16 results about "Linaclotide" patented technology

The present disclosure encompasses combinations of ralinepag with a cGMP-elevating agent or prostanoid such as riociguat, treprostinil, or iloprost for treating PAH. The disclosed combination therapy provides for advantages such as improved efficacy, improved safety, reduced doses and / or frequency of ralinepag and / or riociguat, reduced doses and / or frequency of ralinepag and / or treprostinil, and reduced doses and / or frequency of ralinepag and / or iloprost. In some embodiments, the clinical effectiveness of a reduced dose combination is additive or synergistic compared to that provided by the corresponding ralinepag, riociguat, treprostinil, and / or iloprost monotherapies.

The invention provides a preparation method of linaclotide, which comprises the following steps: cyclizing linear peptide of linaclotide to obtain linaclotide, wherein the cyclization refers to air oxidation in a phosphate and guanidine hydrochloride solution with the pH value of 7.5-8.5.

The invention discloses a linaclotide-containing pharmaceutical composition as well as a preparation method and application thereof, and belongs to the technical field of medicine synthesis. The pharmaceutical composition containing linaclotide comprises linaclotide, polyethylene glycol, an electrolyte agent and a triazolyl derivative, in the synthesis of linaclotide, a side chain phenolic hydroxyl group of Fmoc-Tyr-OtBu is bonded with 2-chlorotrityl chloride resin, amino acids are sequentially coupled, a pair of disulfide bonds are oxidized on the resin, and the linaclotide is obtained through the processes of resin cracking and oxidation. In the preparation of the triazolyl derivative, triethylamine is used as an acid-binding agent, and 3-benzyl-4H-1, 2, 4-triazole and 4-phenylbutyryl chloride are subjected to a reaction to obtain the triazolyl derivative. The pharmaceutical composition containing linaclotide disclosed by the invention has excellent biocompatibility and an excellent effect of relieving constipation.

This invention discloses a method for preparing linaclotide capsules, belonging to the pharmaceutical field. The method involves preparation, coating, drying, and filling to obtain linaclotide capsules. By controlling the acidity of the solution and the proportions of the various components in the formula during the preparation process, the quality content and total impurities of the drug can be controlled. The resulting linaclotide capsules have stable content, low impurities, and good quality.

To provide stable solid formulations of GC-C receptor agonist polypeptide suitable for oral administration.SOLUTION: Described herein are a stable solid formulation of linaclotide suitable for oral administration, and a method for preparing such formulations. The formulation described herein comprises a polypeptide comprising an amino acid sequence Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (linaclotide) or a pharmaceutically acceptable salt thereof. The linaclotide formulation described herein is stable and has an effective period sufficient for preparation, storage and distribution of the drug.SELECTED DRAWING: None

The invention discloses a method for preparing linaclotide through random oxidation, which comprises the following steps: preparing a linear crude peptide into an aqueous solution, in the presence of copper acetate, regulating the pH value with stronger ammonia water, and standing and oxidizing under temperature control; the method is simple and efficient, three pairs of disulfide bonds can be constructed in one step under high concentration, the obtained crude peptide is high in purity and easy to purify, and the production efficiency of preparing linaclotide through oxidation is greatly improved.

The present invention discloses a pharmaceutical composition containing linaclotide, a preparation method, and an application thereof, and belongs to the field of pharmaceutical synthesis technology. The pharmaceutical composition containing linaclotide of the present invention comprises linaclotide, polyethylene glycol, an electrolyte agent, and a triazole derivative. In the synthesis of linaclotide, the side chain phenolic hydroxyl group of Fmoc-Tyr-OtBu is first bonded to a 2-chlorotrityl chloride resin, followed by sequential coupling of amino acids, and then a pair of disulfide bonds are oxidized on the resin to obtain linaclotide through resin cleavage and oxidation. In the preparation of the triazole derivative, triethylamine is used as an acid-binding agent to react 3-benzyl-4H-1,2,4-triazole with 4-phenylbutyryl chloride to obtain the triazole derivative. The pharmaceutical composition containing linaclotide of the present invention has excellent biocompatibility and excellent constipation relief effect.

The present application belongs to the technical field of biological macromolecule pharmaceutical chemistry and tumor targeting delivery system, and particularly relates to a polypeptide conjugate based on linaclotide and a preparation method and application thereof. The present application finds through experiments that linaclotide or its derivative has potential in colorectal cancer (CRC) targeting and deep penetration after proper modification, and therefore proposes a new use of the clinical drug linaclotide or its derivative in a tumor targeting drug delivery system, and constructs a polypeptide conjugate based on linaclotide or its derivative and a tumor targeting drug delivery system based thereon. In-vivo and in-vitro experiments prove that the polypeptide conjugate and the tumor targeting drug delivery system of the present application have precise targeting and deep penetration capabilities in colorectal cancer and metastatic tumors, can effectively enhance the accumulation of an antitumor drug at a tumor site, thereby enhancing the efficacy of the antitumor drug, and have a wide application prospect in the drug delivery system of colorectal cancer.

The invention provides a linaclotide capsule preparation and a preparation method thereof. The linaclotide capsule preparation comprises a plurality of linaclotide particles and a capsule shell, the capsule shell is filled with the linaclotide particles, and each linaclotide particle sequentially comprises a medicine carrying bead, a linaclotide coating layer and a protective coating layer from inside to outside. The linaclotide coating layer at least comprises linaclotide, calcium chloride dihydrate, leucine and steric hindrance primary amine. The linaclotide capsule preparation disclosed by the invention is relatively good in drug effect stability.

The present invention discloses a solid-phase synthesis method of linaclotide, belonging to the technical field of peptide synthesis; the method adopts a solid-phase synthesis method, uses Fmoc-Tyr(tBu)-Wang resin as a starting material, and sequentially couples amino acids from the C-terminus to the N-terminus to obtain linaclotide peptide resin; then, after deprotection treatment, oxidation and cleavage, and purification treatment, linaclotide is obtained. The peptide sequence of linaclotide is as follows: H2N-Cys 1 ‑Cys 2 ‑Glu 3 ‑Tyr 4 ‑Cys 5 ‑Cys 6 ‑Asn 7 ‑Pro 8 ‑Ala 9 ‑Cys 10 ‑Thr 11 ‑Gly 12 ‑Cys 13 ‑Tyr 14 ‑OH (disulfide bridge: Cys 1 ‑Cys 6 &Cys 2 ‑Cys 10 &Cys 5 ‑Cys 13 The total yield of the linaclotide synthesized by the present invention is over 98%, and the purity is over 80.5%.

The invention discloses a linaclotide-containing pharmaceutical composition as well as a preparation method and application thereof, and belongs to the technical field of medicine synthesis. The pharmaceutical composition containing linaclotide comprises linaclotide, polyethylene glycol, an electrolyte agent and a triazolyl derivative, in the synthesis of linaclotide, a side chain phenolic hydroxyl group of Fmoc-Tyr-OtBu is bonded with 2-chlorotrityl chloride resin, amino acids are sequentially coupled, a pair of disulfide bonds are oxidized on the resin, and the linaclotide is obtained through the processes of resin cracking and oxidation. In the preparation of the triazolyl derivative, triethylamine is used as an acid-binding agent, and 3-benzyl-4H-1, 2, 4-triazole and 4-phenylbutyryl chloride are subjected to a reaction to obtain the triazolyl derivative. The pharmaceutical composition containing linaclotide disclosed by the invention has excellent biocompatibility and an excellent effect of relieving constipation.

The invention discloses a solid-phase synthesis method of linaclotide, and belongs to the technical field of polypeptide synthesis. According to the method, a solid-phase synthesis method is adopted, Fmoc-Tyr (tBu)-king resin is taken as an initial raw material, amino acids are sequentially coupled according to the sequence from the C terminal to the N terminal, and linaclotide peptide resin is obtained; and carrying out deprotection treatment, oxidation, cracking and purification treatment to obtain linaclotide. The peptide sequence of the linaclotide is as follows: H2N-Cys1-Cys2-Glu3-Tyr4-Cys5-Cys6-Asn7-Pro8-Ala9-Cys10-Thr11-Gly12-Cys13-Tyr14-OH (a disulfide bond bridge: Cys1-Cys6amp, Cys2-Cys10amp, and Cys5-Cys13), and the peptide sequence of the linaclotide is as follows: the peptide sequence of the linaclotide is as follows: H2N-Cys1-Cys2-Glu3-Tyr4-Cys5-Cys6amp, Cys2-Cys10amp, Cys5-Cys13). The total yield of the synthesized linaclotide reaches 98% or above, and the purity of the linaclotide reaches 80.5% or above.

The invention discloses a method for preparing linaclotide, belongs to the field of polypeptide medicine synthesis, and particularly relates to a method for industrially preparing linaclotide. An amino acid Fmoc-Tyr-OtBu side chain is anchored to a 2-CTC resin carrier through an ether bond, and then subsequent solid-phase synthesis, cutting, oxidation, purification, concentration and freeze drying are performed to prepare linaclotide. Compared with a traditional ester bond anchoring mode, the method has the advantages that the ether bond anchoring resin carrier is adopted, so that the stability of 2-CTC in the subsequent reaction is effectively improved, and the synthesis yield is not reduced due to extension of a peptide chain; meanwhile, impurities such as deleted peptides generated due to unstable carriers in the synthesis process are reduced. The method disclosed by the invention has the advantages of high stability and high product quality level, and is suitable for large-scale linaclotide production.

The present invention provides a linaclotide soluble intermediate and a preparation method for linaclotide. The preparation method comprises: using a host cell containing a recombinant plasmid to express a linaclotide soluble intermediate, wherein the recombinant plasmid contains a gene capable of expressing Sumo tag protein and a gene capable of expressing linaclotide; and the host cell comprises a Shuffle T7-B cell or an Origami B(DE3) cell. The present invention can solve the problem in the prior art of low activity of linaclotide prepared, and is applicable to the field of polypeptide drug biosynthesis.

The application discloses a method for synthesizing a linear linaclotide intermediate and linaclotide in a full liquid phase, and relates to the following process: at least two polypeptide fragments are designed and planned by segmenting a linear linaclotide; amino acid raw materials are selected according to the amino acid sequence order of the planned polypeptide fragments; the target polypeptide fragments are synthesized by using an activating agent one by one; the polypeptide fragments are sequentially connected by step-by-step liquid phase condensation to obtain a fully-protected straight-chain linaclotide; and finally, the side chain and the main chain of the fully-protected straight-chain linaclotide are removed to obtain the linear linaclotide, which is the linaclotide intermediate; and the linaclotide is prepared by further adopting an electrochemical one-step oxidation method. The application provides a method for synthesizing a linear linaclotide intermediate and linaclotide in a full liquid phase, can reduce production cost, improve the quality of linaclotide, is more suitable for industrialized production processes, meets environmental protection and safety requirements, and has better economic benefits and application prospects.

The application discloses a method for preparing linaclotide, and belongs to the field of polypeptide medicine synthesis, and particularly relates to a method for preparing linaclotide in an industrialized manner. In the method, the side chain of an amino acid Fmoc-Tyr-OtBu is anchored to a 2-CTC resin carrier through an ether bond, and then subsequent solid-phase synthesis, cutting, oxidation, purification, concentration and freeze-drying are carried out to prepare linaclotide. Compared with a traditional ester bond anchoring mode, the method adopts the ether bond to anchor the resin carrier, so that the stability of 2-CTC in the subsequent reaction is effectively improved, and the synthesis yield is not reduced due to the elongation of the peptide chain; meanwhile, the method reduces impurities such as missing peptides generated due to the instability of the carrier in the synthesis process. The production process in the method has high stability, the product quality level is high, and the method is suitable for large-scale linaclotide production.