Octreotide orotate crystal as well as preparation method and application thereof

Abstract

The invention provides a salt type crystal of octreotide as well as a preparation method and application of the salt type crystal. The crystal has characteristic peaks when the 2 theta value is 7.7 degrees + / -0.2 degrees, 8.7 degrees + / -0.2 degrees, 9.5 degrees + / -0.2 degrees, 10.2 degrees + / -0.2 degrees, 13.6 degrees + / -0.2 degrees and 18.3 degrees + / -0.2 degrees by using X-ray powder diffraction of Cu-K alpha radiation. The orotate crystal form I of octreotide provided by the invention has the advantages in at least one aspect of solubility, melting point, stability, dissolution rate, hygroscopicity, adhesiveness, fluidity, bioavailability, processability, purification effect, preparation production, safety and the like, and provides a new better choice for preparation of a pharmaceutical preparation containing octreotide; and the method has very important significance on drug development.

Description

Technical Field

[0001] The present invention belongs to the field of chemical medicine and relates to a salt crystal of octreotide and a preparation method and application thereof. Background Art

[0002] Cyclic octapeptide octreotide is one of the famous somatostatin analogs, which has the same biologically active fragment - Phe 7 -Trp 8 -Lys 9 -Thr 10 -, while using D-Trp 8 Replace L-Trp 8 , overcoming the short half-life problem of somatostatin. The peptide sequence of octreotide is as follows:

[0003] HD-Phe-Cys(1)-Phe-D-Trp-Lys-Thr-Cys(1)-Thr-ol,

[0004] The specific structure is shown in Formula I:

[0005]

[0006] Octreotide mimics the biological activity of somatostatin, but it has a high affinity for somatostatin receptor 2 (SSTR2) and can inhibit the abnormal secretion of growth hormone. Octreotide is currently used to treat acromegaly and diarrhea associated with metastatic sarcoids and tumors that secrete vasoactive intestinal peptide. At the same time, clinical trials for its use in the treatment of breast cancer, metastatic cancer, and gastrointestinal pancreatic neuroendocrine tumors are also being actively carried out. Octreotide was first approved in the United States in 1988. Its active ingredient is acetate and its trade name is It has been administered as a regular or extended-release intravenous, subcutaneous, and intramuscular injection for more than 30 years since its initial approval. In 2020, the FDA approved a sustained-release capsule developed by Chiasma (now part of the Amryt Pharma Group). This oral route of administration is enhanced by the Transient Permeability Enhancer (TPE). The technology is based on medium-chain free fatty acids, sodium octanoate, and inert excipients. The enthusiasm for the continued development and improvement of octreotide stems from its broad market prospects, which are expected to reach $3.6 billion by 2032.

[0007] Despite its attractive market value, octreotide has been the active ingredient in its pharmaceutical products since its launch. However, its chemical instability at high temperatures, high humidity, and even at room temperature has been a major obstacle to its development. Until now, all injectable solutions, depot injections, and sustained-release capsules have required storage at low temperatures to maintain the integrity of their chemical composition, which undoubtedly increased development costs and inconvenience.

[0008] Different salt forms of the same drug exhibit significant differences in solubility, melting point, density, and stability, which can impact drug stability, homogeneity, bioavailability, efficacy, and safety to varying degrees. Furthermore, due to the significant difference in molecular arrangement between amorphous and crystalline forms, there are also significant differences in solubility, stability, hygroscopicity, and bioavailability, significantly impacting drugability. Therefore, comprehensive and systematic screening of salt and crystalline forms to select the most suitable salt solid form for development is a crucial research topic that cannot be ignored in drug development.

[0009] Prior art has not yet reported any patents disclosing any crystalline salt form of octreotide with significantly improved chemical stability. Although Pohl et al. obtained the single crystal structure of hydrated octreotide oxalate with space group P212121 in 1995, they have never reported any improvements in properties of the oxalate compared to the acetate. Therefore, it is necessary to screen the salt forms of octreotide (Formula (I)) to provide more and better options for subsequent drug development. Summary of the Invention

[0010] In view of the shortcomings of the prior art, the present invention aims to provide a salt crystal of octreotide and a preparation method and application thereof.

[0011] To achieve this object, the present invention adopts the following technical solutions:

[0012] On the one hand, the present invention provides an orotate salt form I of octreotide, wherein the form I has characteristic peaks at 2θ values of 7.7°±0.2°, 8.7°±0.2°, 9.5°±0.2°, 10.2°±0.2°, 13.6°±0.2° and 18.3°±0.2° using X-ray powder diffraction of Cu-Kα radiation.

[0013] On the other hand, the present invention provides a method for preparing the above-mentioned octreotide orotate crystalline form I, the preparation method comprising the following steps:

[0014] Octreotide acetate solid and orotic acid are mixed and dispersed in methanol and slurried, and the solid is collected and dried to obtain octreotide orotic acid salt form I.

[0015] Preferably, the molar ratio of the octreotide acetate solid to orotic acid is 1:1 to 1:2, for example 1:1, 1:1.2, 1:1.5, 1:1.8 or 1:2.

[0016] Preferably, the beating is performed at room temperature.

[0017] Preferably, the drying is performed at room temperature.

[0018] On the other hand, the present invention provides a method for preparing the octreotide orotate crystalline form I as described above, the preparation method comprising the following steps:

[0019] Octreotide trifluoroacetate solid and tris(hydroxymethylaminomethane) orotate are mixed and dissolved in water, and an anti-solvent, methanol, and seed crystals of octreotide orotate Form I are added to precipitate octreotide orotate Form I from the solution. The solid is collected and dried to obtain octreotide orotate Form I;

[0020] Preferably, the molar ratio of the trepide acetate solid to tris(hydroxymethylaminomethane) orotate is 1:2 to 1:4, for example, 1:2, 1:2.5, 1:2.8, 1:3, 1:3.5, 1:3.8 or 1:4.

[0021] Preferably, the anti-solvent methanol is added to the system at 5-30°C (eg, 5°C, 10°C, 15°C, 20°C, 25°C, 28°C or 30°C).

[0022] In the present invention, octreotide trifluoroacetate solid and tris(hydroxymethylaminomethane) orotate are mixed and dissolved in water, anti-solvent methanol and seed crystals of octreotide orotate form I are added, octreotide orotate form I is precipitated from the solution, and octreotide orotate form I is separated by filtration to obtain octreotide orotate form I.

[0023] Preferably, the drying is performed at room temperature.

[0024] Preferably, the tris(hydroxymethylaminomethane) orotate is prepared by the following preparation method:

[0025] Tris(hydroxymethylaminomethane) and orotic acid are mixed in water, stirred at room temperature to dissolve, and freeze-dried to obtain the tris(hydroxymethylaminomethane) orotic acid salt;

[0026] Preferably, the molar ratio of tris(hydroxymethyl)aminomethane to orotic acid is 1:1.

[0027] In another aspect, the present invention provides a pharmaceutical composition comprising the above-described octreotide orotate crystalline form I and a pharmaceutically acceptable carrier.

[0028] In the pharmaceutical composition of the present invention, the orotate crystal form I of octreotide is used as an active ingredient.

[0029] In another aspect, the present invention provides a therapeutic agent for acromegaly, comprising the above-mentioned octreotide orotate crystal form I as an active ingredient.

[0030] In another aspect, the present invention provides a tumor therapeutic drug comprising the above-mentioned octreotide orotate crystal form I as an active ingredient.

[0031] Preferably, the tumor therapeutic drug is a carcinoid tumor therapeutic drug or a vasoactive intestinal peptide tumor therapeutic drug.

[0032] In another aspect, the present invention provides a drug for treating diarrhea, comprising the above-mentioned octreotide orotate crystal form I as an active ingredient.

[0033] Preferably, the diarrhea therapeutic drug is a drug for treating severe diarrhea and flushing episodes in adults with metastatic carcinoid tumors, treating profuse watery diarrhea in adults associated with tumors that secrete vasoactive intestinal peptide, treating AIDS-related diarrhea, treating ileostomy-related diarrhea, and treating chemotherapy-induced diarrhea.

[0034] In another aspect, the present invention provides a therapeutic agent for esophageal variceal bleeding, comprising the above-mentioned octreotide orotate crystal form I as an active ingredient.

[0035] In another aspect, the present invention provides a drug for treating digestive tract or pancreatic fistula, comprising the above-mentioned octreotide orotate crystal form I as an active ingredient.

[0036] In another aspect, the present invention provides a therapeutic drug for dumping syndrome, comprising the above-mentioned octreotide orotate crystal form I as an active ingredient.

[0037] In another aspect, the present invention provides a therapeutic drug for chylothorax, comprising the above-mentioned octreotide orotate crystal form I as an active ingredient.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] The octreotide orotate crystalline form I provided by the present invention has advantages in at least one of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, flowability, bioavailability, processing performance, purification, formulation production, and safety, providing a new and better option for the preparation of pharmaceutical preparations containing octreotide, and is of great significance for drug development. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 is the PXRD pattern of octreotide orotate form I;

[0041] Figure 2 This is a diagram showing the dynamic moisture sorption (DVS) test results of octreotide orotate form I;

[0042] Figure 3 The PXRD patterns of octreotide orotate form I before and after DVS testing, wherein the upper curve is before the test and the lower curve is after the test;

[0043] Figure 4 is the DVS diagram of octreotide acetate;

[0044] Figure 5 The PXRD patterns of the sample prepared in Comparative Example 7 before and after drying are shown in Figure 7, where the upper curve is the sample before drying and the lower curve is the sample after drying.

[0045] Figure 6 This is a graph showing the dynamic moisture sorption (DVS) test results of the sample prepared in Comparative Example 7;

[0046] Figure 7 The PXRD patterns of the sample prepared in Comparative Example 7 before and after the DVS test are shown, where the upper curve is before the test and the lower curve is after the test. DETAILED DESCRIPTION

[0047] The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0048] In the present invention, "room temperature" generally refers to 22°C to 28°C unless otherwise specified.

[0049] The abbreviations used in the present invention are explained as follows:

[0050] PXRD: X-ray powder diffraction;

[0051] DVS: dynamic moisture sorption;

[0052] HPLC: high performance liquid chromatography;

[0053] The X-ray powder diffraction pattern of the present invention is the Empyrean type and X'Pert type of Panalytical (PANalytical) 3 The X-ray powder diffractometer was used to collect the data. The parameters of the X-ray powder diffraction method of the present invention are as follows:

[0054] X-ray source: Cu, Kα;

[0055] 1.54060; 1.54443;

[0056] Kα2 / Kα1 intensity ratio: 0.50;

[0057] Voltage: 45 kilovolts (kV);

[0058] Current: 40 milliamperes (mA);

[0059] Scanning range: from 3.0 to 40.0 degrees (2θ angle).

[0060] The dynamic moisture adsorption graph described in the present invention was collected on an Intrinsic Plus dynamic moisture adsorption instrument from SMS. The method parameters for the dynamic moisture adsorption test described in the present invention are as follows:

[0061] Temperature: 25℃;

[0062] Protective gas and flow rate: N2, 200 ml / min;

[0063] dm / dt: 0.002% / min;

[0064] Minimum dm / dt balancing time: 10 minutes;

[0065] Maximum balancing time: 180 minutes;

[0066] Relative humidity range: 20%RH-95%RH-0%RH-95%RH or 70%RH-95%RH-0%RH-95%RH; or 50%RH-95%RH-0%RH-95%RH;

[0067] Relative humidity gradient: 10% (0% RH-90% RH-0% RH), 5% (90% RH-95% RH and 95% RH-90% RH);

[0068] The high performance liquid chromatography (HPLC) data in the present invention were collected from a Waters H-Class detector using a diode array detector (PDA). The HPLC method parameters for the purity test described in the present invention are as follows:

[0069] 1. Chromatographic column: Waters C18, 50×2.1mm, 1.6μm;

[0070] 2. Mobile phase: A: 0.1% phosphoric acid aqueous solution;

[0071] B: acetonitrile;

[0072] The elution gradient is shown in Table 1 below.

[0073] Table 1

[0074] Time (min) ％B 0.0 10.0 3.0 10.0 13.0 30.0 15.0 30.0 20.0 80.0 20.1 10.0 25.0 10.0

[0075] 3. Flow rate: 0.3 mL / min;

[0076] 4. Injection volume: 1.0 μL;

[0077] 5. Detection wavelength: 215nm;

[0078] 6. Column temperature: 40°C;

[0079] 7. Diluent: ACN / H2O 1:1.

[0080] Unless otherwise specified, the following examples were all performed at room temperature.

[0081] Example 1: Preparation of Orotate Form I

[0082] At room temperature, 134.0 mg of octreotide acetate solid and 36.6 mg of orotic acid were weighed into a 20 ml glass vial, 5 ml of methanol was added, and the mixture was stirred at room temperature. After three days, the sample became a white suspension. Centrifugation gave a white solid. After testing, the solid obtained in this example was orotic acid. The X-ray powder diffraction data of the sample are shown in Table 2, and its diffraction pattern is shown in the attached figure. Figure 1 The sample has characteristic peaks at about 7.7°±0.2°, about 8.7°±0.2°, about 9.5°±0.2°, about 10.2°±0.2°, about 13.6°±0.2°, and about 18.3°±0.2°.

[0083] Table 2

[0084]

[0085]

[0086] Example 2: Preparation of Orotate Form I

[0087] 40.0 mg of octreotide trifluoroacetate solid and 22.2 mg of tris(hydroxymethyl)aminomethane orotate) were weighed in a glass vial at room temperature, 0.2 ml of water was added, and the mixture was stirred at room temperature until the solid was dissolved. 0.05 ml of methanol and 2.2 mg of orotate crystalline form I seed crystals were added, and the mixture was stirred at room temperature for one hour. The sample was in a white suspension state. 0.35 ml of methanol was added and the mixture was stirred at room temperature for three days. The sample was in a white suspension state. After centrifugation to remove the mother liquor, 0.4 ml of water / methanol (1:2) solvent was added and the mixture was beaten and washed at 5 ° C for one day to obtain a white suspension. The mixture was filtered to separate a white solid, and vacuum dried at room temperature for one day to obtain 31.8 mg of white solid. After testing, the solid obtained in the present embodiment was orotate, and the X-ray powder diffraction data of the sample are as shown in Table 3. The sample has characteristic peaks at about 7.6°±0.2°, about 8.7°±0.2°, about 9.5°±0.2°, about 10.2°±0.2°, about 13.6°±0.2°, 18.3°±0.2°, and about 18.5°±0.2°.

[0088] Table 3

[0089]

[0090]

[0091]

[0092] Example 3: Comparative stability study

[0093] The salt form, octreotide acetate, and octreotide oxalate solid powders of Example 1 were placed in an open-air stabilization chamber at 25°C / 60% RH and 40°C / 75% RH. Samples were taken after 7 weeks to measure HPLC purity. As shown in Table 4, the salt form of the present invention exhibited significantly higher stability at 25°C / 60% RH and 40°C / 75% RH than the prior art octreotide acetate.

[0094] Table 4

[0095]

[0096] Example 4: Comparative study of moisture absorption

[0097] Weigh about 10 mg of octreotide orotate and octreotide acetate of the present invention for dynamic water adsorption (DVS) test, and then take samples for PXRD test. Figure 2 , Attachment Figure 3 and attached Figure 4As shown, the prior art octreotide acetate is in a gel-like state after the DVS test, indicating that it is nearly deliquescent, while the octreotide orotate of the present invention is hygroscopic and has lower hygroscopicity than the prior art octreotide acetate. Moreover, PXRD shows that the crystal form does not change before and after the DVS test.

[0098] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Guidelines for Hygroscopicity Testing of Part Four Drugs in the 2020 Edition of the Chinese Pharmacopoeia):

[0099] Deliquescent: Absorbs enough water to form a liquid

[0100] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%

[0101] Hygroscopic: Weight gain due to moisture absorption is less than 15% but not less than 2%

[0102] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%

[0103] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0104] Comparative Example 1:

[0105] 12.4 mg of octreotide acetate, 3.3 mg of orotic acid, and 0.5 mL of water were mixed in a glass vial at room temperature and stirred at room temperature. After four days, the sample was almost clear and no solids sufficient for detection could be separated.

[0106] Comparative Example 2:

[0107] At room temperature, 11.1 mg of octreotide acetate solid and 3.3 mg of orotic acid were weighed into a glass vial. 0.5 mL of ethyl acetate was added and stirred at room temperature. After six days, the sample became a white suspension. Centrifugation yielded a white solid. Testing showed that the solid obtained in this comparative example was amorphous.

[0108] Comparative Example 3:

[0109] At room temperature, 11.8 mg of octreotide acetate solid and 3.2 mg of orotic acid were weighed into a glass vial. 0.5 mL of tetrahydrofuran was added and stirred at room temperature. After six days, the sample became a white suspension. Centrifugation yielded a white solid. Testing showed that the solid obtained in this comparative example was amorphous.

[0110] Comparative Example 4:

[0111] At room temperature, 12 mg of octreotide acetate, 3.3 mg of orotic acid, and 0.5 mL of isopropanol were mixed in a glass vial and stirred at room temperature. After five days, the sample became nearly clear. 0.5 mL of n-heptane was added to obtain a white suspension. After stirring at room temperature for four days, centrifugation was performed to obtain a white solid. Testing confirmed that the solid obtained in this comparative example was amorphous.

[0112] Comparative Example 5:

[0113] At room temperature, 12.7 mg of octreotide acetate solid and 3.3 mg of orotic acid were weighed into a glass vial. 0.5 mL of acetonitrile was added and stirred at room temperature. After six days, the sample became a white suspension. Centrifugation yielded a white solid. Testing showed that the solid obtained in this comparative example was amorphous.

[0114] Comparative Example 6:

[0115] At room temperature, 11.7 mg of octreotide acetate solid and 3.4 mg of orotic acid were weighed into a glass vial. 0.5 mL of chloroform was added and stirred at room temperature. After four days, the sample became a white suspension. Centrifugation yielded a white solid. Testing showed that the solid obtained in this comparative example was amorphous.

[0116] Comparative Example 7:

[0117] At room temperature, 30.8 mg of octreotide acetate solid and 6.8 mg of orotic acid were weighed into a glass vial, 1.0 ml of ethanol was added, and stirred at room temperature. After one day, the sample became a white suspension. Centrifugation gave a white solid. After testing, the solid obtained in this comparative example had a small amount of diffraction peaks. The X-ray powder diffraction data of the sample are shown in Table 5. After one day of vacuum drying at room temperature, it almost turned into an amorphous form, showing only two weak diffraction peaks (such as Figure 5 As shown). Weigh about 10 mg of the solid sample of this comparative example to conduct dynamic moisture adsorption (DVS) test, and then take a sample to measure PXRD. Figure 6 and attached Figure 7 As shown, after DVS testing, the sample changed from a solid powder to a cohesive solid. DVS data showed that it was hygroscopic, and the moisture absorption weight gain at 25°C / 80% RH was higher than that of the octreotide orotate of the present invention. PXRD showed that the sample was amorphous after DVS testing.

[0118] Table 5

[0119]

[0120]

[0121] The following comparative examples use currently commonly used salt-forming methods to demonstrate that commonly used pharmaceutical salt-forming ligands such as maleic acid, gentisic acid, citric acid, fumaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, and tartaric acid cannot form salts with octreotide, or the corresponding salt forms of octreotide cannot precipitate crystals.

[0122] Comparative Example 8:

[0123] 15 mg of octreotide acetate, 3.2 mg of maleic acid, and 0.5 mL of methanol were mixed in a glass vial at room temperature and stirred at room temperature. The sample became clear after one day. The sample was then transferred to 5°C, where it remained clear after one day. 0.5 mL of methyl tert-butyl ether was added and stirred at 5°C for four days; the sample remained clear. The sample was evaporated at room temperature to yield a jelly-like substance with no solids.

[0124] Comparative Example 9:

[0125] 10.8 mg of octreotide acetate, 2.3 mg of maleic acid, and 0.5 mL of tetrahydrofuran were mixed in a glass vial at room temperature and stirred at room temperature to produce a jelly with no solids produced. After stirring at room temperature for one day, the mixture was transferred to 5°C and stirred. After two days, the sample became almost clear. Addition of 0.5 mL of n-heptane clarified the sample, and stirring was continued at 5°C for three days, still with no solids produced.

[0126] Comparative Example 10:

[0127] 10.1 mg of octreotide acetate, 2.0 mg of maleic acid, and 0.5 mL of isopropanol were mixed in a glass vial at room temperature. After stirring at room temperature for one day, the sample was nearly clear. After stirring at 5°C for two days, it remained nearly clear. 0.5 mL of n-heptane was added and stirred at 5°C for three days. The sample became a white suspension, which was centrifuged to obtain a white solid. Testing confirmed that the solid obtained in this example was amorphous.

[0128] Comparative Example 11:

[0129] Mix 15 mg of octreotide acetate, 2.5 mg of gentisic acid, and 0.5 mL of methanol in a glass vial at room temperature. Stir at room temperature for one day. The sample becomes clear after one day. Transfer to 5°C, and the sample becomes clear after one day. Add 0.5 mL of methyl tert-butyl ether and stir at 5°C for four days. The sample remains clear. Transfer to room temperature for evaporation to obtain a gel with no solids.

[0130] Comparative Example 12:

[0131] 10.1 mg of octreotide acetate, 2.8 mg of gentisic acid and 0.5 ml of isopropanol were mixed in a glass vial at room temperature and stirred at room temperature. After one day, the sample was a white suspension, which was centrifuged to obtain a white solid. After testing, the solid obtained in this comparative example was amorphous.

[0132] Comparative Example 13:

[0133] 15 mg of octreotide acetate, 5.4 mg of citric acid, and 0.5 mL of methanol were mixed in a glass vial at room temperature and stirred at room temperature. The sample became clear after one day. The sample was then transferred to 5°C, where it became clear after one day. 0.5 mL of methyl tert-butyl ether was added and stirred at 5°C for four days. The sample formed a small amount of jelly. The sample was evaporated at room temperature to yield a jelly with no solids.

[0134] Comparative Example 14:

[0135] 10.0 mg of octreotide acetate, 3.2 mg of citric acid and 0.5 ml of tetrahydrofuran were mixed in a glass vial at room temperature and stirred at room temperature. After three days, the sample was a white suspension, which was centrifuged to obtain a white solid. The solid obtained in this comparative example was found to be amorphous.

[0136] Comparative Example 15:

[0137] 10.1 mg of octreotide acetate, 3.4 mg of citric acid and 0.5 ml of isopropanol were mixed in a glass vial at room temperature and stirred at room temperature. After three days, the sample was a white suspension, which was centrifuged to obtain a white solid. The solid obtained in this comparative example was found to be amorphous.

[0138] Comparative Example 16:

[0139] 15 mg of octreotide acetate, 3.1 mg of fumaric acid, and 0.5 mL of methanol were mixed in a glass vial at room temperature and stirred at room temperature. The sample became clear after one day. The sample was then transferred to 5°C, where it became clear after one day. 0.5 mL of methyl tert-butyl ether was added and stirred at 5°C for four days. The sample formed a small amount of jelly. The sample was evaporated at room temperature to yield a jelly with no solids.

[0140] Comparative Example 17:

[0141] At room temperature, 10.0 mg of octreotide acetate, 2.2 mg of fumaric acid and 0.5 ml of water were mixed in a glass vial and stirred at room temperature. The sample was almost clear. After two days, it was transferred to 5 degrees Celsius and stirred. After one day of stirring, it was still clear without solid precipitation.

[0142] Comparative Example 18:

[0143] 11.3 mg of octreotide acetate, 2.4 mg of fumaric acid and 0.5 ml of tetrahydrofuran were mixed in a glass vial at room temperature and stirred at room temperature. After two days, the sample was a white suspension, which was centrifuged to obtain a white solid. The solid obtained in this comparative example was found to be amorphous.

[0144] Comparative Example 19:

[0145] 15 mg of octreotide acetate, 0.82 μL of 37% hydrochloric acid, and 0.5 mL of methanol were mixed in a glass vial at room temperature and stirred at room temperature. The sample became clear after one day. Transferred to 5°C, the sample became clear after one day. 0.5 mL of methyl tert-butyl ether was added and stirred at 5°C for four days; the sample remained clear. Transferred to room temperature for evaporation, a gum was obtained with no solids produced.

[0146] Comparative Example 20:

[0147] 15 mg of octreotide acetate, 6.6 μL of 2M sulfuric acid, and 0.5 mL of methanol were mixed in a glass vial at room temperature and stirred at room temperature. The sample became clear after one day. Transferred to 5°C, the sample became clear after one day. Added 0.5 mL of methyl tert-butyl ether and stirred at 5°C for four days; the sample remained clear. Transferred to room temperature for evaporation, a gum was obtained with no solids produced.

[0148] Comparative Example 21:

[0149] At room temperature, 15 mg of octreotide acetate, 1.5 μL of 85% concentrated phosphoric acid, and 0.5 mL of methanol were mixed in a glass vial. Stirring at room temperature resulted in a clear sample after one day. Transferring to 5°C resulted in a clear sample after one day. Adding 0.5 mL of methyl tert-butyl ether and stirring at 5°C for four days resulted in a small amount of jelly. Transferring to room temperature for evaporation yielded a jelly with no solids.

[0150] Comparative Example 22:

[0151] At room temperature, 15 mg of octreotide acetate, 4.4 mg of tartaric acid, and 0.5 mL of methanol were mixed in a glass vial. Stirring was carried out at room temperature. The sample became clear after one day. Transferring to 5°C resulted in a clear sample after one day. Adding 0.5 mL of methyl tert-butyl ether and stirring at 5°C for four days resulted in a white suspension. Centrifugation yielded a white solid, which was determined to be amorphous.

[0152] The applicant declares that the present invention uses the above-mentioned embodiments to illustrate the octreotide salt crystals, their preparation methods, and applications. However, the present invention is not limited to the above-mentioned embodiments, and it does not mean that the present invention must rely on the above-mentioned embodiments in order to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of raw materials used in the present invention, addition of auxiliary components, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

Claims

1. An octreotide orotate crystalline form I, characterized in that: The X-ray powder diffraction of the crystalline form I using Cu-Kα radiation has characteristic peaks at 2θ values of 7.7°±0.2°, 8.7°±0.2°, 9.5°±0.2°, 10.2°±0.2°, 13.6°±0.2° and 18.3°±0.2°.

2. The method for preparing the orotate crystal form I of octreotide according to claim 1, wherein The preparation method comprises the following steps: The octreotide acetate solid and orotic acid are mixed and dispersed in methanol for slurrying, and the solid is collected and dried to obtain octreotide orotic acid salt form I; Preferably, the molar ratio of the trepide acetate solid to orotic acid is 1:1 to 1:2; Preferably, the beating is carried out at room temperature; Preferably, the drying is performed at room temperature.

3. The method for preparing the orotate crystal form I of octreotide according to claim 1, wherein The preparation method comprises the following steps: Octreotide trifluoroacetate solid and tris(hydroxymethylaminomethane) orotate are mixed and dissolved in water, and an anti-solvent, methanol, and seed crystals of octreotide orotate Form I are added to precipitate octreotide orotate Form I from the solution. The solid is collected and dried to obtain octreotide orotate Form I; Preferably, the molar ratio of the octreotide acetate solid to tris(hydroxymethyl)aminomethane orotate is 1:2 to 1:4; Preferably, the beating is carried out at 5-30°C; Preferably, the drying is carried out at room temperature; Preferably, the tris(hydroxymethylaminomethane) orotate is prepared by the following preparation method: Tris(hydroxymethyl)aminomethane and orotic acid are mixed in water, stirred at room temperature to dissolve, and freeze-dried to obtain the tris(hydroxymethyl)aminomethane orotic acid salt; Preferably, the molar ratio of tris(hydroxymethyl)aminomethane to orotic acid is 1:

1.

4. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the octreotide orotate crystalline form I according to claim 1 and a pharmaceutically acceptable carrier.

5. A drug for treating acromegaly, characterized in that: The acromegaly therapeutic drug comprises the orotate form I of octreotide according to claim 1 as an active ingredient.

6. A tumor therapeutic drug, characterized in that: The tumor therapeutic drug comprises the orotate crystal form I of octreotide according to claim 1 as an active ingredient; Preferably, the tumor therapeutic drug is a carcinoid tumor therapeutic drug or a vasoactive intestinal peptide tumor therapeutic drug.

7. A drug for treating diarrhea, characterized in that: The diarrhea treatment drug comprises the octreotide orotate crystal form I according to claim 1 as an active ingredient; Preferably, the diarrhea therapeutic drug is a drug for treating severe diarrhea and flushing episodes in adults with metastatic carcinoid tumors, treating profuse watery diarrhea in adults associated with tumors that secrete vasoactive intestinal peptide, treating AIDS-related diarrhea, treating ileostomy-related diarrhea, and treating chemotherapy-induced diarrhea.

8. A therapeutic drug for esophageal varicose bleeding, characterized in that: The therapeutic drug for esophageal variceal bleeding contains the orotate crystal form I of octreotide according to claim 1 as an active ingredient.

9. A drug for treating digestive tract or pancreatic fistula, characterized in that: The invention contains the orotate crystal form I of octreotide according to claim 1 as an active ingredient.

10. A therapeutic drug for dumping syndrome or chylothorax, characterized in that: The invention contains the orotate crystal form I of octreotide according to claim 1 as an active ingredient.

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