23 results about "Apremilast" patented technology

Provided herein are oral dosage forms comprising a) a core tablet comprising (i) a drug layer comprising apremilast and hypromellose acetate succinate (HPMCAS) in an amorphous solid dispersion; and (ii) a swellable layer comprising one or more swellable polymers; and b) a coating layer disposed on the core tablet, wherein the oral dosage form surface comprises at least one drug release orifice. The disclosed oral dosage forms provide once-a-day dosing of apremilast and are suitable for treating diseases or disorders ameliorated by inhibiting phosphodiesterase subtype IV (PDE4).

The invention provides a pharmaceutical composition containing a JAK inhibitor and a PDE4 inhibitor, the JAK inhibitor is selected from one or a combination of more of upatinib, digotinib, BMS-986165 or pharmaceutically acceptable salts thereof, and the PDE4 inhibitor is selected from one or a combination of more of apremilast, defamilast or pharmaceutically acceptable salts thereof. The invention finds that the JAK inhibitor and the PDE4 inhibitor are combined to have a synergistic effect and can be used for treating inflammatory diseases.

The invention relates to the field of analytical chemistry, and particularly discloses a method for separating alprimilast intermediate 3 and impurities by high performance liquid chromatography, which adopts octadecylsilane chemically bonded silica as a filler, a dihydric phosphate solution as a mobile phase A and acetonitrile as a mobile phase B to carry out gradient elution, all known impurities and unknown impurities in the alprimilast intermediate 3 can be effectively separated, nine impurities are effectively separated in one chromatography, the separation degree between a main peak and an impurity IX reaches 3.87 and is larger than 1.5, the separation degree between other impurities is larger than 1.5, specificity is good, interference of a blank solvent and other unknown impurities is avoided, and the method is suitable for industrial production. The separation efficiency is high, the anti-interference capability is strong, the analysis speed is high, and the detection accuracy is high, so that the quality of alprimilast is effectively controlled.

The application discloses a compound inhalation powder aerosol and a preparation method thereof. The compound inhalation powder aerosol comprises apremilast or a pharmaceutically acceptable salt thereof and an efficacy enhancing substance, wherein the efficacy enhancing substance is nintedanib or a pharmaceutically acceptable salt thereof; and the amount of the efficacy enhancing substance is 0.1-10 times the amount of the apremilast or the pharmaceutically acceptable salt thereof. In the compound inhalation powder aerosol, the drug exposure of apremilast is greatly improved under the action of nintedanib, and a significant enhancement effect is exhibited. Meanwhile, nintedanib further improves efficacy. The powder aerosol is used for pulmonary inhalation administration, and apremilast or the pharmaceutically acceptable salt thereof and nintedanib or the pharmaceutically acceptable salt thereof are used for treating lung diseases, so that the drugs can be directly delivered to effective sites, the administration dose can be further effectively reduced or the drug utilization rate can be improved, the deposition rate can be improved, and the treatment effect can be greatly improved.

The application discloses a detection method for determining the residual amount of easily hydrolyzed impurities in apremilast, which comprises the following steps: using a high performance liquid chromatograph, adopting polysaccharide derivatives as a filler (CHIRALPAK IH, 4.6mm*150mm, 5um), adopting a n-hexane-tetrahydrofuran (65:35) mobile phase, a flow rate of 1.0ml per minute, a column temperature of 30 DEG C, a detection wavelength of 230nm, and a sample injection volume of 50ul. The application adopts the polysaccharide derivative filler to determine the easily hydrolyzed impurities in the apremilast, has high separation efficiency, strong anti-interference ability, fast analysis speed and high detection sensitivity, and can effectively control the quality of the apremilast by determining the amount of the easily hydrolyzed impurities in the apremilast.

The invention recognizes a combination of drugs that is effective against cancers that exhibit a KRAS mutation. The invention provides a combination therapy that includes the two agents, trametinib and apremilast for the treatment of certain cancers.

The invention belongs to the technical field of medicines, and particularly relates to an apremilast impurity and a preparation method thereof, the compound can be used as a quality control standard substance of apremilast, and the content of the apremilast impurity can be detected in raw materials and preparations thereof so as to ensure that raw material medicines and preparations meeting medicinal standards are prepared.

Provided herein are methods of treating diseases and disorder responsive to the inhibition of PDE4 comprising administering apremilast and a Tyk2 inhibitor to a subject. Also provided herein are pharmaceutical compositions comprising apremilast and a Tyk2 inhibitor.

The invention belongs to the technical field of medicines and chemistry, and discloses a racemization preparation method of a compound shown in a formula II. According to the method, in an organic solvent, a compound shown in a formula III reacts with sulfide and an initiator to obtain a raceme II compound, and the reaction formula of the raceme II compound is shown as follows: # imgabs0 #. Compared with the prior art, the raceme of the formula II is prepared through a one-step method, the reaction is free of high temperature, and the yield is high; the method is free of pressurization, simple in route, low in cost and stable in process, ee of the product is smaller than or equal to 5.0%, preferably smaller than or equal to 2.0%, the yield reaches 95% or above, the recovery reaction can be continuously and repeatedly carried out, and the method has very high application value in industry.

The present invention provides methods of treating diseases and disorders responsive to inhibition of PDE4 comprising administering to a subject apremilast and a Tyk2 inhibitor. The present invention also provides a pharmaceutical composition comprising apremilast and a Tyk2 inhibitor.

The invention discloses an inhalation preparation for treating IPF diseases. The inhalation preparation is an aerosol inhalation liquid preparation, an inhalation aerosol, an inhalation powder aerosol or a soft aerosol. The inhalation preparation comprises an active drug, and the active drug is any one of apremilast, ibudilast, roflumilast, crisaborole and defamilast. A preparation process of an inhalation preparation is introduced into a traditional preparation, active ingredients of a traditional oral preparation are easily damaged in digestive tracts, the bioavailability is low, the liver first-pass effect is achieved, the effect is slow, and the inhalation preparation capable of remarkably improving IPF is prepared. Tests prove that the prepared inhalation preparation can effectively improve the bioavailability and improve the clinical use effect.

The invention provides a method for preparing an apremilast intermediate through biological catalysis. According to the method, a novel nitroreductase mutant is used for catalytically reducing 3-nitrophthalic acid to prepare the apremilast intermediate 3-aminphthalic acid, and the method is easy and convenient to operate, mild in reaction condition, high in conversion rate, free of participation of an organic solvent, more environmentally friendly, low in cost and extremely high in industrial application value.

This invention provides an apremilast-loaded hydrogel of *Callicarpa nudiflora* vesicles, its preparation method, and its application, relating to the field of pharmaceutical formulation technology. This invention utilizes *Callicarpa nudiflora* vesicles to encapsulate apremilast and then reconstitute it into a hydrogel, preparing a drug that can be directly applied to the affected skin of psoriasis patients via local transdermal administration. The hydrogel achieves synergistic treatment of psoriasis through apremilast and *Callicarpa nudiflora* vesicles, improving efficacy.

An inhalation formulation for treating an IPF disease. The inhalation formulation is an aerosol inhalation liquid formulation, an inhalation aerosol, a dry powder inhaler or a soft mist inhaler. The inhalation formulation contains an active drug, and the active drug is any one of apremilast, ibudilast, roflumilast, crisaborole, and difamilast. A preparation process for the inhalation formulation is introduced into a conventional formulation. An active component in a conventional oral formulation is prone to being destroyed in the digestive tract, and has low bioavailability, a liver first pass effect, and a slow onset of action. An inhalation formulation capable of significantly alleviating IPF is prepared. Tests prove that the prepared inhalation formulation can effectively increase the bioavailability, and improve the clinical use effect.

Provided herein are suspensions for oral administration comprising a) apremilast, b) a suspending agent, c) a sweetener, d) one or more of a vehicle, a co-solvent, a buffering agent, a preservative, or a combination thereof. Also provided herein is a suspension for oral administration comprising a) apremilast, b) microcrystalline cellulose / carboxymethylcellulose sodium, c) xanthan gum, d) sucrose, e) sorbitol, f) glycerin, g) propylene glycol, h) citric acid monohydrate, i) methylparaben, j) propylparaben, and h) water.

The invention discloses a synthesis method of a PDE4 inhibitor apremilast, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: taking 3-ethoxy-4-methoxystyrene as an initial raw material, and carrying out aziridine treatment on olefin to obtain an intermediate 1; carrying out nucleophilic ring opening on the intermediate 1 and methyl mercaptide to obtain an intermediate 2; then the intermediate 2 and a tartaric acid resolving agent are subjected to salification and alkali treatment reaction to obtain a chiral intermediate 3, and the intermediate 3 and 3-acetamino phthalic anhydride are subjected to condensation reaction to obtain an intermediate 4; and oxidizing the intermediate 4 to obtain apremilast. The invention develops a green and efficient synthesis process of apremilast, the target product is prepared through five-step reaction, the process breaks through the situation that a traditional route depends on high-pressure hydrogenation conditions and use of highly toxic reagents, normal-pressure operation and mild temperature are adopted in the whole process, and the requirement of low-temperature reaction is avoided. The safety in industrial production is improved to a great extent, and the method is more suitable for industrial continuous production.

To provide an apremilast solid preparation suppressed in increase of related substances with time and excellent in stability.SOLUTION: The apremilast solid preparation contains apremilast and an additive, wherein the additive contains at least one selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, glycerin fatty acid ester, hydrous silicon dioxide, and light anhydrous silicic acid. It is preferable that the additive does not contain at least one selected from the group consisting of a sodium salt, a calcium salt, and a magnesium salt.SELECTED DRAWING: None

Provided herein are processes for synthesizing apremilast comprising reacting 3-acetamidophthalic anhydride and (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine or a salt thereof to form apremilast. Also provided are processes for isolating apremilast from the reaction mixture, as described herein.

The invention discloses a synthesis method of a psoriasis treatment drug apremilast, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: taking 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanone as an initial raw material, and carrying out reductive amination to obtain an intermediate 1; splitting the intermediate 1 by tartrate to obtain an intermediate 2; and finally, carrying out condensation reaction on the intermediate 2 and 3-acetamido phthalic anhydride to obtain apremilast. The invention develops a green and efficient synthesis process of apremilast, the preparation of a target product is realized through three-step reaction, the process breaks through the technical bottleneck that the traditional route depends on high-pressure hydrogenation conditions and noble metal catalysts (such as palladium on carbon), and the whole process adopts normal-pressure operation and mild temperature and avoids high-temperature reaction. The safety in industrial production is improved to a great extent, and the method is more suitable for industrial continuous production.

The present invention relates to a stable pharmaceutical formulation of solid dosage forms for oral administration comprising an immunosuppressive agent such as apremilast as the active ingredient. It also relates to a process for the preparation thereof.

The invention discloses an apremilast inhalation powder and its preparation method and application, wherein the apremilast inhalation powder comprises an active ingredient and an excipient; the active ingredient is apremilast and / or its salt; the excipient comprises an amino acid surface modifier, a phospholipid excipient, a mixture of an amino acid surface modifier and a phospholipid excipient, a mixture of an amino acid surface modifier and a saccharide excipient, or a mixture of an amino acid surface modifier and a sugar alcohol excipient; and the preparation process of the apremilast inhalation powder is a spray drying process. The apremilast inhalation powder prepared by the invention is used for pulmonary administration, and is to administer apremilast in the form of a powder, and is also to use apremilast for the treatment of pulmonary diseases, and can directly deliver the drug to the effective part, effectively reduce the dosage, increase the deposition rate, reduce the systemic exposure and toxicity, and greatly improve the therapeutic effect.

The invention discloses a compound inhalation powder inhalation and a preparation method thereof. The compound inhalation dry powder comprises apremilast or a pharmaceutically acceptable salt thereof, and an efficacy enhancing substance, wherein the efficacy enhancing substance is nintedanib or a pharmaceutically acceptable salt thereof; the dosage of the efficacy enhancing substance is 0.1-10 times of the mass of the dosage of the apremilast or the pharmaceutically acceptable salt of the apremilast. In the compound inhalation powder inhalation provided by the invention, the drug exposure of apremilast is greatly improved under the action of nintedanib, and a remarkable enhancement effect is shown; meanwhile, the effect of the nintedanib is further improved; the apremilast or the pharmaceutically acceptable salt thereof and the nintedanib or the pharmaceutically acceptable salt thereof are used for treating lung diseases, so that the medicines can be directly delivered to effective parts, the administration dosage is further effectively reduced or the utilization rate of the medicines is increased, the deposition rate is increased, and the curative effect is improved. The treatment effect is greatly improved.

The present application provides a pharmaceutical composition for treating psoriasis, which contains a certain amount of apremilast and choline-based ionic liquid, so that the medicine prepared therefrom can directly act on the skin surface, provide an effective concentration of apremilast at the action site, and increase the amount of apremilast penetrating into the skin. The present application also provides a preparation method of the pharmaceutical composition, and a medicine comprising the pharmaceutical composition.