85 results about "Apremilast" patented technology

The invention relates to a preparation method for synthesizing an apremilast intermediate. The preparation method comprises the following steps of: carrying out condensation reaction on 3-ethoxyl-4-methoxyl-benzoate and dimethyl sulfone under an alkaline condition to generate 2-(3-ethoxy-4-methoxyphenyl)-1-methylsulfonyl acetone; reacting the compound II and chiral amine in the presence of an acidic catalyst to obtain 1-N-substituted amino-1-(3-ethoxyl-4-methoxyl) phenyl-2-methylsulfonyl ethylene (III), and directly hydrogenating the obtained compound III in the presence of a hydrogenation catalyst without separating the compound III to obtain a product (S)-1-(3-ethoxyl-4-methoxyl) phenyl-2-methanesulfonyl ethylamine (I), namely the apremilast intermediate, wherein the apremilast intermediate can be further prepared into N-acetyl L-leucinate. The invention also provides a preparation method of apremilast. The preparation method disclosed by the invention has the advantages of simple process flow, safety, environmental friendliness and low cost and is favorable to clean industrialized production.

The invention relates to a synthetic method of an apremilast chiral amine intermediate (S)-2-[1-(3-ethoxyl-4-methoxylphenyl)]-1-methylsulfonyl-2-ethylamine (V). The synthetic method is characterized by including following steps: (1) with 1-(3-ethoxyl-4-methoxylphenyl)-2-(methylsulfonyl)ethyl ketone (I) as a raw material, performing asymmetric hydrogenation reduction to obtain methyl sulfonyl ethanol (II); (2) performing an esterification reaction to obtain methyl sulfonyl ester (III); (3) performing an azidation reaction to obtain an azide compound (IV); and (4) performing hydrogenation reduction to obtain the chiral amine intermediate (V) being high in chiral purity. The synthetic method is simple in process, is stable in reaction processes, and is environmental-protective and low-cost. In the synthetic method, the use amount of a catalyst during catalytic hydrogenation is less and the conversion rate reaches higher than 98%. The chiral amine can be prepared through chiral alcohol with very high yield and purity so that the synthetic method has a quite excellent commercial value and develops a new approach for synthesizing the apremilast chiral amine intermediate.

The invention discloses a high-efficient liquid phase chromatograph separation detection method of apremilast and apremilast enantiomer. A chromatographic condition is to adopt a direct-chain starch chiral column, and an n-hexane-low alcohol solution is adopted as a flow phase to carry out the separation determination for apremilast and apremilast enantiomer. By adopting the high-efficient liquid phase chromatograph separation detection method of the apremilast and apremilast enantiomer, the apremilast enantiomer can be effectively separated and determined, the specificity is high, the accuracy is high, and the method can be used for effectively controlling the quality of apremilast active ingredients.

The invention discloses an industrial method for preparing high-purity apremilast (described in formula I) and an intermediate thereof. With 3-nitrophthalic acid (compound II) adopted as the starting raw material, and organic acid or acid anhydride adopted as the solvent, the method comprises the following steps: preparing high-purity 3-acetamido phthalic anhydride (compound IV) through different intermediates; directly enabling the obtained undried product to react with (S)-1-(3-oxethyl-4-methoxy phenyl)-2-mesyl) ethylamine (compound V) or the salt during reflux in glacial acetic acid, so as to obtain the apremilast. The preparation method is easy to operate, low in energy consumption, high in yield, and applicable to industrial production.

The invention provides an apremilast solid dispersoid and a preparation method thereof. The apremilast solid dispersoid is characterized by having a prescription comprising the following components in percentage by weight: 5-35% of apremilast, 5-70% of a carrier material and 2-30% of an adsorbing agent. The apremilast solid dispersoid has the advantages that drug releasing rate is increased, pharmaceutical function can be realized in short time, and pharmaceutical bioavailability is improved. The apremilast solid dispersoid is prepared by adopting a melting method, steps are simple, technological parameters are easy to control, and the apremilast solid dispersoid is applicable to large-scale production.

The invention relates to a novel substituted isoindoline-1,3-dione derivative and the pharmaceutically acceptable salts thereof. More particularly, the invention relates to a novel substituted isoindoline-1,3-dione derivative used as an analogue of apremilast. The invention further provides a composition containing the compound disclosed by the invention and a carrier, and the application of the disclosed compound and composition in a method for beneficially treating diseases and conditions by administering apremilast.

The invention provides an apremilast oral preparation and a preparation method thereof. The apremilast oral preparation consists of the following ingredients in percentage by weight: 2-20% of apremilast which serves as an active ingredient, 20-70% of a filling agent, 3-30% of a disintegrating agent, 1-10% of a binding agent, 0.2-5% of a lubricating agent and 2-6% of a coating material. The apremilast oral preparation prepared by the invention is above 95% in dissolution rate and high in bioavailability; the shortcomings of poor dissolution degree of the active ingredient and low bioavailability are overcome; and the oral preparation is stable and reliable in quality and is high in market development prospect.

The invention provides an Apremilast oral liquid, including 0.05wt%-0.3wt% of Apremilast, 0.5wt%-20wt% of sulfobutyl- beta-cyclodextrin, 1wt%-30wt% of an alcohol solvent, 0-2wt% of surface active agent and the balance of water. The invention adopts sulfobutyl- beta-cyclodextrin for Apremilast inclusion, so that Apremilast is in an amorphous state, and has increased water solubility, and the concentration of Apremilast is increased to more than 1mg / ml. The prepared oral liquid is easy for the dosing, and has greatly improved bioavailability due to no disintegration and dissolution process of solid preparations. At the same time, and the stability of Apremilast is not affected due to production into oral liquid; and test shows that the stability of the oral liquid is equal to that of tablets.

The invention discloses a method of separation and detection of apremilast and enantiomer thereof by adopting HPLC (high performance liquid chromatography). The chromatographic condition of the method adopts a chiral column taking a silica gel of which the surface is coated with amylose-three(3,5-dimethyl phenyl carbamate) as filler; a mobile phase is prepared from hexane-ethyl alcohol-acetonitrile-diethylamine (the ratio is 45 to 45 to 10 to 0.1); the flow velocity is 0.8ml/min; the wavelength is 230nm; and the column temperature is 35 DEG C.

The invention belongs to the field of analytic chemistry, and concretely relates to a separation and determination method of apremilast and potential genotoxic impurities thereof. The method comprises the steps of adopting a chromatographic column taking octadecyl silane bonded silica gel as filler, and concretely comprises the steps of adding a diluting agent for dissolving each potential genotoxic impurity reference substance so as to prepare a reference substance solution with known concentration; adding a diluting agent for dissolving a sample for test so as to prepare a solution of the sample for test; taking the reference substance solution and the solution of the sample for test respectively for sample injection; adopting a moving phase for carrying out high performance liquid chromatography elution analysis, and recording a chromatogram map; comparing peak areas of impurities, corresponding to peak appearance times, in the reference substance solution and the solution of the sample for test, and calculating the contents of the apremilast and the potential genotoxic impurities contained in the sample for test. The method is high in specificity, high in sensitivity (the limit of detection of the potential genotoxic impurities of SM1 is 0.0004 percent), and simple to operate, and has the advantages of convenience and quickness.

The invention discloses apremilast tablets. Plain tablets of the tablets comprise active components and an excipient, wherein the mass of the active components is 5%-15% of that of the plain tablets,the excipient comprises an excipient A, the excipient A is selected from one or a mixture of more of lactose, microcrystalline cellulose, Ludipress and Ludipress LCE, the mass of the excipient A is 80%-92% of that of the plain tablets, and the excipient A is further selected from 85%-90%. A preparation method of the apremilast tablets comprises the following steps of crushing the active componentsfor standby application, wherein the size distribution d(0.9) of the crushed active components is smaller than or equal to 15.0 [mu]m; screening the excipient for standby application; screening the active components and the excipient, and performing uniform mixing; and performing tabletting and coating. According to the apremilast tablets and the preparation method thereof disclosed by the invention, the dissolution rate of the apremilast in the tablets is greatly increased; and besides, the preparation technology is simple, controllable, environmentally-friendly and sustainable, the production cost is low, the production efficiency is high, and the apremilast tablets and the preparation method are suitable for large-scale industrialization big production.

The invention relates to an apremilast and nicotinamide co-crystal and a preparation method thereof. The co-crystal is subjected to comprehensive characterization by applying means including X-ray powder diffraction analysis, thermogravimetric analysis, differential scanning amount thermal analysis and the like, and the comprehensive characterization finds out that compared with apremilast, the co-crystal has better physical and chemical and drug formation performance. The preparation method of the apremilast and nicotinamide co-crystal is simple, easy to control and good in repeatability; theapremilast and nicotinamide co-crystal can be stably obtained.

The invention provides an apremilast solid composition. The apremilast solid composition is prepared by the following components in parts by weight: 5% to 14% of apremilast; 82% to 90% of a filler; 1%to 1.5% of a disintegrant; 0.5% to 1% of a lubricant; and 2% to 6% of a coating material. The apremila solid composition prepared by the invention has a dissolution rate of more than 95%, has high bioavailability, and stable and reliable quality, and has wide clinical application prospects.

A stable Crystalline Form II of non-solvate of Apremilast (Formula I), methods of making Form II, pharmaceutical compositions comprising Form II, and their uses are disclosed. Also discloses are mixed crystals comprising Form Hand Form B and methods of making the same. The crystalline forms are characterized using X-ray powder diffractometry (XRPD), infrared spectroscopy (IR), differential scanning calorimetry (DSC), and thermal gravimetric analysis (TG). As compared with Forms A, B, C, D, E, F, and G reported in prior art references, Apremilast Form II of the present invention is more stable to temperature, light, and humidity, and is more suitable for long term storage; the crystallization solvents are safe and can be easily removed; the Form II has a white or off white appearance, and can be directly used in preparation processing; the preparation methods are simple and easy to reproduce, and are suitable for industrialized production.

The present invention relates to topical pharmaceutical compositions of apremilast used for the treatment of psoriasis and/or psoriatic arthritis. It further relates to processes of preparation of the compositions and the method of use for these compositions.

The invention provides a method for separating and measuring Apremilast and enantiomer of the Apremilast through liquid chromatography, and relates to the technical field of analytical chemistry. The method comprises the steps that a chiral chromatographic column with silica gel as filler is adopted, the surface of the silica gel is in covalent bonding with amylase-tris(3-chlorobenzene carbamate), methyl tertiary butyl ether-ethyl alcohol-diethylamine (91-9-0.1) serves as a mobile phase, the flow speed is 1 ml/min, the wave length is 230 nm, and the column temperature is 30 DEG C. The high performance liquid chromatography separating and detecting method for the Apremilast and the enantiomer of the Apremilast is high in separation degree and high in specificity, the problem that the Apremilast and corresponding isomer of the Apremilast are hard to separate is solved, and therefore it is guaranteed that the quality of the Apremilast and a preparation of the Apremilast is controllable.

The present disclosure is directed to novel forms of apremilast and pharmaceutical compositions comprising any of the novel forms of apremilast. Also provided are processes for the preparation of novel forms of apremilast.

The invention relates to the technical field of medicinal chemistry, in particular to a new apremilast crystal form H and a preparation method thereof. The crystal form H is characterized in that a. differential scanning calorimetry analysis shows that only one endothermic peak exists within a temperature range of 100-180 DEG C, and the endothermic peak top value is 156 +/-3 DEG C; b. the X-ray powder diffraction pattern has the following characteristic peaks at 2theta+/-0.2: 7.980, 14.494, 14.723, 15.081, 17.317, 18.261, 19.147, 20.362, 21.809, 23.138, 23.505, 25.057; c. the X-ray powder diffraction pattern has no characteristic peak at the position where 2theta+/-0.2 is 8.443 and 15.482. The invention provides the highly dissolved new apremilast crystal form H.

The present invention relates to topical compositions comprising apremilast. It also relates to processes for preparing such compositions and methods of using them in management of skin diseases or disorders such as psoriasis, dermatosis, eczema, rosacea, acne vulgaris, allergies, contact and atopic dermatitis, pruritus, seborrhea, skin cancers, inflammation and other associated skin conditions.

The invention discloses a method for detecting an enantiomer (I) in apremilast. A protein type chiral chromatographic column is adopted in the method; while the defect of shorter service life of an existing starch coating chiral column is overcome, the enantiomer in the apremilast is effectively separated and detected, and a detection result is accurate and reliable; the method has the multiple advantages such as excellent linear relation, high precision, good stability, good repeatability, good recovery rate, simple and convenient operation and low cost, and is suitable for popularization and application. A structural formula is shown in the description.