The development and evaluation of a subcutaneous infusion delivery system based on osmotic pump control and gas drive

Figures & data

Table 1. Comparison on several types of subcutaneous infusion devices.

Pump type	Advantages	Disadvantages	References
Electricity driven	Accurate, adjustable, reusable	Cost-inefficient, complex structure, use difficult	Moulin et al., 1991; Pasero, 2002
Electrochemical gas driven	Economical, reusable, use friendly	Battery required, rate un-changeable	Mikkelsen et al, 2000
Osmosis driven	Economical, accurate, reusable, use friendly	Rate change difficult, lag time of infusion	Herrlich et al., 2012; Ehwald et al., 2006
Spring driven	Economical, use friendly	Un-accurate, rate un-changeable	Ilfeld et al., 2003
Elastomeric driven	Economical, use friendly	Un-accurate, rate un-changeable un-reusable	Ilfeld et al., 2003
Chemical gas driven	Economical, adjustable, reusable, use friendly	Lag time of infusion	Reported in this paper

Figure 1. Schematic representation of the osmotic tablet-controlled infusion system.

Figure 2. Diagram of the infusion flow measurement.

Table 2. The formulation of core tablets.

Formulation number	Osmotic agents	Lactose	Binders	Magnesium stearate	Silicon dioxide
F0	21.3 mg tartaric acid, citric acid	42.6 mg	2.1 mg PVP	2 mg	2 mg
F1	63.9 mg NaHCO3, Na2CO3	0	2.1 mg PVP	2 mg	2 mg
F2	63.9 mg Na2CO3	0	2.1 mg HPC, HPMC, CMC, or PVP	2 mg	2 mg
F3	64.6 mg Na2CO3	0	1.4 mg PVP	2 mg	2 mg

Table 3. Coating formulation and tablet weight gain.

Coating formulation number	PEG (w/v)	DEP (v/v, %)	Weight gain of tablets (%)
C0	2% PEG1500	1.5	10
C1	2% PEG1500, 4000, or 6000	1.5	10
C2	2% PEG1500	0.5, 1.2, or 2.0	10

Figure 3. Influence of the osmotic agents on the infusion flow (n = 6). For tartaric acid and citric acid osmotic tablets, the reaction solution was 5 mg/mL NaHCO₃; and for Na₂CO₃ and NaHCO₃ tablets, the reaction solution was 15 mg/mL citric acid. 1* Significant smaller (p < 0.05) when compared with group Na₂CO₃ and NaHCO₃; 2* Significant smaller (p < 0.05) when compared with group NaHCO₃; 1△ Significant smaller (p < 0.05) when compared with group Na₂CO₃ and NaHCO₃; 2△ Significant smaller (p < 0.05) when compared with group versus NaHCO₃.

Figure 4. Influence of adhesive agents on the infusion flow (n = 6). 1* Significant smaller (p < 0.05) than group HPC and greater (p < 0.05) than group PVP; 2* Significant smaller (p < 0.05) when compared with group HPC, HPMC and CMC; 1△ Significant smaller (p < 0.05) when compared with group CMC; 2△ Significant smaller (p < 0.05) when compared with group HPMC and CMC.

Figure 5. Influence of the amount of PVP on the infusion flow (n = 6). *Significant smaller (p < 0.05) when compared with 3% and 4% PVP; △Significant greater (p < 0.05) when compared with 3% and 4% PVP.

Figure 6. Influence of the PEG on the infusion flow (n = 6). *, △Significant smaller (p < 0.05) when compared with PEG4000 and PEG6000.

Figure 7. Influence of the level of PEG1500 on the infusion flow (n = 6). *Significant smaller (p < 0.05) when compared with other groups; △Significant greater (p < 0.05) when compared with 2.0%, 2.5% DEP.

Figure 8. Influence of the amount of DEP on the infusion flow (n = 6). *Significant smaller (p < 0.05) when compared with other groups.

Figure 9. Influence of weight gain of tablet on the infusion flow (n = 6). *, △ Significant smaller (p < 0.05) when compared with weight gain of 15%.

Figure 10. Temperature effect on the infusion profiles of drug delivery system (n = 6). The same data with error bars (Mean ± SD) was shown in the imbedded figure.

Figure 11. The effect of resistance pressure on the infusion profiles (n = 6). The same data with error bars (Mean ± SD) was shown in the imbedded figure.

Figure 12. Mean plasma ampicillin concentration-time profiles (n = 6).

Table 4. Results of Box-Behnken design.

	Factors
Run	PEG1500 (%)	DEP (%)	Weight gain (%)	S
1	2.00	1.25	11.0	34
2	2.00	1.25	11.0	36
3	2.50	1.25	15.0	106
4	2.00	0.50	7.0	22
5	2.00	1.25	11.0	41
6	1.50	1.25	15.0	56
7	2.00	0.50	15.0	87
8	2.00	2.00	7.0	51
9	1.50	1.25	7.0	48
10	2.00	1.25	11.0	31
11	2.00	1.25	11.0	32
12	2.00	2.00	15.0	118
13	2.50	1.25	7.0	31
14	1.50	0.50	11.0	73
15	1.50	2.00	11.0	66
16	2.50	2.00	11.0	68
17	2.50	0.50	11.0	37

Table 5. Pharmacokinetic parameters of administration means.

Treatment	AUC(0–t) (h*μg/mL)	K10HL (h)	Cmax (μg/mL)	CL (mL/h)	Vss (mL)
Intravenous injection	102.81 ± 19.69	0.53 ± 0.05	134.01 ± 16.38	2157.20 ± 358.52	1629.50 ± 174.58
Developed pump	111.60 ± 18.65	0.94 ± 0.07	18.3 ± 3.15	1976.21 ± 280.62	2694.15 ± 554.03
Reference pump	104.72 ± 16.49	0.65 ± 0.12	17.14 ± 2.77	2148.34 ± 293.17	2003.51 ± 581.08

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