- Inhaled Treprostinil-Prodrug Lipid Nanoparticle Formulations Provide Long-Acting Pulmonary Vasodilation
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Treprostinil (TRE), a prostanoid analogue approved in the USA for the treatment of pulmonary arterial hypertension, requires continuous infusion or multiple dosing sessions per day for inhaled and oral routes of administration due to its short half-life. The inhaled drug is known to induce adverse systemic and local effects including headache, nausea, cough, and throat irritation which may be due at least in part to transiently high drug concentrations in the lungs and plasma immediately following administration [1]. To ameliorate these side effects and reduce dosing frequency we designed an inhaled slow-release TRE formulation. TRE was chemically modified to be an alkyl prodrug (TPD) which was then packaged into a lipid nanoparticle (LNP) carrier. Preclinical screening in a rat model of hypoxia-induced pulmonary vasoconstriction led to selection of a 16-carbon alkyl ester derivative of TRE. The TPD-LNP demonstrated approximately 10-fold lower TRE plasma C max compared to inhaled TRE solution while maintaining an extended vasodilatory effect. The favorable PK profile is attributed to gradual dissociation of TPD from the LNP and subsequent conversion to TRE. Together, this sustained presentation of TRE to the lungs and plasma is consistent with a once- or twice-daily dosing schedule in the absence of high C max -associated adverse events which could provide patients with an improved treprostinil therapy.
- Leifer, Franziska G.,Konicek, Donna M.,Chen, Kuan-Ju,Plaunt, Adam J.,Salvail, Dany,Laurent, Charles E.,Corboz, Michel R.,Li, Zhili,Chapman, Richard W.,Perkins, Walter R.,Malinin, Vladimir
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- Synthetic routes to treprostinil N-acyl methylsulfonamide
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The synthesis of the prodrug candidate, treprostinil N-acyl methylsulfonamide 5 was accomplished from treprostinil 2 utilising protecting group strategies. A more direct synthesis for the prodrug was also achieved using a treprostinil triol precursor 12 and bromoacetyl acylmethylsulfonamide 14. The overall yield of treprostinil N-acyl sulfonamide 5 directly from the triol precursor 12 is similar to the protecting group strategies because deprotonation of the acidic proton in the bromoacetyl acylmethylsulfonamide 14 reduces electrophilicity. However, the more direct route using the treprostinil triol precursor holds greater promise as a strategy to prepare a wide range of treprostinil prodrug candidates. Treprostinil N-acyl methylsulfonamide prodrug 5 exhibited a 30-fold decrease in the potency at the human prostacyclin (IP) receptor compared to treprostinil 2 in an in vitro cyclic AMP assay.
- Brocchini, Steve,Clapp, Lucie H.,Laing, Peter,Picken, Christina,Shen, Lei
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- PROCESS FOR THE PREPARATION OF TREPROSTINIL
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The invention provides a new process for the preparation of treprostinil of formula (I) and its salts using several new intermediates during the building of the ringsystem.
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Page/Page column 54; 55
(2016/05/02)
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- PROSTACYCLIN COMPOUNDS, COMPOSITIONS AND METHODS OF USE THEREOF
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Prostacyclin compounds and compositions comprising the same are provided herein. Specifically, prostacyclin compounds comprising treprostinil covalently linked to a linear C2-C18 alkyl, branched C3-C18 alkyl, linear C2-C18 alkenyl, branched C3-C18 alkenyl, aryl, aryl-C1-C18 alkyl or an amino acid or a peptide (e.g., dipeptide, tripeptide, tetrapeptide) are described, for example, for administration via subcutaneous or intravenous infusion to a patient in need of pulmonary hypertension treatment. The linkage, in one embodiment, is via a carbamate, amide or ester bond. Prostacyclin compounds provided herein can also include at least one hydrogen atom substituted with at least one deuterium atom.
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Paragraph 00274; 00275; 00276
(2016/11/17)
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- AMINE SALTS OF A PROSTACYCLIN ANALOG
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The present invention provides amine salts of the prostacyclin analogue of Formula I and processes for generating these amine salts.
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Paragraph 0410; 0411
(2015/06/03)
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- PROSTACYCLIN COMPOUNDS, COMPOSITIONS AND METHODS OF USE THEREOF
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Prostacyclin compounds and compositions comprising the same are provided herein. Specifically, prostacyclin compounds comprising treprostinil covalently linked to a linear C5-C18 alkyl, branched C5-C18 alkyl, linear C2-C18 alkenyl, branched C3-C18 alkenyl, aryl, aryl-C1-C18 alkyl or an amino acid or a peptide (e.g., dipeptide, tripeptide, tetrapeptide) are described. The linkage, in one embodiment, is via a carbamate, amide or ester bond. Prostacyclin compounds provided herein can also include at least one hydrogen atom substituted with at least one deuterium atom. Methods for treating pulmonary hypertension (e.g., pulmonary arterial hypertension) and portopulmonary hypertension are also provided.
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Paragraph 00223; 00224
(2015/05/06)
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- METHODS OF SYNTHESIZING A PROSTACYCLIN ANALOG
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The present invention provides processes for preparing a prostacyclin analogue of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R10 is a linear or branched C1-6 alkyl. The processes of the present invention comprise steps that generate improved yields and fewer byproducts than traditional methods. The processes of the present invention employ reagents (e.g., the oxidizing reagent) that are less toxic that those used in the traditional methods (e.g., oxalyl chloride). Many of the processes of the present invention generate intermediates with improved e.e. and chemical purity; thereby eliminating the need of additional chromatography steps. And, the processes of the present invention are scalable to generate commercial quantities of the final compound.
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Paragraph 0431-0432
(2014/06/24)
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- Synthesis Of Treprostinil And Intermediates Useful Therein
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Treprostinil is prepared by a process which involves Pauson-Khan cyclization of an an alkene-substituted, alkyne-substituted benzene corresponding to formula: (I) where PMB represents para-methoxy benzyl protecting group and R1 and R2 are alcohol protecting groups. Following cyclization, the resulting compound can be subjected to several chemical trans-formations followed by alkylation, hydrolysis and salt formation to yield treprostinil sodium. The use of para-methoxybenzyl group as the phenolic protecting group confers several process advantages that result in simplified purification of the final product and improved yields.
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- SYNTHESIS OF TREPROSTINIL AND INTERMEDIATES USEFUL THEREIN
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Treprostinil is prepared by a process which involves Pauson - Khan cyclization of an an alkene-substituted, alkyne-substituted benzene corresponding to formula : (I) where PMB represents para-methoxy benzyl protecting group and R1 and R2 are alcohol protecting groups. Following cyclization, the resulting compound can be subjected to several chemical transformations followed by alkylation, hydrolysis and salt formation to yield treprostinil sodium. The use of para-methoxybenzyl group as the phenolic protecting group confers several process advantages that result in simplified purification of the final product and improved yields.
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