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CN-116390762-B - Solid cyclosporin A and dispersion composition containing the same

CN116390762BCN 116390762 BCN116390762 BCN 116390762BCN-116390762-B

Abstract

The present invention provides a dispersion composition comprising a dispersion medium, and particles comprising a target substance. The dispersion composition comprises at least one surfactant above a critical micelle concentration and does not comprise a solubilizing agent. The target substance is cyclosporin a and satisfies the S-parameter >1 defined previously.

Inventors

  • JIN ZHEHUAN
  • JIN JINGXI
  • XU DAXIONG

Assignees

  • 思凯制药有限公司

Dates

Publication Date
20260508
Application Date
20211104
Priority Date
20201109

Claims (8)

  1. 1. A dispersion composition comprising: Dispersion medium, and A particle comprising a substance of interest and, Wherein the dispersion composition comprises at least one surfactant having a critical micelle concentration or higher, The dispersion composition does not contain a solubilizing agent, The particles comprising the substance of interest are a combination of a plurality of molecules of cyclosporin a, The complex of molecules is prepared by the steps of: preparing a mixed solution by mixing cyclosporin a and a solvent for preparing the mixed solution; preparing a medium having multiple surfaces in the form of a packed bed or film or sheet, the medium having multiple surfaces including one or more of silica gel, silica xerogel, mesoporous silica, fumed silica; flowing the mixed liquor through the medium having a plurality of surfaces; Collecting the mixed liquor that has flowed through the medium having a plurality of surfaces; Removing the solvent used for preparing the mixed liquor from the collected mixed liquor, The dispersion medium is water, and the water is used as the dispersion medium, The surfactant is one or more of polysorbate and polyethoxylated castor oil, If the dispersion composition contains at least one surfactant, the S-parameter of equation 3 calculated from equations 1 and 2 satisfies S-parameter > 1, and If the dispersion composition contains at least two kinds of surfactants having critical micelle concentrations or more, S surf(i) is calculated from the following equation 4 for each surfactant, then the S surf value, which is the sum of these S surf(i) , is obtained from the following equation 5, and the S-parameter of equation 3 obtained by applying the calculated S surf value to the above equation 1 satisfies S-parameter > 1; < equation 1> S Micelle = S w + S surf Wherein S w is a concentration corresponding to the saturated solubility of the target substance in the dispersion medium, S surf is calculated by the following equation 2; < equation 2> S surf = k(C surf - CMC) Wherein k is a molar solubilizing ability defined as the number of moles of the target substance that can be dispersed in the dispersion medium by one surfactant at a critical micelle concentration of 1 mole or more, C surf is the molar concentration of the surfactant component in the composition, CMC is the critical micelle molar concentration of the surfactant in the composition; < equation 3> S-parameter = S tot /S Micelle Wherein S tot is the total molar content of the target substance contained in the dispersion composition; < equation 4> S surf(i) = k surf(i) (C surf(i) - CMC surf(i) ) Wherein k surf(i) is a molar solubilizing ability defined as the number of moles of the target substance that can be dispersed in the dispersion medium by any one of the surfactant components at a critical micelle concentration of 1 mole or more, C surf(i) is the concentration of any one of the surfactant components at the critical micelle concentration or more, and CMC surf(i) is the critical micelle concentration of any one of the surfactant components at the critical micelle concentration or more in the dispersion medium; < equation 5> Wherein m is the total number of the kinds of the surfactant component above the critical micelle concentration.
  2. 2. The dispersion composition according to claim 1, wherein the dispersion composition comprises cyclosporin a in an amount exceeding the content corresponding to the saturated solubility in the dispersion medium.
  3. 3. A dispersion composition according to claim 1, wherein, if two or more surfactants of said critical micelle concentration are contained, the types of surfactants are selected such that the total content of dispersible cyclosporin a corresponds to the sum of the content of dispersible cyclosporin a of each surfactant.
  4. 4. The dispersion composition according to claim 1, wherein the particles have a number average diameter of 100 nm or less.
  5. 5. The dispersion composition according to claim 1, wherein the particles have a number average diameter of 50 nm or less.
  6. 6. A pharmaceutical product for animals or humans comprising the dispersion composition of claim 1.
  7. 7. A solid cyclosporin A, wherein, The solid cyclosporin a is prepared by the steps of: preparing a mixed solution by mixing cyclosporin a and a solvent for preparing the mixed solution; preparing a medium having multiple surfaces in the form of a packed bed or film or sheet, the medium having multiple surfaces including one or more of silica gel, silica xerogel, mesoporous silica, fumed silica; flowing the mixed liquor through the medium having a plurality of surfaces; Collecting the mixed liquor that has flowed through the medium having a plurality of surfaces; Removing the solvent used for preparing the mixed liquor from the collected mixed liquor.
  8. 8. A pharmaceutical product for animals or humans comprising the solid cyclosporin a of claim 7.

Description

Solid cyclosporin A and dispersion composition containing the same Technical Field The present invention relates to a solid cyclosporin a having improved dispersibility and a dispersion composition obtained by dispersing the solid cyclosporin a, which exhibits improved dispersibility. Background In the pharmaceutical art, the preparation of aqueous compositions is one of the important tasks. Water is the most common solvent and liquid phase for drinking, the most used solvent in pharmaceutical formulations. However, many drugs are strongly nonpolar and therefore have insufficient solubility in water as a polar solvent. Therefore, even though having excellent therapeutic effects, insoluble or poorly soluble drugs having poor solubility have a problem in that they cannot be formulated into clinically useful pharmaceutical preparations. As a representative known technique for solving these problems, there is a micelle solubilization technique in which a poorly soluble drug is dissolved by a surfactant. A surfactant is a substance having both hydrophilicity and hydrophobicity in one molecule, and generally refers to a substance that can help disperse a target substance or stabilize a dispersed state by being mainly distributed at an interface of the target substance (e.g., a drug) and a dispersion medium (e.g., water), or a substance that performs these functions. The micelle solubilization technique is a technique for causing a target substance to be contained in a dispersion medium at a high content exceeding the saturation solubility by selectively distributing the target substance which is poorly soluble in the dispersion medium into nano-sized micelles formed by self-assembly of a surfactant contained in the dispersion medium at a concentration exceeding a specific concentration (critical micelle concentration). Disclosure of Invention Technical problem Bioavailability is a concept in pharmaceutical technology that represents the amount and rate of drug delivered from a site of administration to a site of action where the drug produces a therapeutic effect in the body, and if the bioavailability is low, even if the drug has a high therapeutic effect in the body, the actual amount delivered to the organ in the body where it should act is low, so the therapeutic effect in the body is maintained at a low or insignificant level. Bioavailability can be understood as flux through biological barriers in the body (e.g., cornea, skin, blood brain barrier, and blood retina barrier) (see equation 8 below). [ Equation 8] Flux = solubilityPermeability of It can be seen therein that in order to increase flux, the solubility and permeability must be highly balanced. According to biopharmaceutical classification systems, 70% of the total drug belongs to class II with high permeability and low solubility, and 20% belongs to class IV with low permeability and low solubility (Reintjes, T., Solubility enhancement with BASF Pharma polymers: Solubilizer Compendium. BASF, (2021) pp.9-10) . If the micelle solubilization technique is applied to a polar dispersion medium (e.g., water), the outer surface of the drug surrounded by the surfactant becomes hydrophilic as compared to the state where the drug exists alone. However, since most in vivo physiological barriers include a phospholipid layer or a hydrophobic layer, the permeability of the biological barrier of the pharmaceutical composition achieved by micelle solubilization techniques is generally reduced. For this reason, micelle solubilization technology has a trade-off between improving solubility and increasing permeability, and thus is limited in that it is difficult to obtain a pharmaceutical composition having improved bioavailability to the extent of improved therapeutic effect. In addition, most surfactants have problems such as environmental pollution or toxicity or side effects in the body, and thus it is required to minimize the amount of the surfactant. Therefore, it can be said that the necessity and commercial value thereof are great for a technique that can achieve an improvement in solubility even if the amount of the surfactant used is lower or minimized than in the prior art. These techniques can improve permeability by less amount of surfactant than required in the prior art, with the result that bioavailability or therapeutic effect can be improved and environmental pollution or in vivo toxicity/side effects can also be minimized. The objects of the present invention are not limited to the above objects, and other objects and advantages of the present invention not mentioned above can be understood by the following description, and can be more clearly understood by the embodiments of the present invention. It will also be readily understood that the objects and advantages of the invention may be realized by the means of the instrumentalities and combinations particularly pointed out in the appended claims. Cyclosporine is an immunosuppressive drug having 11