Nanocarriers as treatment modalities for hypertension

Figures & data

Figure 1. Novel molecular targets for antihypertensives.

Table 1. Some novel antihypertensives with their development phase and mechanism of action.

Mechanism	Drug	Development phase	Company	References
Aldosterone-receptor blocker	Eplerenone	Marketed	Pfizer, USA	ACE 2 modulator
Phosphodiesterase 5 inhibitor	TadalafilKD027	MarketedPhase II	Eli Lilly, USAKadmon Pharmaceuticals	ACE 2 modulator ; Adis Insight
Dopamine β-hydroxylase inhibitor	Etamicastat	Phase I	Bial, Portugal	McLendon et al. (2015)
ACE 2 modulator	APN01 (rhACE2)	Phase II	Apeiron-biologics	Morrell et al. (2013)
Aldosterone synthase inhibitor	ASI LCI699	Phase II	Novartis, Switzerland	Muller et al. (2000)
ACE inhibitor	Imidapril	Marketed	Mitsubishi Tanabe Pharma	Nolte et al. (2011)
AT1R blocker with PPAR-γ activity	Azilsartan (TAK-491)	Marketed	Takeda Pharmaceuticals, Japan	Novartis' new heart failure medicine LCZ696, now called Entresto(TM), approved by FDA to reduce risk of cardiovascular death and heart failure hospitalization [Online]
AT2R agonist	Compound 21	Phase I	Vicore, Sweden	Nunes et al. (2010)
Combined AT1R blocker and  NEP inhibitor	LCZ696Daglutril	Phase IIIPhase II	Novartis, SwitzerlandSolvay, Belgium	O'Driscoll & Griffin (2008); Ohara-ch [Online]
Renin inhibitor	AliskirenVTP27999	MarketedPhase II	Novartis, Switzerland, and Speedel SwitzerlandVitae Pharmaceuticals, USA	ACE 2 modulator; Oparil & Schmieder (2015)
Endothelin A receptor antagonist	Macitentan (PAH)Ambrisentan (PAH)	MarketedMarketed	Actelion PharmaceuticalsGilead	Palatin Technologies, Inc [Online]; Paulis & Unger (2010)
Imidazoline-receptor blocker	Monoxidine	Marketed	Eli Lilly, USA	Paulis et al. (2015)
Natriuretic peptide receptor agonist	PL3994	Phase II	Palatin Technologies, USA	Pridgen et al. (2014)
Endothelila nitric oxide synthase coupler	Cicletanine	Marketed	Gilead Sciences, Inc	Antal et al. (2015); Ranpise et al. (2014)
NO-releasing COX inhibitor	Naproxcinod	Phase III	NicOx, France	Selvamuthukumar & Velmurugan (2012).
Mas GPCR receptor	CGEN-856	Preclinical	BioLineRx	Shafiq et al. (2007)

PAH: pulmonary arterial hypertension, ACE: angiotensin-converting enzyme, AT1R: angiotensin II type 1 receptor, AT2R: angiotensin II type 2 receptor, PPAR-γ: peroxisome proliferator-activated receptor gamma.

Table 2. Physicochemical and metabolic profile of antihypertensives showing poor oral bioavailability.

Class	Drug	Metabolism	Solubility	Log P	Bioavailability
Calcium channel  blocker	Nisoldipine	Extensive gut wall metabolism, CYP3A4 substrate	5.7 μg/ml	3.1	<5%
	Nitrendipine	Extensive hepatic first-pass metabolism by CYP3A4	2 μg/ml	3.59	10–20%
	Lacidipine	Completely metabolized in liver by CYP3A4	0.84 μg/ml	5	10%
	Verapamil	Extensively metabolized by CYP2C8, CYP2C18,  and CYP2C9	7 mg/ml	3.8	10–20%
	Nifedipine	Hepatic metabolism by CYP3A4	20 μg/ml	2.20	45–56
	Amlodipine	Metabolized by CYP3A4	75.3 μg/ml	2.22	64%
	Felodipine	Inclusively metabolized by CYP3A4	7.15 μg/ml	4.36	15%
AT1 blocker	Olmesartan	Not metabolized by cytochrome P450 but is metabolized  by liver esterase	7.75 μg/ml	5.5	26%
	Valsartan	CYP2C9	< 0.1 mg/ml	5.8	<25%
Beta blocker	Carvedilol	CYP1A2, CYP3A4, CYP1A1 CYP2D6, CYP2E1, CYP2C9	0.583 μg/ml	4.1	20%
Renin Inhibitor	Aliskiren	CYP3A4-mediated hepatic metabolism	122 mg/ml as hemifumarate salt	2.45	2.5%

Table 3. Novel delivery system of antihypertensives and their positive outcome.

Type of delivery system	Therapeutic system	Excipients used	In-vivo study model	Comments
Polymeric  nanoparticle	Ramipril	lecithin/chitosan	Male Wistar rats	1.6-fold decrease in systolic blood pressure
	Nifedipine	PCLPLAGAEudragit RL/RS	Male adult SHR	Initial fall in systolic blood pressure was rapid for PEG solution followed by with PCL NP and PLAGA NP.Blood pressure was within normal range after 10 h of dosing with all three NPs while PEG solution failed to achieve such sustained effect.
	Felodipine	PLGA, Pluronic F-68	Male Wistar rats	Systolic blood pressure normalized and elevated ST segment of ECG became normal upto a period of 3 days as compared to drug suspension.
	Lercanidipine	HPMC, TPGS	Male Sprague–Dawley rats	2.47 increase in oral bioavailability than raw drug without TPGS
	Aliskiren	Magnetite, poly (D, L-lactide), Pluronic F-68	Male spontaneouslyhypertensive rats	Significant decrease in mean systolic blood pressure by aliskiren nanoparticle as compared to aliskiren suspension and placebo
Solid Lipid  nanoparticle	Nisoldipine	Trimyristin (TM; Dynasan-114; glyceryl trimyristate), egg lecithin, Poloxamer-188	Male Wistar rats	2.17 times increase in oral bioavailability, significant reduction in systolic blood pressure for a period of 36 h
	Candesartan Cilexetil	GMS, soy lecithin, Tween 80	Male Sprague–Dawley rats	12 times increase in oral bioavailability
	Isradipine	Trimyristin or GMS, poloxamer 188	Wistar rats	Significant decrease in the systolic blood pressure with SLN formulation using two different lipids
Nanostructured  Lipid Carrier	Lacidipine	GMS, Linoleic acid and poloxamer 407	Wistar male albino rats	3.9 times enhancement in the relative bioavailability
	Lercanidipine	Labrafil 2130M, GMS, linseed oil and Tween 80	Male Sprague–Dawley rats	24 h control on the blood pressure by NLC as compared to plain drug suspension
Nanoemulsion	Ramipril	Sefsol 218, Tween 80, carbitol	Wistar male albino rats	229.62% increase in relative bioavailability of ramipril nanoemulsion as compared to ramiprol marketed capsule and 539.49% increase in bioavailability of formulation as compared to drug suspension.
	Amlodipine	DE (Labrafilm 1944 CS and Dextrin)	Male Sprague–Dawley rats	In vitro release studied showed higher release of amlodipine from DE than powdered drug. 2.6 to 2.9 times increase in Cmax and AUC (0–24h) from DE than powder. Marked reduction in photodegradation of drug in DE than powdered drug (5.6% versus 66.9%)
	Olmesartan Medoxomil (Beg et al., 2015)	SNEDDS (SNEOF and CSNEOF)	Unisex Wistar rats	After 0.5 h of dosing, significant reduction in arterial blood pressure (180 to 189 mm Hg) was seen with SNEOF (141 ± 1.36), CSNEOF (136 ± 1.45), and marketed formulation (138 ± 1.98). After 48 h of study, rats were found normotensive (BP < 130 mm Hg) with SNEOF and CSNEOF
	Valsartan	S-SNEDDS (Capmul MCM, Labrasol, Tween 20)	Male Wistar rats	3–3.5 time increase in the rate of dissolution, significant reduction in the mean systolic blood pressure after 0.5 h and 2 h of dosing of S-SNEDDS as compared to valsartan suspension showing faster onset of action of S-SNEDDS thus showing it to have the potential of the bioavailability enhancement of valsartan
	Lacidipine	S-SNEDDS (Labrafil and capmul as oil, Cremophor and Tween 80 as surfactant and transcutol as co-surfactant)	Male Wistar rats	Rate of dissolution increased significantly
	Carvedilol	S-SNEDDS (Capmul MCM, Nikkol HCO 50) L-SNEDDS (Cremophor EL, Transcutol HP)	———	2.34 and 1.85 times enhancement in Cmax and AUC, respectively of S-SNEDDS, thus showing increase in the bioavailability.
Lipotomes	Lacidipine	Cetyl alcohol and Tween 80	Adult male human volunteer	540.11% increase in relative bioavailability of enteric-coated capsule of lipotome as compared to Motens tablet

PCL: poly-e-caprolactone, PLAGA: polylactic and glycolic acid, PEG: Polyethylene glycol, NP: Nanoparticle, SHR: systolic hypertensive rat, DE: Dry emulsion, SNEDDS: Self-Nanoemulsifying drug delivery system, S-SNEDDS: solid self nanoemulsifying drug delivery system, HPMC: Hydroxypropyl methyl cellulose, TPGS: D-α-tocopheryl polyethylene glycol1000 succinate, SNEOF: Self nanoemulsifying oily formulation, CSNEOF: Cationic Self nanoemulsifying oily formulation, GMS: Glyceryl monostearate.

Figure 2. Diagram for currently used nanoparticles utilized in the treatment of hypertension.

Figure 3. Mechanism of gene silencing.

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