JP2002528492A - Isotretinoin composition having small particle size and production method - Google Patents

Abstract

  (57) [Summary] A method for preparing a micronized isotretinoin composition is disclosed. The method is carried out by suspending isotretinoin in an oil vehicle and micronizing it. Also disclosed is a unit dosage form comprising micronized isotretinoin and a composition. Some of these compositions are superior to known compositions in terms of food effect.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for producing a micronized isotretinoin composition, in particular to a method for producing a small particle size isotretinoin, a composition comprising isotretinoin produced by this method, and reduced bioavailability. An isotretinoin composition having an improved food effect.

[0002] Isotretinoin is used for the treatment of severe resistant cystic acne. The currently marketed product, ROACCUTANE®, is a suspension of isotretinoin in soft gelatin capsules. The average particle size of isotretinoin in the suspension is about 90-100 μm (micrometer). The particle size is determined by measuring the isotretinoin suspension in oil (preferably soybean oil),
Produced by subjecting to high shear homogenization for a time sufficient to reduce to 0-100 μm. However, the bioavailability of isotretinoin in ACCUTANE is only about 20%. Accordingly, a reduction in the particle size of isotretinoin in suspension has been desired to improve bioavailability and potentially reduce variability within the patient.

[0003] Reducing the particle size of isotretinoin is not without its problems. Particle size reduction using prior art methods such as hammer mills, ball mills, or air friction (fluid energy) mills results in a significant loss of isotretinoin capacity. Isotretinoin is very susceptible to oxidation, and prolonged exposure to the atmosphere during milling results in a considerable loss of capacity. In addition, ball mills cause contamination of the drug by the milling media. Therefore, these methods are not suitable for the commercial application of isotretinoin.

[0004] Isotretinoin powder is obtained by suspending the isotretinoin in an oily or other pharmaceutically acceptable vehicle and then subjecting the suspension to high shear homogenization, liquid jet micronization (defined below) or wet milling. By subjecting to the shock, shear, and cavitation forces created by the process, micronization can occur with negligible loss of capacity, and efficient particle size reduction can occur with negligible loss of capacity. Was found.
Accordingly, one embodiment of the invention is an improved method for producing micronized isotretinoin. Also, surprisingly, the isotretinoin compositions thus produced are more storage-stable with respect to the ability of isotretinoin than isotretinoin, in which the isotretinoin is first micronized and then suspended in oil. Was found to be high. Thus, according to the present invention, isotretinoin suspended in an oily or other pharmaceutically acceptable vehicle may be micronized by a number of techniques without adversely affecting the ability of the isotretinoin to be suspended, And soft gelatin capsules prepared from this suspension show excellent homogeneity, bioavailability and stability of performance. Accordingly, a further embodiment of the invention comprises: 1) a composition comprising a suspension of isotretinoin in an oil or other pharmaceutically acceptable vehicle produced by micronizing isotretinoin in a vehicle; And 2) a unit dose for enteral administration containing the composition.

[0005] It is an object of the present invention to provide a pharmaceutical composition in unit dosage form. This composition has 5μ
about 7.5 mg to about 22.5 mg of isotretinoin having an average particle size of m to 30 μm;
The suspension comprising 10% to 18% by weight of wax, preferably 18% of wax, and oil. Other useful additives in suspension include disodium edetate and butylated hydroxyanisole. The suspension is typically beeswax,
And wax mixtures comprising oils such as hydrogenated soybean oil flakes, hydrogenated vegetable oils, and soybean oil. Suitable isotretinoin has an average particle size between 5 μm and 26 μm.

As used herein, the term “liquid jet atomizer” is disclosed in US Pat. Nos. 4,533,254 and 4,908,154, the disclosures of which are incorporated herein by reference. Refers to an apparatus using micronization technology.

The term “oil or other pharmaceutically acceptable vehicle” as used herein refers to (i) pharmaceutically acceptable for oral administration to humans, and (ii) the average particle size of isotretinoin. To reduce isotretinoin while the vehicle and isotretinoin are subjected to mechanical means that produces shear, impact, cavitation or friction to reduce to an average particle size in the range of about 5 μm to about 30 μm. Any liquid that has the appropriate fluidity and viscosity and is (iii) compatible to maintain the integrity of the capsule in which the suspension is to be contained. A preferred type of vehicle is an oil vehicle. The oily vehicles may be any conventional vegetable or synthetic oil that is pharmaceutically acceptable for oral administration. Preferred oily vehicles are
Soybean oil, peanut oil, olive oil, of C ₆ -C ₁₈ fatty acid mono-, - di - or triglycerides, C ₆ -C ₁₈ fatty acid, polyethylene glycol, polyglycolized glycerides, glycerol, propylene glycol, propylene glycol mono -, di -Or triesters or polyethylene glycols. Mixtures of two or more oily vehicles useful for the present invention may also be used. A particularly preferred oil vehicle is soybean oil.

[0008] Accordingly, the present invention relates to a composition comprising micronized isotretinoin in a composition having a particle size of about
Comprising micronized isotretinoin dispersed in an oil or other pharmaceutically acceptable vehicle, preferably having an average particle size in the range of about 5 μm to about 26 μm, most preferably about 5 μm to about 20 μm. It is directed to a method for producing a finely divided isotretinoin composition. The method comprises subjecting a suspension of isotretinoin in an oily or other pharmaceutically acceptable vehicle to mechanical means that produces shear, impact, cavitation or friction, thereby reducing the average particle size of isotretinoin. To produce a micronized isotretinoin composition. Starting isotretinoin, which is distinct from micronized isotretinoin, is generally 100 μm-
It has an average particle size in the range of about 300 μm. The method of the present invention may be practiced in one or more steps using different mechanical means for each step, such as high shear homogenization and subsequent liquid jet atomization.

In a preferred embodiment, isotretinoin is suspended in an oily or other pharmaceutically acceptable vehicle and processed by a high shear homogenizer and subsequent liquid jet atomizer. Particle size reduction using a high shear homogenizer is preferably performed until the average particle size of the isotretinoin in the suspension is in the range of 50-65 μm. In these two steps, the average particle size of isotretinoin is 100
~ 300 μm to about 5-30 μm, preferably about 5-26 μm, most preferably about 5-20 μm. The resulting particle size is produced very uniformly, with negligible loss in the performance of isotretinoin.

[0010] A particularly preferred liquid jet atomizer is under the name MICROFLUIDIZER®.
Manufactured by Microfluidics Corp., Newton, MA. US Patent No. 4
533,254 and 4,908,154, the recirculation of the isotretinoin dispersion, if desired, in a liquid jet atomizer also achieves the desired size of the dispersed isotretinoin particles. And / or may be implemented to make them more uniform in size. In liquid jet atomizers, the use of a larger interaction chamber is preferred following a lauter-type interaction chamber.

In a preferred embodiment of the present invention, the suspension from the high shear homogenizer is passed through a liquid jet atomizer at any conventional temperature at which the desired atomization can be achieved. Temperatures in the range of 15 to 50C are preferred. It is particularly preferred to carry out the liquid jet atomization at room temperature. The liquid jet atomizer preferably has a pressure of 5,000 to 40,000 psi, especially 10,000 to 40,000 psi to reduce the final particle size.
It operates at 30,000 psi, most preferably at 12,000 to 18,000 psi. In a typical case, the homogenized suspension is processed twice through a liquid jet atomizer at a pressure of about 12,000 psi.

In another embodiment, the particle size reduction is achieved by using only the high shear homogenizer with sufficient time to produce an average particle size of 5-30 μm, especially 5-26 μm, most preferably 5-20 μm. It may be completed using a wet mill or only using liquid jet atomization. An example of a high shear homogenizer is Ar
de Barinco (New Jersey; for example model CJ4C 16 #), Koruma (Germany; for example model DISHO-V), GEI Krieger (Switzerland; for example model BL) and Silverson (UK;
For example, an impeller type high shear mixer available from model L4 RT). Examples of wet mills are Dipermat SL (VMA-Getzmann GMBH, Germany) and Dyno-Mill Type KD
L (Willy Bachofen AG, Masinen Fabric, Switzerland).

In a preferred embodiment of the invention, the method of the invention can be used in a final dosage form for filling gelatin capsules in an oily or other pharmaceutically acceptable vehicle, preferably an oily vehicle. It is carried out alone or on a dispersion of isotretinoin using only conventional antioxidants, without further excipients. Such "preservative dispersions" of micronized isotretinoin in an oily or other pharmaceutically acceptable vehicle are suitably used to prepare the final dosage form for filling gelatin capsules. In preparation for micronization, the powdered isotretinoin is mixed with an oily or other pharmaceutically acceptable vehicle in a conventional manner. The isotretinoin in the vehicle can be micronized and the resulting preservative dispersion can be mixed with excipients to form the final dosage form used in filling gelatin capsules. A conventional antioxidant that may be incorporated into the preservative dispersion is butylated hydroxyanisole.

One general approach for the preparation of a preservative dispersion is to warm an oily or other pharmaceutically acceptable vehicle to facilitate mixing (about 70 ° C. is preferred). ,
Dissolving the antioxidant in the vehicle using an impeller mixer or equivalent. The solution of the antioxidant in the vehicle is cooled to about 35-40C. The isotretinoin, preferably stored at -20 ° C in a sealed container, is returned to room temperature, the container is opened and the drug is stirred in the antioxidant solution in the vehicle. This dispersion of isotretinoin in the vehicle is then micronized according to the method of the present invention.

[0015] In the preservative dispersion, the concentration (w / w) of isotretinoin in the oil vehicle is 1-50%, preferably 10-40%, most preferably 20-35%.
After micronization, the preservative dispersion is then combined with additional pharmaceutically acceptable ingredients to arrive at a final dosage form for soft gelatin capsule filling. Examples of preservative dispersions containing 20% isotretinoin are shown in Table 1.

TABLE 1 Dosage form of 20% (w / w) isotretinoin storage dispersion

[0017]

[Table 1]

The present invention is also directed to a composition in a unit dosage form for enteral administration comprising the micronized isotretinoin composition of the present invention and a pharmaceutically acceptable carrier. The unit dosage form contains about 1 mg to about 50 mg of isotretinoin, preferably about 3 mg to about 25 mg of isotretinoin. An oleaginous or other pharmaceutically acceptable vehicle may itself act as a pharmaceutically acceptable carrier without the addition of further excipients. The unit dosage form can be any conventional form, such as tablets, capsules, and the like, as known in the art, so long as the micronized isotretinoin composition of the present invention can be incorporated. Preferred unit dosage forms are gelatin capsules, especially Florida,
Soft gelatin capsules such as those manufactured by PR Scherer North America, Inc. of St. Petersburg. Preparation of the final dosage form for filling soft gelatin capsules is described in Example 5.

The analysis of the particle size of the micronized isotretinoin is preferably based on at least three samples taken at random from different parts of the mixing vessel. Particle size analysis of isotretinoin can be performed using a conventional particle size analyzer (eg, Malvern MasterSizer ^™ Model X Ve
rsion 2.5). The resulting micronized isotretinoin suspension must have an average isotretinoin particle size of 5-30 μm, preferably 5-20 μm. Table 2 shows typical average particle size data.

Table 2: Isotretino by homogenization and liquid jet atomization at 12,000 psi
Particle size data for ins (data is the average of two treatments and three measurements )

[0021]

[Table 2]

It has been found that reducing the wax content of an isotretinoin composition having an average particle size between 5 μm and 30 μm unexpectedly results in improved absorption of isotretinoin in the absence of food. . It is known that isotretinoin, including compositions with more than 22 percent (22%) wax, tends to reduce the bioavailability of the active ingredient, but has an average particle size between 5 μm and 30 μm. Studies on isotretinoin with a liposome do not address wax concentration on the "food effect".

[0023] Isotretinoin is a lipophilic substance. Therefore, administration is typically performed in the presence of food to maximize isotretinoin absorption into the blood. It is known that individuals who take isotretinoin (mean particle size between 90 μm and 100 μm) in the absence of food show reduced isotretinoin blood levels compared to individuals who take isotretinoin in the presence of food. Have been.

The following experiments were performed to test the food effect on bioavailability of isotretinoin having an average particle size between 5 μm and 30 μm. The experiment was performed from 5 μm to 30
It shows that for isotretinoin having an average particle size between μm, the food effect decreases as the wax concentration decreases. This decrease in wax concentration correlates to a decrease in viscosity of the composition being tested. Surprisingly, about 18% (especially 18%
. A composition having a wax content of 2%) is a composition containing a wax mixture of 19.7% by weight (European Patent Publication No. 0189 issued August 8, 1990).
42 (disclosed in U.S. Pat. No. 42) has been found to significantly reduce food effects.
The reduced viscosity (185-600 centipoise) of isotretinoin, including compositions having between about 10% and about 18% wax, is achieved by minimizing the food effect on the bioavailability of isotretinoin. It is believed that it will exhibit excellent properties.

[0025] Chemical assays of isotretinoin for the different dosage forms studied were performed using a method showing stability against isotretinoin using high performance liquid chromatography methods. The pump was a Waters 600E multiple solvent delivery system with a Waters WISP 717 Plus automatic sampler and was at a temperature of 5 ° C. The drug was tested at a wavelength of 353 nm using a Thermoseparations Spectromonitor 3200 detector.

EXAMPLE 1 Fluid Energy Grinding Fluid energy (jet) mill size reduction requires particle acceleration so that grinding occurs by particle-particle impact or impact on a solid surface. Fluid energy mills are used for atomization because of the high impact velocity possible as a result of particle acceleration in a high velocity gas stream. Particle velocities in a fluid energy mill range from 300 to 500 meters per second as compared to 50 to 150 meters per second in a mechanical impact mill.

In a typical fluid energy milling process, powdered isotretinoin is milled (Jet-O-Mizer ^™ , Fluid E) using an oscillating feeder that controls the feed rate of the powder.
nergy Aljet, Plumsteadville, Pennsylvania). There are three main factors that control the size reduction process: powder feed rate, air pressure at the extrusion nozzle (25-35 psi for a lab scale mill), and air pressure at the milling nozzle (lab scale). 40-50 psi for the mill). The milling step for isotretinoin was performed with nitrogen or air. Samples were selected from micronized powders and tested for their effectiveness and particle size. The results are shown in Table 3.

The particle size reduction of Example 2 Homogenization isotretinoin, high shear homogenizer (Model CJ4C 16 #, Arde
-Barinco, New Jersey). Isotretinoin is used in soybean oil (
(Formulations in Table 1 with antioxidants) and homogenized at high speed at different times (30 minutes to 6 hours). Samples (2 g) were removed at different mixing times and Malver
n Tested for isotretinoin particle size using MasterSizer Model X Version 2.5. The results are shown in Table 3. Particle size reduction has also been found to be a function of mixing time.

Example 3 Particle size reduction of wet milled isotretinoin was achieved using a medium mill (Dispermat SL, VMA-Getzmann GMBH, Germany) operating at 3000 RPM. Isotretinoin was added to soybean oil (dosage form in Table 1 with antioxidants) and homogenized at high speed using a high shear homogenizer (Model CJ4C 16 #, Arde-Barinco, New Jersey). . The suspension formed was pumped through the grinding chamber of a medium grinding device containing the grinding glass beads. Particle size reduction occurs by both friction and impact, producing a suspension of micronized isotretinoin. Samples (2 g each) are from Malv
Tested for particle size using ern MasterSizer Model X Version 2.5. The results are shown in Table 3.

Example 4 Isotretinoin stored at -20 ° C in a high shear homogenized and liquid jet micronized sealed container was returned to room temperature and suspended in soybean oil (with antioxidant added). With and without the dosage form of Table 1). The isotretinoin suspension was passed through a high shear homogenizer as described in Example 2 until the isotretinoin particle size in the suspension was 50-65 μm. The suspension thus prepared was subjected to a MICROFLUIDIZER® M110F liquid jet atomizer at 12,000 psi and room temperature (Microfluidics International Corp., Newton, NY).
MA). After two passes, the isotretinoin particle size was reduced to Malvern MasterSi
Measured using zer Model X Version 2.5. The results are shown in Table 3.

The following table compares the results for a fluid energy mill using various embodiments of the present invention.

[0032]

[Table 3]

Example 5 Preparation of the final capsule

[0034]

[Table 4]

During the preparation of the final suspension, the remaining BHA was added while the vehicle (soybean oil) was warmed to about 70 ° C. and mixed using a suitable mixer until the BHA was completely dissolved. . The hydrogenated soybean oil flakes were added to the solution of BHA in soybean oil while mixing until it was uniformly incorporated. Subsequently, refined beeswax, hydrogenated vegetable oil, and disodium edetate were added and mixing continued until a homogeneous suspension was formed. Before adding the 20% micronized isotretinoin stock dispersion, the suspension was
Cooled between 0-45 ° C. and continued mixing until a homogeneous suspension was formed. The final suspension was blanketed with nitrogen for storage. The completed suspension was incorporated into soft gelatin capsules using conventional processing techniques.

EXAMPLE 6 Preparation and Testing of Isotretinoin Dosage Forms with Different Wax Concentrations A 35 percent (35%) stock dispersion in soybean oil was prepared at 70 ± 5 ° C.
And then added BHA using an impeller mixer until the BHA was completely dissolved. The mixture was cooled to 40-45 ° C and isotretinoin was added with mixing (under nitrogen). The mixture was homogenized for 1 hour at high speed using a high shear mixing-homogenizer. The mixture was further passed through a wet grinder similar to that described in Example 3. The average particle size (50th 100th quantile) of isotretinoin was 20 μm. The dosage form composition of a 35 percent (35%) isotretinoin stock dispersion in soybean oil is shown in Table 5.

[0037]

[Table 5]

Using a 35 percent (35%) stock dispersion of isotretinoin, different wax concentrations [18.2%, 19.7%, 10% and 15% (w / w), respectively]
] To prepare four dosage forms (P1, P2, P4 and P5). The compositions of each of the four dosage forms, P1, P2, P4 and P5, are shown in Tables 6, 7, 8 and 9, respectively.

[0039]

[Table 6]

[0040]

[Table 7]

^* 1 part of wax mixture : yellow wax (refined beeswax) 4 parts: hydrogenated vegetable oil 4 parts: vegetable shortening (hydrogenated soybean oil flakes)

[0042]

[Table 8]

[0043]

[Table 9]

For dosage forms P1, P4 and P5, add the remaining BHA while warming the vehicle (soybean oil) to about 70 ° C. during final suspension preparation and add until the BHA is completely dissolved. Were mixed with a suitable mixer.

The hydrogenated soybean oil flakes were added to the BHA solution in soybean oil and mixed until homogeneously incorporated. Then refined beeswax, hydrogenated vegetable oil and disodium edetate were added. Mixing was continued to form a homogeneous suspension. The suspension was cooled to 40-45 ° C before the addition of the 35% stock dispersion of isotretinoin, and mixing was continued until a homogeneous suspension was formed. The final suspension was blanketed with nitrogen for storage. The completed suspension was manually filled into hard gelatin capsules.

Dosage form P2 (disclosed in European Patent Publication No. 018942 issued Aug. 8, 1990) was prepared in a similar manner as the other three dosage forms. However, the wax mixture (the composition is described in Table 7) was first prepared according to the published European Patent Publication before the addition of warmed soybean oil. After the addition of the wax mixture, the treatment was continued as for the other three dosage forms, namely P1, P4 and P5.

The viscosities of all dosage forms were determined using Brookfield mini sample adapter Model SSA-15 / 7R with B
Measured at 25 ° C. using a rookfield Digital Viscometer Model DV-II, using spindle # 15 set to a knob speed of 100 rpm. The viscosity data for all four dosage forms are shown in Table 10.

[0048] The four dosage forms were administered orally to fed and fasted dogs to compare their effects on plasma exposure. Six male and six female dogs were divided into two groups of three males and three females by standard random extraction. Four dosage forms (P1, P2, P
4 and P5) were administered to each dog at a rate of 20 / head under feeding and fasting conditions.
mg was administered with isotretinoin. Blood samples were collected from all dogs into tubes containing potassium oxalate and sodium fluoride as anticoagulants and placed on ice before centrifugation. Samples were taken before dosing and at 1, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours after dosing. Plasma was frozen in amber vials at a minimum of −60 ° C. after centrifugation under yellow light and subjected to assays. A minimum of 1.0 ml of plasma was subjected to the assay. All pharmacokinetic parameters of isotretinoin are described in Watson (v 5.4.
00.03) Calculated using a valid laboratory information system. Pharmacokinetic parameters were estimated from individual data. The reported parameters were the maximum plasma concentration (Cmax),
Time to reach maximum plasma concentration (Tmax) and area from 0 to 32 hours under the plasma concentration-time curve (AUC _0-32hr ). The observed Cmax and Tmax were taken directly from the individual plasma concentration-time profiles. AUC _0-32hr was calculated using the linear trapezoidal rule. The average pharmacokinetic data is shown in Table 10.

[0049]

[Table 10]

From reading the present specification, various alternative embodiments will be apparent to persons skilled in the art. It is understood that these variations are within the scope and spirit of the subject invention, limited only by the appended claims and their equivalents.

[Procedure amendment]

[Submission date] June 1, 2001 (2001.6.1)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/44 A61K 47/44 A61P 17/10 A61P 17/10 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY) , KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, Z, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK , LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, T J, TM, TR, TT, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor, Martin Howard United States of America, New Jersey 07043, Upper Monclair, Pureware Place 6 (72) Inventor Shah, Nabnit Harcobindas United States, New Jersey 07012, Clifton, Beverly Hill Road 203 F-term (reference) 4C076 AA22 AA55 BB05 BB31 CC18 DD38 DD39 DD46 DD49 EE51A EE53A E E55A FF25 FF33 FF34 FF65 4C206 AA01 AA02 DA05 MA03 MA05 MA43 MA57 MA75 MA83 NA03 NA11 ZA89

Claims (101)

[Claims] 1. A micronized isotretinoin composition which is a composition comprising isotretinoin suspended in an oily or other pharmaceutically acceptable vehicle and having an average particle size ranging from about 5 μm to about 30 μm. A process for producing a product, comprising: 1) dispersing isotretinoin having an average particle size of greater than about 30 μm in a vehicle to form a suspension containing 1-50% by weight isotretinoin; Subjecting the suspension to mechanical means to create shear, impact, cavitation or friction, reducing the average particle size of isotretinoin to a particle size in the range of about 5 μm to about 30 μm, whereby the micronized isotretinoin composition A method for producing a finely divided isotretinoin composition, comprising producing a product. 2. The method according to claim 1, wherein the mechanical means is a wet mill. 3. The method according to claim 2, wherein the suspension contains from 10 to 40% by weight of isotretinoin. 4. The method according to claim 3, wherein the suspension contains 20 to 35% by weight of isotretinoin. 5. The method according to claim 2, wherein the vehicle is an oily vehicle. 6. The oil-based vehicle may be a soybean oil, a peanut oil, an olive oil, a C ₆ oil.
-C ₁₈ fatty acid mono-, - di - or triglycerides, C ₆ -C ₁₈ fatty acid, polyethylene glycol, polyglycolized glycerides, glycerol, propylene glycol, propylene glycol mono -, di - is or triester or a polyethylene glycol, A method as claimed in claim 5. 7. The method according to claim 6, wherein the oily vehicle is soybean oil. 8. The method of claim 1, wherein the mechanical means is a high shear homogenization. 9. The method according to claim 8, wherein the suspension contains from 10 to 40% by weight of isotretinoin. 10. The method according to claim 9, wherein the suspension contains 20 to 35% by weight of isotretinoin. 11. The method according to claim 8, wherein the vehicle is an oily vehicle. 12. The oil-based vehicle may be soybean oil, peanut oil, olive oil, C ₆ ~ C₁₈Mono-, di- or triglycerides of fatty acids, polyethylene glycol
Glyceride, glycerol, propylene glycol, pro
Mono-, di- or triesters of pyrene glycol or polyethylene glycol
The method according to claim 11, which is a recall. 13. The method according to claim 12, wherein the oily vehicle is soybean oil. 14. The method according to claim 1, wherein the mechanical means is liquid jet atomization. 15. The method according to claim 14, wherein the suspension contains from 10 to 40% by weight of isotretinoin. 16. The method according to claim 15, wherein the suspension contains 20 to 35% by weight of isotretinoin. 17. The method of claim 14, wherein the vehicle is an oil vehicle. 18. The oily vehicle may be soybean oil, peanut oil, olive oil, C ₆ ~ C₁₈Mono-, di- or triglycerides of fatty acids, C₆~ C₁₈Fatty acids, poly
Ethylene glycol, polyglycolized glyceride, glycerol, propylene
Glycols, mono-, di- or triesters of propylene glycol, and
18. The method of claim 17, wherein is a polyethylene glycol. 19. The method according to claim 18, wherein the oily vehicle is soybean oil. 20. The method of claim 1, wherein the mechanical means is high shear homogenization and subsequent liquid jet atomization. 21. The method according to claim 20, wherein the suspension contains from 10 to 40% by weight of isotretinoin. 22. The method according to claim 21, wherein the suspension contains 20 to 35% by weight of isotretinoin. 23. The method of claim 20, wherein the vehicle is an oily vehicle. 24. An oily vehicle comprising soybean oil, peanut oil, olive oil, C ₆ ~ C₁₈Mono-, di- or triglycerides of fatty acids, C₆~ C₁₈Fatty acids, poly
Ethylene glycol, polyglycolized glyceride, glycerol, propylene
Glycols, mono-, di- or triesters of propylene glycol, and
24. The method of claim 23, wherein is a polyethylene glycol. 25. The method of claim 24, wherein the average particle size of the isotretinoin in the suspension ranges from about 50 μm to about 65 μm after high shear homogenization. 26. The method of claim 24, wherein the oily vehicle is soybean oil. 27. An isotretinoin having an average particle size ranging from about 5 μm to about 30 μm, suspended in an oily or other pharmaceutically acceptable vehicle, 1) an average particle size greater than about 30 μm Dispersing in a vehicle to form a suspension containing from 1 to 50% by weight of isotretinoin; 2) mechanical means of subjecting the suspension to shear, impact, cavitation or friction Reducing the average particle size of isotretinoin to a particle size in the range of about 5 μm to about 30 μm, thereby producing a micronized isotretinoin composition. An isotretinoin composition. 28. The composition according to claim 27, wherein the mechanical means is a wet mill. 29. The composition according to claim 28, wherein the suspension contains from 10 to 40% by weight of isotretinoin. 30. The composition according to claim 29, wherein the suspension contains 20-35% by weight of isotretinoin. 31. The composition according to claim 27, wherein the vehicle is an oily vehicle. 32. The oily vehicle may be soybean oil, peanut oil, olive oil, C ₆ ~ C₁₈Mono-, di- or triglycerides of fatty acids, C₆~ C₁₈Fatty acids, poly
Ethylene glycol, polyglycolized glyceride, glycerol, propylene
Glycols, mono-, di- or triesters of propylene glycol, and
32. The composition of claim 31, wherein is a polyethylene glycol. 33. The composition according to claim 32, wherein the oily vehicle is soybean oil. 34. The composition according to claim 27, wherein the mechanical means is high shear homogenization. 35. The composition according to claim 34, wherein the suspension contains from 10 to 40% by weight of isotretinoin. 36. The composition according to claim 35, wherein the suspension contains 20-35% by weight of isotretinoin. 37. The composition according to claim 34, wherein the vehicle is an oleaginous vehicle. 38. The oily vehicle is soybean oil, peanut oil, olive oil, C ₆ ~ C₁₈Mono-, di- or triglycerides of fatty acids, polyethylene glycol
Glyceride, glycerol, propylene glycol, pro
Mono-, di- or triesters of pyrene glycol or polyethylene glycol
38. The composition of claim 37, which is a recall. 39. The composition according to claim 38, wherein the oily vehicle is soybean oil. 40. The composition of claim 27, wherein the mechanical means is liquid jet micronization. 41. The composition according to claim 40, wherein the suspension contains from 10 to 40% by weight of isotretinoin. 42. The composition according to claim 41, wherein the suspension contains 20-35% by weight of isotretinoin. 43. The composition according to claim 40, wherein the vehicle is an oily vehicle. 44. The oily vehicle is soybean oil, peanut oil, olive oil, C ₆ ~ C₁₈Mono-, di- or triglycerides of fatty acids, C₆~ C₁₈Fatty acids, poly
Ethylene glycol, polyglycolized glyceride, glycerol, propylene
Glycols, mono-, di- or triesters of propylene glycol, and
44. The composition of claim 43, wherein is a polyethylene glycol. 45. The composition according to claim 44, wherein the oily vehicle is soybean oil. 46. The composition of claim 27, wherein the mechanical means is high shear homogenization and subsequent liquid jet micronization. 47. The composition according to claim 46, wherein the suspension contains from 10 to 40% by weight of isotretinoin. 48. The composition according to claim 47, wherein the suspension contains from 20 to 35% by weight of isotretinoin. 49. The composition according to claim 46, wherein the vehicle is an oily vehicle. 50. The oily vehicle is soybean oil, peanut oil, olive oil, C ₆ ~ C₁₈Mono-, di- or triglycerides of fatty acids, C₆~ C₁₈Fatty acids, poly
Ethylene glycol, polyglycolized glyceride, glycerol, propylene
Glycols, mono-, di- or triesters of propylene glycol, and
50. The composition of claim 49, wherein is a polyethylene glycol. 51. The method of claim 50, wherein the average particle size of the isotretinoin in the suspension ranges from about 50 μm to about 65 μm after high shear homogenization. 52. The composition according to claim 50, wherein the oily vehicle is soybean oil. 53. A micronized isotretinoin composition which is a composition comprising isotretinoin suspended in an oily or other pharmaceutically acceptable vehicle and having an average particle size in the range of about 5μm to about 30μm. A unit dosage form for enteral administration comprising a composition comprising: 1) isotretinoin having an average particle size of greater than about 30 μm dispersed in a vehicle to provide 1-50% by weight of isotretinoin; 2) subjecting the suspension to mechanical means to produce shear, impact, cavitation or friction, such that the average particle size of isotretinoin ranges from about 5 μm to about 30 μm. Generating a micronized isotretinoin composition, thereby comprising:
A unit dosage form for enteral administration comprising from about 1 mg to about 50 mg of isotretinoin. 54. The unit dosage form of claim 53, wherein the unit dosage form contains about 3 mg to about 25 mg of isotretinoin. 55. The unit dosage form of claim 53, wherein the mechanical means is a wet mill. 56. The unit dosage form of claim 55, wherein the suspension contains 10-40% by weight isotretinoin. 57. The unit dosage form of claim 56, wherein the suspension contains 20-35% by weight isotretinoin. 58. The unit dosage form of claim 55, wherein the vehicle is an oleaginous vehicle. 59. The oily vehicle is soybean oil, peanut oil, olive oil, C ₆ ~ C₁₈Mono-, di- or triglycerides of fatty acids, C₆~ C₁₈Fatty acids, poly
Ethylene glycol, polyglycolized glyceride, glycerol, propylene
Glycols, mono-, di- or triesters of propylene glycol, and
59. The method of claim 58, wherein is a polyethylene glycol. 60. The dosage form of claim 59, wherein the unit dosage form is a capsule. 61. The unit dosage form is a soft gelatin capsule.
The dosage form described in 1. 62. The unit dosage form of claim 59, wherein the oleaginous vehicle is soybean oil. 63. The unit dosage form of claim 53, wherein the mechanical means is high shear homogenization. 64. The unit dosage form of claim 63, wherein the suspension contains 10-40% by weight isotretinoin. 65. The unit dosage form of claim 64, wherein the suspension contains 20-35% by weight isotretinoin. 66. The unit dosage form of claim 63, wherein the vehicle is an oil vehicle. 67. The oily vehicle may be soybean oil, peanut oil, olive oil, C ₆ ~ C₁₈Mono-, di- or triglycerides of fatty acids, polyethylene glycol
Glyceride, glycerol, propylene glycol, pro
Mono-, di- or triesters of pyrene glycol or polyethylene glycol
67. The unit dosage form of claim 66, which is a recall. 68. The dosage form of claim 67, wherein the unit dosage form is a capsule. 69. The unit dosage form is a soft gelatin capsule.
The dosage form described in 1. 70. The unit dosage form of claim 67, wherein the oleaginous vehicle is soybean oil. 71. The unit dosage form of claim 53, wherein the mechanical means is liquid jet micronization. 72. The unit dosage form of claim 71, wherein the suspension contains 10-40% by weight isotretinoin. 73. The unit dosage form of claim 72, wherein the suspension contains 20-35% by weight isotretinoin. 74. The unit dosage form of claim 71, wherein the vehicle is an oil vehicle. 75. The oily vehicle is soybean oil, peanut oil, olive oil, C ₆ ~ C₁₈Mono-, di- or triglycerides of fatty acids, polyethylene glycol
Glyceride, glycerol, propylene glycol, pro
Mono-, di- or triesters of pyrene glycol or polyethylene glycol
75. The unit dosage form of claim 74, which is a recall. 76. The dosage form of claim 75, wherein the unit dosage form is a capsule. 77. The dosage form of claim 76, wherein the unit dosage form is a soft gelatin capsule. 78. The unit dosage form of claim 75, wherein the oleaginous vehicle is soybean oil. 79. The unit dosage form of claim 53, wherein the mechanical means is high shear homogenization and subsequent liquid jet micronization. 80. The unit dosage form of claim 79, wherein the suspension contains 10-40% by weight isotretinoin. 81. The unit dosage form of claim 80, wherein the suspension contains 20-35% by weight isotretinoin. 82. The unit dosage form of claim 79, wherein the vehicle is an oil vehicle. 83. The oily vehicle may be soybean oil, peanut oil, olive oil, C ₆ ~ C₁₈Mono-, di- or triglycerides of fatty acids, polyethylene glycol
Glyceride, glycerol, propylene glycol, pro
Mono-, di- or triesters of pyrene glycol or polyethylene glycol
83. The unit dosage form of claim 82, which is a recall. 84. The dosage form of claim 83, wherein the unit dosage form is a capsule. 85. The unit dosage form is a soft gelatin capsule.
The dosage form described in 1. 86. The dosage form of claim 85, wherein the mean particle size of the isotretinoin in the suspension ranges from about 50 μm to about 65 μm after high shear homogenization. 87. The unit dosage form of claim 83, wherein the oleaginous vehicle is soybean oil. 88. About 7.5 mg to about 2 having an average particle size of about 5 μm to about 30 μm.
A pharmaceutical composition comprising a suspension comprising 2.5 mg of isotretinoin, about 18% by weight of a wax, and an oil. 89. The suspension comprises about 18.2% by weight of a wax.
9. The composition according to 8. 90. The composition of claim 88, wherein the suspension comprises disodium edetate. 91. The composition of claim 88, wherein the suspension comprises butylated hydroxyanisole. 92. The composition of claim 88, wherein the suspension comprises wax containing beeswax, hydrogenated soybean oil flakes, and hydrogenated vegetable oil. 93. The composition of claim 88, wherein the suspension comprises an oil that is soybean oil. 94. Substantially 7.5 mg of isotretinoin, 5 mg of beeswax,
mg hydrogenated soybean oil flakes, 20 mg hydrogenated vegetable oil, 0.5 mg disodium edetate, 0.1 mg butylated hydroxyanisole, and 126.9.
89. The composition of claim 88, consisting of mg of soybean oil. 95. The composition of claim 94, wherein the isotretinoin has an average particle size between and including 5 μm and 26 μm. 96. Substantially 15 mg of isotretinoin, 10 mg of beeswax, 1
0 mg hydrogenated soybean oil flakes, 40 mg hydrogenated vegetable oil, 1.0 mg disodium edetate, 0.2 mg butylated hydroxyanisole, and 253.
89. The composition of claim 88, consisting of 8 mg soybean oil. 97. The composition of claim 96, wherein the isotretinoin has an average particle size between and including 5 μm and 26 μm. 98. Substantially 22.5 mg of isotretinoin, 15 mg of beeswax, 15 mg of hydrogenated soybean oil flakes, 60 mg of hydrogenated vegetable oil, 1.5 mg of disodium edetate, 0.3 mg of butylated Hydroxyanisole, and 38
89. The composition of claim 88, comprising 0.7 mg of soybean oil. 99. The composition of claim 98, wherein the isotretinoin has an average particle size between and including 5 μm and 26 μm. 100. The composition of claim 99, wherein the unit dosage form is a capsule. 101. The unit dosage form is a soft gelatin capsule.
The composition of claim 00.