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Elaboration and evaluation of an intraoral controlled release delivering system
Biomaterials 19 (1998) 1523 — 1527
Elaboration and evaluation of an intraoral controlled release delivering system M. Diarra!,",*, G. Pourroy", D. Muster!, M. Zingraff#, C. Boymond# !LEED Biomate´ riaux CHRU B.P. 426F-67091 Strasbourg Cedex, France "IPCMS, Groupe des Mate´ riaux Inorganiques UMR 046 du CNRS, 23 Rue du Loess F-67037 Strasbourg Cedex, France #Laboratoire de Pharmacotechnie Faculte´ de Pharmacie 74, Route du Rhin BP 24 F-67401 Illkirch Cedex, France
Abstract In order to improve the administration of drugs for all pathology of the oral cavity, we have developed an intraoral controlled release delivering system, permitting to reach high enough local concentrations for desirable therapeutic effect with minimal side effects. We have formulated tablets of 200 mg intended to be fixed on a tooth. These tablets resist food and drink attacks. The tablets we elaborated have a granular matrix composed of hydroxyapatite, ethyl cellulose and EudragitR. Zinc sulfate is used as the first model of an active drug, it has a therapeutic effect on buccal mucous. Profiles of continuous in-vitro drug release in distilled water at 37°C show that zinc sulfate release by the matrix structure for the different tablet formulations is regulated by the proportions of the different components. ( 1998 Elsevier Science Ltd. All rights reserved
1. Introduction A medicinal product consists of more than just the active drug. There are other materials present that are necessary to allow the formulation to achieve the desired pharmacological and/or pharmacokinetic effect. Nowadays, recent developments, particularly the concept of controlled release, have shown that excipients are fundamental to the design of drug delivery system [1]. Currently, acrylic acid polymers, starch, wax, cellulose derivatives, polyethylene glycol, etc. have been used as excipients for formulation of intraoral controlled release delivering system of drugs [2—5]. In order to increase the buccal residence time of the drug, an intraoral controlled release delivering system was developed in the form of a tablet which can resist food and drink attacks. We prepared hydroxyapatite Ca (PO ) (OH) as the raw 10 46 2 material for the tablet formulation. It has the same elemental chemical composition as natural bone and teeth, is biocompatible and stable [6—11], and widely used in orthopedic and odontology. Ethyl cellulose, Eudragit RS100 and RSPM were used as insoluble fillers and zinc sulfate as the first model of active drug because of its therapeutic effect on buccal mucous [12, 13]. The pur-
* Corresponding author. 0142-9612/98/$19.00 ( 1998 Elsevier Science Ltd. All rights reserved. PII S 0 1 4 2 - 9 6 1 2 ( 9 8 ) 0 0 0 7 0 - 2
pose of this work is to adjust the formulation of tablets with the view to elaborate and to evaluate those tablets and regard how the variation of the composition and the formulation influenced the in vitro release of zinc sulfate.
2. Material and methods 2.1. Material Zinc sulfate ZnSO .7H O and magnesium stearate 4 2 were obtained from Prolabo, Ethyl cellulose N 50 NF from Aqualon, Eudragit RS100 and Eudragit RSPM from Ro¨hm Pharma. 2.2. Methods 2.2.1. Preparation of sintered hydroxyapatite A solution of H PO (Prolabo R.P.Normapur) 0.3 M is 3 4 added at a rate of 25 ml min~1 to a suspension of Ca(OH) (Prolabo R.P.Rectapur) 0.5 M in distilled water 2 under vigorous stirring at 80—95°C with the mixing molar ratio Ca/P"1.66 [14, 15]. After the addition of H PO , stirring and heating were maintained 20 min 3 4 followed by 25 min stirring without heating. The resulting precipitate is aged at room temperature for 24 h and then filtered. The filtered cake is dried at 40°C, then the
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M. Diarra et al. / Biomaterials 19 (1998) 1523—1527
temperature is gradually raised up to 80°C over 24 h. The calcination is ended at 800°C after 3 h. The X-ray diffraction pattern recorded at room temperature with a D 500 Siemens diffractometer equipped with a primary beam quartz monochromator (Co Ka "1.78897 A_ ) exhibits 1 the diffraction lines of hydroxyapatite (Fig. 1). No impurities are observed. Its specific area was measured by the nitrogen BET method (Sorpty 1750 Carlo Erba Strumentazione), and its density, by a liquid pycnometer. They are respectively 75 m2 g~1 and 2.044. 2.2.2. Tabletting Tablets were elaborated according to the proportions indicated in Table 1. Zinc sulfate was added either directly and blended with the other excipients (samples T1, T3, T4 and T5) (mechanical mixing), or by the intermediary of an aqueous solution mixed with the hydroxyapatite powder (1 h for T2 and 24 h for T6), then dried at 40°C before the blending with the other excipients (impregnation method). Calcined hydroxyapatite, zinc sulfate and ethyl cellulose or Eudragit RSPM were
Fig. 1. XRD patterns of hydroxyapatite calcined at 800°C for 3 h, and tablet 3 (v-ZnSO .H O). 4 2
blended in a Turbula mixer W.A.B. (Maschinenfabrik Basel) at 35 rev min~1 during 8 min. The mixture was wetted in a mortar by an alcohol solution of ethyl cellulose or/and Eudragit RS 100. The wetted mass was then dried at 55°C for 7—8 min and was granulated in an oscillatory granulator Erweka G.m.b.H equipped with a calibrated sieve of 500 lm. The formed granules were dried at 40°C for 3 h and passed in a Vibrotronic Typ VEL Retsch equipped with calibrated stacked sieves (630, 500, 400, 250, 200 and 160 lm) during 1 min, with an amplitude of 0.5 mm. Every sieve was weighed and granules with a grain size between 160 and 630 lm were lubricated with 0.4% of magnesium stearate in a Turbula mixer at 35 rev min~1 for 10 min. An alternate apparatus (Frogerais), 8 mm H faced punch, was used to make tablets. 2.2.3. Characterization of formulations The formulations were analyzed on one side by X-ray diffraction, on the other side by scanning electron microscope observations by means of a JEOL 840 scanning electron microscope equipped with a KEVEX EDX spectrometer. The average thickness of tablets was measured. The weight uniformity test for uncoated tablets with an average weight higher than 80 mg and less than 250 mg was done according to European pharmacopoeia (2.9.5) (Table 2). The breaking resistance test was realized on 10 tablets of each formulation with an Erweka TBH-55 apparatus according to European pharmacopoeia (2.9.8). Friability was evaluated as weight loss in an Erweka TBH 28 according to European pharmacopoeia (2.9.7). Twenty tablets of each formulation were tested (Table 2). The release study of zinc sulfate was carried on the different formulations given in Table 1, according to European pharmacopoeia (2.9.3). The dissolution medium was 1000 ml of purified water at 37$0.2°C. The amount of zinc sulfate released in the dissolution medium was measured by an electrochemical technique using a Zn(II) indicator electrode XM-610 (Radiometer Copenhagen). The stirring speed was of 50 rev min~1.
Table 1 Composition of prepared and tested tablets %
ZnSO .7H O 4 2
Hap
Eth cell Int
Eth cell Ext
T1 T2! T3 T4 T5 T6!
12.5 12.5 25 12.5 12.5 12.5
62.1 62.1 49.6 62.3 62.3 62.1
20 20 20 20.1
5 5 5
10
2.5
! Loading of zinc sulfate on hydroxyapatite by the intermediary of an aqueous solution. Eth cell"Ethyl cellulose. Int"Internal. Ext"External.
RSPM Int
20.1 10
RS100 Ext
Mg stearate
4.7 4.7 2.5
0.4 0.4 0.4 0.4 0.4 0.4
M. Diarra et al. / Biomaterials 19 (1998) 1523—1527
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3. Results and discussion The pharmacotechnical values of tablets are given in Table 2. Their weight losses are less than 0.5%. The average weights we have found for all tablets are in accordance with the allowed limits i.e. m " %95 m $0.075m . We can see that the breaking !7%3!'% !7%3!'% resistance is increased when the average thickness of tablets decreases, and when Eudragit is used as the filler. The best results are obtained with tablet T5 which does not contain Ethyl cellulose. In all cases, the pharmacotechnical values conform with the pharmacopoeia norms. X-ray diffraction profiles obtained on tablets exhibit the typical ZnSO .H O and hydroxyapatite patterns 4 2 (Fig. 1) showing that during the tabletting process, zinc sulfate lost 6H O. Figs. 2—4 present secondary (left) and 2 backscattered (right) images of samples surfaces of tablets T1 (Fig. 2), T2 (Fig. 3) and T6 (Fig. 4). Zinc sulfate particles appear in white, excipients in gray and pores in black. The surfaces aspect shows that the structure is granular, therefore, by analogy, we can assume that the bulk of the tablets is granular with connecting capillaries.
Fig. 3. SEM micrograph of T2, secondary image (left), backscattered image (right), showing zinc sulfate particles (white), excipients (gray) and pores (black).
Table 2 Pharmacotechnical values of tablets
T1 T2! T3 T4 T5 T6!
Average thickness (mm)
Average weight (mg)
Friability (%)
Breaking resistance (N)
2.62 2.34 2.44 2.40 2.40 2.36
199.4 196.2 197.6 200.8 208.0 204.3
0.41 0.46 0.36 0.38 0.36 0.34
107.95 217.7 123.95 161.10 248.95 237.30
Fig. 4. SEM micrograph of T6, secondary image (left), backscattered image (right), showing zinc sulfate particles (white), excipients (gray) and pores (black).
! Loading of zinc sulfate on hydroxyapatite by the intermediary of an aqueous solurion.
Fig. 2. SEM micrograph of T1, secondary image (left), backscattered image (right), showing zinc sulfate particles (white), excipients (gray) and pores (black).
The particle size of zinc sulfate in the matrix strongly depends on the way of drug loading. The finest zinc sulfate particles are observed when it is introduced by using an impregnation method (Tablet T2 and T6 with respect to tablet T1) and when the mixing time of zinc sulfate with hydroxyapatite is the highest (tablet T6 with respect to tablet T2). Zinc sulfate release follows the relation q/q "kt1@2 for 0 tablets T1—T5 as shown in Figs. 5 and 6. Let us compare Tablets T1 and T3 which have Ethyl cellulose as the filler. The release in T3 is twice higher than in T1 in agreement with the initial ratio. Thus, the release rate of zinc sulfate depends on the amount of initial drug load and is raised when the concentration of the drug is increased. In tablet T2, where zinc sulfate is loaded on hydroxyapatite powder by the intermediary of an aqueous solution during a mixing time of 1 h, the release rate of the drug is greater than in tablet T1 when zinc sulfate is added directly
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M. Diarra et al. / Biomaterials 19 (1998) 1523—1527
Fig. 5. Patterns of zinc sulfate release (mg) from tablet formulations versus square root of time.
Fig. 6. Patterns of zinc sulfate release (%) from tablet formulations versus square root of time.
with the other excipients during the tabletting process. Comparison between Tablets T4 and T1 which have the same amount of drug load, shows that zinc sulfate release is higher when Eudragit is used as the filler. In Fig. 6, tablet T5 which has only Eudragit as the filler exhibits the same pattern of drug release profile as tablet T3 which has twice as much amount of zinc sulfate load initially. Then Eudragits use as the filler increases the release rate of drug by the matrix. In Fig. 7, zinc sulfate release from tablet T6 matrix for which it is loaded by the intermediary of an aqueous solution on hydoxyapatite
powder during a mixing time of 24 h, follows the relation q/q "kt. The amount of drug released by this matrix is 0 smaller than those of the other tablets, although it contains Eudragit and Ethyl cellulose as fillers. Then the mixing time when zinc sulfate is loaded on hydroxyapatite powder by the intermediary of an aqueous solution leads to an important modification of the release rate profile of zinc sulfate by tablets. In conclusion it can be said that the release rate of zinc sulfate from the matrix structure of different tablets depends on the initial amount of drug load, the nature of
M. Diarra et al. / Biomaterials 19 (1998) 1523—1527
1527
Fig. 7. Pattern of zinc sulfate release (%) from T6 versus time.
the fillers and the way of drug loading. The impregnation method improves the dispersion of zinc sulfate on the surface of hydroxyapatite grains and favors binding between both, which allows a better control of release.
References [1] Moreton RC. Drug Dev Ind Pharm 1996;22(1):11—23. [2] Bottenberg P, Cleymaet R, De Muynck C, Remon JP, Coomans D, Michotte T, Slop D. J Pharm Pharmacol 1991;43:457—64. [3] Bottenberg P, Cleymaet R, De Muynck C, Remon JP, Coomans D, Michotte Y, Slop D. J Pharm Pharmacol 1992;44:684—6. [4] Kula K, Kula T, Davidson W, Parker E. J Dent Res 1987;66(10): 1538—42. [5] Morand JM. Inf Dent 1996;4:257—60.
[6] Downes S, Clifford JC, Scotchford C, Klein CPAT. J Biomed Mat Res 1995;29:1053—60. [7] Kokubo T, Yoshihara S, Nishimura N, Yamamuro T, Nakamura T. J Am Ceram Soc 1991;74(7):1739—41. [8] Lacout JL, Mejdoubi E, Hamad M. J Mat Sci Mat Med 1996;7:371—4. [9] Otsuka M, Matsuda Y, Yu D, Wong J, Fox JL, Higuchi WI. Chem Bull 1990;38(12):3500—2. [10] Otsuka M, Matsuda Y, Kokubo T, Yoshihara S, Nakamura T, Yamamuro T. Chem Pharm Bull 1992;40(12):3346—8. [11] Otsuka M, Matsuda Y, Kokubo T, Yoshihara S, Nakamura T, Yamamuro T. J Biomed Mat Res 1996;29:33—8. [12] Bekourian F. Act Odont Stomatol 1996;189:73—85. [13] Wen WS, Housku L, Taian HJY. Rev Stomatol Chir maxillofac 1986;87(5):339—43. [14] Akao M, Aoki H, Kato K. J Mat Sci 1981;16:809—12. [15] Osaka A, Miura Y, Tateuchi K, Asada M, Takashi K. J Mat Sci Mat Med 1991;2:51—5.
Elaboration and evaluation of an intraoral controlled release delivering system M. Diarra!,",*, G. Pourroy", D. Muster!, M. Zingraff#, C. Boymond# !LEED Biomate´ riaux CHRU B.P. 426F-67091 Strasbourg Cedex, France "IPCMS, Groupe des Mate´ riaux Inorganiques UMR 046 du CNRS, 23 Rue du Loess F-67037 Strasbourg Cedex, France #Laboratoire de Pharmacotechnie Faculte´ de Pharmacie 74, Route du Rhin BP 24 F-67401 Illkirch Cedex, France
Abstract In order to improve the administration of drugs for all pathology of the oral cavity, we have developed an intraoral controlled release delivering system, permitting to reach high enough local concentrations for desirable therapeutic effect with minimal side effects. We have formulated tablets of 200 mg intended to be fixed on a tooth. These tablets resist food and drink attacks. The tablets we elaborated have a granular matrix composed of hydroxyapatite, ethyl cellulose and EudragitR. Zinc sulfate is used as the first model of an active drug, it has a therapeutic effect on buccal mucous. Profiles of continuous in-vitro drug release in distilled water at 37°C show that zinc sulfate release by the matrix structure for the different tablet formulations is regulated by the proportions of the different components. ( 1998 Elsevier Science Ltd. All rights reserved
1. Introduction A medicinal product consists of more than just the active drug. There are other materials present that are necessary to allow the formulation to achieve the desired pharmacological and/or pharmacokinetic effect. Nowadays, recent developments, particularly the concept of controlled release, have shown that excipients are fundamental to the design of drug delivery system [1]. Currently, acrylic acid polymers, starch, wax, cellulose derivatives, polyethylene glycol, etc. have been used as excipients for formulation of intraoral controlled release delivering system of drugs [2—5]. In order to increase the buccal residence time of the drug, an intraoral controlled release delivering system was developed in the form of a tablet which can resist food and drink attacks. We prepared hydroxyapatite Ca (PO ) (OH) as the raw 10 46 2 material for the tablet formulation. It has the same elemental chemical composition as natural bone and teeth, is biocompatible and stable [6—11], and widely used in orthopedic and odontology. Ethyl cellulose, Eudragit RS100 and RSPM were used as insoluble fillers and zinc sulfate as the first model of active drug because of its therapeutic effect on buccal mucous [12, 13]. The pur-
* Corresponding author. 0142-9612/98/$19.00 ( 1998 Elsevier Science Ltd. All rights reserved. PII S 0 1 4 2 - 9 6 1 2 ( 9 8 ) 0 0 0 7 0 - 2
pose of this work is to adjust the formulation of tablets with the view to elaborate and to evaluate those tablets and regard how the variation of the composition and the formulation influenced the in vitro release of zinc sulfate.
2. Material and methods 2.1. Material Zinc sulfate ZnSO .7H O and magnesium stearate 4 2 were obtained from Prolabo, Ethyl cellulose N 50 NF from Aqualon, Eudragit RS100 and Eudragit RSPM from Ro¨hm Pharma. 2.2. Methods 2.2.1. Preparation of sintered hydroxyapatite A solution of H PO (Prolabo R.P.Normapur) 0.3 M is 3 4 added at a rate of 25 ml min~1 to a suspension of Ca(OH) (Prolabo R.P.Rectapur) 0.5 M in distilled water 2 under vigorous stirring at 80—95°C with the mixing molar ratio Ca/P"1.66 [14, 15]. After the addition of H PO , stirring and heating were maintained 20 min 3 4 followed by 25 min stirring without heating. The resulting precipitate is aged at room temperature for 24 h and then filtered. The filtered cake is dried at 40°C, then the
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M. Diarra et al. / Biomaterials 19 (1998) 1523—1527
temperature is gradually raised up to 80°C over 24 h. The calcination is ended at 800°C after 3 h. The X-ray diffraction pattern recorded at room temperature with a D 500 Siemens diffractometer equipped with a primary beam quartz monochromator (Co Ka "1.78897 A_ ) exhibits 1 the diffraction lines of hydroxyapatite (Fig. 1). No impurities are observed. Its specific area was measured by the nitrogen BET method (Sorpty 1750 Carlo Erba Strumentazione), and its density, by a liquid pycnometer. They are respectively 75 m2 g~1 and 2.044. 2.2.2. Tabletting Tablets were elaborated according to the proportions indicated in Table 1. Zinc sulfate was added either directly and blended with the other excipients (samples T1, T3, T4 and T5) (mechanical mixing), or by the intermediary of an aqueous solution mixed with the hydroxyapatite powder (1 h for T2 and 24 h for T6), then dried at 40°C before the blending with the other excipients (impregnation method). Calcined hydroxyapatite, zinc sulfate and ethyl cellulose or Eudragit RSPM were
Fig. 1. XRD patterns of hydroxyapatite calcined at 800°C for 3 h, and tablet 3 (v-ZnSO .H O). 4 2
blended in a Turbula mixer W.A.B. (Maschinenfabrik Basel) at 35 rev min~1 during 8 min. The mixture was wetted in a mortar by an alcohol solution of ethyl cellulose or/and Eudragit RS 100. The wetted mass was then dried at 55°C for 7—8 min and was granulated in an oscillatory granulator Erweka G.m.b.H equipped with a calibrated sieve of 500 lm. The formed granules were dried at 40°C for 3 h and passed in a Vibrotronic Typ VEL Retsch equipped with calibrated stacked sieves (630, 500, 400, 250, 200 and 160 lm) during 1 min, with an amplitude of 0.5 mm. Every sieve was weighed and granules with a grain size between 160 and 630 lm were lubricated with 0.4% of magnesium stearate in a Turbula mixer at 35 rev min~1 for 10 min. An alternate apparatus (Frogerais), 8 mm H faced punch, was used to make tablets. 2.2.3. Characterization of formulations The formulations were analyzed on one side by X-ray diffraction, on the other side by scanning electron microscope observations by means of a JEOL 840 scanning electron microscope equipped with a KEVEX EDX spectrometer. The average thickness of tablets was measured. The weight uniformity test for uncoated tablets with an average weight higher than 80 mg and less than 250 mg was done according to European pharmacopoeia (2.9.5) (Table 2). The breaking resistance test was realized on 10 tablets of each formulation with an Erweka TBH-55 apparatus according to European pharmacopoeia (2.9.8). Friability was evaluated as weight loss in an Erweka TBH 28 according to European pharmacopoeia (2.9.7). Twenty tablets of each formulation were tested (Table 2). The release study of zinc sulfate was carried on the different formulations given in Table 1, according to European pharmacopoeia (2.9.3). The dissolution medium was 1000 ml of purified water at 37$0.2°C. The amount of zinc sulfate released in the dissolution medium was measured by an electrochemical technique using a Zn(II) indicator electrode XM-610 (Radiometer Copenhagen). The stirring speed was of 50 rev min~1.
Table 1 Composition of prepared and tested tablets %
ZnSO .7H O 4 2
Hap
Eth cell Int
Eth cell Ext
T1 T2! T3 T4 T5 T6!
12.5 12.5 25 12.5 12.5 12.5
62.1 62.1 49.6 62.3 62.3 62.1
20 20 20 20.1
5 5 5
10
2.5
! Loading of zinc sulfate on hydroxyapatite by the intermediary of an aqueous solution. Eth cell"Ethyl cellulose. Int"Internal. Ext"External.
RSPM Int
20.1 10
RS100 Ext
Mg stearate
4.7 4.7 2.5
0.4 0.4 0.4 0.4 0.4 0.4
M. Diarra et al. / Biomaterials 19 (1998) 1523—1527
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3. Results and discussion The pharmacotechnical values of tablets are given in Table 2. Their weight losses are less than 0.5%. The average weights we have found for all tablets are in accordance with the allowed limits i.e. m " %95 m $0.075m . We can see that the breaking !7%3!'% !7%3!'% resistance is increased when the average thickness of tablets decreases, and when Eudragit is used as the filler. The best results are obtained with tablet T5 which does not contain Ethyl cellulose. In all cases, the pharmacotechnical values conform with the pharmacopoeia norms. X-ray diffraction profiles obtained on tablets exhibit the typical ZnSO .H O and hydroxyapatite patterns 4 2 (Fig. 1) showing that during the tabletting process, zinc sulfate lost 6H O. Figs. 2—4 present secondary (left) and 2 backscattered (right) images of samples surfaces of tablets T1 (Fig. 2), T2 (Fig. 3) and T6 (Fig. 4). Zinc sulfate particles appear in white, excipients in gray and pores in black. The surfaces aspect shows that the structure is granular, therefore, by analogy, we can assume that the bulk of the tablets is granular with connecting capillaries.
Fig. 3. SEM micrograph of T2, secondary image (left), backscattered image (right), showing zinc sulfate particles (white), excipients (gray) and pores (black).
Table 2 Pharmacotechnical values of tablets
T1 T2! T3 T4 T5 T6!
Average thickness (mm)
Average weight (mg)
Friability (%)
Breaking resistance (N)
2.62 2.34 2.44 2.40 2.40 2.36
199.4 196.2 197.6 200.8 208.0 204.3
0.41 0.46 0.36 0.38 0.36 0.34
107.95 217.7 123.95 161.10 248.95 237.30
Fig. 4. SEM micrograph of T6, secondary image (left), backscattered image (right), showing zinc sulfate particles (white), excipients (gray) and pores (black).
! Loading of zinc sulfate on hydroxyapatite by the intermediary of an aqueous solurion.
Fig. 2. SEM micrograph of T1, secondary image (left), backscattered image (right), showing zinc sulfate particles (white), excipients (gray) and pores (black).
The particle size of zinc sulfate in the matrix strongly depends on the way of drug loading. The finest zinc sulfate particles are observed when it is introduced by using an impregnation method (Tablet T2 and T6 with respect to tablet T1) and when the mixing time of zinc sulfate with hydroxyapatite is the highest (tablet T6 with respect to tablet T2). Zinc sulfate release follows the relation q/q "kt1@2 for 0 tablets T1—T5 as shown in Figs. 5 and 6. Let us compare Tablets T1 and T3 which have Ethyl cellulose as the filler. The release in T3 is twice higher than in T1 in agreement with the initial ratio. Thus, the release rate of zinc sulfate depends on the amount of initial drug load and is raised when the concentration of the drug is increased. In tablet T2, where zinc sulfate is loaded on hydroxyapatite powder by the intermediary of an aqueous solution during a mixing time of 1 h, the release rate of the drug is greater than in tablet T1 when zinc sulfate is added directly
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M. Diarra et al. / Biomaterials 19 (1998) 1523—1527
Fig. 5. Patterns of zinc sulfate release (mg) from tablet formulations versus square root of time.
Fig. 6. Patterns of zinc sulfate release (%) from tablet formulations versus square root of time.
with the other excipients during the tabletting process. Comparison between Tablets T4 and T1 which have the same amount of drug load, shows that zinc sulfate release is higher when Eudragit is used as the filler. In Fig. 6, tablet T5 which has only Eudragit as the filler exhibits the same pattern of drug release profile as tablet T3 which has twice as much amount of zinc sulfate load initially. Then Eudragits use as the filler increases the release rate of drug by the matrix. In Fig. 7, zinc sulfate release from tablet T6 matrix for which it is loaded by the intermediary of an aqueous solution on hydoxyapatite
powder during a mixing time of 24 h, follows the relation q/q "kt. The amount of drug released by this matrix is 0 smaller than those of the other tablets, although it contains Eudragit and Ethyl cellulose as fillers. Then the mixing time when zinc sulfate is loaded on hydroxyapatite powder by the intermediary of an aqueous solution leads to an important modification of the release rate profile of zinc sulfate by tablets. In conclusion it can be said that the release rate of zinc sulfate from the matrix structure of different tablets depends on the initial amount of drug load, the nature of
M. Diarra et al. / Biomaterials 19 (1998) 1523—1527
1527
Fig. 7. Pattern of zinc sulfate release (%) from T6 versus time.
the fillers and the way of drug loading. The impregnation method improves the dispersion of zinc sulfate on the surface of hydroxyapatite grains and favors binding between both, which allows a better control of release.
References [1] Moreton RC. Drug Dev Ind Pharm 1996;22(1):11—23. [2] Bottenberg P, Cleymaet R, De Muynck C, Remon JP, Coomans D, Michotte T, Slop D. J Pharm Pharmacol 1991;43:457—64. [3] Bottenberg P, Cleymaet R, De Muynck C, Remon JP, Coomans D, Michotte Y, Slop D. J Pharm Pharmacol 1992;44:684—6. [4] Kula K, Kula T, Davidson W, Parker E. J Dent Res 1987;66(10): 1538—42. [5] Morand JM. Inf Dent 1996;4:257—60.
[6] Downes S, Clifford JC, Scotchford C, Klein CPAT. J Biomed Mat Res 1995;29:1053—60. [7] Kokubo T, Yoshihara S, Nishimura N, Yamamuro T, Nakamura T. J Am Ceram Soc 1991;74(7):1739—41. [8] Lacout JL, Mejdoubi E, Hamad M. J Mat Sci Mat Med 1996;7:371—4. [9] Otsuka M, Matsuda Y, Yu D, Wong J, Fox JL, Higuchi WI. Chem Bull 1990;38(12):3500—2. [10] Otsuka M, Matsuda Y, Kokubo T, Yoshihara S, Nakamura T, Yamamuro T. Chem Pharm Bull 1992;40(12):3346—8. [11] Otsuka M, Matsuda Y, Kokubo T, Yoshihara S, Nakamura T, Yamamuro T. J Biomed Mat Res 1996;29:33—8. [12] Bekourian F. Act Odont Stomatol 1996;189:73—85. [13] Wen WS, Housku L, Taian HJY. Rev Stomatol Chir maxillofac 1986;87(5):339—43. [14] Akao M, Aoki H, Kato K. J Mat Sci 1981;16:809—12. [15] Osaka A, Miura Y, Tateuchi K, Asada M, Takashi K. J Mat Sci Mat Med 1991;2:51—5.