FORMULATION OF A SELF-EMULSIFYING DRUG ......FORMULATION OF A SELF-EMULSIFYING DRUG DELIVERY SYSTEM...
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FORMULATION OF A SELF-EMULSIFYING DRUG DELIVERY SYSTEM OF FENOFIBRATE Courtney McCorkle and Bradley Clark, High Point University Fred Wilson School of Pharmacy High Point University, High Point NC IntroducLon Present-day therapeuLcs are oNen characterized by very poor aqueous solubility which is the driving force for drug absorpLon from the gut. Research is currently being conducted to develop methods to increase the absorpLon of these poorly soluble drugs, including the use of lipid formulaLons and self-emulsifying drug delivery systems (SEDDS). Self-emulsifying formulaLons have the potenLal to improve drug absorpLon by forming droplets with high surface area from which solubilized drug can be released. Fenofibrate is a drug used to treat dyslipidemia. It has very low aqueous solubility which limits its oral bioavailability. It was chosen as a model drug from a number of potenLal compounds based on the improved absorpLon projected with increased solubility using absorpLon simulaLon soNware GastroPlus™ (SimulaLonsPlus, Lancaster, CA, See Figure 1). By creaLng a SEDDS formulaLon of fenofibrate, it is hoped that enhanced release from the dosage form can be achieved, thereby increasing rate and/or extent of drug absorpLon. Methods Various lipids, surfactants, co-solvents, and co-surfactants were screened for their ability to solubilize fenofibrate in a drug-sparing semiqualitaLve solubility procedure. COMPOUND-SPARING SOLUBILITY TESTING FLOW CHART The miscibility of these solvents was also tested by adding 5-10 drops of each into water and visually analyzing the result. Based on the results of the solubility and miscibility tesLng, emulsion technology theory (HLB), and ease of emulsion formaLon, formulaLons where chosen. These formulaLons were then analyzed for emulsion droplet size, drug release in aqueous dissoluLon media, and drug stability. The ability of a formulaLon to form an emulsion with li^le or no agitaLon was assessed by placing 0.5 mL of the respecLve formulaLon into 5 mL of DI water in a test tube and modestly agitaLng. This method was also used to prepare droplets for photomicrography. Images of emulsion droplets were captured using an EVOS FL cell imaging microscope and camera (Thermofisher ScienLfic) at 40X magnificaLon and analyzed using ImageJ image analysis soNware. Results QualitaLve solubility results are presented in Figure 2, showing the poor aqueous solubility of fenofibrate. This was confirmed with UV spectrophotometry, which gave an esLmate of 0.1 µg/mL. This is in agreement with literature 1 . Oils and solvents having a more lipophilic or amphiphilic solubilizaLon profile showed superior solvent capacity. Miscibility determinaLons among formulaLon components showed that Brij 30, Polysorbate 80, PEG 400, TriaceLn, and PEG-40-Castor Oil were all miscible with water, methanol, and acetonitrile. Corn oil, however, was miscible with none of these solvents. Conclusions Fenofibrate was successfully formulated as self 1. -emulsifying drug delivery systems that can potenLally be used in in-vivo evaluaLons of enhanced bioavailability. IniLal drug loading of the 3 SEDDs formulaLons developed was low 2. (3%) and needs to conLnue to be evaluated to achieve higher possible doses (e.g. ≥10%). All three formulaLons resulted in oil 3. -in-water emulsions that had average droplet diameters of greater than 1 μm, and addiLonal formulaLon work with alternaLve solvents and surfactants will need to be pursued to achieve emulsion droplet sizes in the 100s of nm or lower. Fenofibrate 4. release from SEDDs into a water dissoluLon medium was very poor, and needed to be enhanced with the use of a surfactant (SLS). Based on solubility and miscibility results, the following three formulaLons were developed based on each component’s hydrophile- lipophile balance (HLB) and concentraLons 2 : FormaLon of emulsions with each of the three SEDDs formulaLons required li^le or no agitaLon. Droplet sizes for each of the formulaLons ranged from approximately 1 to 50 micron and were similar with all three lipid formulaLons. Differences in the impact of lipid formulaLon: water raLo in the range of 1:1 to 1:15 were evaluated and shown to have li^le impact on emulsion droplet size. DissoluLon profiles of size 0 hard gelaLn capsules filled with 0.5 g were generated, and an example can be seen in Figure 5. The extent of dissoluLon was much be^er in 0.5% SLS as was expected because of fenofibrate’s poor aqueous solubility. It appears that the 0.5% SLS dissoluLon medium solubilized a significant porLon of the capsule contents in addiLon to drug, as when the dissoluLon cooled from 37⁰C to room temperature a noLceable precipitate formed in the dissoluLon vials, necessitaLng the sample chamber of the HPLC autosampler and the column to be adjusted to 37⁰C. Fig 1 GastroPlus graph showing predicted percent absorbed vs ranges of solubility, permeability, dose, and parLcle size Fig 2 SemiquanLtaLve solubility of fenofibrate in mulLple solvents using a compound-sparing procedure Fig 3 Light micrograph of emulsion droplets (FormulaLon C); the reference line corresponds to 100 µm Fig 4 Chromatogram of Fenofibrate soluLon (5 µ/mL); chromatographic condiLons were 80:20 ACN/H 2 O @ 1 mL/min with a C-18 column, λ = 286 nm detecLon Fenofibrate (mw 360.8) References Jamzad 1. and Fassihi, AAPS PharmSciTech, 2006; 7(2) ArLcle 33 “The HLB SYSTEM a Lme 2. -saving guide to emulsifier selecLon”, published by ICI Americas Inc., 1976. 1 10 100 1000 Water Ethanol Propylene Glycol PEG 40 Castor Oil Olive Oil Sesame Oil Corn Oil Polysorbate 80 Captex 355 Tween 20 Carbowax PEG… Brij 30 Triacetin Capmul PG-8 mg/mL Fenofibrate SemiquanLtaLve Solubility Solubility less than Solubility greater than Fig 5 DissoluLon of fenofibrate formulaLon A in water (blue curve) and 0.5% SLS (orange curve); temperature = 37⁰C, paddle speed = 75 rpm, assay by HPLC, N= 2 0 10 20 30 40 50 60 0 5 10 15 20 25 30 35 40 45 50 % of label released Lme, min Fenofibrate 15 mg SEDDS Capsule DissoluLon 10 mg Fenofibrate Tumble 30 min 10 mL solvent Clear SoluLon? Saturated Suspension? “Solubility less than” “Solubility greater than” add addiLonal drug than” Drug release was evaluated using a Vankel DissoluLon Apparatus in a USP Type II (paddle) configuraLon. A 500 mg hard gelaLn capsule of fenofibrate lipid formulaLon (3% w/w, represenLng 15 mg of drug) was placed into the dissoluLon bath and allowed to emulsify. Each vessel was sampled at 10, 20, 30, and 45 minutes using an isocraLc HPLC method. UV spectrophotometry was used to esLmate the solubility of fenofibrate in water at 25°C.
Transcript of FORMULATION OF A SELF-EMULSIFYING DRUG ......FORMULATION OF A SELF-EMULSIFYING DRUG DELIVERY SYSTEM...
FORMULATION OF A SELF-EMULSIFYING DRUG DELIVERY SYSTEM OF FENOFIBRATECourtney McCorkle and Bradley Clark, High Point University Fred Wilson School of Pharmacy
High Point University, High Point NC
IntroducLon Present-day therapeuLcs are oNen characterized by very poor aqueous solubility which
is the driving force for drug absorpLon from the gut. Research is currently being
conducted to develop methods to increase the absorpLon of these poorly soluble
drugs, including the use of lipid formulaLons and self-emulsifying drug delivery systems
(SEDDS). Self-emulsifying formulaLons have the potenLal to improve drug absorpLon
by forming droplets with high surface area from which solubilized drug can be
released.
Fenofibrate is a drug used to treat dyslipidemia. It has very low aqueous solubility
which limits its oral bioavailability. It was chosen as a model drug from a number of
potenLal compounds based on the improved absorpLon projected with increased
solubility using absorpLon simulaLon soNware GastroPlus™ (SimulaLonsPlus,
Lancaster, CA, See Figure 1). By creaLng a SEDDS formulaLon of fenofibrate, it is hoped
that enhanced release from the dosage form can be achieved, thereby increasing rate
and/or extent of drug absorpLon.
Methods Various lipids, surfactants, co-solvents, and co-surfactants were screened for their
ability to solubilize fenofibrate in a drug-sparing semiqualitaLve solubility procedure.
COMPOUND-SPARING SOLUBILITY TESTING FLOW CHART
The miscibility of these solvents was also tested by adding 5-10 drops of each into
water and visually analyzing the result.
Based on the results of the solubility and miscibility tesLng, emulsion technology
theory (HLB), and ease of emulsion formaLon, formulaLons where chosen. These
formulaLons were then analyzed for emulsion droplet size, drug release in aqueous
dissoluLon media, and drug stability.
The ability of a formulaLon to form an emulsion with li^le or no agitaLon was
assessed by placing 0.5 mL of the respecLve formulaLon into 5 mL of DI water in a
test tube and modestly agitaLng. This method was also used to prepare droplets for
photomicrography.
Images of emulsion droplets were captured using an EVOS FL cell imaging microscope
and camera (Thermofisher ScienLfic) at 40X magnificaLon and analyzed using ImageJ
image analysis soNware.
ResultsQualitaLve solubility results are presented in Figure 2, showing the poor aqueous solubility of
fenofibrate. This was confirmed with UV spectrophotometry, which gave an esLmate of 0.1
µg/mL. This is in agreement with literature1. Oils and solvents having a more lipophilic or
amphiphilic solubilizaLon profile showed superior solvent capacity.
Miscibility determinaLons among formulaLon components showed that Brij 30, Polysorbate 80,
PEG 400, TriaceLn, and PEG-40-Castor Oil were all miscible with water, methanol, and acetonitrile.
Corn oil, however, was miscible with none of these solvents.
ConclusionsFenofibrate was successfully formulated as self1. -emulsifying drug
delivery systems that can potenLally be used in in-vivo evaluaLons of
enhanced bioavailability.
IniLal drug loading of the 3 SEDDs formulaLons developed was low 2.
(3%) and needs to conLnue to be evaluated to achieve higher possible
doses (e.g. ≥10%).
All three formulaLons resulted in oil3. -in-water emulsions that had
average droplet diameters of greater than 1 μm, and addiLonal
formulaLon work with alternaLve solvents and surfactants will need to
be pursued to achieve emulsion droplet sizes in the 100s of nm or
lower.
Fenofibrate4. release from SEDDs into a water dissoluLon medium was
very poor, and needed to be enhanced with the use of a surfactant
(SLS).
Based on solubility and miscibility results, the following three
formulaLons were developed based on each component’s hydrophile-
lipophile balance (HLB) and concentraLons2:
FormaLon of emulsions with each of the three SEDDs formulaLons
required li^le or no agitaLon. Droplet sizes for each of the
formulaLons ranged from approximately 1 to 50 micron and were
similar with all three lipid formulaLons.
Differences in the impact of lipid formulaLon: water raLo in the range
of 1:1 to 1:15 were evaluated and shown to have li^le impact on
emulsion droplet size.
DissoluLon profiles of size 0 hard gelaLn capsules filled with 0.5 g were
generated, and an example can be seen in Figure 5. The extent of
dissoluLon was much be^er in 0.5% SLS as was expected because of
fenofibrate’s poor aqueous solubility.
It appears that the 0.5% SLS dissoluLon medium solubilized a significant
porLon of the capsule contents in addiLon to drug, as when the
dissoluLon cooled from 37⁰C to room temperature a noLceable
precipitate formed in the dissoluLon vials, necessitaLng the sample
chamber of the HPLC autosampler and the column to be adjusted to
37⁰C.
Fig 1 GastroPlus graph showing predicted percent absorbed vs
ranges of solubility, permeability, dose, and parLcle size
Fig 2 SemiquanLtaLve solubility of fenofibrate in mulLple
solvents using a compound-sparing procedure
Fig 3 Light micrograph of emulsion droplets (FormulaLon C);
the reference line corresponds to 100 µm
Fig 4 Chromatogram of Fenofibrate soluLon (5 µ/mL);
chromatographic condiLons were 80:20 ACN/H2O @ 1 mL/min
with a C-18 column, λ = 286 nm detecLon
Fenofibrate (mw 360.8)
ReferencesJamzad1. and Fassihi, AAPS PharmSciTech, 2006; 7(2) ArLcle 33
“The HLB SYSTEM a Lme2. -saving guide to emulsifier selecLon”, published
by ICI Americas Inc., 1976.
1
10
100
1000
Wat
er
Ethan
ol
Propyl
ene G
lycol
PEG 40 C
asto
r Oil
Olive O
il
Sesa
me O
il
Corn O
il
Polyso
rbat
e 80
Capte
x 355
Tween
20
Carbow
ax P
EG…
Brij 3
0
Tria
cetin
Capm
ul PG-8
mg
/mL
Fenofibrate SemiquanLtaLve Solubility
Solubility less than
Solubility greater than
Fig 5 DissoluLon of fenofibrate formulaLon A in water (blue
curve) and 0.5% SLS (orange curve); temperature = 37⁰C,
paddle speed = 75 rpm, assay by HPLC, N= 2
0
10
20
30
40
50
60
0 5 10 15 20 25 30 35 40 45 50
% o
f la
be
l re
lea
sed
Lme, min
Fenofibrate 15 mg SEDDS Capsule DissoluLon
10 mg
Fenofibrate
Tumble
30 min10 mL
solvent
Clear SoluLon?
Saturated Suspension? “Solubility less than”
“Solubility
greater than”
add addiLonal drug
than”
Drug release was evaluated using a Vankel DissoluLon Apparatus in a USP Type II (paddle) configuraLon. A 500
mg hard gelaLn capsule of fenofibrate lipid formulaLon (3% w/w, represenLng 15 mg of drug) was placed into
the dissoluLon bath and allowed to emulsify. Each vessel was sampled at 10, 20, 30, and 45 minutes using an
isocraLc HPLC method.
UV spectrophotometry was used to esLmate the solubility of fenofibrate in water at 25°C.
