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Effects of Dose, pH, and Osmolarity on Nasal Absorption of Secretin in Rats
NOTES
Effects of Dose, pH, and Osmolarity on Nasal Absorption of Secretin in Rats TAKAYUKI OHWAKI',
HIDENOBU ANDO,
SUM10 WATANABE, AND YASUO
MIYAKE
Received January 24, 1984, from the Research Laboratories of PharmaceuticalDevelopment, Eisai Co., Ltd., Kawashima-cho, Hashima-gun, Gifu 483, Japan. Accepted for publication February 1, 1985. The effects of dose, pH, and osmolarity on the nasal absorption of a secretin solution were studied in rats. The nasal absorp tion of secretin was determined by measuring the increased secretion of pancreatic juice, and this was compared with the same response on intravenous administration. The relative bioavailability of Secretin on intranasal administration compared with intravenous administration, as estimated from the pharmacological response, was approximately one tenth. It was enhanced in acid solution and reached a maximum in a 0.462 M sodium chloride solution. Abstract
Secretin, a hormone secreted in the digestive tract, is a 27unit polypeptide chain (MW = 3055) containing 11 different amino acids, and is used clinically for the treatment of duodenal ulcers.'-' It is well known that peptides are rarely given orally due to their inactivation in the GI tract. Secretin is also degraded in the GI tract, and therefore is usually administered by injection. However, injections cause discomfort, allergic reactions, and tissue lesion^.^. lo Hirai et al." reported that the administration of insulin by the nasal route was more effective and useful than administration by other nonparenteral routes for long-term therapy. The objective of this study was to assess the absorbability of secretin through the nasal mucosa and to obtain data on the effect of pH and salt concentration on the nasal dosage forms.
Experimental Section Materials-A 24,000 Crick, Happer, and Raper (CHR) units/mg preparation of synthetic secretin (Eisai Co., Ltd., Tokyo) was used in this study. The other chemicals employed were of analytical or reagent grade. Secretin Preparations-For intravenous administration, secretin was dissolved in concentrations ranging from 1 CHR unit/50 ~ Lto L 10 CHR units/50 pL in physiological saline (0.154 M NaCl solution of pH 6.4). For the dose-dependency study on intranasal administration, secretin was dissolved in concentrations ranging from 5 CHR units/50 KL to 40 CHR units/50 pL in physiological saline (0.154 M NaCl solution of pH 6.4). For the pH effect study on intranasal administration, secretin, adjusted to a concentration of 10 CHR units/50 pL, was dissolved in isotonic 0.236 M citric acid0.123 M disodium phosphate buffer (Wako Pure Industries, Ltd., Osaka), ranging in pH from 2.1 t o 6.33, and isotonic 0.171 M potassium phosphate:0.144 M sodium acid carbonate buffer (Wako), ranging in pH from 7 to 8. For the osmolarity effect study on intranasal administration,secretin, adjusted to a concentration of 10 CHR units/50 pL,was dissolved in sodium chloride solutions ranging in molar concentrations from 0 to 1.078 M. Surgical Preparations of Rats-Rats were prepared surgically by the following procedures for the administration of secretin preparations and for the determination of their phar550 /Journal of Pharmaceutical Sciences Vol. 74, No. 5, May 1985
macological responses. Male Sprague-Dawley rats weighing from 250 to 300 g, and fasted previously for 24 h, were anesthetized with an intraperitoneal injection of 170 mg/100 g of urethane (Wako) -30 min before the surgical procedures were performed. For intranasal administration directly into the nasal cavity, the surgical operation described by Hussain et al.'* was employed. For intravenous administration the femoral vein was cannulated with a polyethylene tube (PE10,Intramedic, Clay Adams). The amount of secretin absorbed was measured by biological assay.'3, l4 The abdomen of the rats was incised, and the choledochoduodenal junction was ligated. The end of the common bile duct nearer the pancreas was cannulated with a polyethylene tube (PE50, Intramedic, Clay Adams) to make an artificial pancreatic duct, which was fixed to the abdomen with an adhesive agent (Aron Alph, Toa Gosei Chemical Industry Co., Ltd., Tokyo). The liver end of the common bile duct was cannulated with a PE50 polyethylene tube inserted into the duodenum to drain the secreted bile. The pylorus was ligated to prevent drainage of the gastric juice into the duodenum and extrication of the endogenous secretin (Fig. 1). The rectum temperature was maintained at 34-36°C with an incandescent lamp. After administration of a secretin preparation, the pancreatic juice secreted through the artificial pancreatic duct was collected in a glass tube with divisions in microliters. The volume was noted at 15-min intervals. It has been reported13that the secreted volume of pancreatic juice plotted against the logarithm of the intravenous dose of secretin was linear from 0.5 to 8 CHR units. This indicates that the amount of secretin absorbed through the nasal mucosa
Figure 1-Diagram
of the surgical procedure for biological assay. 0022-3549/85/0500-0550$0 1.0010 0 1985, American Pharmaceutical Association
can be calculated by comparing the amount absorbed on intravenous administration. In this study, the volume of pancreatic juice secreted as a result of the absorption of secretin was calculated by subtracting the amount computed from the amount of secretion during the predose period from the amount of secretion during the administration period. Procedure of Administration-Figure 2 shows the protocol of administration. Before the intravenous administration, the amount of pancreatic juice secreted during the predose period (30 min) was measured to determine the base line (basal secretion). Intravenous Administration-The secretin preparation (50 pL) was administered with a microsyringe through the polyethylene cannula inserted in the femoral vein, and then 0.1 mL of physiological saline (0.154 M NaCl solution at pH 6.4) was immediately injected. Intranasal Administration-A secretin preparation containing 1 CHR unit was administered intravenously to confirm that there were no significant differences between the experimental runs in relation to the total cumulative volume of pancreatic juice secreted16and to the secretion patterns" before the intranasal administration. A 50-pL sample of a secretin preparation was administered with a microsyringe into the nasal cavity through a polyethylene tube (PE160,Clay Adams).
B
mLl 1 - - -. .. .
..
.. ...-
,.
- -. - --
Xhn, 90min (Intravenous administration
)
- - - - -. .- - - - -d- -. . .-.
-.
30min .+
90min
)
(Intr+n+al administrat ,ion
Figure 2-Protocol of administration. Key: (A) intravenous; (6) intranasal; (a) measurement of the secreted volume of pancreatic juice during the predose period (basal secretion); (b) measurement of the secreted volume of pancreatic juice after an intravenous administration; (c) period for washing out secretin; (d) measurement of the secreted volume of pancreatic juice after an intranasal administration.
As a control experiment, a placebo consisting of the medium without secretin was administered under the same experimental protocol as shown in Fig. 2, using other rats.
Results and Discussion Pharmacological responses to four doses of secretin (at 5,10, 20, and 40 CHR units) administered intranasally were determined and compared with responses to intravenous administration. Figure 3 shows typical data from intranasal administration of 10 CHR units and intravenous administration of 1 CHR unit. The height of the solid line indicates the total volume of pancreatic juice as a result of secretin absorbed, and the time taken to reach the plateau was <90 min. The total volume of pancreatic juice secreted during 90 min (TSV,), the maximum volume of pancreatic juice secreted during each 15 min (SVmax), the time to SV,, (t-), and the absorption ratio of each dose of intranasally administered secretin to the 1 CHR unit given intravenously ( r ) are presented in Table I. Linear relationships between TSV, and the logarithm of the dose of secretin administered were obtained from 1 to 5 CHR units with intravenous administration and from 5 to 40 CHR units with intranasal administration. The relative bioavailability of secretin on intranasal administration compared with intravenous administration, as estimated from the pharmacological response, was approximately one-tenth. It is well known that the nature of a protein varies according to the pH and the salinity of a solution. Secretin is a protein, and the nasal mucosa contains protein. In relation to the absorption of secretin through the nasal mucosa, it is interesting to observe the influence of pH or salinity on the secretin preparation. TSV,, SV,,,, t,,,, and r for the various pH levels and molar concentrations of NaCl are given in Tables I1 and 111, respectively. In Table 11, the absorption of secretin through the nasal mucosa increased linearly as the pH decreased from 7 to 2.94, and it was approximately the same at pH 2.1 and 2.94. The absorption ratio in comparison with intravenous administration was one-third or one-fourth at acidic pH values. t,, was prolonged a t pH 2.94, 3.81, and 6.33. The maximum value of TSV, was observed at a sodium chloride solution molarity of 0.462 M, as shown in Table 111. There was a statistically significant difference (p < 0.05) in TSV, between 0.462 and 1.078 M NaCl solutions, as shown by the t test, but not between 0,0.154, and 0.462 M solutions. The bioavailability of sulfisoxazole decreased with increasing osTable I-Results of Dose-Dependency Study in Rat Preparations after Intravenous and lntranasal Administration of Secretin'
Dosage Unit (CHR Unit)
,i'/
Intravenous 0 (control) 1 2 5 10
lntranasal 0 (control)
15 30 45 60 75 90 Time after administration, min Figure 3-Typical secretion patterns of pancreatic juice. Key: Bar graph (A)-pattern of secreted volume during 15 rnin after an intranasal administration of 10 CHR units; solid line (6)-cumulative pattern of secreted volume after an intranasal administration of 70 CHR units; dotted line (C)-cumulative pattern of secreted volume after an intravenous administration of 1 CHR unit.
SV,,,pL
TSV90, -1.33 zk 0.491 15.67 f 3.1 11 31.32 f 2.867 54.77 k 9.264 57.50 zk 3.693
t,,min
-
-
11.96 2 1.359 17.48 f 1.992 26.27 f 3.1 64 18.67 k 1.906
0-15 0-15 15-30 15-30
-
rb
-
-1.17 & 2.732 0-15 -0.43 f 1.31 1 0.98 f 0.374 16.46 f 1.935 5.67 f 0.405 15-30 0.105 29.48 & 5.635 8.73 & 1.079 15-30 0.188 39.63 & 5.447 10.63 f 1.535 15-30 0.253 a The data are expressed as mean & SEM; n = 3-7; total secreted volume of pancreatic juice during 90 min (TSVW, pL); maximum secreted volume of pancreatic juice during 15 min (SV-, p l ) ; time to SV,, (t-, min). r indicates the absorption rate of intranasal admiristration to 5 10 20 40
intravenous administration and is expressed as: r = TSVw (intranasal)/ TSVw intravenous x 1/dosage unit of intranasal administration. Journal of Pharmaceutical Sciences / 551 Vol. 74, No. 5, May 1985
Table Il-Results of pH Effect Study on Rat Preparations after Intravenous and lntranasal Administration of Secretin. Dosage Unit PH (CHR Unit) TsVao, pL sv,, P L f-, min
rb
1 15.67 f 3.111 11.96 f 1.359 0-1 5 10 47.92 f 6.193 (2.67 f 2.596)" 15-30 0.306 11.42 f 1.382 10 48.33 f 8.031 (-1 50 f 1.179) 45-60 0.308 11.17 f 1.910 10 39.06 f 3.238 (1.67 f 1.440) 7.38 f 1.128 60-75 0.249 10 30.13 f 5.271 (-0.67 f 0.892) 15-30 0.192 8.13 f 1.334 10 15.14 f 3.552 (0.67 f 1.656) 45-60 0.097 3.79 f 1.216 10 6.58 f 2.193 (-1.67 f 3.569) 15-30 0.042 2.42 f 0.661 10 8.25 f 2.073 (0.33 f 0.491) 4.50 f 1.031 15-30 0.053 a The data are expressed as mean f SEM; n = 4-8; total secreted volume of pancreatic juice during 90 min (TSV,, pL); maximum secreted volume of pancreatic juice during 15 min (SV-, pL); time to SV- (t-, min). r indicates the absorption ratio of intranasal administration to intravenous administration and is expressed as: r = TSVw (intranasal)/TSV, (intravenous) X I/dosage unit of intranasal administration. " The data enclosed in parentheses are control data (n = 3). Intravenous. Intranasal. 6.40d 2.10' 2.94' 3.81' 4.79' 6.33" 7.00' 8.00"
"
Table Ill-Results of Osmolarity Effect Study in Rat Preparations after Intravenous and lntranasal Administration of Secretin' Dosage Unit NaCI. M PH
C H R Unit)
0-1 5 11.96 2 1.395 3.40 k 1.004 45-60 0.089 5.67 f 0.405 15-30 0.105 10 7.92 f 1.431 15-30 0.142 6.59 -t 0.594 15-30 0.099 10 'The data are expressed as mean f SEM; n = 5-7; total secreted volume of pancreatic juice during 90 min (TSV,, pL); maximum secreted volume of pancreatic juice during 15 min (SV, pL); time to SV- (t-, min). r indicates the absorption ratio of intranasal administration to intravenous administration and is expressed as: r = TSVW (intranasal)/TSV, (intravenous)X 1/dosage unit of intranasal administration. intravenous. Intranasai. 'Significantlydifferent, p c 0.05.'The data enclosed in parentheses are control data (n = 3). 0.154 0 0.154 0.462 1.078
6.4" 6.!jd 6.4" 6.4' 6.4"
1 10 10
15.67 f 3.111 13.90 f 6.287 (0.16 0.360)' 16.46 f 1.935 (-1.17 f 2.732) '22.20 f 2.326 (-0.5f 1.546) 15.58 f 1.287 (2.33 f 1.361)
motic pressure in an NaCl s01ution.l~Moreover, Sakiya et a1.18 reported that the absorption of quinine from the small intestine decreased with increasing osmotic pressure. In our experiments, the maximum absorption of secretin through the nasal mucosa was observed with a 0.462 M NaCl solution, suggesting that there was an optimum molar concentration of NaCl at which secretin was absorbed. The t,, values were more prolonged with water than with NaCl solution. This implies that the presence of NaCl affects the absorption rate of secretin. Further studies are needed to elucidate whether the nature of the nasal mucosa or of secretin is affected by pH or salt in the nasal absorption of secretin. Our results reveal that a nasal dosage form for secretin is feasible and that the nasal absorption of secretin could be improved by variations in the pH and in the concentration of NaCl.
References and Notes 1. Matsuo, H.; Seki, A.; Ishikawa, T. Hormon to Rinsho 1976,23, 507.
552 /Journal of Pharmaceutical Sciences Vol. 74, No. 5, May 1985
*
2. Grossman, M. I. Gastroenterology 1966,50,912. 3. Glass, G. B. Gastroenterology1966,51,580. 4. Miyoshi, A.; Fujii, K.; Okuhara, T.; Suyama, T.; Kai, T.; et al. Shinryo to Shinyaku 1974,11, 1983. 5. Konturek, S. J. Gut 1973,14,842. 6. Konturek, S. J.; Radecki, T.; Thor, P.; Kwiecien, N. Am. J. Dig. Dis. 1973,18,136. 7. Kawai, K.; Misaki, F.; Miyaoka, T.; Kimoto, K.; Shimamoto, K., et al. Gendai no Rinsho 1974,8,177. 8. Nakamura, K. Shinryo to Shinyaku 1974,Il,1929. 9. Gunn, D. R. J. Bone Joint Surg. 1964,46B,492. 10. Saunders, F. P.; Hoefnagel, D.; Staples, 0. S.; J. Bone Joint Surg. 1965,47A,380. 11. Hirai, S.; Ikenaga, T.; Matsuzawa, T. Diabetes 1977,296,27. 12. Hussain, A.; Hirai, S.; Bawarshi, R. J . Phnrm. Sci. 1980,69,1411. 13. Tachibana, S. Jpn. J. Phnrmacol. 1971,21,325. 14. Tachibana, S. Hormon to Rinsho 1975,23,1159. 15. The rats proved in the range of TSV, from 10 p L to 30 p L were employed in our experimental runs. 16. The rats proved in the range of SV,., whose tmaxwere <30 min, from 5 p L to 15 p L were employed in our experimental runs. 17. Morvola, M.; Reinikaine, A.; Heliovaara, M.; Huikari, A. J. Pharm. PhurmacoZ. 1979,31,615. 18. Sakiya, Y.; Miyauchi, Y.; Tsuemura, Y. Chem. Pharm. Bull. 1981, 29,1470; Chem. Abstr. 1981,95,67904~.
Effects of Dose, pH, and Osmolarity on Nasal Absorption of Secretin in Rats TAKAYUKI OHWAKI',
HIDENOBU ANDO,
SUM10 WATANABE, AND YASUO
MIYAKE
Received January 24, 1984, from the Research Laboratories of PharmaceuticalDevelopment, Eisai Co., Ltd., Kawashima-cho, Hashima-gun, Gifu 483, Japan. Accepted for publication February 1, 1985. The effects of dose, pH, and osmolarity on the nasal absorption of a secretin solution were studied in rats. The nasal absorp tion of secretin was determined by measuring the increased secretion of pancreatic juice, and this was compared with the same response on intravenous administration. The relative bioavailability of Secretin on intranasal administration compared with intravenous administration, as estimated from the pharmacological response, was approximately one tenth. It was enhanced in acid solution and reached a maximum in a 0.462 M sodium chloride solution. Abstract
Secretin, a hormone secreted in the digestive tract, is a 27unit polypeptide chain (MW = 3055) containing 11 different amino acids, and is used clinically for the treatment of duodenal ulcers.'-' It is well known that peptides are rarely given orally due to their inactivation in the GI tract. Secretin is also degraded in the GI tract, and therefore is usually administered by injection. However, injections cause discomfort, allergic reactions, and tissue lesion^.^. lo Hirai et al." reported that the administration of insulin by the nasal route was more effective and useful than administration by other nonparenteral routes for long-term therapy. The objective of this study was to assess the absorbability of secretin through the nasal mucosa and to obtain data on the effect of pH and salt concentration on the nasal dosage forms.
Experimental Section Materials-A 24,000 Crick, Happer, and Raper (CHR) units/mg preparation of synthetic secretin (Eisai Co., Ltd., Tokyo) was used in this study. The other chemicals employed were of analytical or reagent grade. Secretin Preparations-For intravenous administration, secretin was dissolved in concentrations ranging from 1 CHR unit/50 ~ Lto L 10 CHR units/50 pL in physiological saline (0.154 M NaCl solution of pH 6.4). For the dose-dependency study on intranasal administration, secretin was dissolved in concentrations ranging from 5 CHR units/50 KL to 40 CHR units/50 pL in physiological saline (0.154 M NaCl solution of pH 6.4). For the pH effect study on intranasal administration, secretin, adjusted to a concentration of 10 CHR units/50 pL, was dissolved in isotonic 0.236 M citric acid0.123 M disodium phosphate buffer (Wako Pure Industries, Ltd., Osaka), ranging in pH from 2.1 t o 6.33, and isotonic 0.171 M potassium phosphate:0.144 M sodium acid carbonate buffer (Wako), ranging in pH from 7 to 8. For the osmolarity effect study on intranasal administration,secretin, adjusted to a concentration of 10 CHR units/50 pL,was dissolved in sodium chloride solutions ranging in molar concentrations from 0 to 1.078 M. Surgical Preparations of Rats-Rats were prepared surgically by the following procedures for the administration of secretin preparations and for the determination of their phar550 /Journal of Pharmaceutical Sciences Vol. 74, No. 5, May 1985
macological responses. Male Sprague-Dawley rats weighing from 250 to 300 g, and fasted previously for 24 h, were anesthetized with an intraperitoneal injection of 170 mg/100 g of urethane (Wako) -30 min before the surgical procedures were performed. For intranasal administration directly into the nasal cavity, the surgical operation described by Hussain et al.'* was employed. For intravenous administration the femoral vein was cannulated with a polyethylene tube (PE10,Intramedic, Clay Adams). The amount of secretin absorbed was measured by biological assay.'3, l4 The abdomen of the rats was incised, and the choledochoduodenal junction was ligated. The end of the common bile duct nearer the pancreas was cannulated with a polyethylene tube (PE50, Intramedic, Clay Adams) to make an artificial pancreatic duct, which was fixed to the abdomen with an adhesive agent (Aron Alph, Toa Gosei Chemical Industry Co., Ltd., Tokyo). The liver end of the common bile duct was cannulated with a PE50 polyethylene tube inserted into the duodenum to drain the secreted bile. The pylorus was ligated to prevent drainage of the gastric juice into the duodenum and extrication of the endogenous secretin (Fig. 1). The rectum temperature was maintained at 34-36°C with an incandescent lamp. After administration of a secretin preparation, the pancreatic juice secreted through the artificial pancreatic duct was collected in a glass tube with divisions in microliters. The volume was noted at 15-min intervals. It has been reported13that the secreted volume of pancreatic juice plotted against the logarithm of the intravenous dose of secretin was linear from 0.5 to 8 CHR units. This indicates that the amount of secretin absorbed through the nasal mucosa
Figure 1-Diagram
of the surgical procedure for biological assay. 0022-3549/85/0500-0550$0 1.0010 0 1985, American Pharmaceutical Association
can be calculated by comparing the amount absorbed on intravenous administration. In this study, the volume of pancreatic juice secreted as a result of the absorption of secretin was calculated by subtracting the amount computed from the amount of secretion during the predose period from the amount of secretion during the administration period. Procedure of Administration-Figure 2 shows the protocol of administration. Before the intravenous administration, the amount of pancreatic juice secreted during the predose period (30 min) was measured to determine the base line (basal secretion). Intravenous Administration-The secretin preparation (50 pL) was administered with a microsyringe through the polyethylene cannula inserted in the femoral vein, and then 0.1 mL of physiological saline (0.154 M NaCl solution at pH 6.4) was immediately injected. Intranasal Administration-A secretin preparation containing 1 CHR unit was administered intravenously to confirm that there were no significant differences between the experimental runs in relation to the total cumulative volume of pancreatic juice secreted16and to the secretion patterns" before the intranasal administration. A 50-pL sample of a secretin preparation was administered with a microsyringe into the nasal cavity through a polyethylene tube (PE160,Clay Adams).
B
mLl 1 - - -. .. .
..
.. ...-
,.
- -. - --
Xhn, 90min (Intravenous administration
)
- - - - -. .- - - - -d- -. . .-.
-.
30min .+
90min
)
(Intr+n+al administrat ,ion
Figure 2-Protocol of administration. Key: (A) intravenous; (6) intranasal; (a) measurement of the secreted volume of pancreatic juice during the predose period (basal secretion); (b) measurement of the secreted volume of pancreatic juice after an intravenous administration; (c) period for washing out secretin; (d) measurement of the secreted volume of pancreatic juice after an intranasal administration.
As a control experiment, a placebo consisting of the medium without secretin was administered under the same experimental protocol as shown in Fig. 2, using other rats.
Results and Discussion Pharmacological responses to four doses of secretin (at 5,10, 20, and 40 CHR units) administered intranasally were determined and compared with responses to intravenous administration. Figure 3 shows typical data from intranasal administration of 10 CHR units and intravenous administration of 1 CHR unit. The height of the solid line indicates the total volume of pancreatic juice as a result of secretin absorbed, and the time taken to reach the plateau was <90 min. The total volume of pancreatic juice secreted during 90 min (TSV,), the maximum volume of pancreatic juice secreted during each 15 min (SVmax), the time to SV,, (t-), and the absorption ratio of each dose of intranasally administered secretin to the 1 CHR unit given intravenously ( r ) are presented in Table I. Linear relationships between TSV, and the logarithm of the dose of secretin administered were obtained from 1 to 5 CHR units with intravenous administration and from 5 to 40 CHR units with intranasal administration. The relative bioavailability of secretin on intranasal administration compared with intravenous administration, as estimated from the pharmacological response, was approximately one-tenth. It is well known that the nature of a protein varies according to the pH and the salinity of a solution. Secretin is a protein, and the nasal mucosa contains protein. In relation to the absorption of secretin through the nasal mucosa, it is interesting to observe the influence of pH or salinity on the secretin preparation. TSV,, SV,,,, t,,,, and r for the various pH levels and molar concentrations of NaCl are given in Tables I1 and 111, respectively. In Table 11, the absorption of secretin through the nasal mucosa increased linearly as the pH decreased from 7 to 2.94, and it was approximately the same at pH 2.1 and 2.94. The absorption ratio in comparison with intravenous administration was one-third or one-fourth at acidic pH values. t,, was prolonged a t pH 2.94, 3.81, and 6.33. The maximum value of TSV, was observed at a sodium chloride solution molarity of 0.462 M, as shown in Table 111. There was a statistically significant difference (p < 0.05) in TSV, between 0.462 and 1.078 M NaCl solutions, as shown by the t test, but not between 0,0.154, and 0.462 M solutions. The bioavailability of sulfisoxazole decreased with increasing osTable I-Results of Dose-Dependency Study in Rat Preparations after Intravenous and lntranasal Administration of Secretin'
Dosage Unit (CHR Unit)
,i'/
Intravenous 0 (control) 1 2 5 10
lntranasal 0 (control)
15 30 45 60 75 90 Time after administration, min Figure 3-Typical secretion patterns of pancreatic juice. Key: Bar graph (A)-pattern of secreted volume during 15 rnin after an intranasal administration of 10 CHR units; solid line (6)-cumulative pattern of secreted volume after an intranasal administration of 70 CHR units; dotted line (C)-cumulative pattern of secreted volume after an intravenous administration of 1 CHR unit.
SV,,,pL
TSV90, -1.33 zk 0.491 15.67 f 3.1 11 31.32 f 2.867 54.77 k 9.264 57.50 zk 3.693
t,,min
-
-
11.96 2 1.359 17.48 f 1.992 26.27 f 3.1 64 18.67 k 1.906
0-15 0-15 15-30 15-30
-
rb
-
-1.17 & 2.732 0-15 -0.43 f 1.31 1 0.98 f 0.374 16.46 f 1.935 5.67 f 0.405 15-30 0.105 29.48 & 5.635 8.73 & 1.079 15-30 0.188 39.63 & 5.447 10.63 f 1.535 15-30 0.253 a The data are expressed as mean & SEM; n = 3-7; total secreted volume of pancreatic juice during 90 min (TSVW, pL); maximum secreted volume of pancreatic juice during 15 min (SV-, p l ) ; time to SV,, (t-, min). r indicates the absorption rate of intranasal admiristration to 5 10 20 40
intravenous administration and is expressed as: r = TSVw (intranasal)/ TSVw intravenous x 1/dosage unit of intranasal administration. Journal of Pharmaceutical Sciences / 551 Vol. 74, No. 5, May 1985
Table Il-Results of pH Effect Study on Rat Preparations after Intravenous and lntranasal Administration of Secretin. Dosage Unit PH (CHR Unit) TsVao, pL sv,, P L f-, min
rb
1 15.67 f 3.111 11.96 f 1.359 0-1 5 10 47.92 f 6.193 (2.67 f 2.596)" 15-30 0.306 11.42 f 1.382 10 48.33 f 8.031 (-1 50 f 1.179) 45-60 0.308 11.17 f 1.910 10 39.06 f 3.238 (1.67 f 1.440) 7.38 f 1.128 60-75 0.249 10 30.13 f 5.271 (-0.67 f 0.892) 15-30 0.192 8.13 f 1.334 10 15.14 f 3.552 (0.67 f 1.656) 45-60 0.097 3.79 f 1.216 10 6.58 f 2.193 (-1.67 f 3.569) 15-30 0.042 2.42 f 0.661 10 8.25 f 2.073 (0.33 f 0.491) 4.50 f 1.031 15-30 0.053 a The data are expressed as mean f SEM; n = 4-8; total secreted volume of pancreatic juice during 90 min (TSV,, pL); maximum secreted volume of pancreatic juice during 15 min (SV-, pL); time to SV- (t-, min). r indicates the absorption ratio of intranasal administration to intravenous administration and is expressed as: r = TSVw (intranasal)/TSV, (intravenous) X I/dosage unit of intranasal administration. " The data enclosed in parentheses are control data (n = 3). Intravenous. Intranasal. 6.40d 2.10' 2.94' 3.81' 4.79' 6.33" 7.00' 8.00"
"
Table Ill-Results of Osmolarity Effect Study in Rat Preparations after Intravenous and lntranasal Administration of Secretin' Dosage Unit NaCI. M PH
C H R Unit)
0-1 5 11.96 2 1.395 3.40 k 1.004 45-60 0.089 5.67 f 0.405 15-30 0.105 10 7.92 f 1.431 15-30 0.142 6.59 -t 0.594 15-30 0.099 10 'The data are expressed as mean f SEM; n = 5-7; total secreted volume of pancreatic juice during 90 min (TSV,, pL); maximum secreted volume of pancreatic juice during 15 min (SV, pL); time to SV- (t-, min). r indicates the absorption ratio of intranasal administration to intravenous administration and is expressed as: r = TSVW (intranasal)/TSV, (intravenous)X 1/dosage unit of intranasal administration. intravenous. Intranasai. 'Significantlydifferent, p c 0.05.'The data enclosed in parentheses are control data (n = 3). 0.154 0 0.154 0.462 1.078
6.4" 6.!jd 6.4" 6.4' 6.4"
1 10 10
15.67 f 3.111 13.90 f 6.287 (0.16 0.360)' 16.46 f 1.935 (-1.17 f 2.732) '22.20 f 2.326 (-0.5f 1.546) 15.58 f 1.287 (2.33 f 1.361)
motic pressure in an NaCl s01ution.l~Moreover, Sakiya et a1.18 reported that the absorption of quinine from the small intestine decreased with increasing osmotic pressure. In our experiments, the maximum absorption of secretin through the nasal mucosa was observed with a 0.462 M NaCl solution, suggesting that there was an optimum molar concentration of NaCl at which secretin was absorbed. The t,, values were more prolonged with water than with NaCl solution. This implies that the presence of NaCl affects the absorption rate of secretin. Further studies are needed to elucidate whether the nature of the nasal mucosa or of secretin is affected by pH or salt in the nasal absorption of secretin. Our results reveal that a nasal dosage form for secretin is feasible and that the nasal absorption of secretin could be improved by variations in the pH and in the concentration of NaCl.
References and Notes 1. Matsuo, H.; Seki, A.; Ishikawa, T. Hormon to Rinsho 1976,23, 507.
552 /Journal of Pharmaceutical Sciences Vol. 74, No. 5, May 1985
*
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