LOW DOSE ORAL PHARMACEUTICAL COMPOSITION OF ISOTRETINOIN
Field of the Invention
The present invention provides a low dose oral pharmaceutical composition of
isotretinoin having reduced food effect. The present invention further relates to a process
for preparing the oral pharmaceutical composition of t e 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.
Isotretinoin has a very high teratogenic potential. This drug may be prescribed
only by or under the supervision of a consultant dermatologist. Therefore, reduction of
dose in case of such a teratogenic drug is highly beneficial. Further, isotretinoin is known
to have a "food effect", i . e., its absorption is dependent on the presence of food in the
stomach. Therefore, there is a need to develop a composition of isotretinoin which has a
lower dose and reduced food effect. The present inventors have developed an oral
pharmaceutical composition of isotretinoin wherein said composition has enhanced
bioavailability, lower dose and reduced food effect in comparison to the marketed
formulations of isotretinoin, i . e., Roaccutane® and Absorica®. These advantages would
lead to better patient compliance.
Summary of the Invention
The present invention provides a low dose oral pharmaceutical composition of
isotretinoin having reduced food effect. The oral pharmaceutical composition of the
present invention comprises isotretinoin and a pharmaceutically acceptable excipient. 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 t e present invention. It also provides a method of treating acne by
administering the oral pharmaceutical composition of the present invention.
Detailed Description of the Invention
In one aspect, the present invention provides a low dose oral pharmaceutical
composition comprising isotretinoin and a pharmaceutically acceptable excipient.
In another aspect, the present invention provides a low dose oral pharmaceutical
composition comprising isotretinoin and a pharmaceutically acceptable excipient, wherein
said composition, when administered orally, provides an equivalent efficacy at a lower
dose of isotretinoin in comparison to the marketed Absorica®capsules, wherein said dose
is at least 10% lower.
In another aspect, the present invention provides a low dose oral pharmaceutical
composition comprising isotretinoin and a pharmaceutically acceptable excipient, wherein
said composition, when administered orally, provides an equivalent efficacy at a lower
dose of isotretinoin in comparison to the marketed Absorica®capsules, wherein said dose
is at least 20% lower.
In another aspect, the present invention provides a low dose oral pharmaceutical
composition comprising isotretinoin and a pharmaceutically acceptable excipient, wherein
said composition exhibits reduced food effect as indicated by comparable Cmax and AUC
in fasting and fed states.
In an embodiment of the above aspect, the composition exhibits a mean Cm a of
about 45 1.38 ng/mL under fed condition and a mean Cmax of about 454.92 ng/mL under
fasting condition.
In another embodiment of the above aspect, the composition exhibits a mean AUC
of about 65 14.86 ng.h/mL under fed condition and a mean AUC of about 5566.90 ng.h/mL
under fasting condition.
In another embodiment of the above aspect, the composition, when administered
orally, has a mean fed/fasted ratio of AUC of about 1.17 and a mean fed/fasted ratio of
Cmax of about 0.99.
In another aspect, t e present invention provides a low dose oral pharmaceutical
composition comprising:
(a) isotretinoin; and
(b) an oily vehicle.
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 16 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 8 mg, 16 mg, 20 mg, 24 mg, 28 mg, or 32 mg.
In another embodiment of the above aspect, said composition is in the form of a
dispersion which is further filled into capsules.
In another embodiment of the above aspect, the oily vehicle includes, but is not
limited to, groundnut oil, olive oil, soybean oil, kernel oil, almond oil, safflower oil,
sunflower oil, palm oil, sesame oil, canola oil, corn oil, castor oil, coconut oil, cotton seed
oil, grape seed oil, and mixtures thereof.
In another embodiment of the above aspect, the oily vehicle is present in an
amount of about 1% w/w to about 99% w/w by the total weight of the composition;
preferably in an amount of about 10% w/w to about 95% w/w by the total weight of the
composition.
In another embodiment of the above aspect, the oily vehicle is present in an
amount of about 71% w/w to about 95% w/w by the total weight of the composition.
In another embodiment of the above aspect, the ratio of isotretinoin to the oily
vehicle ranges from about 1:99 to about 99: 1.
In another embodiment of the above aspect, the composition further comprises a
surfactant.
In another embodiment of the above aspect, the surfactant includes, but is not
limited to, anionic, cationic, or non-ionic surfactants; sorbitan fatty acid esters;
polysorbates prepared from lauric, palmitic, stearic, and oleic acids; mononylphenyl ethers
of polyethylene glycols such as nanoxynols; polyoxyethylene monoesters such as
polyoxyethylethylene monostearate, polyoxyethylene monolaurate, and polyoxyethylene
monooleate; dioctyl sodium sulfosuccinate; sodium lauryl sulphate; lecithin; fatty acid
esters of propylene glycol; fatty acid esters of glycerol; poloxamers; and mixtures thereof.
In another embodiment of the above aspect, the surfactant is present in an amount
of about 0.05% w/w to about 10.0% w/w by the total weight of the composition.
In yet another embodiment of the above aspect, the composition further comprises
other excipients like antioxidants, preservatives, and alkaline stabilizers.
In yet another embodiment of the above aspect, the composition is free of wax.
In yet another embodiment of the above aspect, the composition comprises
isotretinoin wherein the particle size distribution of isotretinoin is such that the D90 is less
than 60 mih, less than 55 mih, less than 50 mih, less than 45 mih, less than 40 mih, less than
35 mih, less than 30 mih, less than 25 mih, less than 20 mih, less than 15 mih, or less than 10
mih.
In yet another embodiment of the above aspect, the composition comprises
isotretinoin wherein the particle size distribution of isotretinoin is such that the D 0 is less
than 30 mih.
In another embodiment of the above aspect, the composition comprises isotretinoin
wherein the particle size distribution of isotretinoin is such that the D 0 is less than 40 mih,
less than 35 mih, less than 30 mih, less than 25 mih, less than 20 mih, less than 15 mih, less
than 10 mih, or less than 5 mih.
In yet another embodiment of the above aspect, the composition comprises
isotretinoin wherein the particle size distribution of isotretinoin is such that the D 0 is less
than 15 mih.
In another embodiment of the above aspect, the composition comprises isotretinoin
wherein the particle size distribution of isotretinoin is such that the Di0 is less than 20 mih,
less than 18 mh , less than 17 mh , less than 15 mh , less than 12 mh , less than 10 mh , less
than 8 mh , less than 7 mh , less than 5 mh , or less than 2 mh .
In yet another embodiment of the above aspect, the composition comprises
isotretinoin wherein the particle size distribution of isotretinoin is such that the Dio is less
than 7 mih.
In yet another embodiment of the above aspect, the composition comprises
isotretinoin wherein the particle size distribution of isotretinoin is such that the D90 is less
than 60 mih and the D 0 is less than 40 mih.
In yet another embodiment of the above aspect, the composition comprises
isotretinoin wherein the particle size distribution of isotretinoin is such that the D90 is less
than 60 mih, D 0 is less than 40 mih, and Di0 is less than 20 mih.
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 the use of the composition.
In another aspect, there is provided a process for the preparation of a low dose oral
pharmaceutical composition comprising isotretinoin and an oily vehicle wherein the
process comprises:
(a) dispersing isotretinoin in an oily carrier;
(b) milling the dispersion to get the desired particle size;
(c) adding one or more excipients to the above dispersion;
(d) optionally adding an oily carrier to the dispersion of step (c); and
(e) filling the dispersion into capsules.
In one embodiment of the above aspect, the oily carrier used in step (a) is present
in an amount which is at least 25% w/w of the total amount of the oily carrier.
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 t e individual in need thereof, a
low dose 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, a low dose oral
pharmaceutical composition of the present invention.
The term "isotretinoin" refers to isotretinoin in its crystalline or amorphous form,
as well as its esters, salts, or derivatives thereof.
The term "low dose," as used herein, refers to the dose of isotretinoin wherein said
dose is at least 10% lower than the presently approved dose.
The bioequivalence is established by comparing pharmacokinetic parameters, for
example, AUC and Cmax of the pharmaceutical composition of the present invention with
Absorica ® formulation in healthy human subjects in fed as well as fasting conditions.
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 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.
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 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.
Isotretinoin shows a food effect, i.e., its absorption is dependent on the presence of food in
the stomach.
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) of the particles have a size less than the defined D 0 value;
"D90" refers to t e particle size of isotretinoin where 90% (w/v) of the particles have a size
less than the defined D90 value.
"Defined D10 value/Dso value/Dgo value" refers to the values defined in the
embodiments.
Examples of suitable antioxidants include, but are not limited to, butylated
hydroxyl anisole, butylated hydroxyl toluene, tocopherol, ascorbyl palmitate, ascorbic
acid, sodium metabisulfite, sodium sulfite, sodium thiosulfate, propyl gallate, and
mixtures thereof. The antioxidant is present in an amount of about 0.002% w/w to about
2% w/w of the total composition.
Examples of alkaline stabilizers include, but are not limited to, sodium hydroxide,
potassium hydroxide, sodium carbonate or bicarbonate, potassium carbonate or
bicarbonate, lithium hydroxide, triethylamine, meglumine, methylamine, and mixtures
thereof.
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, potassium sorbate, and mixtures 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 size reduction of isotretinoin is achieved by wet milling the dispersion of
isotretinoin in an oily vehicle using mechanical means such as a jet mill, ball mill, or
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. Butylated hydroxy anisole and polysorbate 80 were dissolved in soybean oil
(39.36% w/v of t e total composition) to form a clear solution.
2 . Isotretinoin was added to the step 1 solution under stirring to obtain a uniform
dispersion.
3. The dispersion of step 2 was milled to get t e particle size of isotretinoin such that
D 0 was about 20 mih.
4 . The remaining quantity of soybean oil (52.08% w/v of the total composition) was
added to the micronized dispersion of step 3 under stirring to obtain a uniform
dispersion.
5 . The dispersion of step 5 was filled into hard gelatin capsules.
Dissolution Studies
The pharmaceutical composition of Example 1 (containing 16 mg of isotretinoin)
was compared with the marketed formulation of isotretinoin (20 mg Absorica® capsules)
for the release profile in an FDA recommended dissolution medium as given in the
following tables:
Reference (R): Absorica®20 mg capsules
Test (T): Isotretinoin 16 mg capsules (Example 1)
Dissolution Media pH 7.8 phosphate buffer with 0.5% w/v N,N-dimethyl
dodecylamine N-oxide
Apparatus /RPM/Vol USP Type I (20 mesh basket)/ 100/900 mL
Pharmacokinetic study under fed conditions
The pharmaceutical composition of Example 1 (containing 16 mg of isotretinoin)
was compared with the marketed formulation of isotretinoin (20 mg Absorica® capsules)
under fed conditions on 15 healthy adult male subjects.
Values for various pharmacokinetic parameters, including observed Cmax, AUCo-t,
and AUCo-mf were calculated and are provided in Table 1 below.
Reference (R): Absorica®20 mg capsules
Test (T): Isotretinoin 16 mg capsules (Example 1)
Table 1: Comparative pharmacokinetic data for test and reference in 15 healthy
adult human male subjects:
• Average tmaX values for both the test and reference are 4.7888 hours and
5.5 111 hours, respectively, which indicate a comparable absorption pattern.
• Under fed conditions, the test prototype shows a comparable extent of
absorption to reference product with T/R ratios of 90. 12% and 91.59% for
AUCo-t and AUC O-M, respectively. These values are within the regulatory
acceptance criteria of 80% to 125%. However, for rate of absorption (Cmax),
the ratio is observed to be slightly on a higher side (11 1.07%) with 90% CI
ranging between 91.54% and 134.76%.
Pharmacokinetic study comparing the formulation of Example 1 under fed and
fasting conditions
The pharmaceutical composition of Example 1 (16 mg Test capsule) was compared
in fed and fasting conditions on 15 healthy adult male subjects.
Values for various pharmacokinetic parameters, including observed CmaX, AUCo-t,
and AUC O-M were calculated and are provided in Table 2 below.
Test (A): Isotretinoin 16 mg capsules (Example 1) under fasting conditions
Test (B): Isotretinoin 16 mg capsules (Example 1) under fed conditions
Table 2 : Comparative pharmacokinetic data for test (B) vs test (A) in 15 healthy
adult human male subjects:
• Average tma X for the test prototype under fasting condition (3 .7667 hours) is
-1.02 hours earlier than when administered under fed condition (4.7888
hours).
• On comparing the test prototype under fasting and fed conditions, it is
observed that B/A ratio for rate of absorption (Cmax) is close to unity
(99.22%). Even though B/A ratios are on higher side for the AUC values,
(approx. 116% to 117%), the 90% CI for all three PK parameters (Cmax,
AUCo-t, and AUC O- ) are within the 80% to 125% regulatory acceptance
criteria.
Conclusion:
• The 16 mg test prototype has comparable bioavailability to the reference
product (Absorica® 20 mg) under fed conditions. This provides positive
support for up to 20% reduction in the test dose.
• There is no indication that food will significantly impact the rate and extent
of drug absorption from the test prototype. In fact, we observe that T/R ratios
and 90% CI for the PK parameters are within the 80% to 125% regulatory
acceptance criteria.
Example 2
S. No Name of Ingredient Quantity (%w/w)
1. Isotretinoin 13.91
2 . Polysorbate 80 3.86
3 . Butylated hydroxy anisole 0.08
4 . Soybean Oil 82.15
Procedure:
1. Butylated hydroxy anisole and polysorbate 80 were dissolved in t e soybean oil to
form a clear solution.
2 . Isotretinoin was added to the step 1 solution under stirring to obtain a uniform
dispersion.
3. The dispersion of step 2 was milled to get t e particle size of isotretinoin such that
D90 was about 20 mih.
4 . The dispersion of step 3 was filled into hard gelatin capsules.
5 . The filled capsules of step 4 were sealed using a gelatin solution.
Example 3
Procedure:
Butylated hydroxy anisole was dissolved in soybean oil (39.36% w/v of the total
composition) to form a clear solution.
Isotretinoin was added to the step 1 solution under stirring to obtain a uniform
dispersion.
The dispersion of step 2 was milled to get the particle size of isotretinoin such that
D90 was about 20 m i.
The remaining quantity of soybean oil (53.93% w/v of the total composition) was
added to the micronized dispersion of step 3 under stirring to obtain a uniform
dispersion.
The dispersion of step 4 was filled into hard gelatin capsules.
The filled capsules of step 5 were sealed using a gelatin solution.

We claim :
1. A low dose oral pharmaceutical composition comprising isotretinoin and a
pharmaceutically acceptable excipient.
. A low dose oral pharmaceutical composition comprising isotretinoin and a
pharmaceutically acceptable excipient, wherein said composition, when administered
orally, provides equivalent efficacy at a lower dose of isotretinoin in comparison to t e
marketed Absorica®capsules, wherein said dose is at least 10% lower.
3. A low dose oral pharmaceutical composition comprising isotretinoin and a
pharmaceutically acceptable excipient, wherein said composition, when administered
orally, provides equivalent efficacy at a lower dose of isotretinoin in comparison to t e
marketed Absorica®capsules, wherein said dose is at least 20% lower.
4 . The low dose oral pharmaceutical composition according to claim 1, claim 2, or
claim 3, wherein said composition exhibits a reduced food effect as indicated by
comparable Cmax and AUC in fasting and fed state.
5. The low dose oral pharmaceutical composition according to claim 4, wherein said
composition exhibits a mean CmaXof about 45 1.38 ng/mL under fed condition and a mean
Cmax of about 454.92 ng/mL under fasting condition.
6. The low dose oral pharmaceutical composition according to claim 4, wherein said
composition exhibits a mean AUC of about 65 14.86 ng.h/mL under fed condition and a
mean AUC of about 5566.90 ng.h/mL under fasting condition.
7. The low dose oral pharmaceutical composition according to claim 4, wherein the
composition, when administered orally, has a mean fed/fasted ratio of AUC of about 1.17
and a mean fed/fasted ratio of Cmax of about 0.99.
8. The low dose oral pharmaceutical composition according to claim 1, claim 2, or
claim 3, wherein said composition comprises:
(a) isotretinoin; and
(b) an oily vehicle.
9. The low dose oral pharmaceutical composition according to claim 8, wherein
isotretinoin is present 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.
10. The low dose oral pharmaceutical composition according to claim 9, wherein
isotretinoin is present in an amount of about 9 mg to 36 mg.
11. The low dose oral pharmaceutical composition according to claim 9, wherein
isotretinoin is present in an amount of about 8mg to 32 mg.
12. The low dose oral pharmaceutical composition according to claim 9, wherein
isotretinoin is present in an amount of about 16 mg.
13. The low dose oral pharmaceutical composition according to claim 9, wherein
isotretinoin is present in an amount of about 32 mg.
14. The low dose oral pharmaceutical composition according to claim 9, wherein t e
composition comprises isotretinoin in an amount of about 8 mg, 16 mg, 20 mg, 24 mg, 28
mg, or 32 mg.
15. The low dose oral pharmaceutical composition according to claim 8, wherein t e
composition is in the form of a dispersion which is further filled into capsules.
16. The low dose oral pharmaceutical composition according to claim 8, wherein the
oily vehicle includes, but is not limited to, groundnut oil, olive oil, soybean oil, kernel oil,
almond oil, safflower oil, sunflower oil, palm oil, sesame oil, canola oil, corn oil, castor
oil, coconut oil, cotton seed oil, grape seed oil, and combinations thereof.
17. The low dose oral pharmaceutical composition according to claim 16, wherein the
oily vehicle is present in an amount of about 1% w/w to about 99% w/w by the total
weight of the composition.
18. The low dose oral pharmaceutical composition according to claim 17, wherein the
oily vehicle is present in an amount of about 71% w/w to about 95% w/w by the total
weight of the composition.
19. The low dose oral pharmaceutical composition according to claim 8, wherein the
ratio of isotretinoin to the oily vehicle ranges from about 1:99 to about 99: 1.
20. The low dose oral pharmaceutical composition according to claim 8, wherein said
composition further comprises a surfactant.
2 1. The low dose oral pharmaceutical composition according to claim 20, wherein the
surfactant is selected from the group consisting of anionic, cationic, or non-ionic
surfactants; sorbitan fatty acid esters; polysorbates prepared from lauric, palmitic, stearic,
and oleic acids; mononylphenyl ethers of polyethyleneglycols such as nanoxynols;
polyoxyethylene monoesters such as polyoxyethylethylene monostearate, polyoxyethylene
monolaurate, and polyoxyethylene monooleate; dioctyl sodium sulfosuccinate; sodium
lauryl sulphate; lecithin; fatty acid esters of propylene glycol; fatty acid esters of glycerol;
poloxamers; and mixtures thereof.
22. The low dose oral pharmaceutical composition according to claim 20, wherein t e
surfactant is present in an amount of about 0.05% w/v to about 10.0% w/v by the total
weight of the composition.
23. The low dose oral pharmaceutical composition according to claim 8, wherein said
composition further comprises an antioxidant, a preservative, an alkaline stabilizer, or
combinations thereof.
24. The low dose oral pharmaceutical composition according to claim 8, wherein the
composition is free of wax.
25. The low dose oral pharmaceutical composition according to claim 8, wherein the
particle size distribution of isotretinoin is such that the D90 is less than 60 mih, less than 55
mih, less than 50 mih, less than 45 mih, less than 40 mih, less than 35 mih, less than 30 mih,
less than 25 mih, less than 20 mih, less than 15 mih, or less than 10 mih.
26. The low dose oral pharmaceutical composition according to claim 25, wherein the
particle size distribution of isotretinoin is such that the D90 is less than 30 mih.
27. The low dose oral pharmaceutical composition according to claim 8, wherein the
particle size distribution of isotretinoin is such that the D 0 is less than 40 mih, less than 35
mih, less than 30 mih, less than 25 mih, less than 20 mih, less than 15 mih, less than 10 mih,
or less than 5 mih.
28. The low dose oral pharmaceutical composition according to claim 27, wherein the
particle size distribution of isotretinoin is such that the D 0 is less than 15 mih.
29. The low dose oral pharmaceutical composition according to claim 8, wherein the
particle size distribution of isotretinoin is such that the Dio 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.
30. The low dose oral pharmaceutical composition according to claim 29, wherein t e
particle size distribution of isotretinoin is such that t e Di0 is less than 7 mih.
31. The low dose oral pharmaceutical composition according to claim 8, wherein the
distribution of isotretinoin particle sizes is such that the D90 is less than 60 mih and D 0 is
less than 40 mih.
32. The low dose oral pharmaceutical composition according to claim 8, wherein the
distribution of isotretinoin particle sizes is such that the D90 is less than 60 mih, D 0 is less
than 40 mih, and Di0 is less than 20 mih.
33. The low dose oral pharmaceutical composition according to claim 1, claim 2, or
claim 3, wherein 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.
34. A process for preparing the low dose oral pharmaceutical composition according to
claim 1, claim 2, or claim 3, wherein said process comprises:
(a) dispersing isotretinoin in an oily carrier;
(b) milling the dispersion to get the desired particle size;
(c) adding one or more excipients to the above dispersion;
(d) optionally adding an oily carrier to the dispersion of step (c); and
(e) filling the dispersion into capsules.
35. The process according to claim 34, wherein the oily carrier used in the step (a) is
present in an amount which is at least 25% w/w of the total amount of the oily carrier.
36. A low dose oral pharmaceutical composition made by the process of claim 34.
37. The low dose oral pharmaceutical composition according to claim 1, claim 2, or
claim 3, 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, gramnegative
folliculitis, recalcitrant rosacea, pyoderma faciale, psoriasis, cutaneous lupus
erythematosus, acne fulminans, squamous cell carcinoma, or cutaneous photoaging of
isotretinoin.
38. The low dose oral pharmaceutical composition according to claim 37, wherein said
composition is used for the treatment of acne.
39. 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 a low dose oral pharmaceutical composition of claim
1, claim 2, or claim 3 .
40. The method according to claim 39, wherein the patient has acne.