ORAL PHARMACEUTICAL COMPOSITION OF ISOTRETINOIN
Field of the Invention
The present invention provides an oral pharmaceutical composition of isotretinoin
with a reduced food effect. The present invention further relates to a process for preparing
t e oral pharmaceutical composition of the present invention.
Background of the Invention
Isotretinoin is a retinoid (also known as \3-cis retinoic acid). Owing to its low
water solubility, t e oral bioavailability of isotretinoin is low. PCT Publication No. WO
00/25772 discloses that the presently marketed formulation of isotretinoin, i.e. , Accutane®,
contains isotretinoin at a mean particle size of about 100 mih resulting in only 20% oral
bioavailability. Therefore, this application discloses a formulation of isotretinoin having a
reduced particle size, thereby enhancing the oral bioavailability.
U.S. Patent Nos. 7,435,427 and 8,367, 102 cover the marketed formulation of
Absorica®. These patents disclose capsules comprising a semi-solid suspension of
isotretinoin containing at least two lipidic excipients, one having an HLB value equal to or
greater than 10 and the other being an oily vehicle. These patents are based on the use of
the "Lidose technology" to provide a formulation of isotretinoin with enhanced
bioavailability.
The oral bioavailability of a drug is affected by various factors, which include
aqueous solubility, absorption of drug through gastrointestinal tract, first pass effect, or
food effect. The "food effect" as used herein means food-drug interactions which either
decrease or increase the extent of drug absorption. Isotretinoin is known to have a food
effect, i.e. , its absorption is dependent on the presence of the food in the stomach.
Therefore, there is a need to develop a composition of isotretinoin which exhibits a
reduced food effect.
Summary of the Invention
The present invention provides an oral pharmaceutical composition comprising
isotretinoin wherein said composition exhibits a reduced food effect. The present
invention further provides an oral pharmaceutical composition comprising:
a) isotretinoin;
b) one or more surfactants having HLB value of 10 or greater; and
c) one or more co-solvents
wherein said composition is substantially free of oil.
The present composition is in t e form of a dispersion which is further filled into
capsules. The present invention further provides a process for preparing the oral
pharmaceutical composition of the present invention. It also provides a method of treating
acne by administering t e oral pharmaceutical composition of the present invention.
Detailed Description of the Invention
In one aspect, the present invention provides an oral pharmaceutical composition
comprising isotretinoin wherein said composition exhibits a reduced food effect.
In one embodiment of the above aspect, said composition exhibits reduced food
effect in comparison to the marketed Epulis™ capsules as indicated by higher Cmax and
AUC in fasting state.
In another embodiment of the above aspect, said composition exhibits a mean CmaX
under fasting condition which is about 1.9 times higher than the CmaXof Epulis™ capsules.
In another embodiment of the above aspect, said composition exhibits a mean
AUC under fasting condition which is about 1.7 times higher than the AUC of Epulis™
capsules.
In another embodiment of the above aspect, the composition, when administered
orally, has a mean fed/fasted ratio of AUC of about 1.26 and a mean fed/fasted ratio of
Cmax of about 1.10.
In another aspect, the present invention provides an oral pharmaceutical
composition comprising:
a) isotretinoin;
b) one or more surfactants having HLB value of 10 or greater; and
c) one or more co-solvents
wherein said composition is substantially free of oil.
In one embodiment of t e above aspect, said composition comprises isotretinoin in
an amount of about 1mg to 100 mg, 5 mg to 50 mg, 10 mg to 40 mg, 9 mg to 36 mg, or 8
mg to 32 mg.
In another embodiment of the above aspect, said composition comprises
isotretinoin in an amount of about 40 mg.
In another embodiment of the above aspect, said composition comprises
isotretinoin in an amount of about 36 mg.
In another embodiment of the above aspect, said composition comprises
isotretinoin in an amount of about 32 mg.
In another embodiment of the above aspect, said composition comprises
isotretinoin in an amount of about 16 mg.
In one embodiment of t e above aspect, said surfactants include, but are not
limited to, polysorbates prepared from lauric, palmitic, stearic, and oleic acid;
polyoxyethylene monoesters such as polyoxyethylethylene monostearate, polyoxyethylene
monolaurate, and polyoxyethylene monooleate; polyethoxylated castor oils (e.g.,
Cremophor® EL 35); polyethylene glycol glycerides (e.g., Gelucire® 44/14); vitamin E
TPGS; dioctyl sodium sulfosuccinate; sodium lauryl sulfate; poloxamers; and mixtures
thereof.
In another embodiment of the above aspect, the surfactant is present in an amount
of about 1% w/w to about 99% w/w by total weight of the composition; preferably in an
amount of about 10% w/w to about 80% w/w by total weight of the composition; more
preferably in an amount of about 30% w/w to about 80% w/w by total weight of the
composition.
In another embodiment of the above aspect, said co-solvents include, but are not
limited to, propylene glycol, polypropylene glycol, polyethylene glycols, diethyleneglycol
monoethyl ether, glyceryl caprylate, capric/caprylic glyceride, and mixtures thereof.
In another embodiment of the above aspect, the composition further comprises an
antioxidant.
The antioxidant includes, but is not limited to, butylated hydroxy anisole, butylated
hydroxy toluene, tocopherol, ascorbyl palmitate, ascorbic acid, sodium metabisulfite,
sodium sulfite, sodium thiosulfate, propyl gallate, and mixtures thereof.
In one embodiment of the above aspect, t e oral pharmaceutical composition is in
t e form of a dispersion which is further filled into capsules.
In yet another embodiment of the above aspect, the composition comprises
isotretinoin wherein the particle size distribution of isotretinoin is such that D90 is less than
60 m i, less than 55 m i, less than 50 m i, less than 45 m i, less than 40 m i, less than 35
m i, less than 30 m i, less than 25 m i, less than 20 m i, less than 15 m i, or less than 10
m i.
In yet another embodiment of the above aspect, the composition comprises
isotretinoin wherein the particle size distribution of isotretinoin is such that D 0 is less than
30 mth.
In another embodiment of the above aspect, the composition comprises isotretinoin
wherein the particle size distribution of isotretinoin is such that D 0 is less than 40 m i, less
than 35 m i, less than 30 m i, less than 25 m i, less than 20 m i, less than 15 m i, or less
than 10 m i or less than 5 m i.
In yet another embodiment of the above aspect, the composition comprises
isotretinoin wherein the particle size distribution of isotretinoin is such that D 0 is less than
15 m i.
In another embodiment of the above aspect, the composition comprises isotretinoin
wherein the particle size distribution of isotretinoin is such that Di0 is less than 20 m i, less
than 18 m i, less than 17 m i, less than 15 m i, less than 12 m i, less than 10 m i, less than
8 m i, less than 7 m i, less than 5 m i, or less than 2 m i.
In yet another embodiment of the above aspect, the composition comprises
isotretinoin wherein the particle size distribution of isotretinoin is such that Di0 is less than
7 m i.
In yet another embodiment of the above aspect, the oral pharmaceutical
composition comprises isotretinoin wherein the particle size distribution of isotretinoin is
such that D90 is less than 60 m i and D 0 is less than 40 m i.
In yet another embodiment of the above aspect, the oral pharmaceutical
composition comprises isotretinoin wherein the particle size distribution of isotretinoin is
such that D90 is less than 60 m i, D 0 is less than 40 m i, and D i0 is less than 20 m i.
In yet another embodiment, said oral pharmaceutical composition is stable when
stored at 40°C and 75% relative humidity or at 25°C and 60% relative humidity for a
period of at least three months or to the extent necessary for t e use of the composition.
In yet another aspect, there is provided a process for the preparation of an oral
pharmaceutical composition wherein the process comprises:
(a) adding one or more of surfactants in a co-solvent or a mixture of co-solvents;
(b) dispersing isotretinoin into the solution of step (a);
(c) milling the dispersion of step (b) in a milling apparatus; and
(d) filling the milled dispersion of step (d) into a capsule.
In an embodiment of the above aspect, an antioxidant is added in step (a) of the
process.
In still another aspect, the present invention provides a method of treating acne,
musculoskeletal and connective tissue inflammations, emphysema, ulcerating diseases,
cervical tumors in HIV positive women, lung cancer in smokers, skin cancer,
neuroblastoma, recurrent prostate cancer, leukemia, high-grade glioma, head and neck
cancers, multiple myeloma, gram-negative folliculitis, recalcitrant rosacea, pyoderma
faciale, psoriasis, cutaneous lupus erythematosus, acne fulminans, squamous cell
carcinoma, or cutaneous photoaging by administering to the individual in need thereof the
oral pharmaceutical composition of the present invention.
In one embodiment of the above aspect, the present invention provides a method of
treating acne by administering to the individual in need thereof the oral pharmaceutical
composition of the present invention.
The term "isotretinoin" refers to isotretinoin in its crystalline or amorphous form,
its esters, salts, or derivatives thereof.
The term "stable," as used herein, refers to chemical stability, wherein not more
than 1.5% w/w of total related substances are formed on storage at accelerated conditions
of stability at 40°C and 75% relative humidity or at 25°C and 60% relative humidity for a
period of at least three months or to the extent necessary for use of the composition.
The term "AUC" refers to the area under the time/plasma concentration curve after
administration of the pharmaceutical composition. AUCo-Minity denotes the area under the
plasma concentration versus time curve from time 0 to infinity; AUCo-t denotes t e area
under the plasma concentration versus time curve from time 0 to time t .
The term "Cmax" refers to the maximum concentration of isotretinoin in the blood
following administration of the pharmaceutical composition.
The term "tmax" refers to the time in hours when Cmax is achieved following
administration of the pharmaceutical composition.
The term "food effect" as used herein means food-drug interactions which either
decrease or increase the extent of drug absorption. It refers to a relative difference in AUC,
Cmax, and/or tmax of a drug, when said drug or a formulation thereof is administered orally
to a human concomitantly with food or in a fed state as compared to the same values when
the same formulation is administered in a fasted state or without food.
The term "Dio" refers to the particle size of isotretinoin where 10% (w/v) of the
particles have a size less than the defined Di0 value; "D 0" refers to the particle size of
isotretinoin where 50% (w/v) of the particles have a size less than the defined D 0 value;
"D90" refers to the particle size of isotretinoin where 90% (w/v) of the particles have a size
less than the defined D90 value.
"Defined Di0 value/D 0 value/ D90 value" refers to the values defined in the
embodiments.
The term "substantially free of oil" includes the complete absence of oil and the
presence of less than 5% of oil.
The size reduction of isotretinoin is achieved by wet milling the dispersion of
isotretinoin in an oily vehicle or the dispersion of isotretinoin in an aqueous medium using
mechanical means such as a ball mill, and media mills such as a sand mill, DYNO®-mill,
or a bead mill. The grinding media in these mills can comprise spherical particles such as
stainless steel beads or zirconium oxide balls.
The invention may be further illustrated by the following examples, which are for
illustrative purposes only and should not be construed as limiting the scope of the
invention in any way.
EXAMPLES
Example 1
Procedure:
1. Cremophor® EL 35, Tween® 80, and propylene glycol were mixed in a stainless
steel vessel.
2 . Butylated hydroxy toluene and propyl gallate were added to t e mixture of step 1.
3 . Isotretinoin was dispersed under stirring into the mixture of step 2 .
4 . The dispersion of step 3 was milled in a Dyno®-Mill containing zirconium beads to
achieve a particle size of isotretinoin such that D90 was about 22 mih.
5. Vitamin E TPGS was melted at a temperature not exceeding 80°C.
6 . The milled dispersion of step 4 was heated to below 50°C under continuous
stirring.
7 . The melted vitamin E TPGS of step 5 was added under stirring to the heated milled
dispersion of step 6.
8. The dispersion of step 7 was filled into capsules.
Example 2
Ingredients Quantity (%w/w)
Isotretinoin 5.40
Cremophor® EL 35 46.62
Tween® 80 2.70
Butylated hydroxy toluene 0.07
Propyl gallate 0.04
Propylene glycol 19.59
Vitamin E TPGS 7.29
Gelucire® 44/14 18.24
Procedure:
1. Cremophor® EL 35, Tween® 80, and propylene glycol were mixed in a stainless
steel vessel.
2 . Butylated hydroxy toluene and propyl gallate were added to t e mixture of step 1.
3 . Isotretinoin was dispersed under stirring into the mixture of step 2 .
4 . The dispersion of step 3 was milled in a Dyno®-Mill containing zirconium beads to
achieve a particle size of isotretinoin such that D 0 was about 22 mih.
5. Vitamin E TPGS was melted at a temperature not exceeding 80°C.
6 . The milled dispersion of step 4 was heated to below 50°C with continuous stirring.
7 . The melted vitamin E TPGS of step 5 was added under stirring to the heated milled
dispersion of step 6.
8. Gelucire® 44/14 was melted at a temperature not exceeding 80°C and added under
stirring to the dispersion of step 7.
9 . The dispersion of step 8 was filled into capsules.
Dissolution Studies
The pharmaceutical composition of Example 2 (Test; 40 mg of isotretinoin) was
compared with the marketed formulation of isotretinoin (Reference; 40 mg Epulis™
capsules) for t e release profile in the FDA recommended dissolution medium as given
below:
From the above data, it is evident that the test product has a better dissolution
profile in comparison to the reference product.
Pharmacokinetic study under fed condition
The pharmaceutical composition of Example 2 (Test; 40 mg of isotretinoin) was
compared with the marketed formulation of isotretinoin (Reference; 40 mg Epuris™
capsules) under fed conditions on 18 healthy adult male subjects, out of these, 15 subjects
completed all the three periods of the study.
Values for various pharmacokinetic parameters, including observed Cmax, AUCo-t
and AUCo-mf were calculated and are provided in Table 1 below.
Table 1: Comparative pharmacokinetic data for test (T) and reference (R) in 15
healthy adult human male subjects:
· Average tmax values for the Test and Reference were 3.6443 hours and 6.1444
hours, respectively.
• Under fed conditions, the Test prototype showed a comparable behavior to the
Reference product (Epuris™) in terms of both rate and extent of absorption. The
T/R ratios and 90% CIs for all PK parameters are within the acceptable limits of
80% to 125%.
Pharmacokinetic study under fasting condition
The pharmaceutical composition of Example 2 (Test; 40 mg of isotretinoin) was
compared with the marketed formulation of isotretinoin (Reference; 40 mg Epuris™
capsules) under fasting conditions in 18 healthy adult male subjects, out of these 14
subjects completed all the three periods of the study.
Values for various pharmacokinetic parameters, including observed Cmax, AUCo-t
and AUCo-mf were calculated and are provided in Table 2 below:
Table 2 : Comparative pharmacokinetic data for Test (T) vs Reference (R) in 14
healthy adult human male subjects:
C x In AUCo-, In AUCo-i„f
Ratio (T/R) 193.23 179.26 175.24
90% CI 157.56-236.98 156.77-204.98 154.3-199.01
Test has shown 1.9-fold higher Cmax and 1.7-fold higher AUC as compared to
Reference under fasting condition.
The effect of food on the test formulation of Example 2 (40 g capsules) was also
evaluated and results are provided in Table 3 below:
Reference (R): Epuris™ 40 mg capsules.
Test (T): Isotretinoin 40 mg capsules (Example 2).
Table 3 : Relative effect of food (Calculated in number of fold (fed/fasting))
Above data indicates the following:
- For Test prototype the AUC under fed condition is approximately 1.26-fold the
value observed under fasting condition, whereas Cmax under fed condition is approx.
1.1-fold higher as compared to fasting condition.
- For Epuris™, both AUC and CmaX under fed condition are ~ 2-fold higher than under
fasted condition.
Example 3
Procedure:
1. Cremophor® EL 35, Tween® 80, and propylene glycol were mixed in a stainless
steel vessel.
2 . Butylated hydroxy anisole was added to the mixture of step 1.
3 . Isotretinoin was dispersed under stirring into the mixture of step 2 .
4 . The dispersion of step 3 was milled in a Dyno®-Mill containing zirconium beads to
achieve a particle size of isotretinoin such that D 0 was about 22 mih.
Vitamin E TPGS was melted at a temperature not exceeding 80°C.
The milled dispersion of step 4 was heated to below 50°C with continuous stirring.
The melted vitamin E TPGS of step 5 was added under stirring to the heated milled
dispersion of step 6.
Gelucire® 44/14 was melted at a temperature not exceeding 80°C and added under
stirring to the dispersion of step 7.
The dispersion of step 8 was filled into capsules.
Example 4
Procedure:
1. Cremophor® EL 35, Tween® 80, polyethylene glycol, and propylene glycol were
mixed in a stainless steel vessel.
2 . Butylated hydroxy tolune and propyl gallate were added to the mixture of step 1.
3 . Isotretinoin was dispersed under stirring into the mixture of step 2 .
4 . The dispersion of step 3 was milled in a Dyno®-Mill containing zirconium beads to
achieve a particle size of isotretinoin such that D90 was about 22 m i.
5. Vitamin E TPGS was melted at a temperature not exceeding 80°C.
6. The milled dispersion of step 4 was heated to below 50°C with continuous stirring.
7 . The melted vitamin E TPGS of step 5 was added under stirring to the heated milled
dispersion of step 6.
8. Gelucire® 44/14 was melted at a temperature not exceeding 80°C and added under
stirring to the dispersion of step 7.
9 . The dispersion of step 8 was filled into capsules.
Example 5
Procedure
1. Cremophor® EL 35, Tween® 80, polyethylene glycol, Gelucire® 44/14, vitamin E
TPGS, and propylene glycol were mixed in a stainless steel vessel with gentle
heating below 50°C.
2 . Butylated hydroxy tolune and propyl gallate was added to the mixture of step 1.
3 . Isotretinoin was dispersed under stirring into the mixture of step 2 .
4 . The dispersion of step 3 was milled in a Dyno®-Mill containing zirconium beads to
achieve a particle size of isotretinoin such that D90 was about 10 mih.
5 . The dispersion of step 4 was filled into capsules.

We claim:
1. An oral pharmaceutical composition comprising isotretinoin, wherein said
composition exhibits reduced food effect.
2 . The oral pharmaceutical composition according to claim 1, wherein said
composition exhibits reduced food effect in comparison to the marketed Epuris™ capsules
as indicated by higher Cmax and AUC in fasting state.
3. The oral pharmaceutical composition according to claim 1, wherein said
composition exhibits a mean Cmax under fasting condition which is about 1.9 times higher
than the Cmax of Epuris™ capsules under fasting condition.
4 . The oral pharmaceutical composition according to claim 1, wherein said
composition exhibits a mean AUC under fasting condition which is about 1.7 times higher
than the AUC of Epuris™ capsules under fasting condition.
5. The oral pharmaceutical composition according to claim 1, wherein said
composition, when administered orally, has a mean fed/fasted ratio of AUC of about 1.26
and a mean fed/fasted ratio of Cmax of about 1.10.
6. The oral pharmaceutical composition according to claim 1, wherein said
composition comprises:
a) isotretinoin;
b) one or more surfactants having HLB value of 10 or greater; and
c) one or more co-solvents
wherein said composition is substantially free of oil.
7. The oral pharmaceutical composition according to claim 5, wherein said
composition comprises isotretinoin in an amount of about 1mg to 100 mg, 5 mg to 50 mg,
10 mg to 40 mg, 9 mg to 36 mg, or 8 mg to 32 mg.
8. The oral pharmaceutical composition according to claim 7, wherein said
composition comprises isotretinoin in an amount of about 40 mg.
9. The oral pharmaceutical composition according to claim 7, wherein said
composition comprises isotretinoin in an amount of about 36 mg.
10. The oral pharmaceutical composition according to claim 7, wherein said
composition comprises isotretinoin in an amount of about 32 mg.
11. The oral pharmaceutical composition according to claim 7, wherein said
composition comprises isotretinoin in an amount of about 16 mg.
12. The oral pharmaceutical composition according to claim 6, wherein the surfactant
is selected from t e group consisting of polysorbates prepared from lauric, palmitic,
stearic, and oleic acid; polyoxyethylene monoesters; polyethoxylated castor oils;
polyethylene glycol glycerides; vitamin E TPGS; dioctyl sodium sulfosuccinate; sodium
lauryl sulfate; poloxamers; and mixtures thereof.
13 . The oral pharmaceutical composition according to claim 12, wherein the surfactant
is present in an amount of about 1% w/w to about 99% w/w by total weight of the
composition.
14. The oral pharmaceutical composition according to claim 13, wherein the surfactant
is present in an amount of about 30% w/w to about 80% w/w by total weight of the
composition.
15 . The oral pharmaceutical composition according to claim 6, wherein the co-solvent
is selected from the group consisting of propylene glycol, polypropylene glycol,
polyethylene glycols, diethyleneglycol monoethyl ether, glyceryl caprylate, capric/caprylic
glyceride, and mixtures thereof.
16. The oral pharmaceutical composition according to claim 6, wherein said
composition further comprises an antioxidant.
17. The oral pharmaceutical composition according to claim 16, wherein the
antioxidant is selected from the group consisting of butylated hydroxy anisole, butylated
hydroxy toluene, tocopherol, ascorbyl palmitate, ascorbic acid, sodium metabisulfite,
sodium sulfite, sodium thiosulfate, propyl gallate, and mixtures thereof.
18. The oral pharmaceutical composition according to claim 6, wherein said
composition is in the form of a dispersion which is further filled into capsules.
19. The oral pharmaceutical composition according to claim 1, wherein the particle
size distribution of isotretinoin is such that D90 is less than 60 m i, less than 55 m i, less
than 50 m i, less than 45 m i, less than 40 m i, less than 35 m i, less than 30 m i, less than
25 m i, less than 20 m i, less than 15 m i, or less than 10 m i.
20. The oral pharmaceutical composition according to claim 19, wherein the particle
size distribution of isotretinoin is such that D90 is less than 30 m i.
2 1. The oral pharmaceutical composition according to claim 1, wherein the particle
size distribution of isotretinoin is such that D 0 is less than 40 m i, less than 35 m i, less
than 30 m i, less than 25 m i, less than 20 m i, less than 15 m i, less than 10 m i, or less
than 5 m i.
22. The oral pharmaceutical composition according to claim 21, wherein the particle
size distribution of isotretinoin is such that D 0 is less than 15 mih .
23. The oral pharmaceutical composition according to claim 1, wherein the particle
size distribution of isotretinoin is such that D i0 is less than 20 mih, less than 18 mih, less
than 17 mih, less than 15 mih, less than 12 mih, less than 10 mih, less than 8 mih, less than 7
mih, less than 5 mih, or less than 2 mih .
24. The oral pharmaceutical composition according to claim 23, wherein the particle
size distribution of isotretinoin is such that D i0 is less than 7 mih .
25. The oral pharmaceutical composition according to claim 1, wherein the particle
size distribution of isotretinoin is such that D90 is less than 60 mih and D 0 is less than
40mih .
26. The oral pharmaceutical composition according to claim 1, wherein the particle
size distribution of isotretinoin is such that D90 is less than 60 mih, D 0 is less than 40 mih,
and D i0 is less than 20 mih .
27. The oral pharmaceutical composition according to claim 1, wherein said
composition is stable when stored at 40°C and 75% relative humidity or at 25°C and 60%
relative humidity for a period of at least three months.
28. A process for the preparation of an oral pharmaceutical exhibiting reduced food
effect wherein the process comprises:
a) adding one or more of surfactants in a co-solvent or a mixture of cosolvents;
b) dispersing isotretinoin into the solution of step a);
c) milling the dispersion of step b) in a milling apparatus; and
d) filling the milled dispersion of step c) into a capsule.
29. The process according to claim 28, wherein an antioxidant is added in step a) of
the process.
30. The oral pharmaceutical composition according to claim 1, wherein said
composition is used for the treatment of acne, musculoskeletal and connective tissue
inflammations, emphysema, ulcerating diseases, cervical tumors in HIV positive women,
lung cancer in smokers, skin cancer, neuroblastoma, recurrent prostate cancer, leukemia,
high-grade glioma, head and neck cancers, multiple myeloma, gram-negative folliculitis,
recalcitrant rosacea, pyoderma faciale, psoriasis, cutaneous lupus erythematosus, acne
fulminans, squamous cell carcinoma, or cutaneous photoaging.
31. The oral pharmaceutical composition according to claim 30, wherein said
composition is used for the treatment of acne.
32. A method of treating acne, musculoskeletal and connective tissue inflammations,
emphysema, ulcerating diseases, cervical tumors in HIV positive women, lung cancer in
smokers, skin cancer, neuroblastoma, recurrent prostate cancer, leukemia, high-grade
glioma, head and neck cancers, multiple myeloma, gram-negative folliculitis, recalcitrant
rosacea, pyoderma faciale, psoriasis, cutaneous lupus erythematosus, acne fulminans,
squamous cell carcinoma, or cutaneous photoaging, comprising administering a
therapeutically effective amount of t e oral pharmaceutical composition of claim 1.
33. The method according to claim 32, wherein the patient has acne.