Review and analysis of FDA approved drugs using lipid-based formulations

Figures & data

Table 1. FDA approved drugs utilizing lipid systems.

Molecule/trade name	New drug application (NDA) Year	Biopharmaceutics classification system (BCS)	Developability classiciation system	Lipid formulation classification system (LFCS)	Drug category	Dose	Dosage form, strength	Oils: triglycerides or mixed mono and diglycerides	Water-insoluble surfactants (HLB <12)	Water-soluble surfactants (HLB >12)	Hydrophilic cosolvents
Ergocalciferol (Drisdol^®)	1941	3	IIb	I	Vitamin D analog	Vitamin D Resistant Rickets: 12,000 to 500,000 IU units daily. Hypoparathyroidism: 50,000 to 200,000 IU units daily concomitantly with calcium lactate 4 g, six times per day	LFHS, 50,000 IU	Soybean oil
Calcitriol (Rocaltrol^®)	1978	2/4	I	I	Vitamin D analog	0.25–0.5 μg qd	Soft gelatin capsule, 0.25 and 0.5 μg	Fractionated triglycerides of coconut oil
Valproic acid (Depakene^®)	1978	1	I	I	Anti-epileptic	10–15 mg/kg/day	Soft gelatin capsule, 250 mg	Corn oil
Isotretinoin (Accutane^®) Discontinued	1982	2	IIb	I	Retinoid	0.5–2 mg/kg in 2 divided doses	Soft gelatin capsule, 10, 20, 40 mg	Beeswax, hydrogenated soybean oil flakes, hydrogenated vegetable oil, soybean oil
Cyclosporin A (Sandimmune^®)	1983	2	IIb	II	Calcineurin inhibitor	2–10 mg/kg/day in two divided doses	Oral solution, 100 mg/mL	Olive oil		polyoxyethylated oleic glycerides	Ethanol 12.5%
Dronabinol (Marinol^®)	1985	2/4	IIb	I	Cannabinoid	2.5–20 mg/day	Soft gelatin capsule, 2.5, 5, 10 mg	Sesame oil
Clofazimine (Lamprene^®) 100 mg Discontinued	1986	2		I	Antileprosy	100 mg/day	Soft gelatin capsule, 50 and 100 mg	Beeswax
Cyclosporin A (Sandimmune^®)	1990	2	IIb	II	Calcineurin inhibitor	2–10 mg/kg/day in 2 divided doses	Soft gelatin capsule, 25 and 100 mg	Corn oil	Linoleic macroglycerides		Ethanol 12.7%
Ranitidine (Zantac^®) Discontinued	1994	3			H2-receptor antagonist	150 mg bid or 300 mg qd	Soft gelatin capsule, 150 and 300 mg	Medium chain triglycerides	Mixed glycerides of long chain fatty acids (Gelucire 33/01)
Cyclosporin A (Neoral^®)	1995	2	IIb	IIIA/IIIB	Calcineurin inhibitor	2–10 mg/kg/day in two divided doses	Soft gelatin capsule, 10, 25, 60, 100 mg	Corn oil mono-di-triglycerides		Polyoxyl 40 hydrogenated castor oil	Ethanol 11.9%, glycerol, propylene glycol
Cyclosporin A (Neoral^®)	1995	2	IIb	IIIA/IIIB	Calcineurin inhibitor	2–10 mg/kg/day in 2 divided doses	Oral solution, 100 mg/mL	Corn oil-mono-di-triglycerides		Polyoxyl 40 hydrogenated castor oil	Ethanol 11.9%, propylene glycol
Tretinoin (Vesanoid^®) Discontinued	1995		IIb	I	Retinoid	45 mg/m^2/day as two evenly divided doses	Soft gelatin capsule, 10 mg	Beeswax, hydrogenated soybean oil flakes, hydrogenated vegetable oil, soybean oil
Ritonavir (Norvir^®)	1996	4	IIb	IIIA	Protease inhibitor	600 mg bid (adults)	Soft gelatin capsule, 100 mg		Oleic acid	Polyoxyl 35 castor oil	Ethanol
Saquinavir (Fortovase^®) Discontinued	1997	4	IIb		Protease inhibitor	1200 mg bid without ritonavir; 1000 mg bid with ritonavir	Soft gelatin capsule, 200mg	Medium chain mono- and di-glycerides
Progesterone (Prometrium^®)	1998	2	IIb	I (susp)	Hormone	200 mg qd	Soft gelatin capsule, 100 and 200 mg	Peanut oil
Amprenavir (Agenerase^®) discontinued	1999	2	IIb	IV	Protease inhibitor	1200 mg bid or 1200 mg qd with ritoanvir	Soft gelatin capsule, 50 mg			Vitamin E TPGS	PEG400, propylene glycol
Bexarotene (Targretin^®)	1999		IIb	IV	Retinoid	300-750 mg qd	Soft gelatin capsule, 75 mg			Polysorbate 20	PEG400
Doxercalciferol (Hectorol^®)	1999	2/4	I	I	Vitamin D analog	Determined by target intact parathyroid hormone level (iPTH) Usually 10 mcg three times weekly at dialysis	Soft gelatin capsule, 0.5, 1, 2.5 mcg	Coconut oil			Alcohol
Sirolimus (Rapamune^®)	1999		IIa	III	mTOR kinase inhibitor	6 mg loading dose followed by 2 mg qd	Oral solution, 1 mg/mL	Phosphatidylcholine, mono- and di-glycerides, soy fatty acids, ascorbyl palmitate		Polysorbate 80	1.5–2.5% ethanol, propylene glycol
Cyclosporin A (Gengraf^®)	2000	2	IIb	IV	Calcineurin inhibitor	1:1 dose conversion from Sandimmune 2.5 mg/kg/day in two divided dose (RA and Psoriasis)	LFHS, 25, 50, 100 mg			Polysorbate 80, Polyoxyl 35 castor oil	Propylene glycol, alcohol 12.8% v/v
Cyclosporin A (Gengraf^®)	2000	2	IIb	IV	Calcineurin inhibitor	1:1 dose conversion from Sandimmune 2.5 mg/kg/day in two divided dose (RA and Psoriasis)	Oral solution, 100mg/ml			Polyoxyl 40 hydrogenated castor oil, Polysorbate 80	Propylene glycol
Ritonavir/lopinavir (Kaletra^®) Discontinued	2000	4		III	Protease inhibitors	400/100 mg (3 Soft gelatin capsule) bid 800/200 mg (6 Soft gelatin capsule) qd	Soft gelatin capsule, 133.3 mg lopinavir/33.3 mg ritonavir		Oleic acid	Polyoxyl 35 castor oil	Propylene glycol
Dutasteride (Avodart^®)	2001	2/4	IIa	I	5 alpha-reductase inhibitor	0.5 mg qd	Soft gelatin capsule, 0.5 mg	Mono-di-glycerides of caprylic/capric acid
Isotretinoin (Claravis^®)	2003 (ANDA)	2	IIb		Retinoid	0.5–1 mg/kg/day given in two divided doses	LFHS, 20, 30, 40 mg	Hydrogenated vegetable oil, soybean oil, white wax		Polysorbate 80
Omega-3-acid ethyl esters (Lovaza^®)	2004			I	Fish oils for lipid regulation	4 g qd or 2 g bid	Soft gelatin capsule, 1 g	Soybean oil
Tipranavir (Aptivus^®)	2005	4	IIb	IIIA	Protease inhibitor	500 mg with 200 mg ritonavir qd (adults) 14 mg/kg with 6mg/kg ritonavir (pediatric)	Soft gelatin capsule, 250 mg	Mono-/di-glycerides of caprylic/capric acids		Polyoxyl 35 castor oil	Ethanol, propylene glycol
Tipranavir (Aptivus^®)	2005	4	IIb	IV	Protease inhibitor	500 mg with 200 mg ritonavir qd (adults) 14 mg/kg with 6mg/kg ritonavir (pediatric)	Oral solution, 100 mg/ml			Vitamin E TPGS	PEG 400, propylene glycol, water
Paricalcitol (Zemplar^®)	2005	4	IIa	I	Vitamin D analog	1 or 2 mcg daily 2 or 4 mcg three times a week	Soft gelatin capsule, 1 and 2 mcg	Medium chain triglycerides fractionated from coconut oil or palm kernel oil			Alcohol
Lubiprostone (Amitiza^®)	2006	2/4	I	I	Chloride channel activator	24 mcg bid for chronic idiopathic constipation and opioid-induced constipation 8 mcg bid for irritable bowel syndrome with constipation	Soft gelatin capsule, 8 and 24 mcg	Medium chain triglycerides
Fenofibrate (Lipofen^®)	2006	2	IIb	III	Peroxisome proliferator activated receptor α (PPARα) acvtivator	50 to 150 mg daily	HSC, 50 and 150 mg			Gelucire 44/14 (lauroyl macrogol glyceride type 1500)
Topotecan HCl (Hycamtin^®)	2007	1	I	I	Topoisomerase inhibitor	2.3 mg/m2/day orally once daily for 5 consecutive days repeated every 21 days	LFHS, 0.25 and 1 mg base	Hydrogenated vegetable oil	Glyceryl monostearate
Loratadine (Claritin^®)	2008	2			Antihistamine	10 mg qd	Soft gelatin capsule, 10 mg	Caprylic/capric glycerides		Polysorbate 80
Isotretinoin (Absorica^®)	2012	2	IIb		Retinoid	0.5–1 mg/kg/day given in two divided doses	LFHS, 10, 20, 25, 30, 35, 40 mg	Soybean oil, stearoyl polyoxylglycerides	Sorbitan monooleate
Enzalutamide (Xtandi^®)	2012	2	IIb	I	Androgen receptor inhibitor	160 mg qd	Soft gelatin capsule, 40 mg	Caprylocaproyl polyoxyglycerides
Nintedanib (Ofev^®)	2014	2/4	IIb	II	Tyrosine kinase inhibitor	150 mg bid with food (Ofev)	Soft gelatin capsule, 50 and 100 mg	MCTs, hard fat	Lecithin
Calcifediol (Rayaldee™)	2016	2/4	I	II/III	Vitamin D analog	60 mcg qd at bedtime	Soft gelatin capsule, 30 mcg	Mixture of lipophilic emulsifier with a HLB <7 and an absorption enhancer with HLB of 13–18 Oily vehicle- mineral oil, liquid paraffins, or squalene

Figure 1. Multidimensional (2D) scaling of the chemical structures of the dataset reveals high structural diversity. The axes (V1 and V2) represent chemical space in two directions.

Table 2. Lipid formulation classification system.

		Excipients in formulation Content of formulation (%w/w)
	Characteristics	Oils: triglycerides or mixed mono and diglycerides	Water-insoluble surfactants (HLB <12)	Water-soluble surfactants (HLB >12)	Hydrophilic cosolvents (e.g. PEG, proylene glycol, transcutol)
Type I	Pure oils Limited or no dispersion Digestion required	100	—	—	—
Type II	SEDDS Moderate dispersion needed to form an emulsion Likely to require digestion	40–80	20–60	—	—
Type IIIA	SMEDDS Rapid dispersion to form micro- or nano-emulsion May need digestion	40–80	—	20–40	0–40
Type IIIB	SMEDDS Rapid dispersion to form micro- or nano-emulsion Digestion likely not needed	<20	—	20–50	20–50
Type IV	Oil free Rapid dispersion results in micellar solution No digestion needed	—	0–20	30–80	0–50

Figure 2. Quantitative assessment of chemical properties. (A) molecular weight, (B) polar surface area, (C) LogP, (D) logarithm of octanol solubility, and (E) correlation between octanol solubility and LogP.

Figure 3. Integration of different classification systems. (A) applicability of lipid formulation based on compound’s LogP. Markers represent individual LogP and line represents median LogP (B) relationship between BCS and DCS.

Figure 4. DCS plot of FDA approved drugs formulated using LBDDS with LFCS represented by different markers.

Table 3. Food effects and pharmacokinetics of approve drugs.

Molecule/trade name	BCS/DCS	With food	With or without food	Increased	Decreased	No change
Isotretinoin (Accutane^®)	2/IIb	X		Cmax and AUC more than doubled following high fat meal
Ritonavir (Norvir^®)	4/IIb	X		Absorption +13% with a meal
Clofazimine (Lamprene^®)	2	X		Bioavailability +62% with food, higher peak concentration, faster Tmax
Saquinavir (Fortovase^®)	4/IIb	x		12-h AUC after single dose was increased from when given with breakfast
Bexarotene (Targretin^®)	?/IIb	X		AUC +35% and Cmax +48%
Ritonavir/lopinavir (Kaletra^®)		X		Moderate fat meal: AUC +48% and Cmax +23% High fat meal: AUC +97% and Cmax +43%
Lubiprostone (Amitiza^®)	2,4/I	X			Cmax decreased by55%	AUC was unchanged when administered with high fat meal
Fenofibrate (Lipofen^®)	2/IIb	X		AUC +58% and +25% when administered with high fat and low fat meals
Nintedanib (Ofev^®)	2,4/IIb	X		AUC increased by 20% and Tmax delayed
Tipranavir (Aptivus^®)	4/IIb	X	X			No clinically significant changes
Cyclosporin A (Neoral^®)	2/IIb		X		Decreased AUC by 13% and Cmax by 33%
Progesterone (Prometrium^®)	2/IIb		X	Increased bioavailability with food
Amprenavir (Agenerase^®)	2/IIb		X	Not taken with high fat meal	Cmax and AUC decreased and Tmax prolonged
Sirolimus (Rapamune^®)	?/IIa		X	AUC +23–35%		Effect on CMAX was inconsistent
Dutasteride (Avodart^®)	2,4/IIa		X		Cmax decreased by 10–15%
Loratadine (Claritin^®)	2		X			No clinically significant changes
Omega-3-acid ethyl esters (Lovaza^®)			X
Paricalcitol (Zemplar^®)	4/IIa		X			AUC and Cmax were unchanged. Tmax was delayed by 2 h
Topotecan HCl (Hycamtin^®)	1/I		X			AUC similar. Tmax was delayed
Isotretinoin (Absorica^®)	2/IIb		X	AUC and Cmax +50% and +26%, respectively. Tmax was delayed
Enzalutamide (Xtandi^®)	2/IIb		X			Similar AUC when fasting or fed

Table 4. Oral amphotericin formulations in development.

Formulation	Type of DDS	Relative oral bioavailability^a compared to oral Fungizone^®	Preclinical efficacy
Deoxycholate/phytantriol/poloxamer 407 [60]	Nanostructured liquid-crystalline particles (cubosomes)	2.85 (rats, 10mg/kg)	nd
Copaiba oil, phosphatidylcholine, surfactants [77]	Nanoemulsified carrier system	10.5 (rats, 10 mg/kg)	nd
Mono- and diglycerides, Vitamin E-TPGS [78,79]	SEDDS	nd Fabs 6.25%^b	Visceral leishmaniasis (mice): 10 mg/kg bid ×5 d: 99% inhibition liver parasites
Glyceryl monooleate [70,73]	Lipid suspension	2.21 (rats, 50mg/kg)	Aspergillus fumagatus (rats) 50mg/kg ×1 dose: 95% reduction in organ CFUs
Phosphatidylserine, calcium [80]	Cochleate	nd	Aspergillus fumagatus (immunocompromised mice) 40 mg/kg/day: 70% survival on day 14
Glyceryl dilaurate, phosphatidylcholine and polyethylene glycol (15)-hydroxystearate [62]	Solid lipid nanoparticles	Fabs 105%

^a AUC oral formulation/AUC oral Fungizone, at the same dose.

^b Oral bioavailability of 10 mg/kg compared to IV Fungizone 0.8 mg/kg over 48 h.

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