OA12008A - Bioavailable dosage form of isotretinoin. - Google Patents
Bioavailable dosage form of isotretinoin. Download PDFInfo
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- OA12008A OA12008A OA1200200055A OA1200200055A OA12008A OA 12008 A OA12008 A OA 12008A OA 1200200055 A OA1200200055 A OA 1200200055A OA 1200200055 A OA1200200055 A OA 1200200055A OA 12008 A OA12008 A OA 12008A
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- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 title claims abstract description 31
- 229960005280 isotretinoin Drugs 0.000 title claims abstract description 31
- 239000002552 dosage form Substances 0.000 title abstract description 3
- 229940079593 drug Drugs 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 30
- 239000000203 mixture Substances 0.000 claims description 34
- 238000009472 formulation Methods 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 18
- 239000002245 particle Substances 0.000 claims description 18
- 239000003921 oil Substances 0.000 claims description 10
- 235000019198 oils Nutrition 0.000 claims description 10
- 239000000375 suspending agent Substances 0.000 claims description 8
- 244000068988 Glycine max Species 0.000 claims description 7
- 235000010469 Glycine max Nutrition 0.000 claims description 7
- 239000002738 chelating agent Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 5
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 5
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 5
- 229940095259 butylated hydroxytoluene Drugs 0.000 claims description 5
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 3
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 235000010385 ascorbyl palmitate Nutrition 0.000 claims description 3
- 239000007963 capsule composition Substances 0.000 claims description 3
- 239000002385 cottonseed oil Substances 0.000 claims description 3
- 235000012343 cottonseed oil Nutrition 0.000 claims description 3
- 239000002480 mineral oil Substances 0.000 claims description 3
- 235000010446 mineral oil Nutrition 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000008159 sesame oil Substances 0.000 claims description 3
- 235000011803 sesame oil Nutrition 0.000 claims description 3
- 235000012424 soybean oil Nutrition 0.000 claims description 3
- 235000004835 α-tocopherol Nutrition 0.000 claims description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229930002330 retinoic acid Natural products 0.000 claims description 2
- 239000003549 soybean oil Substances 0.000 claims description 2
- 229940045860 white wax Drugs 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 5
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims 4
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims 2
- SHWNNYZBHZIQQV-UHFFFAOYSA-J EDTA monocalcium diisodium salt Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-J 0.000 claims 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims 2
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims 2
- 239000007800 oxidant agent Substances 0.000 claims 2
- 235000010388 propyl gallate Nutrition 0.000 claims 2
- 239000000473 propyl gallate Substances 0.000 claims 2
- 229940075579 propyl gallate Drugs 0.000 claims 2
- 239000011782 vitamin Substances 0.000 claims 2
- 229930003231 vitamin Natural products 0.000 claims 2
- 235000013343 vitamin Nutrition 0.000 claims 2
- 229940088594 vitamin Drugs 0.000 claims 2
- 150000003722 vitamin derivatives Chemical class 0.000 claims 2
- 150000003772 α-tocopherols Chemical class 0.000 claims 2
- 238000003801 milling Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 3
- 239000001301 oxygen Substances 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 239000012876 carrier material Substances 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-HWCYFHEPSA-N 13-cis-retinol Chemical compound OC/C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-HWCYFHEPSA-N 0.000 description 1
- 208000006069 Corneal Opacity Diseases 0.000 description 1
- 208000001140 Night Blindness Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- RXDLGFMMQFNVLI-UHFFFAOYSA-N [Na].[Na].[Ca] Chemical compound [Na].[Na].[Ca] RXDLGFMMQFNVLI-UHFFFAOYSA-N 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 231100000269 corneal opacity Toxicity 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 208000037828 epithelial carcinoma Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910000679 solder Inorganic materials 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/07—Retinol compounds, e.g. vitamin A
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
1 2008
BIOAVAILABLE DOSAGE FORM OF ISOTRETINOIN
FIELD OF THE INVENTION
The présent invention relates to a bioavailable pharmaceutical 5 composition of 13-cis vitamin A acid (also known as 13-cis retinoic acid andisotretinoin) and a process for preparing the same. 13-cis vitamin A acid is arelatively water insoluble compound that dégradés when exposed to light andatmospheric oxygen. Due to its instability and relative insolubility, thebioavailability of the drug after oral administration is difficult to achieve and 10 has always been a challenge to a development pharmacist. It would thereforebe désirable to provide a dosage form in which the drug is stable andpredictably bioavailable.
BACKGROUND OF THE INVENTION U.S. Patent No. 4,464,394 assigned to Hoffman LaRoche Inc. 15 discloses compositions and methods of using 13-cis vitamin A acid againstthe development of epithélial carcinomas of the skin, gastrointestinal tract,respiratory tract or genrto-urinary tract. However, only a general description ofthe composition is given in this patent and no data on the bioavailability of theactive ingrédient in the composition is disclosed. 20 European Patent No. 184942 assigned to Ortho Pharmaceutical Corp. discloses pharmaceutical compositions having not more than 22% waxcontent which is a critical limitation of this patent, as higher wax content tendsto diminish the bioavailability. The partie,e size of the drug is also reduced toless than 12pm prior to its incorporation into the formulation. Said objectives 1 1 2008 of the bioavailability are achieved by controlling the particle size and the waxcontent. As 13-cis vitamin A may cause decreased night vision and cornealopacities at higher concentrations, its micronization in the powder State canbe hazardous as this involves a lot of dry powder handling. Further, handling 5 of isotretinoin at room température under atmospheric oxygen can lead to itsdégradation, as it is a highly unstable drug.
SUMMARY OF THE INVENTION
It is an object of the présent invention to solve the problems associatedwith the prior art and to provide a process which uses conditions thaï are 10 convenient to perform on a commercial scale and are operationally safe.
More particularly, the présent invention relates to a process of makingbioavailable capsule formulation of 13-cis vitamin A acid comprising the stepsof (a) mixing the drug with the carrier to form the médicament paste (b) millingthe médicament paste to achieve a particle size less than 300 pm, and (c) 15 mixing the milled médicament paste with the suspending agent, and optionallywith carrier material and other pharmaceuticaliy acceptable excipients.
It is observed that the particle size is critical in achieving the bio-equivaience against the commercially available marketed formulation ofisotretinoin sold under the trade name of "Accutane". In preferred 20 embodiments of the invention, the particle size of 13-cis vitamin A acid in themédicament paste is less than 275 μιτι. The surface area of the drug in themédicament paste varies between 0.05 - 0.3 sq m/g. The medicated paste ismilled using any of the conventionally known techniques, such as bail mlll,colloid mill etc. 2 1 2008
The carrier material used in accordance with the présent invention maybe selected from the group consisting of peanut oïl, soyabean oïl, sesame oil,minerai oil, cotton seed oil, polyethylene glycol and mixtures thereof.
The suspending agent used in accordance with the présent invention is5 a wax mixture comprising 1 part hydrogenated soyabean oil, 1.2 parts whitewax and 4.2 parts hydrogenated vegetable oil. The suspending agent is usedin amounts of more than 30% of the formulation. More preferably, thesuspending agent is used in amounts between 30-40% w/w of the formulation.
The formulation of the présent invention may further contain suitable10 pharmaceutical excipients such as anti-oxidants and chelating agents.
The anti-oxidant employed in the présent invention may be selectedfrom the group consisting of α-tocopherol, butyiated hydroxyanisole (BHA),butylated hydroxytoluene (BHT), ascorbyl palmitate and propyi gallate.Chelating agents may be chosen amongst disodium edetate and calcium 15 disodium edetate.
Investigations were conducted in order to détermine the effect ofparticle size on the bioavailability of 13-cis vitamin A acid in the formulationsof this invention. The blood levels of the drug were compared with that of thecommercially available formulation of 13-cis vitamin A acid sold as a soft 20 gelatin capsule, under the trade name of "Accutane". The area under theplasma concentration (13-cis vitamin A acid) vs. time curve (AUC) wasdetermined between time "0" and time "t" to give the AUC(0-t) values and wasthen extrapolated to infinity («> ) to calculate the value till there was no moredrug in the plasma. This value is reported as AUC^j. The maximum plasma 3 1 2008 concentration (Cmax) was also determined for each subject after each treatment.
DETAILED DESCRIPTION OF THE INVENTION
The following examples further illustrate the invention but are not5 intended to limit the scope of the invention.
Soft gelatin capsules were prepared as described in Table 1.
Table 1
Amount (mg) Isotretinoin 40 Wax mixture* 97.86 Butylated hydroxytoluene 0.032 Disodium edetate 0.160 Soyabean oil 181.0 Total 320.0 * The wax mixture was composed of hydrogenated soyabean oil> white 10 wax and hydrogenated vegetable oil in the ratio of 1:1.2:4.2.
Isotretinoin was mixed with soyabean oil to form a 25% dispersion ormedicated paste. The medicated paste was milled and the particle size of thedrug in the paste following milling was determined. The remaining amount ofthe carrier material (soyabean oil), wax mixture and other ingrédients were 15 then added to the milled medicated paste and mixed with stining. Theformulation so prepared was used to study the effect of particle size on thebioavailability of the drug keeping ail the other formulation parametersconstant. 4 1 2008 EXAMPLE 1
The particle size of the drug in the medicated paste was 90% less than240 pm and 50% less than 118 pm. The surface area of the drug in the pastevaried between 0.06 - 0.13 sq m/g. 5 This formulation was subjected to a two way cross over bioequivalence study with Accutane (which was the référencé product). Seventeen normal,male subjects were enrolled in each study. Whole blood samples were drawnat selected times following each treatment. Biood levels of the drug for bothtest and référencé were determined and compared for the two critical 10 parameters of AUC and Cmax. (Table 1.1). Test is the formulation madeaccording to the présent invention and référencé is the formulation of 13-cisVitamin A acid sold under the trade name of "Accutane''.
Table 1.1 AUC (o_t) AUC (o-«} Cmax (pg/ml) Test/Reference (%) 110 108 107.8 15 EXAMPLE 2
Keeping ail the other parameters constant, the average particle size ofthe drug in the medicated paste was increased to 90% below 276 pm and50% below 169 pm and its surface area was between 0.05 - 0.18 sq. m/g.
This formulation was subjected to a bioequivalence study on 1920 healthy, male subjects. Blood samples were drawn at selected intervalsfollowing each treatment, the plasma samples were assayed for 13-cis 5 1 2008
Vitamin A acid to détermine the AUC and Cmax as compared to "Accutane".
The resuits are shown in Table 2.1.
Table 2.1 AUC (o-t) AUC (ο.») Cmax (pg/ml) Test/Reference (%) 76.72 80.60 84.64 5 EXAMPLE 3
In the next experiment the particle size was reduced to study its effecton the bioavailability of the drug when compared with "Accutane". Theparticle size of the drug in the medicated paste was reduced to 90% beiow131 pm and 50% below 52.4pm. The surface area was around 0.20 sq. m/g. 10 Bioequivalence study was carried on 19 healthy male subjects and the test / référencé ratios for AUC and Cmax were compared with Accutane asthe référencé product.
Table 3.1 AUC (o-t) AUC (ο-») Cmax (pg/ml) Test/Reference (%) 124.5 126.8 127.0 15 EXAMPLE 4
The particle size of the drug in the medicated paste was 90% less than225 pm and 50% less than 110 pm. The particle size was between 0.09 to0.11 sq m/g. The effect of this particle size on the bioavailability of the drug 20 was determined as described in Example 1 and the test référencé ratios were compared with Accutane as the référencé product (Table 4.1). 6
Table 4.1 1 2008 AUC (o-t) AUC (o-oo) Cmax (pg/ml) Test/Reference (%) 91.5 9.2.7 94.0
While the présent invention has been described in terms of its spécifie5 embodiments, certain modifications and équivalents will be apparent to thoseskilled in the art and are intended to be included withïn the scope of the présent invention. 7
Claims (26)
1 2008 WE CLAIM:
1. A bioavailable capsule formulation of 13-cis vitamin A acid, saidformulation comprising: (a) a médicament paste of 13-cis vitamin A acid and a carrier, saidacid having a particle size of less than 300 μηη; and 5 (b) a suspending agent and other pharmaceutically acceptable excipi-ents.
2. The formulation of claim 1 wherein the acid has a particle size of 90%less than about 240 pm and 50% less than about 118 gm.
3. The formulation of claim 1 wherein the acid has a particle size of 90% 10 less than about 131 pm and 50% less than about 52 μηη.
4. The formulation of claim 1 wherein the particle size of the acid is lessthan 275 μπι.
5. The formulation of claim 1 wherein the surface area of 13-cis vitamin Aacid is between 0.05 - 0.3 sq. m/g.
6. The formulation of claim 1 wherein the carrier is selected from thegroup consisting of peanut oil, soyabean oil, sesame oïl, minerai oil,cotton seed oil and polyethylene glycol.
7. The formulation of claim 1 wherein the suspending agent is a wax mix- St© ture comprising 1 part hydrogenated soyabean oil, 1.2 parts white waxand 4.2 parts hydrogenated vegetable oil. 8 1 2008
8. The formulation of claim 7 comprising more thah 30 weight percent ofthe suspending agent.
9. The formulation of claim 8 wherein the suspending agent is preferablybetween 30-40 weight percent.
10. The formulation of claim 1 wherein the dosage form may contain other pharmaceutically acceptable excipients such as chelating agents andanti-oxidants. 15
11. The formulation of claim 10 wherein the chelating agent is selectedfrom amongst disodium edetate and calcium disodium edetate.
12. The formulation of claim 10, wherein the anti-oxidants are selectedfrom the group consisting α-tocopherols, butylated hydroxyanisole,butylated hydroxytoluene, ascorbyl palmitate and propyl gallate.
13. The formulation of claim 1 wherein the drug in the médicament paste ismilled by conventional techniques such as bail mill or colloid mill.
14. A process for the préparation of a bioavailable capsule formulation of13-cis vitamin A acid comprising the steps of: (a) mixing the acid with the carrier to form a médicament paste; (b) milling the médicament paste to achieve a particle size of said acidof less than 300 pm; and (c) mixing the milled medicated paste with a suspending agent andother pharmaceutically acceptable excipients. 2© 9 1 2008 10 15
15. The process of claim 14 wherein the acid has a particle size of 90%less than about 240 pm and 50% less than about 118 pm.
16. The process of claim 14 wherein the acid has a particle size of 90%less than about 131 pm and 50% less than about 52 pm.
17. The process of claim 14 wherein the particle size of the acid is lessthan 275 pm.
18. The process of claim 14 wherein the surface area of 13-cis vitamin Aacid is between 0.05 - 0.3 sq m/g.
19. The process of claim 14 wherein the carrier is seiected from the groupconsisting of peanut oïl, soyabean oil, sesame oil, minerai oil, cottonseed oil and polyethylene glycol.
20. The process of claim 14 wherein the suspendïng agent is a waxmixture comprising 1 part hydrogenated soyabean oil, 1.2 parts whitewax and 4.2 parts hydrogenated vegetable oil.
21. The process of claim 20 comprising more than 30 weight percent of thesuspending agent.
22. The process of claim 21 wherein the suspending agent is preferablybetween 30-40 weight percent.
23. The process of claim 14 wherein the dosage form may contain otherpharmaceutically acceptable excipients such as chelating agents andanti-oxidants. 20 10 1 2008 1 t.
24. The process of claim 23 wherein the chelating agent is selected fromamongst disodium edetate and calcium disodium edetate.
25. The process of claim 23 wherein the anti-oxidants are selected fromthe group consisting α-tocopherols, butylated hydroxyanisole, butylatedhydroxytoluene, ascorbyl palmitate and propyl gallate.
26. The process of claim 14 wherein the drug in the médicament paste ismilled by conventional techniques such as bail mill or colloid mill. 11
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN596DE2000 IN192188B (fr) | 2000-06-16 | 2000-06-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA12008A true OA12008A (en) | 2006-04-19 |
Family
ID=11097063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| OA1200200055A OA12008A (en) | 2000-06-16 | 2001-04-09 | Bioavailable dosage form of isotretinoin. |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US6740337B2 (fr) |
| EP (1) | EP1294357A1 (fr) |
| JP (1) | JP2004503493A (fr) |
| CN (1) | CN1196475C (fr) |
| AP (1) | AP2002002423A0 (fr) |
| AU (1) | AU782094B2 (fr) |
| BG (1) | BG106414A (fr) |
| BR (1) | BR0106752A (fr) |
| CA (1) | CA2382065A1 (fr) |
| CZ (1) | CZ2002694A3 (fr) |
| EA (1) | EA004808B1 (fr) |
| EE (1) | EE200200074A (fr) |
| HK (1) | HK1052302A1 (fr) |
| HR (1) | HRP20020148A2 (fr) |
| HU (1) | HUP0203717A3 (fr) |
| IL (1) | IL148176A0 (fr) |
| IN (1) | IN192188B (fr) |
| MX (1) | MXPA02001669A (fr) |
| NZ (1) | NZ517142A (fr) |
| OA (1) | OA12008A (fr) |
| PL (1) | PL352838A1 (fr) |
| SK (1) | SK2252002A3 (fr) |
| UA (1) | UA74793C2 (fr) |
| WO (1) | WO2001095886A1 (fr) |
| ZA (1) | ZA200201240B (fr) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2001289438A1 (en) * | 2000-09-22 | 2002-04-02 | Galephar M/F | Pharmaceutical semi-solid composition of isotretinoin |
| EP1527774A1 (fr) | 2003-11-03 | 2005-05-04 | Basilea Pharmaceutica AG | Formulations nouvelle pour retinoides contenant capsules de gélatine molle |
| MXPA05012632A (es) * | 2003-05-20 | 2006-02-22 | Ranbaxy Lab Ltd | Composiciones farmaceuticas de acitretin. |
| US20070254858A1 (en) * | 2006-04-27 | 2007-11-01 | Cronk Peter J | Contraceptive and Acne Medication Combination and Treatment of Acne and Other Diseases with Reduced Side Effects |
| US20070254025A1 (en) * | 2006-04-27 | 2007-11-01 | Cronk Peter J | Oral contraceptive and acne medication combination and treatment of acne with reduced side effects |
| RU2322998C1 (ru) * | 2006-11-16 | 2008-04-27 | Общество с ограниченной ответственностью "Березовый мир" | Носитель лекарственных и диагностических средств |
| AU2008215659B2 (en) | 2007-02-16 | 2012-11-01 | Aska Pharmaceutical Co., Ltd. | Pharmaceutical composition comprising microparticle oily suspension |
| US7763748B2 (en) * | 2007-02-20 | 2010-07-27 | Ipca Laboratories Limited | Process for preparation of highly pure isotretinoin |
| US9078925B2 (en) | 2012-06-18 | 2015-07-14 | Galephar Pharmaceutical Research, Inc. | Pharmaceutical semi-solid composition of isotretinoin |
| RU2017141029A (ru) * | 2015-05-25 | 2019-06-25 | Сан Фармасьютикал Индастриз Лимитед | Фармацевтическая пероральная композиция изотретиноина для применения один раз в сутки |
| WO2017203365A1 (fr) | 2016-05-26 | 2017-11-30 | Dr. Reddy's Laboratiories Ltd. | Compositions pharmaceutiques pour le traitement de l'acné |
| US12016830B2 (en) * | 2022-07-01 | 2024-06-25 | Acrotech Biopharma, LLC | Pharmaceutical compositions comprising isotretinoin and processes for preparation and uses thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4016254A (en) * | 1972-05-19 | 1977-04-05 | Beecham Group Limited | Pharmaceutical formulations |
| CA1282326C (fr) * | 1984-12-14 | 1991-04-02 | Paul J. Jarosz | Compose pharmaceutique contenant de la vitamine a 13-cis acide comme ingredient actif |
| US4808630A (en) | 1987-01-16 | 1989-02-28 | United States Of America | Method of treating psychotic illnesses |
| US6045829A (en) * | 1997-02-13 | 2000-04-04 | Elan Pharma International Limited | Nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers |
| PE20001227A1 (es) * | 1998-10-30 | 2000-11-06 | Hoffmann La Roche | Procesos para producir una composicion de isotretinoina |
| US6284283B1 (en) * | 1999-10-21 | 2001-09-04 | Alkermes Controlled Therapeutics, Inc. | Method of producing sub-micron particles of biologically active agents and uses thereof |
-
2000
- 2000-06-16 IN IN596DE2000 patent/IN192188B/en unknown
-
2001
- 2001-04-09 CA CA002382065A patent/CA2382065A1/fr not_active Abandoned
- 2001-04-09 EE EEP200200074A patent/EE200200074A/xx unknown
- 2001-04-09 IL IL14817601A patent/IL148176A0/xx unknown
- 2001-04-09 BR BR0106752-4A patent/BR0106752A/pt not_active IP Right Cessation
- 2001-04-09 WO PCT/IB2001/000581 patent/WO2001095886A1/fr not_active Ceased
- 2001-04-09 HK HK03104641.2A patent/HK1052302A1/zh unknown
- 2001-04-09 AU AU44459/01A patent/AU782094B2/en not_active Ceased
- 2001-04-09 EA EA200200166A patent/EA004808B1/ru not_active IP Right Cessation
- 2001-04-09 SK SK225-2002A patent/SK2252002A3/sk unknown
- 2001-04-09 HR HR20020148A patent/HRP20020148A2/hr not_active Application Discontinuation
- 2001-04-09 CN CNB018024173A patent/CN1196475C/zh not_active Expired - Fee Related
- 2001-04-09 MX MXPA02001669A patent/MXPA02001669A/es active IP Right Grant
- 2001-04-09 JP JP2002510065A patent/JP2004503493A/ja active Pending
- 2001-04-09 NZ NZ517142A patent/NZ517142A/en unknown
- 2001-04-09 AP APAP/P/2002/002423A patent/AP2002002423A0/en unknown
- 2001-04-09 OA OA1200200055A patent/OA12008A/fr unknown
- 2001-04-09 HU HU0203717A patent/HUP0203717A3/hu unknown
- 2001-04-09 US US09/829,246 patent/US6740337B2/en not_active Expired - Fee Related
- 2001-04-09 PL PL01352838A patent/PL352838A1/xx not_active Application Discontinuation
- 2001-04-09 EP EP01917381A patent/EP1294357A1/fr not_active Withdrawn
- 2001-04-09 CZ CZ2002694A patent/CZ2002694A3/cs unknown
- 2001-09-04 UA UA2002031946A patent/UA74793C2/uk unknown
-
2002
- 2002-02-13 ZA ZA200201240A patent/ZA200201240B/en unknown
- 2002-02-14 BG BG06414A patent/BG106414A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SK2252002A3 (en) | 2002-08-06 |
| ZA200201240B (en) | 2002-09-02 |
| BR0106752A (pt) | 2002-04-16 |
| AP2002002423A0 (en) | 2002-03-31 |
| HRP20020148A2 (en) | 2003-12-31 |
| AU782094B2 (en) | 2005-06-30 |
| HUP0203717A2 (hu) | 2003-04-28 |
| PL352838A1 (en) | 2003-09-08 |
| IN192188B (fr) | 2004-03-13 |
| WO2001095886A1 (fr) | 2001-12-20 |
| BG106414A (en) | 2002-09-30 |
| EA004808B1 (ru) | 2004-08-26 |
| HUP0203717A3 (en) | 2003-05-28 |
| EA200200166A1 (ru) | 2002-10-31 |
| NZ517142A (en) | 2003-08-29 |
| CZ2002694A3 (cs) | 2002-08-14 |
| US20020025338A1 (en) | 2002-02-28 |
| EE200200074A (et) | 2003-04-15 |
| UA74793C2 (en) | 2006-02-15 |
| AU4445901A (en) | 2001-12-24 |
| HK1052302A1 (zh) | 2003-09-11 |
| EP1294357A1 (fr) | 2003-03-26 |
| CA2382065A1 (fr) | 2001-12-20 |
| JP2004503493A (ja) | 2004-02-05 |
| US6740337B2 (en) | 2004-05-25 |
| CN1388757A (zh) | 2003-01-01 |
| CN1196475C (zh) | 2005-04-13 |
| IL148176A0 (en) | 2002-09-12 |
| MXPA02001669A (es) | 2002-08-06 |
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