Octreotide deoxycholate hydrophobic ion pair solid dispersion and preparation method thereof

Abstract

The invention relates to an octreotide deoxycholate hydrophobic ion pair solid dispersion and a preparation method thereof, and belongs to the technical field of medicines. The octreotide deoxycholate hydrophobic ion pair solid dispersion is composed of a compound formed by octreotide acetate and an anionic surfactant and a solid dispersion carrier material, the anionic surfactant is deoxycholate, and the solid dispersion carrier material is one of an enteric-coated carrier and a hydrophilic carrier. The octreotide and deoxycholate form hydrophobic ion pairs, so that the lipophilicity and transmembrane permeability of the octreotide are improved, the stability and bioavailability of the octreotide in an oral administration system are enhanced, meanwhile, the preparation process is simple, the cost is low, and compared with a self-emulsifying preparation, the preparation process is simplified, the dosage is flexible, and the preparation cost is low. And meanwhile, the product has better stability, is easier to store and transport, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to an octreotide deoxycholate hydrophobic ion pair solid dispersion and a preparation method thereof, belonging to the technical field of medicine. Background Art

[0002] Compared with small molecule drugs, polypeptide drugs are mostly endogenous substances, with characteristics such as strong specificity, good efficacy, and relatively low toxicity, playing a crucial role in the treatment of various diseases. However, due to various physiological barriers, including enzyme barriers, mucus barriers, cell membrane barriers, and low intestinal permeability, especially in the presence of proteolytic enzymes, it is easily degraded in the gastrointestinal (GI) tract, resulting in low bioavailability and thus limiting the oral delivery of macromolecules. Because of its more specific action and less toxicity, the main route of macromolecule administration is still through the parenteral route. However, the parenteral route may cause pain at the injection site and systemic circulation adverse reactions, limiting the patient's compliance with drug treatment.

[0003] Octreotide (OCT) is a cyclic oligopeptide composed of eight amino acids. According to biopharmaceutics classification, it belongs to BCS class III drugs. This drug has the characteristics of high solubility and low permeability, can inhibit the secretion of growth hormone, and is mainly used clinically for the treatment of acromegaly and the hormonal monotherapy of malignant endocrine diseases. Currently, the marketed octreotide preparations are mostly injection dosage forms, mainly administered through intravenous or intramuscular injection routes. However, due to its short half-life, it must be administered frequently, which is not ideal for the long-term treatment of chronic diseases. The (SRLs) preparation is administered only once a month by intramuscular injection, effectively reducing the dosing frequency and the inconvenience it brings, and thus is more suitable for acromegaly patients who need daily OCT treatment. A survey of acromegaly patients receiving SRLs treatment showed that up to 11% of patients experienced pain during injection, which made patients more inclined to choose an alternative to injection administration. The OCT enteric-coated capsule adopts the transient permeation enhancer technology. This product uses a large dose of the permeation enhancer sodium caprylate, which can instantaneously release a high concentration of OCT and a large dose of the permeation enhancer C8, but its oral bioavailability is only 0.7%. In addition, long-term use of permeation enhancers may cause toxicity problems, so there is an urgent need for a more reliable carrier-mediated transport method to overcome the epithelial barrier.

[0004] Self-emulsifying drug delivery systems (SEDDS) are a type of liquid formulation technology that forms microemulsions or nanoemulsions spontaneously, mainly used to improve the oral bioavailability of poorly soluble drugs. However, many problems in the preparation process limit its development. First, when octreotide is used as a drug for treating neuroendocrine tumors or acromegaly, a relatively high dose is usually required. However, octreotide is a hydrophilic polypeptide with low solubility in the oil phase of SEDDS liquid formulations, and the drug loading is low (usually less than 5% in the SEDDS system), unable to meet the high-dose treatment requirements. Second, SEDDS systems usually require a high concentration of surfactants to stabilize the emulsion droplets, and too high a proportion of excipients is likely to cause safety risks. For example, when the concentration of plasma reagents such as deoxycholate is too high, it may induce bile acid imbalance or intestinal inflammation. Third, SEDDS liquid formulations are bulky and have poor patient compliance. Fourth, the formulation of SEDDS liquid formulations requires precise control of the proportions of surfactants, co-solvents, and oily components, and the preparation process is complex, increasing the complexity of the formulation and production costs. At the same time, SEDDS liquid formulations are prone to phase separation or oxidation and need to be stored at low temperature and protected from light, making it difficult to store for a long time.

[0005] Bile salts are natural components synthesized in the body, with biocompatibility and biodegradability. Since bile acids are effectively absorbed through the terminal ileum, bile salt-mediated peptide delivery can be used to develop new oral drug delivery systems. Using bile salts as anionic surfactants, electrostatic complexation with octreotide acetate forms a lipophilic ion pair complex, improving the lipophilicity of OCT. However, the solubility of the complex is relatively low, so it is necessary to prepare a high-dose drug-loaded solid dosage form to instantaneously release a large dose of the complex, thereby improving the intestinal permeability and in vivo bioavailability of OCT. Summary of the Invention

[0006] To solve the above problems, the present invention provides an octreotide deoxycholate hydrophobic ion pair solid dispersion and its preparation method. The present invention forms a lipophilic ion pair complex by electrostatic complexation of an anionic surfactant with octreotide acetate, improving the lipophilicity of OCT. By adding a solid dispersion carrier material, an octreotide deoxycholate hydrophobic ion pair solid dispersion is formed, improving the solubility of the above complex, enabling it to instantaneously release a large dose of the complex, and improving the intestinal permeability and in vivo bioavailability of OCT. Through in vitro release experiments, in vitro permeability experiments, and in vivo pharmacokinetic studies on the octreotide deoxycholate hydrophobic ion pair solid dispersion preparation obtained in the present invention, it is found that the octreotide deoxycholate hydrophobic ion pair solid dispersion obtained in the present invention can significantly improve the oral bioavailability of OCT.

[0007] An octreotide deoxycholate hydrophobic ion pair solid dispersion, which is composed of a complex formed by octreotide acetate and an anionic surfactant and a solid dispersion carrier material, wherein the anionic surfactant is deoxycholate, and the solid dispersion carrier material is one of enteric-coated carriers or hydrophilic carriers.

[0008] Furthermore, the solid dispersion is in the form of powder or granules.

[0009] Preferably, the deoxycholate is sodium deoxycholate or sodium ursodeoxycholate.

[0010] Preferably, the enteric-coated carrier is one of HP-55, HP-50 or HPMCAS, and the hydrophilic carrier is one of PVP-K30 or PVP-K90.

[0011] More preferably, the solid dispersion carrier material is the hydrophilic carrier PVP-K30.

[0012] In the above technical solution, the molar ratio of octreotide acetate to the anionic surfactant in the complex formed by octreotide acetate and the anionic surfactant is 1:1 to 6, and the mass ratio of the complex formed by octreotide acetate and the anionic surfactant to the solid dispersion carrier material is 1:1 to 6.

[0013] Preferably, the molar ratio of octreotide acetate to the anionic surfactant in the complex formed by octreotide acetate and the anionic surfactant is 1:4.

[0014] The drug loading of the octreotide deoxycholate hydrophobic ion pair solid dispersion obtained in the present invention can be adjusted by adjusting the mass ratio of the complex formed by octreotide acetate and the anionic surfactant to the solid carrier dispersion carrier material.

[0015] Preferably, the mass ratio of the complex formed by octreotide acetate and the anionic surfactant to the solid dispersion carrier material is 1:3.

[0016] In the above technical solution, the complex formed by octreotide acetate and the anionic surfactant can be obtained by dropping an aqueous solution of the anionic surfactant into an aqueous solution of octreotide acetate, adjusting the pH to 5.0 to 8.0, vortexing, and centrifuging to remove the supernatant.

[0017] Octreotide acetate in the present invention is easily decomposed into acetic acid and octreotide in an aqueous solution. Due to the protonation of lysine residues and the N-terminal amino group in the octreotide molecular structure, it carries a positive charge. When the positively charged octreotide binds to the anionic surfactant to form a complex, acetic acid can be used as a counterion to stabilize the structure of the obtained complex.

[0018] Another object of the present invention is to provide a method for preparing the above solid dispersion, which is prepared by adding the complex formed by octreotide acetate and an anionic surfactant obtained by the above method to a carrier solution, followed by stirring reaction, and then drying, grinding and sieving.

[0019] Preferably, the method for preparing the solid dispersion comprises the following steps: dropping an aqueous solution of an anionic surfactant into an aqueous solution of octreotide acetate under continuous stirring, adjusting the pH to 5.0 - 8.0 with PBS buffer solution, vortexing to obtain a white suspension, centrifuging to remove the supernatant to obtain a complex; adding the obtained complex to a carrier solution, stirring and reacting, drying, grinding and sieving to obtain the product.

[0020] Preferably, the pH is adjusted to 7.0 with PBS buffer solution.

[0021] Preferably, the pH of the PBS buffer solution is 6.8.

[0022] In the above technical solution, the vortexing time is 30 - 120 s, and the temperature is 4°C or 25°C.

[0023] Preferably, the vortexing time is 60 s, and the temperature is 25°C.

[0024] In the above technical solution, the stirring reaction condition is to react at 300 - 500 rpm for 15 min.

[0025] In the above technical solution, the solvent in the carrier solution is an organic solution.

[0026] Further, the organic solution is a tert-butanol-water organic solution or an ethanol-dichloromethane organic solution.

[0027] Furthermore, in the tert-butanol-water organic solution, the volume ratio of tert-butanol to water is 1:1, and in the ethanol-dichloromethane organic solution, the volume ratio of ethanol to dichloromethane is 1:1.

[0028] In the above technical solution, the principle for the amount of the solvent used in the carrier solution is that if the carrier material can be fully dissolved, the amount of the organic solvent used should be as small as possible.

[0029] In the above technical solution, vacuum drying or freeze drying can be adopted during the drying process.

[0030] Further, the conditions for vacuum drying are vacuum drying at 40°C for 24 h.

[0031] Further, the conditions for freeze drying are pre-freezing at -55°C for 2 h and then quickly transferring to a freeze dryer for freeze drying for 24 h.

[0032] Preferably, freeze-drying is used during the drying process.

[0033] During the preparation process of the solid dispersion of the present invention, freeze-drying is preferably used for drying. This method cools the material to a temperature below its eutectic point temperature to completely freeze it, and then under high vacuum, the ice in the material is directly sublimated into water vapor by heating, so that a higher recovery rate can be obtained.

[0034] In the above technical solution, the mesh number of the grinding and sieving is 80 meshes.

[0035] Preferably, after the preparation obtained in the present invention is administered through the jejunum, the relative oral bioavailability of the OCT-NaDC HIP complex and the OCT-NaDC HIP solid dispersion reaches 6.04% and 11.54% respectively relative to subcutaneous administration, indicating that the preparation of the OCT-NaDC HIP solid dispersion can significantly improve the bioavailability of OCT in vivo.

[0036] Advantages of the present invention:

[0037] 1. By forming a hydrophobic ion pair between octreotide and deoxycholate, the present invention improves the lipophilicity and transmembrane permeability of octreotide, protects it from enzymatic degradation, and thus enhances its stability and bioavailability in the oral administration system.

[0038] 2. The octreotide-deoxycholate hydrophobic ion pair solid dispersion in the present invention has high lipophilicity, good absorption promotion effect, and high in vivo bioavailability. At the same time, its preparation process is simple, the cost is low, and it is suitable for industrial production.

[0039] 3. The solid dispersion prepared in the present invention is in the form of powder or granules. Compared with self-emulsifying formulations (SEDDS), the preparation process is simplified, the dosage is flexible, and at the same time, it has good stability and is easier to store and transport. Description of the drawings

[0040] Figure 1 It is a graph of the remaining octreotide acetate content in the supernatant obtained under different conditions in Example 1.

[0041] Figure 2 (a) and (b) are dissolution curves of OCT in the OCT-DC-HIP solid dispersion obtained in Example 5 and Examples 7 to 11; Figure 2 (c) is the dissolution curve of the OCT-DC-HIP solid dispersion obtained in Example 5 and Example 12.

[0042] Figure 3 It is a dissolution curve of the OCT-DC HIP complex and the OCT-DC HIP solid dispersion under different pH conditions in Example 12.

[0043] Figure 4 It is the graph showing the change of the saturated solubility of the OCT-DC HIP complex and the OCT-DC HIP solid dispersion over time in Example 12. Detailed implementation manners

[0044] The following non-limiting examples can enable those of ordinary skill in the art to understand the present invention more comprehensively, but do not limit the present invention in any way.

[0045] In the test methods described in the following examples, unless otherwise specified, they are all conventional methods; the reagents and materials, unless otherwise specified, can all be obtained from commercial channels.

[0046] One of the detailed implementation manners:

[0047] A preparation method of an octreotide deoxycholate hydrophobic ion pair solid dispersion includes the following steps:

[0048] (1) Preparation of the octreotide deoxycholate complex (OCT-DC HIP complex): Weigh octreotide acetate and deoxycholate respectively and dissolve them in ultrapure water. Under continuous stirring, drop the deoxycholate solution into the octreotide acetate solution, adjust the pH of the solution to 5.0 - 8.0 with PBS, vortex to obtain a white suspension, centrifuge, remove the supernatant to obtain the octreotide deoxycholate complex;

[0049] (2) Preparation of the octreotide deoxycholate hydrophobic ion pair solid dispersion (OCT-DC HIP solid dispersion): Weigh the solid dispersion carrier material and dissolve it in an organic solution to obtain a carrier solution, then add the octreotide deoxycholate complex obtained in step (1) to the above carrier solution, stir and react, mix and disperse fully, place it in a fume hood until the solvent evaporates, dry, grind and sieve to obtain.

[0050] In the method of the present invention, the molar ratio of octreotide acetate to the anionic surfactant in the complex formed by octreotide acetate and the anionic surfactant is 1:1 - 6.

[0051] In the method of the present invention, the mass ratio of the complex formed by octreotide acetate and the anionic surfactant to the solid dispersion carrier material is 1:1 - 6.

[0052] In the method of the present invention, the deoxycholate is sodium deoxycholate or sodium ursodeoxycholate.

[0053] In the method of the present invention, the enteric-coated carrier is one of HP-55, HP-50 or HPMCAS, and the hydrophilic carrier is one of PVP-K30 or PVP-K90.

[0054] In the method of the present invention, the pH value of the PBS buffer solution is 6.8.

[0055] In the method of the present invention, the vortex time is 30 - 120 s, and the temperature is 4°C or 25°C.

[0056] In the method of the present invention, the conditions for the stirring reaction are to stir at 300 - 500 rpm for 15 min.

[0057] In the method of the present invention, vacuum drying or freeze-drying can be used during the drying process. Among them, the conditions for vacuum drying are to vacuum dry at 40°C for 24 h; the conditions for freeze-drying are to pre-freeze at -55°C for 2 h and then quickly transfer to a freeze-dryer for freeze-drying for 24 h.

[0058] In the method of the present invention, the mesh number for grinding and sieving is 80 mesh.

[0059] Example 1

[0060] Optimization of the preparation conditions of octreotide deoxycholate complex (OCT-DC HIP complex):

[0061] (1) Molar ratio of octreotide acetate to deoxycholate: Octreotide acetate, sodium deoxycholate (NaDC), and sodium ursodeoxycholate (NaUDC) were respectively dissolved in ultrapure water to make their concentrations 5 mg·mL -1 ; Under the condition of continuous stirring (stirring rate is 300 rpm), the NaDC solution and the NaUDC solution were respectively mixed with the octreotide acetate solution, so that the molar ratios of octreotide acetate to NaDC and NaUDC were 1:1, 1:2, 1:3, 1:4, 1:5, 1:6 respectively, to obtain OCT-NaDC mixed solution and OCT-NaUDC mixed solution; Then the pH of the solution was adjusted to 7.0 with PBS with a pH of 6.8 to produce white complex precipitates; Vortex at 25°C for 60 s to obtain a white suspension; Centrifuge at 10000 rpm for 10 min to remove the supernatant to obtain OCT-NaDCHIP complex and OCT-NaUDC HIP complex.

[0062] (2) Reaction pH: Octreotide acetate, NaDC, and NaUDC were respectively dissolved in ultrapure water to make their concentrations 5 mg·mL -1; Under the condition of continuous stirring (stirring rate: 300 rpm), the NaDC and NaUDC solutions were respectively mixed with the octreotide acetate solution so that the molar ratios of octreotide acetate to NaDC and NaUDC were 1:4, obtaining an OCT-NaDC mixed solution and an OCT-NaUDC mixed solution; then the pH of the solutions was adjusted to 5.0, 6.0, 7.0, and 8.0 respectively with PBS at pH 6.8 to produce white complex precipitates; vortexed at 25 °C for 60 s to obtain white suspensions; centrifuged at 10000 rpm for 10 min to remove the supernatant, obtaining OCT-NaDC HIP complexes and OCT-NaUDC HIP complexes.

[0063] (3) Vortex time: Octreotide acetate, NaDC, and NaUDC were respectively dissolved in ultrapure water to make their concentrations 5 mg·mL -1 ; Under the condition of continuous stirring (stirring rate: 300 rpm), the NaDC and NaUDC solutions were respectively mixed with the octreotide acetate solution so that the molar ratios of octreotide acetate to NaDC and NaUDC were 1:4, obtaining an OCT-NaDC mixed solution and an OCT-NaUDC mixed solution; then the pH of the solutions was adjusted to 7.0 respectively with PBS at pH 6.8 to produce white complex precipitates; vortexed at 25 °C for 30 s, 60 s, and 120 s respectively to obtain white suspensions; centrifuged at 10000 rpm for 10 min to remove the supernatant, obtaining OCT-NaDC HIP complexes and OCT-NaUDC HIP complexes.

[0064] (4) Vortex temperature: Octreotide acetate, NaDC, and NaUDC were respectively dissolved in ultrapure water to make their concentrations 5 mg·mL -1 ; Under the condition of continuous stirring (stirring rate: 300 rpm), the NaDC and NaUDC solutions were respectively mixed with the octreotide acetate solution so that the molar ratios of octreotide acetate to NaDC and NaUDC were 1:4, obtaining an OCT-NaDC mixed solution and an OCT-NaUDC mixed solution; then the pH of the solutions was adjusted to 7.0 respectively with PBS at pH 6.8 to produce white complex precipitates; vortexed at 4 °C and 25 °C for 60 s respectively to obtain white suspensions, centrifuged at 10000 rpm for 10 min to remove the supernatant, obtaining OCT-NaDC HIP complexes and OCT-NaUDC HIP complexes.

[0065] Collect the supernatants after centrifugation of the white suspensions obtained under the above various conditions, and then determine the unbound octreotide acetate by HPLC method. The results are as Figure 1 , thereby determining the optimal reaction conditions of octreotide acetate with deoxycholate (DC) as follows:

[0066] Octreotide acetate, NaDC, and NaUDC were separately dissolved in ultrapure water to make their concentrations 5 mg·mL -1 ; Under the condition of continuous stirring (stirring rate: 300 rpm), the NaDC and NaUDC solutions were separately mixed with the octreotide acetate solution so that the molar ratio of octreotide acetate to NaDC and NaUDC was 1:4, obtaining an OCT-NaDC mixed solution and an OCT-NaUDC mixed solution; Then the pH of the solutions was adjusted to 7.0 with PBS at pH 6.8, generating white complex precipitates; Vortexed at 25 °C for 60 s to obtain white suspensions; Centrifuged at 10,000 rpm for 10 min to remove the supernatant, obtaining OCT-NaDC HIP complexes and OCT-NaUDC HIP complexes.

[0067] Example 2

[0068] A preparation method of an octreotide deoxycholate hydrophobic ion pair solid dispersion, comprising the following steps:

[0069] Precisely weigh the enteric-coated carrier HP-55 and dissolve it in an organic solution (ethanol:dichloromethane = 1:1 (v / v)) to obtain a 5% carrier solution; Then separately weigh a certain amount of the OCT-DC HIP complexes (including OCT-NaDC HIP complexes and OCT-NaUDC HIP complexes) obtained under the optimal preparation conditions of Example 1 and add them to the already dissolved carrier solution respectively, wherein the mass ratio of the OCT-DC HIP complexes to the carrier is 1:3; Finally, stir and react at 300 rpm for 15 min, mix and disperse fully, and after completion, place it in a fume hood until the solvent evaporates completely, put it into a vacuum drying oven, and vacuum dry at 40 °C for 24 h, grind through an 80-mesh sieve to obtain Preparation #1 (OCT-NaDC HIP solid dispersion) and Preparation #2 (OCT-NaUDC HIP solid dispersion).

[0070] Example 3

[0071] Accurately weigh the enteric-coated carrier HP-50 and dissolve it in an organic solution (ethanol: dichloromethane = 1:1 (v / v)) to obtain a carrier solution with a concentration of 5%; then weigh a certain amount of the OCT-DC HIP complex (including the OCT-NaDC HIP complex and the OCT-NaUDC HIP complex) obtained under the optimal preparation conditions of Example 1, and add them to the dissolved carrier solution, wherein the mass ratio of the OCT-DC HIP complex to the carrier is 1:3; finally, stir and react at a speed of 300 rpm for 15 minutes, fully mix and disperse, and after the end, place it in a fume hood until the solvent evaporates, put it in a vacuum drying oven, and dry it under reduced pressure at 40° C. for 24 hours, grind it through an 80-mesh sieve to obtain preparations #3 and #4.

[0072] Example 4

[0073] Accurately weigh the enteric-coated carrier HPMCAS and dissolve it in an organic solution (ethanol: dichloromethane = 1:1 (v / v)) to obtain a carrier solution with a concentration of 5%; then weigh a certain amount of the OCT-DC HIP complex (including the OCT-NaDC HIP complex and the OCT-NaUDC HIP complex) obtained under the optimal preparation conditions of Example 1, and add them to the dissolved carrier solution, wherein the mass ratio of the OCT-DC HIP complex to the carrier is 1:3; finally, stir the reaction at a speed of 300 rpm for 15 minutes, fully mix and disperse, and after the reaction, place it in a fume hood until the solvent evaporates, put it in a vacuum drying oven, and dry it under reduced pressure at 40° C. for 24 hours, grind it through an 80-mesh sieve to obtain preparations #5 and #6.

[0074] Example 5

[0075] Accurately weigh the enteric carrier PVP-K30 and dissolve it in an organic solution (tert-butyl alcohol: water = 1:1 (v / v)) to obtain a carrier solution with a concentration of 5%; then weigh a certain amount of OCT-DC HIP complex (including OCT-NaDC HIP complex and OCT-NaUDC HIP complex) obtained under the optimal preparation conditions of Example 1, and add them to the dissolved carrier solution, wherein the mass ratio of the OCT-DC HIP complex to the carrier is 1:3; finally, stir the reaction at a speed of 300 rpm for 15 minutes, fully mix and disperse, and after the end, place it in a fume hood until the solvent evaporates, put it in a vacuum drying oven, and dry it under reduced pressure at 40° C. for 24 hours, grind it through an 80-mesh sieve to obtain preparations #7 and #8.

[0076] Example 6

[0077] Accurately weigh the enteric carrier PVP-K90 and dissolve it in an organic solution (tert-butyl alcohol: water = 1:1 (v / v)) to obtain a carrier solution with a concentration of 5%; then weigh a certain amount of OCT-DC HIP complex (including OCT-NaDC HIP complex and OCT-NaUDC HIP complex) obtained under the optimal preparation conditions of Example 1, and add them to the dissolved carrier solution, wherein the mass ratio of the OCT-DC HIP complex to the carrier is 1:3; finally, stir the reaction at a speed of 300 rpm for 15 minutes, fully mix and disperse, and after the end, place it in a fume hood until the solvent evaporates, put it in a vacuum drying oven, and dry it under reduced pressure at 40° C. for 24 hours, grind it through an 80-mesh sieve to obtain preparations #9 and #10.

[0078] Example 7

[0079] Accurately weigh the enteric carrier PVP-K30 and dissolve it in an organic solution (tert-butyl alcohol: water = 1:1 (v / v)) to obtain a carrier solution with a concentration of 5%; then weigh a certain amount of OCT-DC HIP complex (including OCT-NaDC HIP complex and OCT-NaUDC HIP complex) obtained under the optimal preparation conditions of Example 1, and add them to the dissolved carrier solution, wherein the mass ratio of the OCT-DC HIP complex to the carrier is 1:1; finally, stir the reaction at a speed of 300 rpm for 15 minutes, fully mix and disperse, and after the end, place it in a fume hood until the solvent evaporates, put it in a vacuum drying oven, and dry it under reduced pressure at 40° C. for 24 hours, grind it through an 80-mesh sieve to obtain preparations #11 and #12.

[0080] Example 8

[0081] Accurately weigh the enteric carrier PVP-K30 and dissolve it in an organic solution (tert-butyl alcohol: water = 1:1 (v / v)) to obtain a carrier solution with a concentration of 5%; then weigh a certain amount of OCT-DC HIP complex (including OCT-NaDC HIP complex and OCT-NaUDC HIP complex) obtained under the optimal preparation conditions of Example 1, and add them to the dissolved carrier solution, wherein the mass ratio of the OCT-DC HIP complex to the carrier is 1:2; finally, stir the reaction at a speed of 300 rpm for 15 minutes, fully mix and disperse, and after the end, place it in a fume hood until the solvent evaporates, put it in a vacuum drying oven, and dry it under reduced pressure at 40° C. for 24 hours, grind it through an 80-mesh sieve to obtain preparations #13 and #14.

[0082] Example 9

[0083] Accurately weigh the enteric carrier PVP-K30 and dissolve it in an organic solution (tert-butyl alcohol: water = 1:1 (v / v)) to obtain a carrier solution with a concentration of 5%; then weigh a certain amount of OCT-DC HIP complex (including OCT-NaDC HIP complex and OCT-NaUDC HIP complex) obtained under the optimal preparation conditions of Example 1, and add them to the dissolved carrier solution, wherein the mass ratio of the OCT-DC HIP complex to the carrier is 1:4; finally, stir the reaction at a speed of 300 rpm for 15 minutes, fully mix and disperse, and after the end, place it in a fume hood until the solvent evaporates, put it in a vacuum drying oven, and dry it under reduced pressure at 40° C. for 24 hours, grind it through an 80-mesh sieve to obtain preparations #15 and #16.

[0084] Example 10

[0085] Accurately weigh the enteric carrier PVP-K30 and dissolve it in an organic solution (tert-butyl alcohol: water = 1:1 (v / v)) to obtain a carrier solution with a concentration of 5%; then weigh a certain amount of OCT-DC HIP complex (including OCT-NaDC HIP complex and OCT-NaUDC HIP complex) obtained under the optimal preparation conditions of Example 1, and add them to the dissolved carrier solution, wherein the mass ratio of the OCT-DC HIP complex to the carrier is 1:5; finally, stir the reaction at a speed of 300 rpm for 15 minutes, fully mix and disperse, and after the end, place it in a fume hood until the solvent evaporates, put it in a vacuum drying oven, and dry it under reduced pressure at 40° C. for 24 hours, grind it through an 80-mesh sieve to obtain preparations #17 and #18.

[0086] Embodiment 11

[0087] Accurately weigh the enteric carrier PVP-K30 and dissolve it in an organic solution (tert-butyl alcohol: water = 1:1 (v / v)) to obtain a carrier solution with a concentration of 5%; then weigh a certain amount of OCT-DC HIP complex (including OCT-NaDC HIP complex and OCT-NaUDC HIP complex) obtained under the optimal preparation conditions of Example 1, and add them to the dissolved carrier solution, wherein the mass ratio of the OCT-DC HIP complex to the carrier is 1:6; finally, stir the reaction at a speed of 300 rpm for 15 minutes, fully mix and disperse, and after the end, place it in a fume hood until the solvent evaporates, put it in a vacuum drying oven, and dry it under reduced pressure at 40° C. for 24 hours, grind it through an 80-mesh sieve to obtain preparations #19 and #20.

[0088] Example 12

[0089] Accurately weigh the enteric carrier PVP-K30 and dissolve it in an organic solution (tert-butyl alcohol: water = 1:1 (v / v)) to obtain a carrier solution with a concentration of 5%; then weigh a certain amount of OCT-DC HIP complex (including OCT-NaDC HIP complex and OCT-NaUDC HIP complex) obtained under the optimal preparation conditions of Example 1, and add them to the dissolved carrier solution, respectively, wherein the mass ratio of OCT-DC HIP complex to the carrier is 1:3; finally, stir the reaction at 300 rpm for 15 min, fully mix and disperse, and after the end, pre-freeze it in liquid nitrogen at -55°C for 2 h and then quickly transfer it to a freeze dryer. After freeze drying for 24 h, grind it through an 80-mesh sieve to obtain preparation #21 and preparation #22.

[0090] Study on the in vitro release of the OCT-DC HIP solid dispersion preparations obtained in Examples 2 to 12 of the present invention:

[0091] The experimental operation was carried out in accordance with the small cup method in the dissolution and release determination method of Part IV of the 2020 edition of the Pharmacopoeia of the People's Republic of China, with a temperature of 37°C, a rotation speed of 100 rpm, and a medium volume of 100 mL. The OCT-DC HIP solid dispersion obtained in each example (equivalent to OCT 1.0 mg) was accurately added, and the sampling time points were 0, 5, 10, 15, 30, and 60 min, with 5 mL sampled each time, and an isothermal and equal volume of release medium was added at the same time, wherein the release medium was water and a PBS solution with a pH of 6.8, respectively. The sample to be tested was filtered through a 0.22 μm PTFE filter membrane, the initial filtrate was discarded, 10 μL of the subsequent filtrate was taken for sample injection and measurement, the chromatogram was recorded, and the concentration and cumulative release amount (Accumulated dissolution, D A ), the result is as follows Figure 2 And Table 1, the calculation method is as follows:

[0092] D A (%) = {[(C1+C2+…+C n-1 )×5mL+C n ×100mL] / 1mg}×100

[0093] Among them, C n is the concentration of samples taken out at each time point.

[0094] Table 1 Apparent solubility of OCT-DC HIP solid dispersions obtained in Examples 2 to 6 in different release media

[0095]

[0096] As shown in the results in Table 1, when the carrier material is PVP-K30, the saturated solubility of the OCT-DC HIP solid dispersion is the largest, and there is no significant difference in the dissolution trend of the solid dispersions prepared with different carrier materials in pH 6.8 PBS. Therefore, PVP-K30 with the best solubilization effect can be used as the optimal carrier material for preparing the hydrophobic ion pair solid dispersion of octreotide deoxycholate in the present invention.

[0097] In Example 5 and Example 12 of the present invention, the study on the drying process for preparing the OCT-DC HIP solid dispersion. Among them, before freeze-drying and vacuum drying, the total mass of the OCT-DC HIP complex and PVP-K30 is denoted as m1; the mass of the OCT-DC HIP solid dispersion obtained after sieving by freeze-drying and vacuum drying is denoted as m2. Comparing the recovery rates of the two processes, the results are shown in Figure 2 (c) and Table 2. It can be seen that the recovery rate of the freeze-drying method can reach about 87%, while the recovery rate of the vacuum drying method is only about 50% at the lowest, indicating that the solid dispersion prepared by the vacuum drying method has more losses during the subsequent grinding and sieving processes. Therefore, the freeze-drying method can be used as the optimal drying method for preparing the hydrophobic ion pair solid dispersion of octreotide deoxycholate in the present invention.

[0098] Table 2 Influence of drying process on recovery rate

[0099]

[0100] In Example 12 of the present invention, the in vitro release study of the OCT-DC HIP complex and the OCT-DC HIP solid dispersion in the simulated medium. Among them, the simulated medium is PBS solutions with different pH values, and the pH values are 1.2, 4.8, 5.5, 6.0, 6.8, and 7.4 respectively. Accurately weigh octreotide acetate and dissolve it in PBS buffers with different pH values to prepare a stock solution of 1.0 mg·mL -1 and dilute it with PBS buffers with different pH values to 10.0 μg·mL -1 , place it at room temperature, measure the drug concentration at regular intervals, and obtain the dissolution curve. The results are shown in Figure 3 . The results show that the release trends of the OCT-DC HIP solid dispersion in different media are basically the same, and it is released completely in about 10 minutes. Compared with the OCT-DC HIP complex, the solid dispersion significantly improves the in vitro release rate of the OCT-DC HIP complex and is not easily affected by the pH of the release medium.

[0101] Referring to the third method in General Chapter 0931 of the Chinese Pharmacopoeia (2020 Edition), set the dissolution medium as 100 mL of pH 6.8 PBS, and the rotation speed as 100 r·min -1, the temperature was 37 °C. An excessive amount of the OCT-DC HIP solid dispersion obtained in Example 12 was added to the dissolution medium, which was in a supersaturated state. Samples of 3 mL were taken at 5, 10, 15, 30, 45 min and 1, 2, 4, 6, 8, 12, 24 h, and at the same time, an equal volume of the dissolution medium at the same temperature was replenished. The solution taken out was filtered through a 0.22 μm hydrophilic PTFE microporous membrane, and after appropriate dilution, high performance liquid chromatography was used for analysis to obtain the time-varying curve of the saturated solubility. The results are as Figure 4 . By comparing the time-varying curves of the saturated solubility of the complex and the solid dispersion, it can be seen that: the preparation of the solid dispersion increased the saturated solubility of the complex; the solubility of the OCT-DC HIP solid dispersion first gradually increased, decreased slightly and then remained unchanged with time; after the OCT-NaDC HIP solid dispersion reached supersaturation, its decreasing trend was gentler than that of the OCT-NaUDC HIP solid dispersion, indicating that its stability was better than that of the OCT-NaUDC HIP solid dispersion.

[0102] In vivo pharmacokinetic study of the OCT-DC HIP complex and the OCT-DC HIP solid dispersion in Example 12 of the present invention:

[0103] Thirty healthy male SD rats were randomly divided into 6 groups, with 5 rats in each group. The OCT-DC HIP complex and the OCT-DC HIP solid dispersion required for the experiment were both prepared one day in advance. The subcutaneous injection of the OCT saline solution was the s.c. group, and the intragastric administration of the OCT aqueous solution was the control group. The OCT-NaDC HIP complex and the OCT-NaDC HIP solid dispersion groups were prepared by adding each solid powder to PBS (pH 6.8) to form a suspension, and the dosing regimens are shown in Table 3.

[0104] Table 3 Dosing dose regimen

[0105]

[0106] Before dosing, blank blood was taken first. For the s.c. group, blood was taken at 1, 10, 30, 60, 90, 120, 180, 240 min after dosing; for the other groups, blood was taken at 3, 10, 30, 60, 90, 120, 180, 240, 360 min after dosing and coated in an EP tube with EDTA (0.6 mL). Immediately, it was centrifuged at 4 °C and 10000 rpm for 10 min, and the upper plasma was aspirated to calculate the blood drug concentration. The relative bioavailability (F%) can reflect the in vivo absorption of the test preparation compared with the reference preparation, and the calculation method is as follows.

[0107] F(%) = (AUC T / AUC s.c. ) × (Doses.c. / Dose T )×100

[0108] Among them, T represents the test preparation, s.c. represents subcutaneous injection, AUC represents the area under the plasma concentration-time curve after administration of different preparations; Dose represents the administered dose.

[0109] Table 4 Summary of Pharmacokinetic Parameters

[0110]

[0111] The in vivo pharmacokinetic study results of the OCT-DC HIP complex and the OCT-DC HIP solid dispersion are shown in Table 4. The results show that OCT has poor gastrointestinal absorption. Compared with the s.c. administration method in the OCT-NaDC HIP complex group and the OCT-NaUDC HIP complex group, the bioavailability is 6.04% and 6.94%, respectively. Compared with the OCT solution group, the bioavailability is significantly increased by 4.38 times and 5.03 times; by preparing a hydrophobic ion pair complex (OCT-DC HIP complex) from OCT and deoxycholate, the absorption of OCT is significantly improved, and the absorption of the OCT-DC HIP complex in vivo is more persistent; the preparation of the solid dispersion significantly increases the solubility of the OCT-DC HIP complex and improves the dissolution rate of the complex. When the OCT-NaDC HIP solid dispersion contacts the intestine, a high concentration of OCT and deoxycholate are rapidly released. The local NaDC and OCT in the intestine rapidly increase, and OCT is rapidly released, opening the tight cell junctions. Through the transport of the ASBT protein, the bioavailability of OCT in vivo is significantly increased (11.54%).

Claims

1. An octreotide deoxycholate hydrophobic ion pair solid dispersion, characterized in that: The solid dispersion is composed of a complex formed by octreotide acetate and an anionic surfactant and a solid dispersion carrier material, wherein the anionic surfactant is deoxycholate, and the solid dispersion carrier material is one of an enteric-coated carrier and a hydrophilic carrier.

2. The solid dispersion according to claim 1, characterized in that: The molar ratio of octreotide acetate to the anionic surfactant in the complex formed by octreotide acetate and the anionic surfactant is 1:1-6, and the mass ratio of the complex formed by octreotide acetate and the anionic surfactant to the solid dispersion carrier material is 1:1-6.

3. The solid dispersion according to claim 1, characterized in that: The deoxycholate is sodium deoxycholate or sodium ursodeoxycholate; the enteric carrier material is one of HP-55, HP-50 or HPMCAS; and the hydrophilic carrier is one of PVP-K30 or PVP-K90.

4. The solid dispersion according to claim 1, characterized in that: The complex formed by octreotide acetate and anionic surfactant can be obtained by dropping anionic surfactant aqueous solution into octreotide acetate aqueous solution, adjusting pH to 5.0-8.0, vortexing, and centrifuging to remove supernatant.

5. The method for preparing a solid dispersion according to any one of claims 1 to 4, characterized in that: The complex formed by octreotide acetate and anionic surfactant is added to a solid dispersion carrier material solution and stirred for reaction, and then dried, ground and sieved to obtain the complex, wherein the complex formed by octreotide acetate and anionic surfactant is the complex obtained by the preparation method described in claim 4.

6. The method for preparing a solid dispersion according to claim 5, characterized in that: Under continuous stirring conditions, an anionic surfactant aqueous solution is added dropwise to an octreotide acetate aqueous solution, and a PBS buffer is used to adjust the pH to 5.0-8.0 to produce a white complex precipitate, which is vortexed to obtain a white suspension, centrifuged, and the supernatant is removed to obtain a complex; the obtained complex is added to a solid dispersion carrier material solution, stirred for reaction, dried, ground and sieved to obtain the product.

7. The preparation method according to claim 4 or 6, characterized in that: The pH value of the PBS buffer is 6.

8.

8. The preparation method according to claim 4 or 6, characterized in that: The vortex time is 30 to 120 seconds, and the temperature is 4° C. or 25° C.

9. The preparation method according to claim 6, characterized in that: The stirring reaction was carried out at 300-500 rpm for 15 min.

10. The preparation method according to claim 6, characterized in that: The drying process may be carried out by reduced pressure drying or freeze drying, wherein the reduced pressure drying condition is reduced pressure drying at 40° C. for 24 hours; the freeze drying condition is pre-freezing at -55° C. for 2 hours and then quickly transferring to a freeze dryer and freeze drying for 24 hours.

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