J.
MICROENCAPSULATION, 1990,
VOL.
7,NO. 4,447454
Preparation of controlled release anticancer agents I: 5-fluorouracil-ethyl cellulose microspheres
Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
M A H M O U D M. GHORABt, H O S S E I N ZIA and LOUIS A. L U Z Z I Department of Pharmaceutics, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA (Received 18 October 1989; accepted 13 November 1989)
Microspheres of 5-fluorouracil have been prepared, using three grades of ethyl cellulose as wall forming materials, and utilizing a solvent evaporation technique under ambient conditions. An alcoholic solution of 5-fluorouracil and polymer was dispersed in liquid paraffin containing 33.3 per cent n-heptane. The effect of stirring rate, time of stirring, drug loading, and polymer grade on drug release in two different media were evaluated. The drug loaded particles were spherical in shape and had a diameter range of 25-200 mm and were suitable for incorporating into a gel base. Drug release studies in aqueous media, showed that acidic media provide a faster release rate than neutral media. The drug release study from an aqueous gel base preparation at pH 7.0through a synthetic membrane was found to be promising for formulation of a gel-microsphere product for the treatment of skin lesions.
Introduction Microencapsulation techniques have been used for many years to separate chemically incompatible substances, to convert liquids to free flowing powders, to increase stability of the compounds, and to modify the dissolution rates and subsequently the bioavailability of drugs (Luzzi and Palmier 1984). Numerous methods have been used to prepare microcapsules. These include pan coating, fluidized bed, spray drying, solvent evaporation, interfacial polymerization, and coacervation techniques (Lachman et al. 1986). T h e solvent evaporation technique is simple and works best for water insoluble drugs, yielding a payload usually of less than 30 per cent (Bodmeier and McGinity 1987). I n the case of water-soluble pharmaceuticals a number of techniques have been patented and a few detailed reports have been published. I n 1967, Miller et al. patented a method of temperature change coacervation by which they were able to encapsulate acetaminophen in a cyclohexane-ethyl cellulose system. However, due to the high temperature involvement (80"C), this method does not work for thermoliable drugs. Recently Huang and Sellassie (1989) published the first trial reporting the preparation of water soluble pharmaceuticals in controlled release microcapsules, using a solvent evaporation technique. 5-Fluorouracil is an anticancer agent, commonly used for the palliative treatment of carcinoma of the colon, rectum, breast, stomach, and pancreas, when administered intravenously (McEvoy 1989). I t is also used topically as 1-5 per cent cream for the treatment of precancerous dermatosis especially actinic kenatosis, where it is the treatment of choice.
t Senior Fulbright-Hays Scholar from Cairo University, Cairo, Egypt. 0265-2048/90 $3.00 0 1990 Taylor & Francis Ltd.
Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
448
M. M. Ghorab et al.
Several publications have reported the use of ethyl cellulose as a biodegradable convenient polymer in the preparation of microspheres. On the other hand, 5fluorouracil also had been prepared in microspheres using various polymers, such as gelatin (Jeyanthi and Panduranga Rao 1988), alginate (Ouchi et al., 1988), and poly(glyco1ic acid), poly(1actic acid) and their copolymers (Hazrati and DeLuca 1989). However, nothing was found in the available literature on the preparation of 5-fluorouracil microspheres using ethyl cellulose as the polymer of choice. T h e objectives of the present report were to: (i) incorporate 5-fluorouracil into polymer microspheric matrices and characterize the drug loaded microspheres for particle size and shape, total drug content and their in oitro drug release; (ii) evaluate, if possible, the suitability of incorporating these microspheres into an aqueous gel base for topical use.
Materials and methods 5-Fluorouracil (Sigma Chemical Co., St Louis, M O 63178, USA), ethyl cellulose (Dow Chemical Co., Midland, M I 48640, USA), 95 per cent alcohol (Industrial Chemical Co., Tuscola, I L 61963, USA), polyethylene glycol (Ruger Chemical Co. Inc., Irvington, NJ 071 11, USA) and n-heptane (Fisher Scientific, Fair Lawn, NJ 07410, USA) were used as received. All other chemicals were reagent grade.
Preparation of stock polymer solutions Three 2 g portions of ethyl cellulose grade 50, 100 and LOO were accurately weighed and transferred into separate measuring flasks. Three portions of 0.4 g of polyethylene glycol were weighed and carefully transferred into each flask, alcohol (95 per cent) was added and flasks were shaken for 10 minutes and left over night in a cooler at 5°C. The volumes were then brought up to 100 ml with 95 per cent alcohol. Fabrication of microspheres Nine portions each of 50 mg of 5-fluorouracil (previously sieved through sieve no. 90) were accurately weighed. Each weight was dissolved in the proper volume of the polymer stock solution (5,7.5,12.5ml), corresponding to drug/polymer ratios of 1 : 2, 1 :3, 1 : 5 respectively. T h e dispersion phase (a mixture of light mineral oil and n-heptane with the ratio of 2 : 1 ) containing 1 per cent Span 85 was stirred at a rate of 400 rpm using a counter-rotating double blade stirrer (Brookfield Engineering Laboratories Inc., Stoughton, MA, USA). T h e drug/polymer solution then was added dropwise to the dispersion phase by the aid of a syringe fitted with a 12 gauge needle at a rate of 5 drops per minute. After 4 h of stirring, the products were filtered, washed with separate three portions of n-hexane, and air dried at room temperature. Payload determination A 10mg sample of prepared 5-fluorouracil microspheres was accurately weighed and dissolved in alcohol in a 25 ml volumetric flask and the volume was made u p to 25 ml. T h e analysis of the drug was carried out spectrophotometrically at 266 flm using a Diod Ray Spectrophotometer (Hewlett-Packard Co., Corvallis, OR 97330, USA).
Preparation of controlled release anticancer agents. I
449
Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
Dissolution studies Dissolution profiles of microspheres were determined at 37°C in purified water and 0.1 N HCl. Three 10 mg samples of microspheres were weighed and transferred into 30 ml screw cap glass tubes and 20 ml of dissolution media was added to each tube and rotated in a rotating bottle dissolution apparatus at 40 rpm. At appropriate times 0.5 ml of samples were withdrawn through a 2 p filter tip and replaced with fresh media. Samples were then diluted with appropriate dissolution media and analysed spectrophotometrically at 266 pm. Preparation of gel and release study Preparation of gel was based on incorporation of crystalline 5-fluorouracil or its microspheres in a 1 per cent gel by presoaking 1 g Carbapol 934 into l00ml of an isotonic phosphate buffer, p H 7-4, containing 0.05 and 0 2 per cent disodium E D T A and chlorobutanol respectively. Then the adjustment of p H was made by adding concentrated NaOH solution dropwise to p H 7.0. Drug release study from gel was done by taking 1 g of the gel and using a paddle over disc method with 500ml of purified water as dissolution medium at 32°C and using a Cuprophan membrane in a triplicate manner. At an appropriate time, samples were withdrawn and analysed spectrophotometrically at 266 pm for drug content.
Results and discussion T h e solvent evaporation technique, using an oil-in-water emulsion to make microcapsules, works best for water insoluble drugs. In cases of water soluble drugs, alteration of phases may work, if the selected polar phase is a solvent for both drug and polymer and somewhat immiscible with the dispersing medium. In this respect, acetone and mineral oil have been used in most of the reported investigations as dissolving and dispersing media respectively. Recently, Huang and Sellassie (1989) used alcohol instead of acetone and encapsulated diphenhydramine HCl and found the method effective. In the present study, 95 per cent alcohol was used as the organic solvent which dissolves both 5-fluorouracil and ethyl cellulose. T h e dispersion media was a mixture of light mineral oil and n-heptane (2: l), a non-solvent for both 5fluorouracil and the ethyl cellulose. A typical photomicrograph obtained from a 1 : 5 ratio of 5-fluorouracilLethy1 cellulose 200 is shown in figure 1. As is evident from this photograph the drug-loaded microspheres are spherical in shape and have particle sizes ranging between 25-200pm in diameter (see table 1). Compared to microspheres of diphenhydramine HCl reported by Huang and Sellassie (1989), the 5 fluorouracil microspheres are somewhat smaller in size, probably due to the higher stirring speed and longer stirring period, used in this study. T h e yield was about 8085 per cent and drug loading ranged from 61-95, depending on the grades of polymer, drug-polymer ratio and the degree of agglomeration (table 1). Effect of stirrer, stirring rate and time of stirring Initially a three blade stirring shaft fitted to a variable-speed motor was used; however, serious agglomeration was observed during the process, especially with higher molecular weight polymer, presumably due to the vortex formation in the mixing vessel. T h e exchange of the mixer with a Brookfield counter-rotating double blade shaft reduced the problem considerably. In addition, with this mixer it was
M. M . Ghorab et al.
Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
450
Figure 1. Photomicrograph showing microspheres obtained 5-fluorouracil-ethyl cellulose 200.
from
a 1 : 5 ratio of
Table 1. Characteristics of 5-fluorouracil-ethyl cellulose microspheres. Ethocel grade
Drug/polymer ratio
Size range (P)
Percent yield
Percent of drug payload
50 50 50 100 100 100 200 200 200
1:2 1:3 1:s 1:2 1:3 1:s 1:2 1:3 1:s
50-200 50-150 25-100 50-150 50-100 25-100 100-200 50-1 50 50-150
79.5 840 82.0 80.0 83.0 848 807 848 79.9
61.0 89.0 77.0 63.5 946 825 65.0 91.7 804
possible to operate at higher speed and relatively longer period of time with much less agglomeration to the walls of the mixing vessel. In general, a 400 rpm stirring rate for a period of 4 h under ambient conditions produced spherical microspheres with an average size of 25-200pm diameter.
Drug release studies T h e drug-loaded microspheres containing different payloads and/or various grades of polymer were tested for drug release in two media, 0.1 N HCl and purified
Preparation of controlled release anticancer agents. I
45 1
100
YO u
-
80
2 70 u
60
m
50 c
40
:
Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
30
o
l 00
1 00
200
300
400
Time in Minutes
Figure 2.
Percentage of 5-fluorouracil released from various drug-ethyl cellulose 50 ratios in water versus time. 100
YO 80
30
m 10 ~~
" I
0
100
200
300
400
Tune m Mmutes
Figure 3.
Percentage of 5-fluorouracil released from various drug-ethyl cellulose 100 ratios in water versus time. YO 20
70 0
-P
60 50
5
40
L
30
0
05% Re.from 1 :3M200
20 10
06 0
I
100
200 Time m Minutes
300
400
Figure 4. Percentage of 5-fluorouracil released from various drug-ethyl cellulose 200 ratios in water versus time.
M . M . Ghorab et al.
452 100
90 80 v
f 70
-p 01
60
m
n 2 50 'c
i 40 Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
30
-0-95 Re from 1 3M50
20
'0 0
100
200 O
400 3
300
Time in Minutes
Figure 5.
Percentage of 5-fluorouracil released from various drug-ethyl cellulose 50 ratios in 0 1 N HCI versus time. t 00
90 v
80
2 70
-$ ed
60
m
50 *.
40
-0- % Re.from 1 .2M100
30 20 10
t
Oh 0
I
100
200 Time in Minutes
400
300
Figure 6 . Percentage of 5-fluorouracil released from various drug-ethyl cellulose 100 ratios in 0.1 N HCl versus time. 100
90 80
m
50 b-
w
40
30
-0 % Re from 1
20
3M200
10
, 0
100
I
200
300
400
Time in Minutes
Figure 7.
Percentage of 5-fluorouracil released from various drug-ethyl cellulose 200 ratios in 0.1 N HCI versus time.
Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
Preparation of controlled release anticancer agents. I
453
water. In all cases, the 0.1 N HCI medium showed faster release rate than purified water (figures 5-7). This may be due to the higher solubility of ethyl cellulose in acidic media. A common method for reducing drug release rate from microspheres is to lengthen the diffusional pathway through the polymer membrane by decreasing drug to polymer ratio and/or by increasing the tourosity of the membrane by increasing the molecular weight of the polymer. Figures 2-7 indicate the effect of drug-ethyl cellulose ratio on the release of 5fluorouracil. It is evident from these figures that microspheres composed of higher polymer content show slower drug release rates. It is also seen from these figures that low and moderate molecular weight polymer, at low drug-polymer ratio show an initial fast release. This pattern of release could be due to the dissolution of drug from the surface of microspheres and/or due to the protrusion of drug particles through the surrounding membrane, which upon exposure to the dissolution media causes a sudden release of drug. Usually, higher molecular weight polymers have better retarding ability than low molecular ones. In the present study, three grades of ethyl cellulose, 50,100 and 200, were investigated. In general, although this trend was found to be true, there were some exceptions, probably due to the initial solution volume differences in the fabrication processes. In order to evaluate the suitability of microspheres as an aqueous gel base product, the drug release from a 1 per cent polyacrylic acid gel base at p H 7.0 and 32°C temperature, containing crystalline 5-fluorouracil was carried out and compared to the gel formula of microspheres. Figure 8 is a typical plot of per cent drug released versus time from a 2 per cent drug-load gel formula. As is clear from this plot the release of 5-fluorouracil is very much retarded by the microencapsulation process. In fact, the release from microencapsulated gel has a two-phase release, an initial fast, followed by a constant slow release pattern. In conclusion, an alcohol-in-oil emulsion and a solvent evaporation technique was used for preparation of 5-fluorouracil microspheres using three grades of ethyl cellulose as the coating polymer. T h e effect of stirring rate, time of stirring, drug loading, and polymer grade on drug release in two different media were evaluated. T h e microspheres ranging from 50 to 200pm can be manufactured with properties which make them suitable for topical gel formulations. 100
n
0
90
MICROENCAPSULATION, 1990,
VOL.
7,NO. 4,447454
Preparation of controlled release anticancer agents I: 5-fluorouracil-ethyl cellulose microspheres
Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
M A H M O U D M. GHORABt, H O S S E I N ZIA and LOUIS A. L U Z Z I Department of Pharmaceutics, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA (Received 18 October 1989; accepted 13 November 1989)
Microspheres of 5-fluorouracil have been prepared, using three grades of ethyl cellulose as wall forming materials, and utilizing a solvent evaporation technique under ambient conditions. An alcoholic solution of 5-fluorouracil and polymer was dispersed in liquid paraffin containing 33.3 per cent n-heptane. The effect of stirring rate, time of stirring, drug loading, and polymer grade on drug release in two different media were evaluated. The drug loaded particles were spherical in shape and had a diameter range of 25-200 mm and were suitable for incorporating into a gel base. Drug release studies in aqueous media, showed that acidic media provide a faster release rate than neutral media. The drug release study from an aqueous gel base preparation at pH 7.0through a synthetic membrane was found to be promising for formulation of a gel-microsphere product for the treatment of skin lesions.
Introduction Microencapsulation techniques have been used for many years to separate chemically incompatible substances, to convert liquids to free flowing powders, to increase stability of the compounds, and to modify the dissolution rates and subsequently the bioavailability of drugs (Luzzi and Palmier 1984). Numerous methods have been used to prepare microcapsules. These include pan coating, fluidized bed, spray drying, solvent evaporation, interfacial polymerization, and coacervation techniques (Lachman et al. 1986). T h e solvent evaporation technique is simple and works best for water insoluble drugs, yielding a payload usually of less than 30 per cent (Bodmeier and McGinity 1987). I n the case of water-soluble pharmaceuticals a number of techniques have been patented and a few detailed reports have been published. I n 1967, Miller et al. patented a method of temperature change coacervation by which they were able to encapsulate acetaminophen in a cyclohexane-ethyl cellulose system. However, due to the high temperature involvement (80"C), this method does not work for thermoliable drugs. Recently Huang and Sellassie (1989) published the first trial reporting the preparation of water soluble pharmaceuticals in controlled release microcapsules, using a solvent evaporation technique. 5-Fluorouracil is an anticancer agent, commonly used for the palliative treatment of carcinoma of the colon, rectum, breast, stomach, and pancreas, when administered intravenously (McEvoy 1989). I t is also used topically as 1-5 per cent cream for the treatment of precancerous dermatosis especially actinic kenatosis, where it is the treatment of choice.
t Senior Fulbright-Hays Scholar from Cairo University, Cairo, Egypt. 0265-2048/90 $3.00 0 1990 Taylor & Francis Ltd.
Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
448
M. M. Ghorab et al.
Several publications have reported the use of ethyl cellulose as a biodegradable convenient polymer in the preparation of microspheres. On the other hand, 5fluorouracil also had been prepared in microspheres using various polymers, such as gelatin (Jeyanthi and Panduranga Rao 1988), alginate (Ouchi et al., 1988), and poly(glyco1ic acid), poly(1actic acid) and their copolymers (Hazrati and DeLuca 1989). However, nothing was found in the available literature on the preparation of 5-fluorouracil microspheres using ethyl cellulose as the polymer of choice. T h e objectives of the present report were to: (i) incorporate 5-fluorouracil into polymer microspheric matrices and characterize the drug loaded microspheres for particle size and shape, total drug content and their in oitro drug release; (ii) evaluate, if possible, the suitability of incorporating these microspheres into an aqueous gel base for topical use.
Materials and methods 5-Fluorouracil (Sigma Chemical Co., St Louis, M O 63178, USA), ethyl cellulose (Dow Chemical Co., Midland, M I 48640, USA), 95 per cent alcohol (Industrial Chemical Co., Tuscola, I L 61963, USA), polyethylene glycol (Ruger Chemical Co. Inc., Irvington, NJ 071 11, USA) and n-heptane (Fisher Scientific, Fair Lawn, NJ 07410, USA) were used as received. All other chemicals were reagent grade.
Preparation of stock polymer solutions Three 2 g portions of ethyl cellulose grade 50, 100 and LOO were accurately weighed and transferred into separate measuring flasks. Three portions of 0.4 g of polyethylene glycol were weighed and carefully transferred into each flask, alcohol (95 per cent) was added and flasks were shaken for 10 minutes and left over night in a cooler at 5°C. The volumes were then brought up to 100 ml with 95 per cent alcohol. Fabrication of microspheres Nine portions each of 50 mg of 5-fluorouracil (previously sieved through sieve no. 90) were accurately weighed. Each weight was dissolved in the proper volume of the polymer stock solution (5,7.5,12.5ml), corresponding to drug/polymer ratios of 1 : 2, 1 :3, 1 : 5 respectively. T h e dispersion phase (a mixture of light mineral oil and n-heptane with the ratio of 2 : 1 ) containing 1 per cent Span 85 was stirred at a rate of 400 rpm using a counter-rotating double blade stirrer (Brookfield Engineering Laboratories Inc., Stoughton, MA, USA). T h e drug/polymer solution then was added dropwise to the dispersion phase by the aid of a syringe fitted with a 12 gauge needle at a rate of 5 drops per minute. After 4 h of stirring, the products were filtered, washed with separate three portions of n-hexane, and air dried at room temperature. Payload determination A 10mg sample of prepared 5-fluorouracil microspheres was accurately weighed and dissolved in alcohol in a 25 ml volumetric flask and the volume was made u p to 25 ml. T h e analysis of the drug was carried out spectrophotometrically at 266 flm using a Diod Ray Spectrophotometer (Hewlett-Packard Co., Corvallis, OR 97330, USA).
Preparation of controlled release anticancer agents. I
449
Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
Dissolution studies Dissolution profiles of microspheres were determined at 37°C in purified water and 0.1 N HCl. Three 10 mg samples of microspheres were weighed and transferred into 30 ml screw cap glass tubes and 20 ml of dissolution media was added to each tube and rotated in a rotating bottle dissolution apparatus at 40 rpm. At appropriate times 0.5 ml of samples were withdrawn through a 2 p filter tip and replaced with fresh media. Samples were then diluted with appropriate dissolution media and analysed spectrophotometrically at 266 pm. Preparation of gel and release study Preparation of gel was based on incorporation of crystalline 5-fluorouracil or its microspheres in a 1 per cent gel by presoaking 1 g Carbapol 934 into l00ml of an isotonic phosphate buffer, p H 7-4, containing 0.05 and 0 2 per cent disodium E D T A and chlorobutanol respectively. Then the adjustment of p H was made by adding concentrated NaOH solution dropwise to p H 7.0. Drug release study from gel was done by taking 1 g of the gel and using a paddle over disc method with 500ml of purified water as dissolution medium at 32°C and using a Cuprophan membrane in a triplicate manner. At an appropriate time, samples were withdrawn and analysed spectrophotometrically at 266 pm for drug content.
Results and discussion T h e solvent evaporation technique, using an oil-in-water emulsion to make microcapsules, works best for water insoluble drugs. In cases of water soluble drugs, alteration of phases may work, if the selected polar phase is a solvent for both drug and polymer and somewhat immiscible with the dispersing medium. In this respect, acetone and mineral oil have been used in most of the reported investigations as dissolving and dispersing media respectively. Recently, Huang and Sellassie (1989) used alcohol instead of acetone and encapsulated diphenhydramine HCl and found the method effective. In the present study, 95 per cent alcohol was used as the organic solvent which dissolves both 5-fluorouracil and ethyl cellulose. T h e dispersion media was a mixture of light mineral oil and n-heptane (2: l), a non-solvent for both 5fluorouracil and the ethyl cellulose. A typical photomicrograph obtained from a 1 : 5 ratio of 5-fluorouracilLethy1 cellulose 200 is shown in figure 1. As is evident from this photograph the drug-loaded microspheres are spherical in shape and have particle sizes ranging between 25-200pm in diameter (see table 1). Compared to microspheres of diphenhydramine HCl reported by Huang and Sellassie (1989), the 5 fluorouracil microspheres are somewhat smaller in size, probably due to the higher stirring speed and longer stirring period, used in this study. T h e yield was about 8085 per cent and drug loading ranged from 61-95, depending on the grades of polymer, drug-polymer ratio and the degree of agglomeration (table 1). Effect of stirrer, stirring rate and time of stirring Initially a three blade stirring shaft fitted to a variable-speed motor was used; however, serious agglomeration was observed during the process, especially with higher molecular weight polymer, presumably due to the vortex formation in the mixing vessel. T h e exchange of the mixer with a Brookfield counter-rotating double blade shaft reduced the problem considerably. In addition, with this mixer it was
M. M . Ghorab et al.
Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
450
Figure 1. Photomicrograph showing microspheres obtained 5-fluorouracil-ethyl cellulose 200.
from
a 1 : 5 ratio of
Table 1. Characteristics of 5-fluorouracil-ethyl cellulose microspheres. Ethocel grade
Drug/polymer ratio
Size range (P)
Percent yield
Percent of drug payload
50 50 50 100 100 100 200 200 200
1:2 1:3 1:s 1:2 1:3 1:s 1:2 1:3 1:s
50-200 50-150 25-100 50-150 50-100 25-100 100-200 50-1 50 50-150
79.5 840 82.0 80.0 83.0 848 807 848 79.9
61.0 89.0 77.0 63.5 946 825 65.0 91.7 804
possible to operate at higher speed and relatively longer period of time with much less agglomeration to the walls of the mixing vessel. In general, a 400 rpm stirring rate for a period of 4 h under ambient conditions produced spherical microspheres with an average size of 25-200pm diameter.
Drug release studies T h e drug-loaded microspheres containing different payloads and/or various grades of polymer were tested for drug release in two media, 0.1 N HCl and purified
Preparation of controlled release anticancer agents. I
45 1
100
YO u
-
80
2 70 u
60
m
50 c
40
:
Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
30
o
l 00
1 00
200
300
400
Time in Minutes
Figure 2.
Percentage of 5-fluorouracil released from various drug-ethyl cellulose 50 ratios in water versus time. 100
YO 80
30
m 10 ~~
" I
0
100
200
300
400
Tune m Mmutes
Figure 3.
Percentage of 5-fluorouracil released from various drug-ethyl cellulose 100 ratios in water versus time. YO 20
70 0
-P
60 50
5
40
L
30
0
05% Re.from 1 :3M200
20 10
06 0
I
100
200 Time m Minutes
300
400
Figure 4. Percentage of 5-fluorouracil released from various drug-ethyl cellulose 200 ratios in water versus time.
M . M . Ghorab et al.
452 100
90 80 v
f 70
-p 01
60
m
n 2 50 'c
i 40 Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
30
-0-95 Re from 1 3M50
20
'0 0
100
200 O
400 3
300
Time in Minutes
Figure 5.
Percentage of 5-fluorouracil released from various drug-ethyl cellulose 50 ratios in 0 1 N HCI versus time. t 00
90 v
80
2 70
-$ ed
60
m
50 *.
40
-0- % Re.from 1 .2M100
30 20 10
t
Oh 0
I
100
200 Time in Minutes
400
300
Figure 6 . Percentage of 5-fluorouracil released from various drug-ethyl cellulose 100 ratios in 0.1 N HCl versus time. 100
90 80
m
50 b-
w
40
30
-0 % Re from 1
20
3M200
10
, 0
100
I
200
300
400
Time in Minutes
Figure 7.
Percentage of 5-fluorouracil released from various drug-ethyl cellulose 200 ratios in 0.1 N HCI versus time.
Journal of Microencapsulation Downloaded from informahealthcare.com by University of Limerick on 05/16/13 For personal use only.
Preparation of controlled release anticancer agents. I
453
water. In all cases, the 0.1 N HCI medium showed faster release rate than purified water (figures 5-7). This may be due to the higher solubility of ethyl cellulose in acidic media. A common method for reducing drug release rate from microspheres is to lengthen the diffusional pathway through the polymer membrane by decreasing drug to polymer ratio and/or by increasing the tourosity of the membrane by increasing the molecular weight of the polymer. Figures 2-7 indicate the effect of drug-ethyl cellulose ratio on the release of 5fluorouracil. It is evident from these figures that microspheres composed of higher polymer content show slower drug release rates. It is also seen from these figures that low and moderate molecular weight polymer, at low drug-polymer ratio show an initial fast release. This pattern of release could be due to the dissolution of drug from the surface of microspheres and/or due to the protrusion of drug particles through the surrounding membrane, which upon exposure to the dissolution media causes a sudden release of drug. Usually, higher molecular weight polymers have better retarding ability than low molecular ones. In the present study, three grades of ethyl cellulose, 50,100 and 200, were investigated. In general, although this trend was found to be true, there were some exceptions, probably due to the initial solution volume differences in the fabrication processes. In order to evaluate the suitability of microspheres as an aqueous gel base product, the drug release from a 1 per cent polyacrylic acid gel base at p H 7.0 and 32°C temperature, containing crystalline 5-fluorouracil was carried out and compared to the gel formula of microspheres. Figure 8 is a typical plot of per cent drug released versus time from a 2 per cent drug-load gel formula. As is clear from this plot the release of 5-fluorouracil is very much retarded by the microencapsulation process. In fact, the release from microencapsulated gel has a two-phase release, an initial fast, followed by a constant slow release pattern. In conclusion, an alcohol-in-oil emulsion and a solvent evaporation technique was used for preparation of 5-fluorouracil microspheres using three grades of ethyl cellulose as the coating polymer. T h e effect of stirring rate, time of stirring, drug loading, and polymer grade on drug release in two different media were evaluated. T h e microspheres ranging from 50 to 200pm can be manufactured with properties which make them suitable for topical gel formulations. 100
n
0
90
