Search

CN-122005762-A - Tenipotene oral self-emulsifying preparation and preparation method thereof

CN122005762ACN 122005762 ACN122005762 ACN 122005762ACN-122005762-A

Abstract

The invention discloses a telipopeptide oral self-emulsifying preparation and a preparation method thereof, and relates to the technical field of pharmaceutical preparations. The preparation is prepared by forming a freeze-dried complex of a polypeptide in a highly hydrophobic free state (such as a salt-free telipopeptide) and a phospholipid, and then mixing the freeze-dried complex with a SEDDS pre-concentrate consisting of an oil phase, a surfactant and a cosurfactant. The molar ratio of the polypeptide to the phospholipid is 1:20-1:120, the oil phase in the SEDDS pre-concentrate accounts for 40-60%, the surfactant is 10-30%, and the cosurfactant is 5-20%. The preparation solves the problems of poor fat solubility and low loading efficiency of the polypeptide in a salt form, can protect the polypeptide from being degraded by gastrointestinal enzymes, promote intestinal permeation, remarkably improve oral bioavailability, and is suitable for oral treatment of metabolic diseases such as type 2 diabetes, obesity and the like.

Inventors

  • LIU TING
  • ZHANG WEIMING
  • TANG YANGMING

Assignees

  • 深圳翰宇药业股份有限公司

Dates

Publication Date
20260512
Application Date
20251225

Claims (10)

  1. 1. An oral polypeptide self-emulsifying formulation, characterized in that it is prepared by the following method: S1) preparing a polypeptide-phospholipid complex, wherein the polypeptide-phospholipid complex is a freeze-dried complex comprising a mixed solution of a polypeptide and a phospholipid; S2) preparing self-emulsifying drug delivery pre-concentrate, wherein the self-emulsifying drug delivery concentrate is a mixture of oil phase, surfactant and cosurfactant; S3) uniformly mixing the freeze-dried compound obtained in the S1) and the self-emulsifying drug delivery concentrated solution obtained in the S2) to obtain the oral telipopeptide self-emulsifying preparation.
  2. 2. The oral polypeptide self-emulsifying formulation of claim 1, wherein the polypeptide is in free molecular form; Preferably, the polypeptide is a polypeptide to be orally administered, preferably at least one from the group consisting of telpofungin, semaglutin, liraglutide, duloxetine, lozenith, exenatide, pramlintide, octreotide, leuprorelin.
  3. 3. The oral polypeptide self-emulsifying formulation of claim 1, wherein the phospholipid is selected from at least one of Soybean Phosphatidylcholine (SPC), egg yolk phosphatidylcholine (EPC).
  4. 4. The oral polypeptide self-emulsifying formulation of claim 1, wherein the molar ratio of the polypeptide to the phospholipid is 1:20 to 1:120.
  5. 5. The oral polypeptide self-emulsifying formulation of claim 1 wherein the oil phase is selected from at least one of long chain triglycerides, medium chain mono-di-glycerides; The surfactant is at least one selected from polysorbate, sorbitan ester, polyoxyethylene castor oil derivative and polyethylene glycol fatty acid ester; The cosurfactant is at least one selected from short-chain alcohols, polyethylene glycols, glycerin and derivatives, propylene glycol, diethylene glycol monoethyl ether and other polar solvents.
  6. 6. The oral polypeptide self-emulsifying preparation as claimed in claim 1, wherein the self-emulsifying drug delivery pre-concentrate comprises the following components in mass: 40-90 parts of oil phase 10-40 Parts of surfactant 5-20 Parts of auxiliary surface activity.
  7. 7. The oral polypeptide self-emulsifying formulation of claim 1, wherein step S1) comprises the steps of: s101) weighing the polypeptide and the phospholipid according to a certain proportion, and dissolving the polypeptide and the phospholipid in an organic solvent-water mixed solution; s102) mixing at 37 ℃ until the mixture is completely dissolved, and freezing at-80 ℃; S103) obtaining a freeze-dried compound through freeze drying.
  8. 8. The oral polypeptide self-emulsifying formulation of claim 1, wherein the mixture in step S2) is mixed at 37 ℃ until a homogeneous transparent liquid is formed; In step S3), the polypeptide-phospholipid complex is added into the self-emulsifying drug delivery pre-concentrate, and stirred at 37 ℃ until the polypeptide-phospholipid complex is fully dissolved and uniformly dispersed.
  9. 9. The oral polypeptide self-emulsifying formulation of claim 1, wherein the ratio of the polypeptide-phospholipid complex to the self-emulsifying drug delivery pre-concentrate in step S3) is 1-500:1000.
  10. 10. A method of preparing an oral polypeptide self-emulsifying drug delivery system according to any one of claims 1 to 9, characterized in that it comprises the steps of: s1) preparing a polypeptide-phospholipid complex, wherein the polypeptide-phospholipid complex is a freeze-dried complex of a polypeptide and phospholipid mixed solution; S2) preparing self-emulsifying drug delivery pre-concentrate, wherein the self-emulsifying drug delivery concentrate is a mixture of oil phase, surfactant and cosurfactant; S3) uniformly mixing the freeze-dried compound obtained in the S1) and the self-emulsifying drug delivery concentrated solution obtained in the S2) to obtain the oral telipopeptide self-emulsifying preparation.

Description

Tenipotene oral self-emulsifying preparation and preparation method thereof Technical Field The invention relates to the technical field of pharmaceutical preparations, in particular to a telipopeptide oral self-emulsifying preparation and a preparation method thereof. Background GLP-1 polypeptides (such as telipopeptide, semaglutin, liraglutide and the like) are first-line medicaments for treating type 2 diabetes mellitus and obesity at present, promote insulin secretion through glucose dependence, inhibit glucagon release and delay gastric emptying to play a role in reducing weight and protecting cardiovascular system, and have huge clinical requirements. However, the oral administration of the polypeptides faces inherent technical difficulties: Has extremely poor stability, and is easy to hydrolyze by gastric acid (pH 1-3) and protease (such as alpha-chymotrypsin and trypsin) in gastrointestinal tract after oral administration; Insufficient permeability, high molecular weight (4-5 kDa) and high hydrophilicity (salt form contains polar ionic group), and is difficult to pass through lipid bilayer membrane of intestinal epithelial cells, and the oral bioavailability is usually <1%. At present, polypeptide medicaments mainly depend on injection administration, and have the problems of poor compliance of patients, invasive risks, inconvenient administration and the like. Commercially available oral polypeptide preparations are very limited, and the existing oral delivery technology relies on complex auxiliary materials (such as SNAC, sodium octoate and the like) to promote absorption, but the bioavailability is still low, so that clinical requirements are difficult to fully meet. Therefore, developing an oral polypeptide preparation which can synchronously overcome multiple oral barriers, has high stability and excellent bioavailability is a key requirement in the field of current polypeptide preparations. The self-emulsifying drug delivery system (SEDDS) is a promising oral polypeptide delivery technology because of the advantages of good biocompatibility, capability of protecting the polypeptide from enzyme degradation, promotion of gastrointestinal tract permeation and the like. However, the existing SEDDS preparation still has the defects of poor compatibility of hydrophilic polypeptide and hydrophobic lipid and limited loading capacity, and easy damage to carrier structures in gastrointestinal tract environments (such as pH change, bile salts and digestive enzymes) to lead the polypeptide to be released and deactivated in advance. In summary, in the prior art, the lipid solubility defect of the GLP-1 polypeptide and the insufficient suitability of the SEDDS formula are core bottlenecks for restricting the improvement of the oral bioavailability. Therefore, the development of an oral delivery system which takes polypeptide as an active ingredient and is synergistically optimized by phospholipid complexing and SEDDS formula has important clinical value and innovation significance. Disclosure of Invention Based on the defects of the prior art, the invention provides a polypeptide oral self-emulsifying drug delivery system, which aims at solving the problems of poor fat solubility, low loading efficiency and insufficient bioavailability of the existing polypeptide in an oral SEDDS preparation. The core of the invention is that polypeptide medicine is adopted as an active ingredient, and can form a compound with phospholipid with high efficiency, thereby being matched with fat-soluble SEDDS pre-concentrated solution and solving the key problems of oral loading and absorption of polypeptide. In one aspect, the invention provides an oral polypeptide self-emulsifying formulation prepared by the following method: s1) preparing a polypeptide-phospholipid complex, wherein the polypeptide-phospholipid complex is a freeze-dried complex comprising a mixed solution of a polypeptide and a phospholipid; S2) preparing self-emulsifying drug delivery pre-concentrate, wherein the self-emulsifying drug delivery concentrate is a mixture of oil phase, surfactant and cosurfactant; S3) uniformly mixing the freeze-dried compound obtained in the S1) and the self-emulsifying drug delivery concentrated solution obtained in the S2) to obtain the oral telipopeptide self-emulsifying preparation. Further, the polypeptide is a polypeptide to be orally administered, preferably at least one selected from the group consisting of telipopeptide, semaglutin, liraglutide, duloxetine, lozenith, exenatide, pramlintide, octreotide and leuprorelin. Further, the polypeptide is in the form of a free molecule. Further, the phospholipid is at least one selected from Soybean Phosphatidylcholine (SPC), egg yolk phosphatidylcholine (EPC). Further, the molar ratio of the polypeptide to the phospholipid is 1:20-1:120, preferably 1:40-1:120. For example, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120. Further, the oil phase is selected from at least one of