Nanoparticulate carrier system: a novel treatment approach for hyperlipidemia

Figures & data

Table 1. Normal adult blood cholesterol level (Brahm & Hegele, 2013).

Total cholesterol (mg/dl)	Low-density lipoproteins (mg/dl)	Category
<200	<130	Desirable
200–239	130–159	Borderline high
240 and over	160 and over	High

Table 2. Causes of hyperlipidemia (Starc, 2001).

Diseases	Drug associated with hyperlipidemia	Dietary causes	Lifestyle contributing causes
Insulin-dependent diabetes mellitus	Retinoids	Fat intake per total calories >40%	Habitual excessive alcohol use
Non-insulin-dependent diabetes mellitus	Anabolic steroids	Saturated fat intake per total calories >10%	Lack of exercise
Cushing’s syndrome	Birth control pills and estrogens	Habitual excessive alcohol use	Overweight or obesity
Hypothyroidism	Corticosteroids	Cholesterol intake >300 mg/day	Cigarette smoking lowers HDL
Nephrotic syndrome and renal failure	Thiazide diuretics		Herbs and supplements produce side effects that may be harmful
Dysproteinemias	Protease inhibitors
Cholestatic disorders	Beta-blockers

Table 3. Classification of hyperlipidemia (WHO/Modified Fredrickson) (Hegele, 2009).

		Lipid profile
Types	Lipoprotein abnormality	Total cholesterol	LDL cholesterol	Plasma TGs	Clinical manifestations	Population prevalence
Familial chylomicronemia (HLP type 1)	Excess chylomicrons	Elevated	Low or normal	Elevated	Lipemia retinalis, focal neurologic symptoms, failure to thrive, recurrent epigastric pain, hepatosplenomegaly	1 in 1 million
Combined hyperlipidemia (HLP type 2)	Excess LDL and VLDL	Elevated or normal	Elevated	Normal	Physical stigmata such as xanthomas or xanthelasmas are rare	1 in 40
Dysbetalipidemia (HLP type 3)	Excess IDL Elevated chylomicron remnants	Elevated	Low or normal	Elevated	Tuberous and palmar xanthomata Elevations in atherogenic IDL leads to increased risk for CVD	1 in 10 000
Primary simple hyperlipidemia (HLP type 4)	Excess VLDL	Elevated or normal	Normal	Elevated	Associated with increased risk of obesity, CVD, DM2, hypertension, insulin resistance and hyperuricemia	1 in 20
Primary mixed hyperlipidemia (HLP type 5)	Excess chylomicrons and VLDL	Elevated	Normal	Elevated	Similar clinical manifestations as type I but develops in adulthood	1 in 600

HLP, hyperlipoproteinemia; TC, total cholesterol; VLDL, very low-density lipoprotein; LDL, low-density lipoprotein; IDL, intermediate density lipoprotein.

Table 4. Classification of current conventional marketed formulations for hyperlipidemia.

				Manufacturers
Classes of drugs	Generic names	Formulation	Dosage and administration	Brand names	Companies
1. Statins	Atorvastatin	Tablet	80 mg/day with or without food	Lipitor Atorlip-10 Lipigoal Quest	Pfizer Inc Cipla Abbott India Limited Ind-Swift Limited
	Pravastatin sodium	Tablet	40 mg/day with or without food	Pravachol Pravator	Lupin pharmaceuticals, INC. Ranbaxy Laboratories Ltd
	Fluvastatin	Tablets/extended release Capsule	80 mg/day empty or full stomach 40 mg capsule	Lescol/Lescol XL	Novartis India
	Lovastatin	Mevacor tablet/ immediate release, Altoprev (extended release)	80 mg/day 10–60 mg/day extended release	Lovacard Lovastat Lochol	Cipla Torrent Pharmaceuticals Ltd Micro Labs Ltd
	Simvastatin	Tablet/oral disintegrating tablet	80 mg/day with or without food	Simlup	Lupin
2. Fibrates	Fenofibrate oral	Tablet/capsule	160 mg/day with or without food 200 mg capsule	Triglide Supralip	Shionogi Inc. Abbott Laboratories
	Gemfibrozil	Tablet	600 mg twice a day 30 min before meal (breakfast and dinner)	Lopid Gempar	Pfizer Inc Cadila Pharmaceuticals Ltd.
3. Cholesterol absorption inhibitors	Ezetamide	Tablet	10 mg daily with or without food	Ezedoc Zetica Zetimax	Lupin Ltd. Torrent Pharmaceuticals Ltd USV Limited
4. Nicotinic acid group	Niacin, nicotinic acid, Vit B3	Tablet (controlled/ extended release) Capsules	250 500 and 750 tablets; 250 and 500 mg capsules three times a day with or after meal	Niaspan	Teva Pharmaceuticals
5. Fish oil	Omega-3-acid ethyl ester 90	Granular capsule	2 gm twice a day immediately after meals	Lotriga	Takeda Pharmaceutical Co Ltd.
6. Bile acid sequestrants	Colestipol hydrochloride	Tablets Oral suspension	2–16 gm/day once or twice a day using plenty of water and other appropriate liquid	Colestid tablets	Pfizer Inc
	Cholestyramine	Oral suspension	4–8 gm once or twice daily Max dose – 24 gm/day at mealtime	Questran powder	Bristol–Myers pharmaceuticals
	Colesevelam	Tablet and oral suspension	625 mg Colesevelam HCL tablet, 1.875 gm or 3.75 gm oral suspension three tablets twice a day with meal and liquid	Welchol Lodalis	Sankyo Parke-Davis Valeant Canada LP

Figure 1. Mechanism of action of different antihyperlipidemic agents: HMG CoA reductase inhibitors (statins), cholesterol absorption inhibitors, nicotinic acid group and bile acid sequestrants.

Table 5. Work done of different nanoparticles with hyperlipidemia.

Drug	Formulation	Polymer/lipids	Method of preparation	Size	Inference	References
Atorvastatin calcium	Chitosan nanoparticles	Chitosan	Solvent evaporation method	150.5 ± 1.24 nm	Effective carrier for the design of controlled drug delivery	Bathool et al. (2012)
Atorvastatin calcium	Amorphous atorvastatin calcium nanoparticles	–	Supercritical antisolvent (SAS) process	152–863 nm	Talented approach to improve dissolution, supersaturation and absorption properties of atorvastatin	Kim et al. (2008)
Chitosan	Chitosan nanoparticles	–	Ionotropic gelation, rotary evaporation and spray-drying technique	500 and 1000 nm	Chitosan nanoparticles are non-toxic and useful in lowering body weight gain and serum lipid levels	Zhang et al. (2011)
Atorvastatin calcium	Oral nanoparticulate atorvastatin calcium	Poly lactide-co-glycolic acid	Emulsion–diffusion–evaporation method	120.0 ± 4.2 nm and 140.0 ± 1.5 nm	Improving the safety and efficacy of atorvastatin calcium	Meena et al. (2008)
Chitosan	Water-soluble chitosan nanoparticles	–	Ionic gelation method and the spray-drying technique	650 nm	Hypercholesterolemia is affected by WSC-NPs even more than the WSC	Tao et al. (2011)
Lovastatin	Nanostructured lipid carriers	Squalene, Pluronic F68	High shear homogenization followed by sonication	180–290 nm	More stable in the gastric environment and improve the clinical efficacy of lovastatin	Chen et al. (2010)
Atorvastatin	Atorvastatin-loaded solid–lipid nanoparticles	Trimyristin and soy phosphatidylcholine 99%	Hot homogenization followed by ultrasonication technique	50.0 ± 6.12 nm	SLNs are the promising delivery systems for poorly water-soluble drugs	Kumar et al. (2012b)
Simvastatin	Simvastatin-loaded lipid nanoparticles	Tween-20 and oleic acid or Solutol	Emulsification solvent evaporation technology	48.9 and 68.3 nm	Promising delivery system to enhance the oral bioavailability of Simvastatin	Zhang et al. (2010)
Rosuvastatin calcium	Solid–lipid nanoparticles of rosuvastatin calcium	Glyceryl behenate (compritol ATO 888), glyceryl monostearate and glyceryl monooleate	Hot homogenization followed by ultrasonication	69–987 nm	Nanoparticles formulations with least mean particle size depicted better permeability than the pure drug solution	Sathali et al. (2013)
Lovastatin	Lovastatin nanoparticle	Precirol and squalene	Hot homogenization followed by ultrasonication	65.6 nm	Nano-aided drug delivery system is an suitable Choice for poorly soluble lipophilic drugs	Seenivasan et al. (2011)
Protein	Protein-nanoparticle conjugates	Polylactide	–	100 nm	Digestion of bad cholesterol (LDL)	Maximov et al. (2010)
Estradiol	Oral estradiol nanoparticles	Poly(lactide-co-glycolide) (PLGA)	Emulsion–diffusion–evaporation	–	Reduced dose and frequency in comparison to that of drug suspension administered orally	Mittal et al. (2009)

Figure 2. Pathways involved chylomicrons synthesis by the intestine and VLDL synthesis by the liver and mechanisms of diverse systems in hyperlipidemia. Abbreviations: LDL, IDL and VLDL – level inhibition of chylomicrons, FFA – free fatty acids, LPL – lipoprotein lipase, LDL – low-density lipoproteins, IDL – intermediate density lipoproteins, VLDL – very low-density lipoproteins, LPL – lipoprotein lipase,

– inhibition,

– activation.

Figure 3. Common approaches for hyperlipidemia.

Table 6. Different applications of nanoparticles.

Nanoparticle	Application	References
Quantum dots	Imaging of multiple endogenous proteins Cancer targeting and imaging Ultrasensitive non-isotopic detection Probing of DNA structure Phagokinetic studies	Giepmans et al. (2005) Gao et al. (2004) Chan & Nie (1998) Mahtab et al. (1995) Parak et al. (2002)
Nanoparticles probes	Diagnosis (single-molecule detection) (molecular diagnosis)	Agrawal et al. (2008) Emerich & Thanos (2006)
Lipid- or polymer-based nanoparticles	Drug delivery (improve the pharmacological and therapeutic properties of drugs administered parenterally) (biodegradable nanoparticle drug delivery systems in the lung)	Allen & Cullis (2004) Dailey et al. (2006)
Magnetic nanoparticles	Drug targeting and bioseparation including cell sorting Therapeutic drug, gene and radionuclide delivery	Ito et al. (2005) Pankhurst et al. (2003)
Dendrimers	Tissue engineering Solubility enhancement, sustained release and drug delivery	Joshi & Grinstaff (2008) Singh et al. (2008)
Nanoparticles biosensors	Bibliometric analysis	Huang et al. (2010)
Nanoparticle bioconjugates	Fluorescent biological labels	Wang et al. (2002)
Bead ARray counter biosensors	Bio-detection of pathogens	Edelstein et al. (2000)
Nanoparticle-based bio-bar codes	Detection of proteins	Nam et al. (2003)
Ceramic nanoparticles	Tissue engineering	De La Isla et al. (2003)
Polymer-brush-afforded iron oxide magnetic nanoparticles	Magnetic resonance imaging MRI contrast enhancement	Ohno et al. (2013) Weissleder et al. (1990)
Nanoparticles and nanocapsules Silver nanoparticles	Agricultural applications Pesticide	Nair et al. (2010)

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