ORAL PHARMACEUTICAL COMPOSITION OF ISOTRETINOIN
Field of the Invention
The present invention provides an oral pharmaceutical composition of isotretinoin having
enhanced bioavailability. The present invention further relates to a process for preparing the oral
pharmaceutical composition of the present invention.
Background of the Invention
Isotretinoin is a retinoid (also known as 13-cw retinoic acid). Owing to its low water
solubility, the 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 urn 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 the aqueous
solubility, first pass effect, or food-effect. The low water solubility of isotretinoin affects its oral
bioavailability. Therefore, there is a need to develop an oral pharmaceutical composition of
isotretinoin having enhanced bioavailability. The present inventors have developed an oral
pharmaceutical composition of isotretinoin having enhanced bioavailability in comparison to the
already marketed formulations of isotretinoin, i.e., Roaccutane® and Absorica®/Epuris™. This

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In another embodiment of the above aspect, the pH of the dispersion obtained in step iii or
the solid particles or powder or granules obtained in step iv when dispersed in water ranges from 3
to 11; preferably the pH ranges from 7 to 10.
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, gramnegative
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 "AUC" refers to the area under the time/plasma concentration curve after
administration of the pharmaceutical composition. AUCo-infmity denotes the area under the plasma
concentration versus time curve from time 0 to infinity; AUCo-t denotes the 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.
2 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.
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o The term "Dio" refers to the particle size of isotretinoin where 10% (w/v) of the particles have
a size less than the defined Dio value; "D50" refers to the particle size of isotretinoin where "50% (w/v)
g> of the particles have a size less than the defined D50 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.
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"Defined Dio value/Dso value/ Devalue" refers to the values defined in the embodiments.
Examples of suitable liquid vehicles include, but are not limited to, water, propylene glycol,
dipropylene glycol, polypropylene glycol, ethylene glycol, polyethylene glycol, glycerin, butylene
glycol, hexylene glycol, polyoxyethylene, and mixtures thereof.
Examples of suitable carrier substrates include, but are not limited to, lactose;
microcrystalline cellulose; calcium phosphate; dextrin; dextrose; sucrose; mannitol; maltodextrin;
sodium alumino silicate; clays, including bentonite, kaolin, montmorrillonite, attapulgite, halloysite,
laponite, and the like; silica, including colloidal silica, mesoporous silica, and fumed silica; zeolites;
talc; cholesteramine; polystyrene sulfonates; mono and polysulfonated resins; activated charcoal; and
mixtures thereof.
Examples of suitable surfactants include, but are not limited to, lecithin; sorbitan
monostearate; polysorbates prepared from lauric, palmitic, stearic, and oleic acid; polyoxyethylene
monoesters such as polyoxyethyl ethylene monostearate, polyoxyethylene monolaurate, and
polyoxyethylene monooleate; dioctyl sodium sulfosuccinate; sodium lauryl sulfate; and poloxamers.
Examples of suitable surface stabilizers include, but are not limited to, gelatin, casein, gum
acacia, stearic acid, calcium stearate, glycerol monostearate, sorbitan esters, macrogol ethers such as
cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters
such as Tween®; polyoxyethylene stearates, colloidal silicon dioxide, sodium dodecylsulfate,
carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxyethylcellulose,
hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone (PVP), poloxamers
such as Pluronics® F 68 and F 108, dioctyl sodium sulfosuccinate (DOSS), docusate sodium, sodium
lauryl sulfate, Span® 20 and 80, and macrogolglycerol esters such as Cremophor® EL.
Examples of suitable antioxidants include, but are not limited to, butylated hydroxyl anisole,
I butylated hydroxyl toluene, tocopherol, ascorbyl palmitate, ascorbic acid, sodium metabisulfite,
jj sodium sulfite, sodium thiosulfate, propyl gallate, and mixtures thereof.
ST Examples of suitable alkaline stabilizers include, but are not limited to, sodium hydroxide,
o potassium hydroxide, sodium carbonate or bicarbonate, potassium carbonate or bicarbonate, lithium
S hydroxide, triethylamine, meglumine, methylamine, and mixtures thereof.
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g Examples of suitable preservatives include, but are not limited to, methyl paraben, ethyl
paraben, propyl paraben, butyl paraben, benzoic acid, sodium benzoate, benzyl alcohol, sorbic acid,
g potassium sorbate, and mixtures thereof.
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£ Examples of suitable tablet adjuvants include diluents, binders, disintegrants, lubricants,
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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 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 jet mill, 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 anyway.
EXAMPLES
Example 1
S.No.
1
2
3
4
5
6
Ingredients
Isotretinoin
Hydroxypropylmethyl cellulose
Sodium hydroxide
Water
Sodium alumino silicate
Butylated hydroxy anisole
Quantity (% w/w)
9.64
4.82
1.45
59.75
24.10
0.24
Procedure:
1. Sodium hydroxide was dissolved in water.
2. Hydroxypropylmethyl cellulose was dissolved in the solution of step 1.
3. Butylated hydroxy anisole was dissolved in the solution of step 2.
4. Isotretinoin was dissolved in the solution of step 3 to form a gel.
5. The gel of step 4 was adsorbed onto sodium alumino silicate to form solid particles,
6. The solid particles of step 5 were filled into capsules.
Example 2
S.No.
1
2
3
4
5
6
Ingredients
Isotretinoin
Hydroxypropylmethyl cellulose
Sodium hydroxide
Propylene glycol
Sodium alumino silicate
Butylated hydroxy anisole
Quantity (% w/w)
9.64
4.82
1.45
59.75
24.10
0.24
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Procedure:
1. Sodium hydroxide was dissolved in propylene glycol.
2. Hydroxypropylmethyl cellulose was dissolved in the solution of step 1.
3. Butylated hydroxy anisole was dissolved in the solution of step 2.
4. Isotretinoin was dispersed into the solution of step 3 to form a dispersion.
5. The dispersion of step 4 was adsorbed onto sodium alumino silicate to form solid particles.
6. The solid particles of step 5 were filled into capsules.
Example 3
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S.No.
1
2
3
4
5
6
Ingredients
Isotretinoin
Hydroxypropylmethyl cellulose
Sodium hydroxide
Polyethylene glycol
Sodium alumino silicate
Butylated hydroxy anisole
Quantity (% w/w)
9.64
4.82
1.45
59.75
24.10
0.24
Procedure:
1. Sodium hydroxide was dissolved in polyethylene glycol.
2. Hydroxypropylmethyl cellulose was dissolved in the solution of step 1.
3. Butylated hydroxy anisole was dissolved in the solution of step 2.
4. Isotretinoin was dispersed into the solution of step 3 to form a dispersion.
5. The dispersion of step 4 was adsorbed onto sodium alumino silicate to form solid particles.
6. The solid particles of step 5 were filled into capsules.
Example 4
S.No.
1
2
3
4
5
6
Ingredients
Isotretinoin
Hydroxypropylmethyl cellulose
Sodium hydroxide
Glycerin
Sodium alumino silicate
Butylated hydroxy anisole
Quantity (% w/w)
9.64
4.82
.1.45
59.75
24.10
0.24
Procedure:
1. Sodium hydroxide was dissolved in glycerin.
2. Hydroxypropylmethyl cellulose was dissolved in the solution of step 1.
3. Butylated hydroxy anisole was dissolved in the solution of step 2.
EOHIIE
5. The dispersion of step 4 was adsorbed onto sodium alumino silicate to form solid particles.
6. The solid particles of step 5 were filled into capsules.
Example 5
S.No.
1
2
3
4
5
6
7
Ingredients
Isotretinoin
Hydroxypropylmethyl cellulose
Sodium hydroxide
Water
Glycerin
Sodium alumino silicate
Butylated hydroxy anisole
Quantity (% w/w)
9.64
4.82
1.45
11.56
48.19
24.10
0.24
Procedure
1. Sodium hydroxide was dissolved in a mixture of water and glycerin.
2. Hydroxypropylmethyl cellulose was dissolved in the solution of step 1.
3. Butylated hydroxy anisole was dissolved in the solution of step 2.
4. Isotretinoin was dispersed into the solution of step 3 to form a gel.
5. The gel of step 4 was adsorbed onto sodium alumino silicate to form solid particles.
6. The solid particles of step 5 were filled into capsules.
Example 6
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S.No.
1
2
3
4
5
6
7
Ingredients
Isotretinoin
Hydroxypropylmethyl cellulose
Sodium hydroxide
Butylated hydroxy anisole
Water
Lactose
Cremophor® EL
Quantity (% w/w)
9.97
5.01
1.50
0.12
q.s.
78.39
5.01
Procedure:
1.
2.
3.
4.
5.
6.
Sodium hydroxide was dissolved in water.
Hydroxypropylmethyl cellulose was dissolved in the solution of step 1.
Butylated hydroxy anisole was dissolved in solution of step 2. ,
Isotretinoin was dissolved in the solution of step 3.
Cremophor® EL was added to the solution of step 4.
The solution of step 5 was adsorbed onto lactose to form solid particles.
Example 7
S.No.
1
2
3
4
5
6
7
Ingredients
Isotretinoin
Meglumine
Water
Hydroxypropyl methylcellulose
Lactose
Cremophor® EL
Butylated hydroxyl anisole
Quantity (% w/w)
20.15
4.03
q.s.
5.04
25.19
45.34
0.25 ,
Procedure:
1. Hydroxypropyl methylcellulose was dissolved in water.
2. Butylated hydroxyl anisole and meglumine were dissolved in the solution of step 1.
3. Isotretinoin was suspended in the solution of step 2.
4. The drug suspension of step 3 was milled in a Dyno®-Mill containing zirconium beads to
achieve a particle size of isotretinoin such that D90 was about 2 jam.
5. Cremophor® EL was added at the end of the milling process.
6. The dispersion of step 5 was adsorbed onto lactose in a fluid bed processor and dried.
7. The dried powder of step 6 was filled into size 00 capsules.
Example 8
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S.No.
1
2
3
4
5
6
7
8
9
Ingredients
Isotretinoin
Meglumine
Water
Hydroxypropyl methylcellulose
Lactose
Mannitol
Cremophor® EL
Butylated hydroxyl toluene
Propyl gallate
Quantity (% w/w)
8.47
1.06
q.s.
4.26
40.25
40.68
5.08
0.12
0.08
Procedure:
1.
2.
3.
4.
Hydroxypropyl methylcellulose was dissolved in water.
Butylated hydroxyl toluene, propyl gallate, and meglumine were dissolved in the solution of
step 1.
Isotretinoin was suspended in the solution of step 2.
The drug suspension of step 3 was milled in a Dyno®-mill containing zirconium beads to
achieve a particle size of isotretinoin such that D90 was about 2 fim.
12
6. The dispersion of step 5 was adsorbed onto a lactose and mannitol mixture in a fluid bed
processor and dried.
7. The dried powder of step 6 was filled into size 00 capsules.
Dissolution Studies
I) The pharmaceutical composition of Example 8 (Test; 40 mg of isotretinoin) was compared
with the marketed formulation of isotretinoin (Reference; 40 mg Epuris™ capsules) for the release
profile in the FDA recommended dissolution medium as given below:
Dissolution Media
Apparatus/RPM/Vol
0.05M buffer pH 7.8 with 0.5% w/v N,N-dimethyl
dodecylamine N-oxide
USP Type I (20 mesh basket)/100/900 mL
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Sample
Test
Reference
% of Drug Released Over Time (minutes)
15
94
1
30
99
9
45
99
24
60
100
49
90
100
89
120
100
100
180
100
100
From the above data, it is evident that the test product has a better dissolution profile in
comparison to the reference product.
II) The pharmaceutical composition of Example 8 (Test; 32 mg of isotretinoin) was compared
with the marketed formulation of isotretinoin (Reference; 40 mg Absorica® capsules) for the
release profile in the FDA recommended dissolution medium as given below:
Dissolution Media
Apparatus/RPM/Vol
0.05M buffer pH 7.8 with 0.5% w/v N,N-dimethyl
dodecylamine N-oxide
USP Type I (20 mesh basket)/100/900 mL
Sample
Test
Reference
15
95
0
% of Drug Released Over Time
30
95
2
45
96
9
60
96
18
(minutes)
90
96
54
120
96
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From the above data, it is evident that the test product has a better dissolution profile in
comparison to the reference product at a lower dose, wherein the dose is at least 20% lower.
Pharmacokinetic study under fed condition
The pharmaceutical composition of Example 8 (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 three periods of
the study.
Values for various pharmacokinetic parameters, including observed Cmax, AUCo-t, and AUCoinf
were calculated and are provided in Table 1 below.
Table 1: Comparative Pharmacokinetic Data for Test and Reference in 15 Healthy Adult
Human Male Subjects:
Parameter
Ratio (T7R)
90% CI
In l^max
125.41
112.76-139.47
In AUCo-t
116.55
111.51-121.83
In AUCo-inf
116.48
111.72-121.46
• Average Tmax values for the test and reference were 2.6778 hours and 6.1444 hours,
respectively.
• Under fed conditions, the Test prototype showed 1.25-fold higher Cmax and 1.16-fold higher
' AUC as compared to the reference. However, we do observe that for AUC, T/R ratio and
90% CI are within acceptable limits of 80% to 125%.
Pharmacokinetic study under fasting condition
The pharmaceutical composition of Example 8 (Test; 40 mg of isotretinoin) was compared
o) with the marketed formulation of isotretinoin (Reference; 40 mg Epuris™ capsules) under fasting
o conditions on 18 healthy adult male subjects, out of these 14 subjects completed all three periods of
t* the study.
£
£ Values for various pharmacokinetic parameters, including observed Cmax, AUCo-t, and AUCooo
inf were calculated and are provided in Table 2 below.
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Table 2: Comparative Pharmacokinetic Data for Test and Reference in 14 Healthy Adult
Human Male Subjects:
Ratio (T/R)
90% CI
In Lmax
340.10
275.29-420.15
In AUCo-,
250.36
217.9-287.66
In AUCo-inf
243.25
213.22-277.5
Test prototype under fasting condition showed 3.4-fold higher Cmax and 2.5-fold higher AUC
as compared to Reference.
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The effect of food on the test formulation of Example 8 (40 mg capsules) was also evaluated
and results are given in Table 3.
Reference (R): Epuris™40 mg capsules.
Test (T): Isotretinoin 40 mg capsules (Example 8).
Table 3: Relative effect of food (Calculated in number of fold (Fed/Fasting) on Isotretinoin
capsule 40 mg)
Formulation
Test
Reference
v^max
0.71
1.95
AUCot
0.99
2.12
The above data indicates that:
- The extent of absorption for the Test prototype under fasting and fed conditions are
comparable (0.99) to each other, whereas Cmax under fed conditions is lower than in fasting
condition (approx. 0.7-fold).
- For Epuris™, both AUG and Cmax under fed condition are ~ 2-fold higher than under fasted
condition.
Study to evaluate if a dose reduction of example 8 test formulation can be achieved, and
would that formulation still be bioequivalent to Epuris™ under fasted and fed conditions.
Test (T): Isotretinoin 36 mg capsules (Example 8).
Reference (R): Epuris™ 40 mg capsules.
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Simulated T/R ratios for Test under fasting and fed conditions versus Epuris™ under fed
condition.
Parameter
v^max
AUCo-t
Simulated T/R ratios
Test - Fasting/Reference - Fed
160.44
105.84
Test - Fed/Reference - Fed
114.35
104.82
The above evaluation indicates the following:
• The Test prototype (dose corrected to 36 mg under fasting condition) is expected to provide
approx. 1.6-fold higher Cmax as compared to Epuris™ fed whereas AUC is comparable to
Epuris™ fed.
Conclusion:
• The Test prototype under fasting and fed conditions has a higher or enhanced bioavailability
in comparison to the Reference product when dosed under fed condition.
Example 9
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S.No.
1
2
3
4
5
6
7
8
Ingredients
Isotretinoin
Hydroxypropyl methylcellulose
Butylated hydroxyl toluene
Propyl gallate
Water
Lactose
Mannitol
Kolliphor® EL
Quantity (%w/w)
8.47
4.26
0.14
0.095
q.s.
41.27
40.69
5.08
Procedure:
1. Hydroxypropyl methylcellulose was dissolved in water.
2. Butylated hydroxyl toluene and propyl gallate were dissolved in the solution of step 1.
3. Isotretinoin was suspended in the solution of step 2.
4. The drug suspension of step 3 was milled in a Dyno®-Mill containing zirconium beads to
achieve a particle size of isotretinoin such that D90 was about 2 jim.
5. Kolliphor® EL was added at the end of the milling process.
6. The dispersion of step 5 was adsorbed onto a lactose and mannitol mixture in a fluid bed
processor and dried.
7. The dried powder of step 6 was filled into capsules.
WE CLAIM:
1. An oral pharmaceutical composition of isotretinoin having-enhanced bioavailability,
wherein said composition exhibits improved pharmacokinetic profile as compared to
Epuris™ capsules under fed as well as fasting conditions.
2. The oral composition according to claim 1, wherein said composition exhibits a mean Cmax
and AUC under fed condition which is about 1.25 and about 1.16 times higher than the
mean Cmax and AUC of Epuris™ capsules under fed condition, respectively.
3. The oral composition according to claim 1, wherein said composition exhibits a mean Omax
and AUC under fasting condition which is about 3.4 and about 2.5 times higher than the
mean Cmax and AUC of Epuris™ capsules under fasting condition, respectively.
4. The oral composition according to claim 1, wherein said composition releases more than
50% of isotretinoin in 15 minutes in a media with a pH of 7.4 to 10.5.
5. The oral composition according to claim 1, wherein said enhancement in the bioavailability
is directly correlated to a reduction in dose in order to have a bioequivalent product.
6. The oral composition according to claim 5, wherein the dose is reduced by at least 10% in
comparison to the marketed Epuris™ capsules.
7. The oral composition according to claim 5, wherein the dose is reduced by at least 20% in
comparison to the marketed Epuris™ capsules.
8. The oral composition according to claim 1, wherein said composition comprises isotretinoin
and a pharmaceutical^ acceptable excipient
9. The oral composition according to claim 1, wherein isotretinoin is dissolved or dispersed in
a liquid vehicle selected from water, a water-miscible solvent, and mixtures thereof.
10. The oral composition according to claim 1, wherein said composition comprises isotretinoin
and a carrier substrate.
11. The oral composition according to claim 10, wherein the carrier substrate is present in an
amount of about 1% w/w to about 90% w/w by total weight of the composition.
12. The oral composition according to claim 10, wherein the carrier substrate is present in an
amount of about 20% w/w to about 85% w/w by total weight of the composition.
13. The oral composition according to claim 10, wherein said composition further comprises a
surfactant, a surface stabilizer, an antioxidant, or an alkaline stabilizer.
14. The oral composition according to claim 13, wherein said composition comprises isotretinoin,
meglumine, a surface stabilizer, a surfactant, and a carrier substrate.
15. The oral composition according to claim 1, wherein said composition is in the form of a gel,
a dispersion, a solution, a suspension, or an emulsion.
16. The oral composition according to claim 15, wherein said gel, dispersion, solution,
suspension, or emulsion is filled into capsules.
17. The oral composition according to claim 15, wherein said gel, dispersion, solution,
suspension or emulsion is absorbed or loaded onto a carrier substrate to form solid particles,
powder, or granules.
18. The oral composition according to claim 17, wherein said solid particles, powder, or granules
are filled into capsules.
19. The oral composition according to claim 17, wherein said solid particles, powder, or granules
are processed with tablet adjuvants and compressed into tablets.
20. The oral composition according to claim 1, wherein said composition comprises isotretinoin
in an amount of about 1 mg to 100 mg, 5 mg to 50 mg, 10 mg to 40 mg, 9 m-g to 36 mg, or 8
mg to 32 mg.
21. The oral composition according to claim 20, wherein said composition comprises isotretinoin
in an amount of about 40 mg.
22. The oral composition according to claim 20, wherein said composition comprises isotretinoin
in an amount of about 32 mg.
23. The oral composition according to claim 20, wherein said composition comprises isotretinoin
in an amount of about 16 mg.
24. The oral composition according to claim 1, wherein the particle size distribution of
isotretinoin is such that D90 is less than 60 jam, less than 55 jam, less than 50 jim, less than 45
jam, less than 40 fim, less than 35 fim, less than 30 jam, less than 25 jam, less than 20 p,m, less
than 15 jam, or less than 10 jam.
25. The oral composition according to claim 24, wherein the particle size distribution of
isotretinoin is such that D90 is less than 10 jam.
26. The oral composition according to claim 1, wherein the particle size distribution of
isotretinoin is such that D50 is less than 40 jam, less than 35 jam, less than 30 jam, less than 25
jam, less than 20 jam, less than 15 ^im, less than 10 jam, or less than 5 jam.
27. The oral composition according to claim 26, wherein the particle size distribution of
isotretinoin is such that D50 is less than 5 jam.
28. The oral composition according to claim • 1, wherein the particle size distribution of
isotretinoin is such that D10 is less than 20 jam, less than 18 jam, less than 17 jam, less than 15
jam, less than 12 jim, less than 10 fim, less than 8 jim, less than 7 jam, less than 5 jam, or less
than 2 jam.
29. The oral composition according to claim 28, wherein the particle size distribution of
isotretinoin is such that Dio is less than 2 |im.
30. The oral composition according to claim 1, wherein the particle size distribution of
isotretinoin is such that D90 is less than 60 jam and D50 is less than 40 jam.
31. The oral composition according to claim 1, wherein the particle size distribution of
isotretinoin is such that D90 is less than 60 jam, D50 is less than 40-jim, and Dio is less than 20
Jim.
32. The oral 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.
33. An oral pharmaceutical composition of isotretinoin having enhanced bioavailability, prepared
using a process that comprises wet or dry granulation; using fluidized bed granulator or high
shear mixer granulator; direct compression; extrusion-spheronization; melt
granulation/extrusion; spray-drying; spray-congealing; and freeze-drying.
34. An oral pharmaceutical composition of isotretinoin having enhanced bioavailability, wherein
the 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, wherein said
composition is prepared using a process that comprises the following steps:
(a) dissolving/dispersing an antioxidant in water, a water-miscible solvent, or a
combination thereof;
(b) adding one or more excipients selected from a surfactant, a surface-stabilizer, and an
alkaline stabilizer to the solution or dispersion of step (a) to form a gel, a dispersion, a
solution, a suspension, or an emulsion;
(c) dissolving/dispersing isotretinoin into the gel, dispersion, solution, suspension, or
emulsion of step (b);
(d) optionally milling the gel, dispersion, solution, suspension, or emulsion of step (c);
(e) adsorbing/loading the gel, dispersion, solution, suspension, or emulsion of step (d)
onto a carrier substrate to obtain solid particles, powder, or granules; and
(f) filling the solid particles, powder, or granules of step (e) into capsules or processing
the solid particles, powder, or granules of step (e) with tablet adjuvants and compressing into
tablets.
35. A process for preparing an oral pharmaceutical composition of isotretinoin having enhanced
bioavailability comprising:
(a) isotretinoin;
(b) meglumine;
(c) a surfactant;
(d) a surface stabilizer; and
(e) a carrier substrate;
wherein the process comprises:
i. dissolving/dispersing meglumine, a surfactant, and a surface stabilizer in water;
ii. dispersing isotretinoin into the solution of step i;
iii. milling the dispersion of step ii in a milling apparatus;
iv. adsorbing the milled dispersion of step iii onto a carrier substrate to obtain solid
particles, powder, or granules; and
v. filling the solid particles, powder, or granules of step iv into capsules or processing
the solid particles, powder, or granules of step iv with tablet adjuvants and compressing into
tablets.
36. The process according to claim 35, wherein in step i, an antioxidant is added.
37. The process according to claim 35, wherein the pH of the dispersion obtained in step iii, or
the solid particles, powder, or granules obtained in step iv, when dispersed in water, ranges
from 3 to 11.
38. The process according to claim 35, wherein the pH of the dispersion obtained in step iii, or
the solid particles, powder, or granules obtained in step iv, when dispersed in water, ranges
from 7 to 10.
39. 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, and
cutaneous photoaging.
40. The oral pharmaceutical composition according to claim 39, wherein said composition is used
for the treatment of acne.
41. A method of treating acne comprising administering a therapeutically effective amount of
an oral pharmaceutical composition according to claim i to a patient in need thereof.