US 201202590 13A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0259013 A1 Motwani et al. 43) Pub. Date: Oct. 11,9 2012 54) LIQUID DOSAGE FORMS OF ISOTRETINOIN 3O ForeignO Applicationication PriorityPriori D ata (75) Inventors: Sanjay Kumar Motwani, Bhopal May 20, 2009 (IN) ........................... 1039/DELA2009 (IN); Shashikanth P. Isloor, Publication Classification his (IN) Vinod Arora, (51) Int. Cl. urgaon (IN) A6II 3/19 (2006.01) A6IP 9/00 (2006.01) (73) Assignee: RANBAXY LABORATORIES A6IP 7/06 (2006.01) LIMITED, New Delhi, Delhi (IN) A6IP35/00 (2006.01) A6IP 700 (2006.01) A6IP 7/10 (2006.01) (21) Appl. No.: 13/320,164 A6IP 29/00 (2006.01) (52) U.S. Cl. ........................................................ 514/557 (22) PCT Filed: May 20, 2010 (57) ABSTRACT (86). PCT No.: PCT/B2O1O/O52254 The present invention relates to a pharmaceutical Solution comprising isotretinoin or salts thereof. The present invention S371 (c)(1), further relates to the processes for preparing Such composi (2), (4) Date: Jun. 25, 2012 tions. US 2012/02590 13 A1 Oct. 11, 2012 LIQUID DOSAGE FORMS OF ISOTRETINOIN forms like tablets or capsules. Thus an oral liquid is the preferred dosage form for pediatric patients. TECHNICAL FIELD OF THE INVENTION I0010 Apart from the alterations in the pharmacodynamics and pharmacokinetics, the geriatric population suffers from a 0001) The present invention relates to a pharmaceutical number of chronic conditions and physical limitations. Swal Solution comprising isotretinoin or a pharmaceutically lowing or chewing may be a problem for the elderly. For acceptable salt of isotretinoin and a process for the prepara example, patients suffering from dry mouth or who are eden tion thereof. tulous are incapable of chewing or Swallowing. This makes the liquid dosage form a popular choice with the elderly. BACKGROUND OF THE INVENTION I0011) A softgel capsule is the only dosage form available 0002) Isotretinoin is a retinoid, approved for the treatment for the oral administration of isotretinoin. However, the oral of severe recalcitrant nodular acne. Chemically, isotretinoin administration of solid forms such as tablets and capsules can is 13-cis-retinoic acid and is related to both retinoic acid and prove difficult or even dangerous for children and the elderly retinol (vitamin A). who prefer to take liquid dosage forms. Further, it has been 0003 Presently isotretinoin is marketed by Hoffman La reported that for administering isotretinoin to children or Roche under the brand name Accutane(R). This product com infants extemporaneous liquid formulations are made by prises a suspension of isotretinoin filled in soft gelatin cap piercing/cut-opening or squeezing the contents of the cap Sules. Sule. These extemporaneous preparations lead to an increased 0004 U.S. Pat. No. 4,322,438, assigned to Hoffman-La dosing variability and toxicity due to the metabolism of Roche, discloses a method of treating nodulocystic and con isotretinoin (13-cis retinoic acid) to tretinoin (all trans-ret globate acne in humans by oral administration of 13-cis inoic acid). Furthermore, the extemporaneous preparation retinoic acid in amounts and for periods of time which afford and dispensing of isotretinoin solution is not possible in a an effectively complete remission from the condition even typical hospital pharmacy set-up because of the poor solubil after administration of the compound ceases. ity, longer solubilization time, safety issues in handling a 0005 PCT Publication No. WO 00/25772, filed by Hoff teratogenic drug and photo-instability of the drug. man-La Roche, relates to soft gel capsules of isotretinoin (0012 Neuroblastoma is an embryonic malignancy of having improved bioavailability. This application discloses sympathetic nervous system and occurs almost exclusively in that the currently marketed AccutaneR) formulation of isotre infants and young children commonly aged between 1 and 5 tinoin has a mean particle size of 100 um and has a bioavail years. Currently, clinical trials are going forward to study the ability of only about 20%. Therefore, it discloses a process of effectiveness of isotretinoin in the treatment of neuroblas further reducing the particle size of isotretinoin to a range of toma in children. Treatment with isotretinoin is initiated dur about 5um to about 30 Jum, thereby improving the bioavail ing the maintenance phase. Alternate courses of isotretinoin ability of isotretinoin. and an anticancer drug are given. For example, Phase II 0006) European Patent No. EP 0 184942 B1, assigned to studies (sponsored by St. Jude Children's Research Hospital, Ortho Pharmaceutical Corporation discloses pharmaceutical NIH, AstraZeneca) on oral maintenance therapy with isotre compositions in the form of a soft gelatin capsule having no tinoin and topotecan, has been completed. These trials have more than a 22% wax content, as a critical limitation of the been conducted using isotretinoin soft gel capsules. During patent. Higher wax content tends to diminish the bioavailabil these trials children were either trained to swallow the capsule ity. or the contents from the capsule were squeezed into food 0007 U.S. Pat. No. 7,435,427, assigned to Galephar, dis causing increased dosing variability. Therefore, in the light of closes gelatin capsules comprising a semi solid suspension of prior art there is an unmet need of a stable oral liquid formu isotretinoin containing at least two lipidic excipients. lation of isotretinoin. 0008 Isotretinoin was initially developed and approved in 0013 Liquids are homogeneous preparations containing 1982 for the treatment of acne. There area number of ongoing one or more active ingredients dissolved or suspended in a Studies regarding the use of isotretinoin for treatment of mus Suitable vehicle or carrier. These include solutions, syrups, culoskeletal and connective tissue inflammations, emphy Suspensions, elixirs, or concentrates. Oral liquid dosage Sema, ulcerating diseases and various cancers, namely treat forms offer unique advantages over the solid dosage forms ing cervical tumors in HIV positive women, the prevention of like tablets and capsules. In addition to being more patient lung cancer in Smokers and the prevention of skin cancer. compliant, liquid dosage forms provide a more reproducible Studies have been recently completed or ongoing regarding bioavailability. These dosage forms provide rapid absorption the role of isotretinoin (usually in combination with other of drug from the GI tract. Additionally, liquid dosage forms drugs) in the treatment of neuroblastoma, recurrent prostrate allow the use of flavoring and/or palatability agents, which cancer, leukemia, high-grade glioma, head and neck cancers further promotes patient acceptance and compliance. Further, and multiple myeloma. Isotretinoin has also been proved to liquid formulations provide the option of a flexible dosing be useful in the treatment of certain dermatological condi regime based on body weight or body surface area. The most tions such as gram-negative folliculitis, recalcitrant rosacea, common liquid dosage forms include suspensions and solu pyoderma faciale, generalized lichen planus, psoriasis, cuta t1OnS. neous lupus erythematosus and acne fulminans, squamous (0014 Solutions offer several advantages over other liquid cell carcinoma. It is also used for the treatment of cutaneous dosage forms. These are absorbed faster and generally cause photoaging. less irritation of the gastrointestinal mucosa. Moreover, phase 0009. As is evident, many of these studies would target separation upon storage is not a concern with solutions. Com either pediatric or geriatric patients. Oral administration is the pared with suspensions, solutions are free from the gritty preferred route for children. However, children younger than feeling that particles in a suspension might cause. The other 5-6 years of age have a difficulty in Swallowing solid dosage advantages offered by the solution dosage form is that these US 2012/O2590 13 A1 Oct. 11, 2012 do not need to be shaken before use, the accuracy of the dose patient in a fed State, the Solution exhibits a maximum plasma is likely to be more than with the equivalent Suspension, no concentration (C) of isotretinoin comparable to that exhib particle growth is observed over time and it presents a homo ited under fasting state. geneous feel and taste. Another important advantage offered 0023. In another general aspect, the present invention also by solution is the reduction of lower inter-subject variability provides for a process of preparing a pharmaceutical Solution in pharmacokinetics, especially for highly variable molecules of isotretinoin. The process includes: (i) dissolving isotretin for e.g., isotretinoin. Further, a solution dosage form of isotre oin in a carrier by continuous stiffing at room temperature, or tinoin has not been available. at higher temperatures, till a homogenous solution is formed; 0015 Isotretinoin is a relatively water insoluble com and (ii) cooling the solution of step (i) to room temperature, pound and it degrades when exposed to light and atmospheric optionally, adding one or more excipients. oxygen. Further isotretinoin i.e., 13-cis retinoic acid, is a 0024. In another general aspect there is provided a process geometric isomer of tretinoin i.e., all-trans retinoic acid. of preparing a pharmaceutical Solution of isotretinoin. The These isomers show reversible interconversion. This inter process includes: (i) dissolving