the surfactant mixture rather than by its con- centration. Decreasing the HLB value of the surfactant mixture in a w/o/w emulsion favours the bioavaila- bility, the intensity of drug action and the duration of drug action.

Lin et al. [ 261 demonstrated that the HLB value of the surfactant effected the absorption rate and extent of ephedrine recovery from the orally administered min- eral oil-water emulsified system.

Table 3, showing the significance level of differences between the different systems in relation to the HLB of the surfactant mixture, reveals the following:

( 1) Differences with regard to AUC are statistically significant for 80% of the comparisons. (2) Differences with regard to HVD were statistically significant for 60% of the comparisons. (3) Differences with regard to MR are statistically significant for 30% of the comparisons. (4) Differences with regard to TMR are statistically significant for 10% of the comparisons.

3.2. O/w/O emulsions

For the case of o/w/o emulsion, Table 1 and Fig. 5 depict the time course of the IOP post instillation of prednisolone for both the standard o/w/o emulsion and emulsions containing different Tween and Span con- centrations based on liquid paraffin.

Table 2 gives the parameters of activity and Table 3 gives the significance level of differences for the par- ameters of activity. Although the general trend applies i.e., the parameters of activity are influenced in the first place by the HLB of the surfactant mixture, yet the correlation coefficient is generally lower than that

observed for w/o/w emulsions. The general trend is the increase in value of the parameters of activity with decreasing HLB, yet this increase is minimal for the

TMR parameter. For the parameters AUC, MR and HVD, the values are almost independent on HLB in the

HLB range above 8.13 and increase to a significant extent in the HLB range below 8.13.

4. Conclusion

The emulsion delivery systems of prednisolone based on liquid paraffin give rise to a tremendous

increase of the parameters of activity (AUC, MR, TMR, HVD) . The individual variations in parameters of activity are a function of the delivery system. Within the emulsion systems, the variations are less in emul- sion with an external oily phase compared to those with

an external aqueous phase. Generally, o/w/o emulsion systems represent an

optimal delivery system, maximizing drug bioavaila-

bility and minimizing individual variations. Increasing the concentration of a hydrophilic emulsifier (Tween- 20) in w/o/w/ and o/w/o prednisolone emulsions

based on liquid paraffin reduces the bioavailability, the MR, the TMP and the HVD. However, the effect becomes statistically significant only at higher Tween concentrations. On the other hand, increasing the con- centration of a lipophilic emulsifier (Span-60) was found to bring about the reverse effect. The HLB of a surfactant mixture in a multiple emulsion was found to highly correlate to the values of the parameters of pred- nisolone activity. The correlation is negative.

The above studies lead to the identification of design and formulation parameters in emulsion delivery sys-

268 S.M. Sajivat et al. / Joumal of Controlled Release 32 (1994) 25%268

terns which may be useful in modulating drug action in terms of intensity and duration.

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