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  • C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes

Definitions

• Prostacyclin derivatives are useful pharmaceutical compounds possessing activities such as platelet aggregation inhibition, gastric secretion reduction, lesion inhibition, and bronchodilation.
• Treprostinil the active ingredient in Remodulin ® , was first described in US patent 4,306,075.
• Treprostinil, and other prostacyclin derivatives have been prepared as described in Moriarty, et al in J. Org. Chem. 2004, 69, 1890-1902, Drug of the Future, 2001, 26(4), 364-374, U.S. Pat. Nos. 6,441,245, 6,528,688, 6,700,025, 6,809,223, 6,756,117 and U.S. Patent Application No. 12/334,731 filed on December 15, 2008 to Batra et al.
• U.S. Patent No. 5,153,222 describes use of treprostinil for treatment of pulmonary hypertension. Treprostinil is approved for the intravenous as well as subcutaneous route, the latter avoiding septic events associated with continuous intravenous catheters.
• U.S. patents Nos. 6,521,212 and 6,756,033 describe administration of treprostinil by inhalation for treatment of pulmonary hypertension, peripheral vascular disease and other diseases and conditions.
• U.S. patent No. 6,803,386 discloses administration of treprostinil for treating cancer such as lung, liver, brain, pancreatic, kidney, prostate, breast, colon and head-neck cancer.
• 2005/0165111 discloses treprostinil treatment of ischemic lesions.
• U.S. patent No. 7,199,157 discloses that treprostinil treatment improves kidney functions.
• U.S. patent application publication No. 2005/0282903 discloses treprostinil treatment of neuropathic foot ulcers.
• U.S. Patent application publication No. 2008/0280986 discloses treprostinil treatment of pulmonary fibrosis.
• U.S. 6,054,486 discloses treatment of peripheral vascular disease with treprostinil.
• U.S. Patent application publication No. 2009/0036465 discloses combination therapies comprising treprostinil.
• 2008/0200449 discloses delivery of treprostinil using a metered dose inhaler.
• U.S. Patent application publication No. 2008/0280986 discloses treatment of interstitial lung disease with treprostinil and treatment of asthma with treprostinil.
• treprostinil is of great importance from a medicinal point of view. Therefore, a need exists for a stable form of treprostinil which presents advantage in storage, shipment, handling, and formulation, for example.
• One embodiment of the present invention relates to a monohydrate of treprostinil, a pharmaceutical formulation comprising treprostinil monohydrate, and methods of making and using the same.
• the monohydrate is stable at room temperature over a longer period of time than other forms of treprostinil.
• a pharmaceutical formulation comprising a therapeutically effective amount of treprostinil monohydrate and a pharmaceutically acceptable carrier therefore.
• treprostinil monohydrate in treating medical conditions, including those for which it is known in the art to use treprostinil, such as those described in aforementioned J. Org. Chem. 2004, 69, 1890-1902, Drug of the Future, 2001, 26(4), 364-374, U.S. Patent Nos. 5,153,222, 6,054,486, 6,521,212, 6,756,033, 6,803,386, and 7,199,157, U.S. patent application publication Nos. 2005/0165111, 2005/0282903, 2008/0200449, 2008/0280985 and 2009/0036465.
• Figure Ia is an IR (infrared) spectrum of anhydrous treprostinil.
• Figure Ib is an IR (infrared) spectrum of treprostinil monohydrate.
• Treprostinil is the active ingredient of Remodulin®, which has been approved by the U.S. FDA for the treatment of Pulmonary Arterial Hypertension (PAH) in patients with NYHA Class II, III and IV symptoms to diminish symptoms associated with exercise using subcutaneous or intravenous administration.
• PAH Pulmonary Arterial Hypertension
• Treprostinil's chemical name is 2-((lR,2R,3aS,9aS)-2-hydroxy-l-((S)-3- hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-lH-cyclopenta[b]naphthalen-5-yloxy)acetic acid of the following structure:
• treprostinil The anhydrous form of treprostinil (TREPROSTINIL) has been previously described, e.g., inJ. Org. Chem. 2004, 69, 1890-1902.
• the anhydrous form is not stable at room temperature. Stability tests show that the anhydrous TREPROSTINIL is not stable at 25 0 C and dimers formed upon standing. A larger amount of dimers can form at higher temperatures. However, dimer formation is negligible at 5 0 C. Therefore, anhydrous treprostinil must be refrigerated for storage and transport. In the past, treprostinil had to be refrigerated and shipped with ice packs to maintain low (2°C -8 0 C) temperatures.
• anhydrous treprostinil In addition to instability, the anhydrous treprostinil is difficult to handle.
• the anhydrous form is a fine, fly-away material that is difficult to weigh because of the static electrical charge that it produces. Because treprostinil is a potent prostaglandin analogue that has strong biological activity, analysts and operators must use extreme caution when handling this material to avoid exposure.
• treprostinil can exist in a monohydrate form.
• Data has been generated to characterize a monohydrate form of treprostinil.
• One advantage of the monohydrate is that it is stable at room temperature. Stability data show that the monohydrate form is more stable than the anhydrous form at room temperature, e.g. 25°C.
• Treprostinil monohydrate can be stored and shipped with no special handling. The stability of treprostinil has been significantly improved, such that it no longer needs to be stored in a refrigerator or shipped under cold conditions.
• the second advantage of the monohydrate is that it is much easier to weigh and handle the material because the static electrical charge is greatly reduced in this form. It is much easier for personnel to avoid exposure when working with the monohydrate form. Thus, the safety in handling the material has also been improved because of the improved physical properties of the mono-hydrate.
• a monohydrate form of treprostinil In one embodiment, there is provided a monohydrate form of treprostinil. In one embodiment, the treprostinil monohydrate is in crystalline form. In one embodiment, the treprostinil monohydrate is in a form having a purity of at least 90% by weight of the composition. In one embodiment, the treprostinil monohydrate in a form having a purity of at least 95% by weight of the composition. In one embodiment, the treprostinil monohydrate has a purity of at least 99% by weight of the composition.
• the treprostinil monohydrate is stable at room temperature, and further exhibits stability across a range of temperatures from about 15°C to about 35°C, and more preferably from about 20 0 C to about 30 0 C.
• a process for the preparation of treprostinil monohydrate comprising a. recrystallizing anhydrous or wet treprostinil from an organic solvent/water combination to provide a solid; and b. air-drying the solid at ambient temperature until no additional solvents evaporate.
• the temperature for air-drying in the above process is preferably from about 15°C to about 35°C, and more preferably from about 20 0 C to about 30 0 C.
• the anhydrous or wet treprostinil being recrystallized may have a range of purity. In some embodiments, it is pure. In some embodiments, it is substantially pure. In some embodiments, it may be crude product from the synthesis. In some embodiment, the crude product of treprostinil may be solid or semisolid.
• the organic solvent may be water soluble solvent including but not limited to lower alcohol, lower ketone, and lower ether.
• the lower alcohol may be methanol, ethanol, or isopropanol for example.
• the lower ketone may be acetone, for example.
• Lower ether may be tetrahydrofuran or dioxane, for example.
• the ratio of organic solvent/water may be about 1 : 1 , or about 1 :2, or about 1 :3, or about 1 :4, or about 1 :5, or about 2: 1 , or about 3 : 1 , or about 4: 1 , or about 5:1.
• the organic solvent is ethanol.
• the ratio of organic solvent/water is 1 :1.
• One embodiment of the invention is treprostinil monohydrate prepared according to the aforementioned process.
• Another embodiment is a pharmaceutical formulation comprising treprostinil monohydrate and a pharmaceutically acceptable carrier or excipient.
• pharmaceutical when used herein as an adjective means substantially non-deleterious to the recipient mammal.
• pharmaceutical formulation it is meant the carrier, diluent, excipients and active ingredient(s) must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
• Treprostinil monohydrate can be formulated prior to administration.
• the selection of the formulation should be decided by the attending physician taking into consideration the same factors involved with determining the effective amount.
• the total active ingredients in such formulations comprises from 0.1% to 99.9% by weight of the formulation.
• Treprostinil monohydrate can be formulated with one or more additional active ingredients or as the sole active ingredient.
• compositions of the present invention are prepared by procedures known in the art using well known and readily available ingredients.
• treprostinil monohydrate either alone, or in combination with other active ingredient(s) are formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, solutions, injectables, aerosols, powders, and the like.
• compositions of this invention for parenteral administration comprise sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders which are reconstituted immediately prior to use into sterile solutions or suspensions.
• suitable sterile aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, physiological saline solution, ethanol, polyols (such as glycerol, propylene glycol, poly(ethylene glycol), and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
• Parenteral formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms is ensured by the inclusion of antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like.
• Injectable formulations are sterilized, for example, by filtration through bacterial- retaining filters, or by presterilization of the components of the mixture prior to their admixture, either at the time of manufacture or just prior to administration (as in the example of a dual chamber syringe package).
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• treprostinil monohydrate is mixed with at least one inert, pharmaceutical carrier such as sodium citrate, or dicalcium phosphate, and/or (a) fillers or extenders such as starches, sugars including lactose and glucose, mannitol, and silicic acid, (b) binding agents such as carboxymethyl- cellulose and other cellulose derivatives, alginates, gelatin, poly(vinylpyrrolidine), sucrose and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, sodium bicarbonate, potato or tapioca starch, alginic acid, silicates and sodium carbonate, (e) moisturizing agents such as glycerol; (f) solution retarding agents such as paraffin, (g) absorption accelerating agents such as quatern
• Solid formulations of a similar type may also comprise the fill in soft or hard gelatin capsules using excipients such as lactose as well as high molecular weight poly(ethylene glycols) and the like.
• Solid dosage forms such as tablets, dragees, capsules, pills and granules can also be prepared with coatings or shells such as enteric coatings or other coatings well known in the pharmaceutical formulating art.
• the coatings may contain opacifying agents or agents which release the active ingredient(s) in a particular part of the digestive tract, as for example, acid soluble coatings for release of the active ingredient(s) in the stomach, or base soluble coatings for release of the active ingredient(s) in the intestinal tract.
• the active ingredient(s) may also be microencapsulated in a sustained-release coating, with the microcapsules being made part of a pill of capsule formulation.
• Liquid dosage forms for oral administration of monohydrate treprostinil include solution, emulsions, suspensions, syrups and elixirs.
• liquid formulations may include inert diluents commonly used in the art such as water or other pharmaceutical solvents, solubilizing agents and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, ground nut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, poly(ethylene glycols), fatty acid esters of sorbitol, and mixtures thereof.
• inert diluents commonly used in the art such as water or other pharmaceutical solvents
• solubilizing agents and emulsifiers such
• liquid oral formulations may also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
• Liquid suspension in addition to the active ingredient(s) may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite clay, agar-agar, and tragacanth, and mixtures thereof.
• Another embodiment is a method of treating a medical condition comprising administering a therapeutically effective amount of the aforementioned pharmaceutical formulation comprising the treprostinil monohydrate to a subject in need thereof.
• the medical conditions being treated include but not limited to pulmonary hypertension (including primary and secondary pulmonary hypertension and pulmonary arterial hypertension), congestive heart failure, peripheral vascular disease, asthma, severe intermittent claudication, immunosuppression, proliferative diseases, cancer such as lung, liver, brain, pancreatic, kidney, prostate, breast, colon and head-neck cancer, ischemic lesions, neuropathic foot ulcers, and pulmonary fibrosis, kidney function, and interstitial lung disease.
• the pharmaceutical formulation may comprise one or more active ingredients in addition to treprostinil monohydrate.
• active ingredients in addition to treprostinil monohydrate.
• TREPROSTINIL was recrystallized from a 50% aqueous solution of ethanol. The "wet" solid was collected by filtration and air-dried at ambient temperature until no additional solvents evaporate. The monohydrate was the result of this drying process.
• the anhydrous treprostinil was prepared according to the following procedure.
• a 3.34-kg sample of treprostinil diethanolamine salt was dissolved in 40 L of sterile water, 60 L of ethyl acetate and 3.2 L of 3 M HCl were added and the mixture stirred. The layers were separated and the aqueous layer was extracted thrice with 20-L portions of ethyl acetate. The four organic layers were combined, the organic solution washed twice with 20-L portions of sterile water, once with 20 L of brine and dried over 2.97 kg of anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to yield treprostinil as a gummy solid. This solid was transferred to glass drying trays and let air-dry for 93 hours.
• the treprostinil monohydrate was prepared according to the following procedure.
• a 3.4-kg sample of treprostinil diethanolamine salt was dissolved in 36 L of sterile water, 60 L of ethyl acetate and 3.6 L of 3 M HCl were added and the mixture stirred. The layers were separated and the aqueous layer was extracted thrice with 20- L portions of ethyl acetate. The four organic layers were combined, the organic solution washed twice with 20-L portions of sterile water, once with 20 L of brine and dried over 2.86 kg of anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to yield treprostinil as a gummy solid. This solid was transferred to glass drying trays and let air-dry for 66 hours.
• This solid was then dissolved in 23.8 kg of ethanol, warmed to 48 0 C and treated with 23.8 kg of warm (40-50 0 C) sterile water. The solution was stirred and then stirring was stopped to allow the treprostinil to slowly crystallize. The resulting white solid was collected by filtration in an Aurora filter, washed with 45 L of a cold (6 0 C) 20% ethanol in sterile water solution, the filter moved to a Hepa-filtered Finishing Room and the solid dried under house vacuum for 23 hours. The solid was transferred to glass drying trays and further air-dried for 115 hours until the total weight of the material was constant (no further solvent loss).
• Stability data collected on TREPROSTINIL lot D- 1007-089 shows that the monohydrate is more stable than the anhydrous form at ambient temperatures.
• One of the stability studies has followed the monohydrate of TREPROSTINIL stored in an open container. The one mole of water has not disappeared from the solid over 18- months indicating that the water is an integral part of the crystalline structure, and the material is not just a "wet" solid.
• Treprostinil monohydrate samples were stored in Nalgene 125 ml, HDPE bottles.
• the experimental procedure used in this experiment was the same as the described above procedure for lot D- 1007-089.

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