Development and in vitro evaluation of an oral SEDDS for desmopressin

Figures & data

Figure 1. Anionic surfactants capable of precipitating desmopressin from aqueous solution. The surfactants likely formed an ion pair with the positively charged guanidine group.

Table 1. Classification of lipid-based excipients used in the study.

Functionality	Commercial name	Chemical name	HLB
Water-insoluble oils	Dermofeel BGC	Butylene glycol dicaprylate/dicaprate	<1
	Demofeel MCT	Tricaprylin	<1
	Dermofeel TC-7	Triheptanoin	<1
	Captex 300	Glyceryl tricaprylate/tricaprate	<1
	Mygliol 840	Propylene glycol tricaprylate/tricaprate	<1
	Ethyl oleate	Ethyl oleate	<1
Water-insoluble surfactants (HLB < 12)	Peceol	Glycerol monooleate	3
	CapmulPG-12	Propylene glycol monolaurate	4.5
	Capmul MCM EP	Caprylic/capric mono- and diglycerides	5.5
	Caprol 3GO	Polyglyceryl-3 oleate	6
	Capmul PG-8	Propylene glycol monocaprylate	6.7
	Capmul 907 P	Propylene glycol monoheptanoate	7.5
	Labrafll M 1944 CS	Oleoyl macrogol-6 glycerides	9
Water-soluble surfactants (HLB > 12)	Acconon MC-82	Polyoxyethylene-8 caprylic/capric glycerides	14
	Cremophor RH40	Polyethylene-40 hydrogenated castor oil	15
	Tween 80	Sorbitan monooleate	15
	Tween20	Sorbitan monolaurate	17
Co-solvents	Transcutol	Diethylene glycol monoethyl ether	NA

HLB, hydrophilic lipophilic balance (practical); NA, not applicable.

Figure 2. Hydrophobic ion pairing of desmopressin acetate with sodium octadecyl sulfate (○), sodium stearate (▴), sodium dodecyl sulfate (□), sodium oleate (•), and sodium docusate (▪). After the addition of surfactants, the precipitated desmopressin complex was centrifuged and the amount of remaining peptide in supernatant determined by HPLC. Data are shown as mean ± SD (n = 3).

Figure 3. (A) Partitioning coefficient log P (Capmul 907 P/water) of DES/SOL (•), DES/AOT (▪) and DES/SDS (□). Surfactant solutions were added in a dropwise manner to desmopressin solution to precipitate the peptide-surfactant complex. After 5 min 100 μL of Capmul 907 P was added and the mixture stirred for 30 min. The amount of desmopressin in both phases was determined by HPLC. (B) Zoomed log P (Capmul 907 P/water) for DES/AOT (▪) and DES/SDS (□).

Figure 4. Solubility of desmopressin acetate (white bars) and DES/AOT (black bars) in chosen water insoluble lipids and surfactants after 48 h of incubation at 25 °C. Data are shown as mean ± SD (n = 3).

Table 2. SEDDS formulation development with Capmul 907P as main solvent.

	Cremophor RH40	Tween 80	Tween 20	Acconon MC8-2	Capmul 907P	Transcutol	Mean droplet size(nm)	Polydispersity index
FI	50				50	0	83 ± 19	0.64
F2	50				40	10	238 ± 10	0.46
F3	50				30	20	308 ± 16	0.38
F4	40				50	10	33 ± 1	0.05
F5	40				40	20	120 ± 13	0.25
F 6	40				30	30	152 ±4	0.30
F7		50			50	0	924 ± 22	0.55
F8		50			40	10	332 ±75	0.55
F9		50			30	20	250 ±7	0.40
FIO		40			50	10	2030 ± 124	0.11
Fll		40			40	20	633 ± 156	0.48
F12		40			30	30	220 ± 24	0.34
F13			20	60	20		748± 190	0.33
F14			30	50	20		29 ± 1	0.36
F15			40	40	20		19 ± 1	0.26
F16			50	30	20		12 ±4	0.31
F17			60	20	20		No droplets
F18			20	50	30		2236 ± 666	7.64
F19			30	40	30		1377 ±91	5.81
F20			35	35	30		1492 ±186	7.10
F21			40	30	30		1550 ±384	11.26
F22			50	20	30		1275 ± 189	4.87

Data are shown as mean ± SD (n = 3).

Figure 5. Consumption of 0.1 M NaOH during in vitro digestion of SEDDS formulations F4 (○) and F15 (•) by pancreatic lipase at 37 °C. Data are shown as mean ± SD (n = 3).

Figure 6. Degradation of desmopressin acetate (▪), DES/AOT-SEDDS-F15 (•) and DES/AOT-SEDDS-F4 (○) at 37 °C in 50 mM acetate buffer pH 5.5 by reduced glutathione. Data are shown as mean ± SD (n = 3).

Figure 7. Enzymatic degradation of desmopressin acetate (▪), DES/AOT-SEDDS-F15, (•) and DES/AOT-SEDDS-F4 (○) at 37 °C in 50 mM HEPES buffer pH 7.4 with 2 mM CaCl₂ by α-chymotrypsin. Data are shown as mean ± SD (n = 3).

Figure 8. Cell viability rates of Caco-2 cells after incubation for 1 h and 4 h with 0.25% (w/v) and 0.375% (w/v) DES/AOT-SEDDS-F4 and DES/AOT-SEDDS-F15. Data are shown as mean ± SD (n = 3).