Orthonate miscella pharmaceutical excipient

Abstract

The application discloses an orthoester miscella medicinal adjuvant, relates to the field of medicinal adjuvants, and mainly comprises different orthoester compounds which are miscible with each other at different proportions or orthoester compounds and biocompatible medical polymer materials which are miscible at different proportions; the chemical formula of the orthoester compound is shown in formula I: wherein R represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl or phenyl. The application also provides a preparation method of the above-mentioned medicinal adjuvant and a local sustained-release preparation comprising the adjuvant. The orthoester miscella medicinal adjuvant has the following beneficial effects: the flowability of the orthoester miscella medicinal adjuvant can be adjusted; the degradation rate can be controlled, and the drug release rate can be adjusted; the solvent is good, and can dissolve small molecule drugs and protein drugs; the local injection ampoule, cream and ointment can be prepared; the biocompatibility is good, the metabolism is clear, and the clinical transformation is easy.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical excipients, specifically to an orthoester ester miscible pharmaceutical excipient, a preparation method thereof, and a locally sustained-release drug delivery formulation containing the excipient. Background Technology

[0002] Poly(ortho esters) (POE) are acid-sensitive, biodegradable polymers. Since their first synthesis by Jorge Heller and colleagues in the United States in the 1960s, they have been widely studied and applied in clinical practice due to their unique properties. The orthoester bonds possess autocatalytic functionality, allowing pharmaceutical excipients to be endowed with specific physiological microenvironment responsiveness as needed. Through dynamic changes in physicochemical properties, long-term sustained release and targeted accumulation of drugs at the site of action can be achieved, enhancing therapeutic efficacy. Therefore, constructing pharmaceutical excipients based on orthoesters that are highly sensitive to specific pH levels in the human body has significant scientific and clinical application value.

[0003] Traditional polyorthoesters have been developed for four generations. The commonly used preparation methods are transesterification condensation of orthoesters and polyols and addition polymerization of polyols with a di(enone diol) monomer. However, both of these methods have significant limitations: (1) Transesterification requires high temperature, high pressure, long reaction time, and uncontrollable molecular weight, and this method is no longer being developed; (2) Although addition polymerization has achieved great success, it requires a di(enone diol) monomer (DETOSU), which is very sensitive to light and moisture, and requires harsh conditions for preparation, storage, and use; (3) The above-mentioned polyorthoester materials are all solid or semi-solid polymers, which are difficult to mix with active loading agents (drugs) and will affect the release of active loading agents (drugs) in an easy, reliable, and controllable manner. Therefore, the preparation of orthoester excipients with certain fluidity based on simple processes and the exploration of their application in the pharmaceutical field are among the hot research topics.

[0004] The patent with publication number CN103804684B discloses a polyorthoester pharmaceutical excipient and a new sustained-release drug formulation thereof. The polyorthoester pharmaceutical excipient obtained by amide reaction has the following problems, although the orthoester monomer is stable and the polymerization conditions are mild: (1) It is a solid powder with no flowability, so it cannot be used directly as a good solvent to dissolve drugs, nor can it be used directly for local injections, creams and ointments; (2) Although the synthesis and purification process has been improved by amide polymerization, it is still complicated and the reproducibility of each batch is poor; (3) There are a large number of amide bonds in the structure. Once the amino group is hydrolyzed in vivo, it can easily destroy the structure of some drugs as a nucleophile.

[0005] Patent application CN101052376A discloses a semi-solid delivery carrier, which includes polyorthoester and excipient, but it also has the following problems: (1) It is semi-solid and has poor flowability, so a liquid excipient compatible with polyorthoester is required; (2) It requires a dienoketal glycol monomer (DETOSU), which is very sensitive to light and moisture, and its preparation, storage and use require harsh conditions; (3) As a polymer, polyorthoester has a certain degree of dispersion in its molecular weight distribution and poor batch repeatability. Summary of the Invention

[0006] The technical problem to be solved by the present invention is that the pharmaceutical excipients in the prior art are solid or semi-solid, have no flowability or poor flowability, cannot be used directly as a good solvent to dissolve drugs, and cannot be directly used in local injections, creams and ointments. The reproducibility of each batch is poor and the structure of the drug is easily destroyed. The present invention provides an orthoester ester miscible pharmaceutical excipient, a preparation method, and a local sustained-release drug delivery formulation containing the excipient.

[0007] The present invention solves the above-mentioned technical problems through the following technical means:

[0008] A pharmaceutical excipient of orthoester ester miscible, mainly obtained by mixing different orthoester ester compounds in different proportions or by mixing orthoester ester compounds with biocompatible medical polymer materials in different proportions;

[0009] The chemical formula of the orthoester compound is shown in Formula I:

[0010]

[0011] Where R represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, or phenyl.

[0012] Beneficial effects: The orthoester compounds in this invention have only carbon-oxygen bonds and will not destroy the drug structure. The orthoester compounds themselves are liquids, and can be mixed with each other or miscible with biocompatible medical polymers such as liquids, solids, and semi-solids as needed to obtain orthoester miscible pharmaceutical excipients with adjustable flowability, solubility, degradation rate, and sustained release rate.

[0013] Compared with polyorthoesters in the prior art, their molecular weight has a certain degree of dispersion and the reproducibility of each batch is poor. In contrast, the orthoester monomer compound in this invention has a clear structure and is completely reproducible in each batch, which facilitates clinical translation.

[0014] Orthoester ester miscible pharmaceutical excipients have excellent solubility and can dissolve small molecule and protein drugs; they have good biocompatibility, clear metabolism, and are easy to translate into clinical use. They can be used to prepare local injections, creams, and ointments. After local injection or application, they can slowly and evenly release active substances and have a long-lasting therapeutic effect, which significantly improves the patient's treatment index and compliance, and has broad clinical application value.

[0015] In this invention, the substituents at both ends of the O in the chemical formula of the orthoester compound are methyl groups. If these substituents are changed, it will affect the physical form and degradation rate of the orthoester. If the methyl group is replaced with a group that is too hydrophobic, a semi-solid or solid will be formed, and the degradation rate will also be slower. In this invention, the substituents at both ends of the O in the chemical formula are methyl groups. By changing the R group, the obtained orthoester compound is still in liquid form.

[0016] Preferably, the ratio between the different orthoester compounds is 1:1000-1000:1, and the ratio between the orthoester compound and the biocompatible medical polymer material is 1:1000-1000:1.

[0017] Beneficial effects: The flowability, solubility, and degradation rate of the miscibles can be adjusted by using the different proportions mentioned above.

[0018] Preferably, the biocompatible medical polymer material comprises:

[0019] (i) Polycaprolactone

[0020]

[0021] Where m represents an integer value from 2 to 100;

[0022] (ii) Polycaprolactone diol

[0023]

[0024] Where n represents an integer value from 1 to 50;

[0025] (iii) Polylactic acid

[0026]

[0027] Where x represents an integer value between 2 and 100;

[0028] (iv) Polyethylene glycol

[0029]

[0030] Where y represents an integer value from 2 to 150.

[0031] Preferably, the preparation method of the orthoester compound includes the following steps: under nitrogen protection, diglycerides, trimethyl esters and catalysts are dissolved in a first organic solvent at a molar ratio of 1:(2.2-5.0):(0.01-0.04), and the mixture is stirred at room temperature for 12-48 hours. Then, the mixture is extracted with saturated sodium carbonate, dried with anhydrous magnesium sulfate, and the excess trimethyl ester raw material is removed by vacuum distillation to obtain the orthoester compound.

[0032] Beneficial effects: The orthoester compound in this invention is simple to synthesize, can be prepared in one step at room temperature and pressure, and has only carbon-oxygen bonds in its structure, which will not destroy the drug structure.

[0033] The existing method for synthesizing polyorthoesters is addition polymerization, which requires a di(enone diol) monomer. This monomer is very sensitive to light and moisture, and its preparation, storage and use all require harsh conditions.

[0034] Preferably, the first organic solvent includes acetonitrile, dichloromethane, tetrahydrofuran, and dioxane; the trimethyl ester raw materials include trimethyl orthoformate, trimethyl orthoacetate, trimethyl orthopropionate, trimethyl orthoisopropionate, trimethyl orthobutyrate, and trimethyl orthobenzoate; and the catalyst includes p-toluenesulfonic acid and pyridinium p-toluenesulfonic acid.

[0035] The preparation method of the above-mentioned orthoester miscible pharmaceutical excipients includes the following steps: miscible with different orthoester compounds or orthoester compounds and biocompatible medical polymer materials, wherein the miscible method includes miscible at 25-140°C under negative pressure or miscible at 25-140°C under nitrogen atmosphere, or miscible after dissolving with a second organic solvent and removing the organic solvent under reduced pressure.

[0036] Beneficial effects: The preparation method of pharmaceutical excipients in this invention is simple. Orthoester compounds only have carbon-oxygen bonds and will not destroy the drug structure. Orthoester compounds themselves are liquids. Orthoester compounds can be mixed with each other or miscible with solid, semi-solid, or liquid biocompatible medical polymer materials as needed to obtain orthoester miscible pharmaceutical excipients with adjustable flowability, solubility, degradation rate, and sustained release rate. Moreover, each batch is completely reproducible.

[0037] Orthoester ester miscible pharmaceutical excipients have excellent solubility and can dissolve small molecule and protein drugs; they have good biocompatibility, clear metabolism, and are easy to translate into clinical use. They can be used to prepare local injections, creams, and ointments. After local injection or application, they can slowly and evenly release active substances and have a long-lasting therapeutic effect, which significantly improves the patient's treatment index and compliance, and has broad clinical application value.

[0038] Preferably, the second organic solvent includes tetrahydrofuran, dichloromethane, dioxane, ethanol, methanol, chloroform, acetone, dimethyl sulfoxide, and N,N-dimethylformamide.

[0039] A locally sustained-release formulation comprising the above-mentioned orthoester-ester miscible pharmaceutical excipients and active substance, wherein the solubility, flowability, degradation and drug release rate of the active substance in the orthoester-ester miscible pharmaceutical excipients are determined by measuring the active substance’s weight percentage of 0.1-50% and the orthoester-ester miscible pharmaceutical excipients’ weight percentage of 50-99.9%.

[0040] Beneficial effects: The orthoester miscible pharmaceutical excipients in this invention can be compounded with active substances to form drug delivery formulations. The formulations can be injections, creams, and ointments. They can be prepared to slowly and uniformly release active substances after local injection or application, and have a long-lasting therapeutic effect, significantly improving the patient's treatment index and compliance, and have broad clinical application value.

[0041] The solubility, flowability, degradation, and drug release rate of the active substance in the orthoester-based pharmaceutical excipients can be adjusted by adjusting the weight percentage of the active substance and the orthoester-based pharmaceutical excipients.

[0042] Preferably, the active substance is selected from one or more of antitumor drugs, anti-inflammatory drugs, hypoglycemic drugs, antihypertensive drugs, analgesics, and protein vaccines.

[0043] Preferably, the active substance is selected from sedative-hypnotic drugs, antiepileptic drugs, antipsychotic drugs, antidepressants, anti-anxiety drugs, antimanic drugs, analgesics, anesthetics, nonsteroidal anti-inflammatory drugs, cholinergic and anticholinergic drugs, antiulcer drugs, prokinetic drugs, antiemetics, antiallergic drugs, drugs acting on adrenergic receptors, hypoglycemic drugs, antihypertensive drugs, diuretics, cardiotonics, antiarrhythmic drugs, antianginal drugs, lipid-regulating drugs, steroid hormones, antibiotics, synthetic antibacterial drugs, antiviral drugs, antitumor drugs, and therapeutic peptides or proteins, wherein the active substance is in the form of a topical ointment, cream, or injectable fluid.

[0044] Preferably, the antitumor drugs include, but are not limited to, chemotherapy drugs such as paclitaxel, doxorubicin, gemcitabine, 5-fluorouracil, camptothecin, hydroxycamptothecin, cisplatin, and carboplatin, as well as targeted therapy drugs such as PD-1 inhibitors, gefitinib, erlotinib, sorafenib, and dasatinib. Administration can be achieved through local sustained-release of the active substance.

[0045] Preferably, the anti-inflammatory drugs include, but are not limited to, aspirin, diclofenac sodium, ibuprofen, flurbiprofen, ketoprofen, naproxen, indobufen, indomethacin, piroxicam, meloxicam, celecoxib, dexamethasone, hydrocortisone, prednisolone, methylprednisolone, triamcinolone, fluocinolone acetonide, fludrocortisone, beclomethasone, etc. The amount of anti-inflammatory drugs added is a therapeutically effective amount.

[0046] Preferably, the hypoglycemic drug includes, but is not limited to, insulin and its analogues, sulfonylurea secretagogues, metformin, α-glucosidase inhibitors, thiazolidinedione derivative sensitizers, benzoic acid derivative secretagogues, GLP-1 receptor agonists, DPP-4 enzyme inhibitors, and other first-line hypoglycemic drugs. The dosage of the hypoglycemic drug is a therapeutically effective amount.

[0047] Preferably, the antihypertensive drug includes, but is not limited to, thiazides, potassium-sparing diuretics, aldosterone antagonists, loop diuretics, centrally acting antihypertensive drugs, ganglion blockers, noradrenergic nerve ending blockers, adrenergic receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, renin inhibitors, dihydropyridines, and vasodilators, among other common antihypertensive drugs. The dosage of the antihypertensive drug is a therapeutically effective amount.

[0048] Preferably, the analgesic drug includes, but is not limited to, a range of clinical drugs such as receptor agonists, partial receptor agonists, opioid receptor antagonists, and antipyretic analgesics. The amount of analgesic drug added is a therapeutically effective amount.

[0049] Preferably, the protein vaccine comprises all natural proteins and chemically inactivated toxoids. The amount of protein vaccine added is a therapeutically effective dose.

[0050] The advantages of this invention are: the orthoester compounds in this invention have only carbon-oxygen bonds and will not destroy the drug structure; the orthoester compounds themselves are liquids, and the orthoester compounds can be mixed with each other or miscible with biocompatible medical polymers such as liquids, solids, and semi-solids as needed to obtain orthoester miscible pharmaceutical excipients with adjustable flowability, solubility, degradation rate, and sustained release rate.

[0051] Compared with polyorthoesters in the prior art, their molecular weight has a certain degree of dispersion and the reproducibility of each batch is poor. In contrast, the orthoester monomer compound in this invention has a clear structure and is completely reproducible in each batch, which facilitates clinical translation.

[0052] Orthoester ester miscible pharmaceutical excipients have excellent solubility and can dissolve small molecule and protein drugs; they have good biocompatibility, clear metabolism, and are easy to translate into clinical use. They can be used to prepare local injections, creams, and ointments. After local injection or application, they can slowly and evenly release active substances and have a long-lasting therapeutic effect, which significantly improves the patient's treatment index and compliance, and has broad clinical application value.

[0053] The solubility, flowability, degradation, and drug release rate of the active substance in the orthoester-mixed pharmaceutical excipients can be adjusted by adjusting the weight percentage of the active substance and the orthoester-mixed pharmaceutical excipients. Attached Figure Description

[0054] Figure 1 The orthoester OE-1 in Example 1 of this invention 1 H NMR spectrum;

[0055] Figure 2 The orthoester OE-2 in Example 2 of this invention 1 H NMR spectrum;

[0056] Figure 3 The orthoester OE-3 in Example 3 of this invention 1 H NMR spectrum;

[0057] Figure 4 This is a graph showing the trend of mass loss changes of E-1 to E-7 at different pH values ​​in Example 5 of the present invention, where A and G represent E-1 to E-7 respectively.

[0058] Figure 5 The graph shows the changes in the cytotoxicity of E-1—E-7 (A and B) and EA—ED (C and D) against 3T3 and QSG cells as a function of concentration in Example 6 of this invention.

[0059] Figure 6 The graph shows the drug release results of paclitaxel injection in phosphate buffer solutions at pH 7.4, 6.5 and 5.0 in Example 7 of this invention.

[0060] Figure 7 This is a graph showing the tumor inhibition results after subcutaneous injection of paclitaxel in tumor-bearing mice in Example 7 of the present invention;

[0061] Figure 8 The graph shows the drug release results of celecoxib injection in phosphate buffer solutions at pH 7.4, 6.5 and 5.0 in Example 8 of this invention.

[0062] Figure 9 This is a graph showing the expression levels of vascular endothelial growth factor, COX-2, and prostaglandin E2 in mice seven days after subcutaneous injection of celecoxib in Example 8 of the present invention; in the graph, A represents vascular endothelial growth factor, B represents COX-2, and C represents prostaglandin E2.

[0063] Figure 10 The graph shows the drug release results of the insulin injection in phosphate buffer solutions at pH 7.4, 6.5, and 5.0 in Example 9 of this invention.

[0064] Figure 11 This is a graph showing the trend of changes in insulin levels and blood glucose concentration in a rat diabetic model after subcutaneous injection of insulin in Example 9 of the present invention; in the graph, A represents the insulin level and B represents the blood glucose concentration.

[0065] Figure 12 The graph shows the drug release results of irbexa injection in phosphate buffer solutions with pH values ​​of 7.4, 6.5, and 5.0 in Example 10 of this invention.

[0066] Figure 13 This is a graph showing the trend of blood drug concentration and blood pressure changes in a rat hypertension model after subcutaneous injection of irbesartan injection in Example 10 of the present invention; A in the graph represents blood drug concentration, and B represents average blood pressure.

[0067] Figure 14 The graph shows the drug release results of ovalbumin injection in phosphate buffer solutions at pH 7.4, 6.5, and 5.0 in Example 11 of this invention.

[0068] Figure 15 This is a graph showing the concentration of IgG antibodies in mice after subcutaneous injection of ovalbumin in Example 11 of the present invention.

[0069] Figure 16 The graph shows the drug release results of mepivacaine injection in phosphate buffer solutions at pH 7.4, 6.5, and 5.0 in Example 12 of this invention. Detailed Implementation

[0070] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0071] Unless otherwise specified, all test materials and reagents used in the following examples are commercially available.

[0072] Unless otherwise specified in the embodiments, the techniques or conditions described in the literature in this field or in accordance with the product manual may be followed.

[0073] Example 1

[0074] Synthesis of the orthoester compound 4,4'-(oxybis(methylene))bis(2-methoxy-1,3-dioxolane) (OE-1)

[0075] Under nitrogen protection, diglycerol (16.6 g, 0.1 mol), trimethyl orthoformate (31.84 g, 0.3 mol), and p-toluenesulfonic acid (344.4 mg, 0.002 mol) were added to a reaction flask, dissolved in acetonitrile (150 mL), and reacted overnight at room temperature. The crude product was then subjected to vacuum distillation to remove acetonitrile, dissolved in ethyl acetate, extracted with saturated sodium carbonate solution, dried over anhydrous magnesium sulfate, and the remaining ethyl acetate and excess trimethyl orthoformate were removed by vacuum distillation to obtain a colorless oily product in 83% yield. 1 H NMR such as Figure 1 As shown.

[0076] Example 2

[0077] Synthesis of the orthoester compound 4,4'-(oxybis(methylene))bis(2-methoxy-4-methyl-1,3-dioxolane) (OE-2)

[0078] Under nitrogen protection, diglycerol (16.6 g, 0.1 mol), trimethyl orthoformate (36.05 g, 0.3 mol), and p-toluenesulfonic acid (344.4 mg, 0.002 mol) were added to a reaction flask, dissolved in acetonitrile (150 mL), and reacted overnight at room temperature. The crude product was then subjected to vacuum distillation to remove acetonitrile, dissolved in ethyl acetate, extracted with saturated sodium carbonate solution, dried over anhydrous magnesium sulfate, and the remaining ethyl acetate and excess trimethyl orthoformate were removed by vacuum distillation to obtain a colorless oily product in 78% yield. 1 H NMR such as Figure 2 As shown.

[0079] Example 3

[0080] Synthesis of the orthoester compound 4,4'-(oxybis(methylene))bis(4-ethyl-2-methoxy-1,3-dioxolane) (OE-3)

[0081] Under nitrogen protection, diglycerol (16.6 g, 0.1 mol), trimethyl orthopropionate (40.25 g, 0.3 mol), and p-toluenesulfonic acid (344.4 mg, 0.002 mol) were added to a reaction flask, dissolved in dichloromethane (150 mL), and reacted overnight at room temperature. The crude product was then subjected to vacuum distillation to remove acetonitrile, dissolved in ethyl acetate, extracted with saturated sodium carbonate solution, dried over anhydrous magnesium sulfate, and then subjected to vacuum distillation to remove ethyl acetate and excess trimethyl orthopropionate, yielding a colorless oily product in 81% yield. 1 H NMR such as Figure 3 As shown.

[0082] Example 4

[0083] Preparation of OE-1 with polycaprolactone diol (Mn=530), polycaprolactone (Mn=2000), polyethylene glycol (Mn=500), polylactic acid (Mn=600), and OE-3 miscibles

[0084] At room temperature and under a nitrogen atmosphere, OE-1 and polycaprolactone diol (Mn = 530) were weighed into beakers at mass ratios of 1:1, 1:3, 1:5, 1:7, 1:9, 1:11, and 1:13, respectively. After stirring and mixing for 30 minutes, the resulting mixtures were named E-1 to E-7.

[0085] At 75℃ and under negative pressure, OE-1, polycaprolactone (Mn=2000), polyethylene glycol (Mn=500), polylactic acid (Mn=3000), and OE-3 were weighed into pear-shaped reaction flasks at mass ratios of 20:3, 30:1, 15:1, and 1:4, respectively. After stirring and mixing for 30 minutes, the resulting mixtures were named EA, EB, EC, and ED, respectively.

[0086] Example 5

[0087] Quality loss detection

[0088] Accurately weigh 0.5g of the E-1–E-7 blend into capped screw-top bottles. Add 20mL of phosphate buffer solution with pH values ​​of 5.0, 6.5, and 7.4 to each bottle, respectively. Incubate at 37°C. At predetermined time points, remove the bottles, discard any excess phosphate buffer solution, weigh the remaining mass, and calculate the mass loss. Repeat the above procedure three times. The results are as follows: Figure 4 As shown, on the one hand, the seven polymers have similar mass loss trends, and the mass loss accelerates with increasing acidity; on the other hand, the mass loss rate slows down as the hydrophobic environment around the orthoester bond strengthens, and they exhibit tunable long-term degradation capabilities.

[0089] Example 6

[0090] Cytotoxicity detection

[0091] Mouse embryonic fibroblasts (3T3) and human hepatocytes (QSG) were added to 96-well cell culture plates, ensuring 10 cells per well. 4Cells were cultured overnight. After removing the original culture medium, 180 μL of fresh culture medium was added. Then, 20 μL of E-1–E-7 and EA–ED blends with concentrations ranging from 1–5000 mg / mL were added to each well. After co-culturing for 48 hours, the original culture medium was removed, and 180 μL of fresh culture medium and 20 μL of MTT (5 mg / mL) were added. After co-incubation for 4 hours, the culture medium was removed, and 150 μL of DMSO was added. After shaking for 10 minutes, the OD values ​​were measured at 570 nm using a microplate reader. The cell viability of each group was determined by comparing it with the control group. The results are as follows: Figure 5 As shown, none of the seven polymers caused cytotoxicity, indicating their good biocompatibility.

[0092] Example 7

[0093] Preparation, in vitro release assay, and tumor suppression efficacy evaluation of a novel liquid sustained-release drug formulation using paclitaxel as the active ingredient.

[0094] Preparation method of paclitaxel injection as active ingredient: Under nitrogen protection, 800 mg of E-1 blend and 200 mg of paclitaxel are heated and mixed at 60°C, and then naturally cooled to room temperature to obtain paclitaxel injection (E-1-PTX), wherein the weight content of paclitaxel is 20% and the weight content of E-1 is 80%.

[0095] Accurately weigh 0.5 g of paclitaxel injection (E-1-PTX) and transfer it to a capped screw-on bottle. Add 50 mL of 20 mL phosphate buffer solution (pH 5.0, 6.5, and 7.4) to each bottle, respectively. Incubate at 37°C. At predetermined time points, remove the bottle, collect the phosphate buffer solution, add an equal volume of fresh buffer solution, and incubate again. Then, take 1 mL of the old buffer solution and determine the paclitaxel concentration. Calculate the amount of paclitaxel released. Repeat the above procedure three times. Results are as follows: Figure 6 As shown, paclitaxel injection exhibits zero-order release and a significant long-lasting sustained-release effect. Furthermore, the drug release rate is positively correlated with the acidity of the buffer solution.

[0096] The prepared paclitaxel injection (E-1-PTX) was administered intratumorally to different tumor-bearing mice at a dose of 30 mg / kg. Tumor volume, tumor weight, and mouse body weight were recorded at different time points. Results are as follows: Figure 7 As shown, paclitaxel injection (E-1-PTX) exhibits long-lasting tumor suppression capabilities and can significantly reduce toxic side effects.

[0097] Example 8

[0098] Preparation, in vitro release assay, and anti-inflammatory efficacy evaluation of a novel liquid sustained-release formulation of celecoxib as the active ingredient.

[0099] Preparation method of injectable formulation using celecoxib as active agent: Under nitrogen protection, 750 mg ED and 250 mg celecoxib were mixed and dissolved in 20 mL of anhydrous ethanol and heated to 40 °C. The anhydrous ethanol was removed by vacuum distillation, and then cooled to room temperature to obtain celecoxib injection (ED-CXB), wherein the weight content of celecoxib was 25% and the weight content of ED was 75%.

[0100] Accurately weigh 0.5 g of celecoxib injection (ED-CXB) and transfer it to a capped screw-on bottle. Add phosphate buffer solutions with pH values ​​of 5.0, 6.5, and 7.4 to the bottle, respectively. Incubate at 37°C. At predetermined time points, remove the screw-on bottle, collect the phosphate buffer solution, add an equal volume of fresh buffer solution, and continue incubation. Then, take 1 mL of the old buffer solution to determine the celecoxib concentration and calculate the amount of celecoxib released. Repeat the above procedure three times. The results are as follows: Figure 8 As shown, celecoxib injection exhibits zero-order release and a significant long-lasting effect. Furthermore, the drug release rate is positively correlated with the acidity of the buffer solution.

[0101] Mice with an inflammatory model were treated with celecoxib injection (ED-CXB) at a dose of 20 mg / kg. Celecoxib was administered orally, while ED-CXB was administered subcutaneously. The expression levels of vascular endothelial growth factor, COX-2, and prostaglandin E2 were measured 7 days after administration. The results are as follows: Figure 9 As shown, celecoxib injection (ED-CXB) can significantly reduce the expression levels of vascular endothelial growth factor, COX-2 and prostaglandin E2 in mice, exhibiting a significant long-lasting anti-inflammatory effect.

[0102] Example 9

[0103] Preparation, in vitro release assay, and hypoglycemic effect evaluation of novel liquid sustained-release drug formulations using insulin as the active substance.

[0104] Preparation method of injection with insulin as active agent: 840 mg of EB and 160 mg of insulin are dissolved under reduced pressure and stirring to obtain insulin injection (EB-INS), wherein the weight content of insulin is 16% and the weight content of EB is 84%.

[0105] Accurately weigh 0.5g of insulin injection (EB-INS) and transfer it to a capped screw-on vial. Add 20mL of phosphate buffer solution with pH values ​​of 5.0, 6.5, and 7.4 to the vial, respectively. Incubate at 37°C. At predetermined time points, remove the vial, collect the phosphate buffer solution, add an equal volume of fresh buffer solution, and incubate again. Then, take 1mL of the old buffer solution and measure the insulin concentration. Calculate the insulin release. Repeat the above procedure three times. The results are as follows: Figure 10 As shown, the insulin injection exhibits zero-order release and a significant long-acting sustained-release effect. Furthermore, the drug release rate is positively correlated with the acidity of the buffer solution.

[0106] The prepared insulin injection (EB-INS) was administered subcutaneously to different hyperglycemic model rats at a dose of 5 IU / kg. Blood insulin concentration and blood glucose levels were then measured. Results are as follows: Figure 11 As shown, the insulin injection (EB-INS) can continuously release insulin in the body for a long period of time, maintaining the blood glucose level of rats at a normal level.

[0107] Example 10

[0108] Preparation, in vitro release assay, and evaluation of antihypertensive efficacy of a novel liquid sustained-release formulation of irbesartan as the active ingredient.

[0109] Preparation method of injection with irbesartan as active agent: 770 mg of E-1 and 230 mg of irbesartan are mixed and heated to 70 °C under nitrogen atmosphere and stirring to dissolve, and then cooled to room temperature to obtain irbesartan injection (E-1-Irbe), wherein the weight content of irbesartan is 23% and the weight content of E-1 is 77%.

[0110] Accurately weigh 0.5 g of irbesartan injection (E-1-Irbe) and transfer it to a capped screw-on bottle. Add 20 mL of phosphate buffer solution with pH values ​​of 5.0, 6.5, and 7.4 to the bottle, respectively. Incubate at 37°C. At the predetermined time points, remove the screw-on bottle, collect the phosphate buffer solution, add an equal volume of fresh buffer solution, and continue incubation. Then, take 1 mL of the old buffer solution to determine the irbesartan concentration and calculate the irbesartan release. Repeat the above procedure three times. The results are as follows: Figure 12 As shown, irbesartan injection exhibits zero-order release and a significant long-lasting sustained-release effect. Furthermore, the drug release rate is positively correlated with the acidity of the buffer solution.

[0111] Irbesartan and a prepared irbesartan injection (E-1-Irbe) were administered to hypertensive rats at a dose of 40 mg / kg. Irbesartan was administered orally, while the irbesartan injection (E-1-Irbe) was administered subcutaneously. Blood drug concentrations and blood pressure levels were measured at pre-set time points. Results are as follows: Figure 13 As shown, irbesartan can lower blood pressure, but its concentration drops rapidly, and the blood pressure of the rats rises rapidly accordingly. Irbesartan injection can continuously release irbesartan in the body, maintaining the blood pressure of the rats at a normal level.

[0112] Example 11

[0113] Preparation of novel liquid sustained-release drug formulations using ovalbumin as the active ingredient, and detection of antibody production effects.

[0114] Preparation method of injection using ovalbumin as active agent: 950 mg of EC and 50 mg of ovalbumin are mechanically mixed and dissolved under reduced pressure and stirring to obtain ovalbumin injection (EC-Ova), wherein the weight content of ovalbumin is 5% and the weight content of EC is 95%.

[0115] Accurately weigh 0.5g of ovalbumin injection (EC-Ova) and transfer it to a capped screw-top bottle. Add 20mL of phosphate buffer solution with pH values ​​of 5.0, 6.5, and 7.4 to the bottle, respectively. Incubate at 37°C. At the preset time points, remove the screw-top bottle, collect the phosphate buffer solution, add an equal volume of fresh buffer solution, and continue incubation. Then, take 1mL of the old buffer solution to determine the ovalbumin concentration and calculate the ovalbumin release. Repeat the above operation three times. The results are as follows: Figure 14 As shown, the ovalbumin injection exhibits zero-order release and a significant long-lasting sustained-release effect. Furthermore, the drug release rate is positively correlated with the acidity of the buffer solution.

[0116] Ovalbumin injection solution and the prepared ovalbumin injection (EC-Ova) were administered subcutaneously to different mice on days 1 and 15 at a dose of 50 mg / kg ovalbumin content, and the IgG concentration was measured. Results are as follows: Figure 15 As shown, ovalbumin can induce mice to produce certain antibodies, but its concentration drops rapidly. Ovalbumin injection (EC-Ova) can continuously release ovalbumin in the body, maintaining the antibody level in mice at a high level and achieving a good immune effect.

[0117] Example 12

[0118] Preparation and analgesic effect evaluation of a novel liquid sustained-release formulation of mepivacaine as the active ingredient.

[0119] Preparation method of injection with mepivacaine as active agent: 550 mg of EA and 450 mg of mepivacaine are mixed and heated to 45 °C under nitrogen atmosphere and stirring to dissolve, and then cooled to room temperature to obtain mepivacaine injection (EA-Mep), wherein the weight content of mepivacaine is 45% and the weight content of EA is 55%.

[0120] Accurately weigh 0.5 g of mepivacaine injection (EA-Mep) and transfer it to a capped screw-on bottle. Add 20 mL of phosphate buffer solution with pH values ​​of 5.0, 6.5, and 7.4 to the bottle, respectively. Incubate at 37°C. At predetermined time points, remove the screw-on bottle, collect the phosphate buffer solution, add an equal volume of fresh buffer solution, and continue incubation. Then, take 1 mL of the old buffer solution and determine the mepivacaine concentration. Calculate the amount of mepivacaine released. Repeat the above procedure three times. Results are as follows: Figure 16 As shown, mepivacaine injection exhibits zero-order release and a significant long-lasting sustained-release effect. Furthermore, the drug release rate is positively correlated with the acidity of the buffer solution.

[0121] Mepivacaine injection solution and the prepared mepivacaine injection (EA-Mep) were injected subcutaneously into rats with different pain models at a dose of 200 mg / kg of mepivacaine. The time required for the rats to reach a normal response to deep pain and electrical stimulation, as well as the time required for the rats to recover from a state of motor weakness to normal, were recorded. The testing was stopped when half of the rats recovered to normal. The results are shown in Table 1. The analgesic duration of mepivacaine injection (EA-Mep) was significantly longer than that of mepivacaine alone, demonstrating a good therapeutic effect.

[0122] Table 1 shows the treatment results of mepivacaine injection and mepivacaine alone.

[0123]

[0124] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. The application of an orthoester miscible as a pharmaceutical excipient, characterized in that: The orthoester miscibles are mainly obtained by mixing different orthoester compounds in different proportions or by mixing orthoester compounds with biocompatible medical polymer materials in a mass ratio of 1:13-30:

1. The chemical formula of the orthoester compound is shown in Formula I: （I） Where R represents hydrogen or ethyl; Different orthoester compounds in different proportions refer to: and By mass ratio 1:4; The biocompatible medical polymer material includes: (i) Polycaprolactone (II) Where m represents an integer value from 2 to 100; (ii) Polycaprolactone diol (III) Where n represents an integer value from 1 to 50; (iii) Polylactic acid (IV) Where x represents an integer value between 2 and 100; (iv) Polyethylene glycol （V） Where y represents an integer value from 2 to 150.

2. The application of the orthoester miscible according to claim 1 as a pharmaceutical excipient, characterized in that: The preparation method of the orthoester compound includes the following steps: under nitrogen protection, diglycerides, trimethyl esters and catalysts are dissolved in a first organic solvent at a molar ratio of 1:(2.2-5.0):(0.01-0.04), and the mixture is stirred at room temperature for 12-48 hours. Then, the mixture is extracted with saturated sodium carbonate, dried with anhydrous magnesium sulfate, and the excess trimethyl ester raw material is removed by vacuum distillation to obtain the orthoester compound.

3. The application of the orthoester miscible as described in claim 2 as a pharmaceutical excipient, characterized in that: The first organic solvent includes acetonitrile, dichloromethane, tetrahydrofuran, and dioxane; the trimethyl ester raw materials include trimethyl orthoformate, trimethyl orthoacetate, trimethyl orthopropionate, trimethyl orthoisopropionate, trimethyl orthobutyrate, and trimethyl orthobenzoate; and the catalyst includes p-toluenesulfonic acid and pyridinium p-toluenesulfonic acid.

4. The application of the orthoester miscible according to claim 3 as a pharmaceutical excipient, characterized in that: The first organic solvent is acetonitrile.

5. The application of the orthoester miscible according to claim 3 as a pharmaceutical excipient, characterized in that: The first organic solvent is dichloromethane.

6. The application of the orthoester miscible according to claim 3 as a pharmaceutical excipient, characterized in that: The trimethyl ester raw material is trimethyl orthoformate.

7. The application of the orthoester miscible according to claim 3 as a pharmaceutical excipient, characterized in that: The trimethyl ester raw material is trimethyl orthoacetate.

8. The application of the orthoester miscible according to claim 1 as a pharmaceutical excipient, characterized in that: The orthoester miscible is prepared by the following process: mixing different orthoester compounds or orthoester compounds with biocompatible medical polymer materials. The mixing method includes mixing at 25-140°C under negative pressure or at 25-140°C under nitrogen atmosphere, or dissolving in a second organic solvent and then mixing, and removing the organic solvent under reduced pressure.

9. The application of the orthoester miscible according to claim 8 as a pharmaceutical excipient, characterized in that: The second organic solvent includes tetrahydrofuran, dichloromethane, dioxane, ethanol, methanol, chloroform, acetone, dimethyl sulfoxide, and N,N-dimethylformamide.

10. The application of the orthoester miscible according to claim 9 as a pharmaceutical excipient, characterized in that: The second organic solvent is tetrahydrofuran.

11. The application of the orthoester miscible according to claim 9 as a pharmaceutical excipient, characterized in that: The second organic solvent is dichloromethane.

12. The application of the orthoester miscible according to claim 9 as a pharmaceutical excipient, characterized in that: The second organic solvent is dioxane.

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