WO2023103137A1

WO2023103137A1 - Orthoester mixture pharmaceutical excipient, preparation method, and topical sustained-release drug delivery preparation containing excipient

Info

Publication number: WO2023103137A1
Application number: PCT/CN2022/070666
Authority: WO
Inventors: 唐汝培; 闫国卿
Original assignee: 安徽大学
Priority date: 2021-12-09
Filing date: 2022-01-07
Publication date: 2023-06-15
Also published as: CN114366711A

Abstract

An orthoester mixture pharmaceutical excipient, relating to the field of pharmaceutical excipients, and mainly obtained by mixing different orthoester compounds in different proportions or by mixing orthoester compounds with biocompatible medical polymer materials in different proportions. Also disclosed are a preparation method for the pharmaceutical excipient, and a topical sustained-release drug delivery preparation containing the excipient. The beneficial effects are that: the fluidity of the orthoester mixture pharmaceutical excipient can be adjusted; the degradation rate can be controlled, and the drug release rate can be adjusted; the orthoester mixture pharmaceutical excipient can be used as a good solvent, and can dissolve small molecule and protein drugs; topical injections, creams and ointments can be prepared; good biocompatibility is achieved, metabolism is clear, and clinical translation and use are facilitated.

Description

Orthoester miscible pharmaceutical excipient, preparation method, local sustained-release drug preparation containing the excipient

technical field

The invention relates to the field of pharmaceutical excipients, in particular to an orthoester miscible pharmaceutical excipient, a preparation method, and a local sustained-release drug preparation containing the excipient.

Background technique

Poly (ortho esters), POE is an acid-sensitive biodegradable polymer material, since it was first synthesized by Jorge Heller and his colleagues in the United States in the 1960s, because of its unique properties, it has been widely used in clinical practice. has been extensively researched and applied. The orthoester bond has a self-catalytic function, which can endow drug excipients with specific physiological and microenvironmental responsiveness as required, and achieve long-term sustained release and targeted enrichment of drugs at the site of action through dynamic changes in physical and chemical properties, thereby enhancing the therapeutic effect. Therefore, the construction of human body-specific pH (ultra)sensitive pharmaceutical excipients based on orthoesters has important scientific significance and clinical application value.

Traditional polyorthoesters have been developed for four generations, and the commonly used preparation methods mostly use the transesterification condensation method of orthoesters and polyols and the addition polymerization of polyols and a di(ketene acetal) monomer However, these two methods have relatively large limitations: (1) the transesterification method requires high temperature, high pressure, long reaction time and uncontrollable molecular weight and other shortcomings, and this method has no longer been developed; (2) addition polymerization Although the method has achieved greater success, it needs a di(ketene acetal) 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. On the one hand, it is difficult to be miscible with the active load agent (drug), and on the other hand, it will affect the active load agent (drug) to be easily, reliably and controllable. way released. Therefore, the preparation of orthoester excipients with certain fluidity based on a simple process and the exploration of its application in the field of medicine are one of the hotspots of research.

The patent with the publication number CN103804684B discloses a polyorthoester pharmaceutical excipient and its new formulation for slow-release drugs. The polyorthoester pharmaceutical excipient obtained by amide reaction, although the orthoester monomer is stable and the polymerization conditions are mild, but The auxiliary material has the following problems: (1) solid powder, no fluidity, can not be directly used as a good solvent to dissolve drugs, and can not be directly used in local injections, creams and ointments; (2) obtained by amide polymerization, synthesis and Although the purification process has been improved, it is still complicated and the repeatability 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 is easy to destroy the structure of some drugs as a nucleophile.

Publication No. CN101052376A patent application discloses a semi-solid delivery carrier, but includes polyorthoester and excipient, but it also has the following problems: (1) semi-solid, poor fluidity, therefore, it needs to be combined with polyorthoester Ester-compatible liquid excipient; (2) need a kind of bis (ketene ketal) monomer (DETOSU), this monomer is very sensitive to light and moisture, preparation, storage and use all need harsh conditions. Conditions; (3) Polyorthoester is used as a polymer, and its molecular weight distribution has a certain dispersion and the repeatability of each batch is poor.

Contents of the invention

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 fluidity or poor fluidity, and cannot be directly used as good solvents to dissolve medicines, nor can they be directly used in local injections, creams and The ointment has poor reproducibility in each batch and is easy to destroy the drug structure. It provides an orthoester miscible pharmaceutical excipient, a preparation method, and a local sustained-release drug preparation containing the excipient.

The present invention realizes solving above-mentioned technical problem by following technical means:

An orthoester miscible pharmaceutical excipient, which is mainly obtained by mixing different orthoester compounds with each other in different proportions or orthoester compounds with biocompatible medical polymer materials in different proportions;

The chemical formula of the orthoester compound is as shown in formula I:

wherein R represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl or phenyl.

Beneficial effects: the orthoester compound in the present invention has only carbon-oxygen bonds, which will not destroy the structure of the drug. The orthoester compound itself is liquid, and the orthoester compound can be mixed with each other or mixed with liquid, solid, semi-solid and other biological substances according to requirements. Compatible medical polymer materials are miscible to obtain orthoester miscible pharmaceutical excipients with adjustable fluidity, solubility, degradation rate, and sustained release rate.

Compared with the polyorthoester in the prior art, its molecular weight has a certain dispersion and the repeatability of each batch is poor, while the orthoester monomer compound in the present invention has a clear structure and is completely repeatable in each batch. Facilitate clinical translation.

Orthoester miscible pharmaceutical excipients have excellent solubility, and can dissolve small molecules and protein drugs; good biocompatibility, clear metabolism, easy clinical transformation and use, can be prepared for local injection injections, creams and ointments, through local After injection or smearing, the active substance can be released slowly and uniformly, and the therapeutic effect is long-lasting, which significantly improves the therapeutic index and compliance of patients, and has a wide range of clinical application value.

The substituent on the two ends of the chemical formula of the orthoester compound of the present invention is a methyl group. If the substituent changes, it will affect the physical form and degradation rate of the orthoester. If the methyl group is replaced by a hydrophobic one The group will form semi-solid and solid, and the degradation rate will also slow down. In the present invention, the substituents on the O at both ends of the chemical formula are methyl groups. By changing the group R, the obtained orthoester compound is still liquid.

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 .

Beneficial effects: the fluidity, solubility and degradation rate of the miscible are adjusted through the above-mentioned different proportions.

Preferably, the biocompatible medical polymer material includes:

(i) Polycaprolactone

Wherein, m represents an integer value 2-100;

(ii) Polycaprolactone diol

Wherein, n represents an integer value 1-50;

(iii) Polylactic acid

where x represents an integer value 2-100;

(iv) polyethylene glycol

where y represents an integer value 2-150.

Preferably, the preparation method of the ortho ester compound comprises the following steps: under the protection of nitrogen, diglycerol, trimethyl esters and catalysts are dissolved in the first organic solvent according to the molar ratio of 1:(2.2-5.0):(0.01-0.04) , and stirred at room temperature for 12-48 hours, then extracted with saturated sodium carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove excess trimethyl ester raw materials to obtain orthoester compounds.

Beneficial effect: the synthesis method of the ortho ester compound in the present invention is simple, can be prepared in one step at normal temperature and pressure, and only has carbon-oxygen bonds in the structure, which will not damage the drug structure.

The synthetic method of polyorthoester in the prior art is addition polymerization method, and it needs a kind of bis (ketene acetal) monomer, and this monomer is very sensitive to light and moisture, and preparation, storage and use are all difficult. Harsh conditions are required.

Preferably, the first organic solvent includes acetonitrile, dichloromethane, tetrahydrofuran, and dioxane, and the trimethyl ester raw materials include trimethyl orthoformate, trimethyl orthoacetate, trimethyl orthopropionate, ortho Trimethyl isopropionate, trimethyl orthobutyrate, trimethyl orthobenzoate, the catalyst includes p-toluenesulfonic acid, pyridinium p-toluenesulfonate.

The preparation method of the above-mentioned orthoester miscible pharmaceutical excipients comprises the following steps: miscible different orthoester compounds or orthoester compounds with biocompatible medical polymer materials, and the miscibility method is included in 25- 140°C, miscible under negative pressure or 25-140°C, miscible under nitrogen atmosphere, or miscible after dissolving with a second organic solvent, and remove the organic solvent under reduced pressure.

Beneficial effects: the preparation method of the pharmaceutical excipient in the present invention is simple, the orthoester compound has only carbon-oxygen bonds, and will not destroy the drug structure, and the orthoester compound itself is liquid, and the orthoester compound can be mixed or mixed with solid, Semi-solid and liquid biocompatible medical polymer materials are miscible to obtain orthoester miscible pharmaceutical excipients with adjustable fluidity, solubility, degradation rate, and sustained release rate, and each batch is completely reproducible.

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

Local sustained-release drug preparations, including the above-mentioned orthoester miscible pharmaceutical excipients and active substances, are determined by measuring the solubility, fluidity, degradation and drug release rate of the active substances in the orthoester miscible pharmaceutical excipients. The weight percentage of the active substance is 0.1-50%, and the weight percentage of the orthoester miscible pharmaceutical excipient is 50-99.9%.

Beneficial effects: the orthoester miscible pharmaceutical excipients in the present invention can be compounded with active substances to form drug preparations, and the preparation forms can be injections, creams and ointments, and can be prepared locally after administration by local injection or smearing The active substance can be released slowly and uniformly, and the therapeutic effect is long-lasting, which significantly improves the therapeutic index and compliance of patients, and has wide clinical application value.

The solubility, fluidity, degradation and drug release rate of the active substance in the orthoester miscible pharmaceutical excipient are adjusted through the weight percentage of the active substance and the orthoester miscible pharmaceutical excipient.

Preferably, the active substance is selected from one or more of antitumor drugs, anti-inflammatory drugs, hypoglycemic drugs, hypotensive drugs, analgesic drugs, and protein vaccines.

Preferably, the active substance is selected from the group consisting of sedative-hypnotics, antiepileptics, antipsychotics, antidepressants, anxiolytics, antimanics, analgesics, narcotics, NSAIDs, cholemimetics Alkaline and anticholinergic drugs, antiulcer drugs, gastric motility drugs, antiemetics, antiallergic drugs, drugs acting on adrenergic receptors, hypoglycemic drugs, antihypertensive drugs, diuretics, cardiotonic drugs, antiarrhythmic drugs, antihypertensive drugs Angina drugs, blood lipid regulating drugs, steroid hormone drugs, antibiotics, synthetic antibacterial drugs, antiviral drugs, antineoplastic drugs and therapeutic polypeptides or proteins, wherein the active substance is a topical ointment, cream or injectable fluid form.

Preferably, the anti-tumor drugs include but are not limited to chemotherapy drugs paclitaxel, doxorubicin, gemcitabine, 5-fluorouracil, camptothecin, hydroxycamptothecin, cisplatin, carboplatin, and targeted therapy drugs PD-1, Gefitinib, Erlotinib, Sorafenib, Dasatinib. Administration may be by local sustained release of the active substance.

Preferably, the anti-inflammatory drugs include and are not limited to aspirin, diclofenac sodium, ibuprofen, flurbiprofen, ketoprofen, naproxen, indobufen, indomethacin, piroxicam, meloxime Kang, Erecoxib, Celecoxib, Dexamethasone, Hydrocortisone, Prednisolone, Methylprednisolone, Triamcinolone acetonide, Fluocinolone, Fludrocortisone, Beclomethasone, etc. Inflammation drugs. The added amount of anti-inflammatory drugs is a therapeutically effective amount.

Preferably, the hypoglycemic drugs include and are not limited to insulin and its analogs, sulfonylurea secretagogues, metformin, α-glucosidase inhibitors, thiazolidinedione derivative sensitizers, fennel Acid derivative secretagogues, GLP-1 receptor agonists, DPP-4 enzyme inhibitors and other first-line hypoglycemic drugs. The added amount of the hypoglycemic drug is a therapeutically effective amount.

Preferably, the antihypertensive drugs include but are not limited to thiazides, potassium retention diuretics, aldosterone antagonists, loop diuretics, central antihypertensive drugs, ganglion blocking drugs, noradrenergic nerve terminal blockers common antihypertensive drugs, adrenergic receptor blocking drugs, angiotensin converting enzyme inhibitors, angiotensin II receptor blocking drugs, renin inhibitors, dihydropyridines, dihydropyridines and vasodilators drug. The added amount of antihypertensive drugs is a therapeutically effective amount.

Preferably, the analgesic drugs include but are not limited to a series of clinical drugs such as receptor agonists, partial receptor agonists, opioid receptor antagonists, and antipyretic analgesics. The added amount of analgesics is a therapeutically effective amount. The added amount of analgesics is a therapeutically effective amount.

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

The advantage of the present invention is that: the orthoester compound in the present invention has only carbon-oxygen bonds, which will not destroy the structure of the drug, and the orthoester compound itself is liquid, and the orthoester compound can be mixed with each other or mixed with liquid, solid, semi- Biocompatible medical polymer materials such as solids are miscible to obtain orthoester miscible pharmaceutical excipients with adjustable fluidity, solubility, degradation rate, and sustained release rate.

Description of drawings

Fig. 1 is the ¹ H NMR figure of orthoester OE-1 in the embodiment 1 of the present invention;

Fig. 2 is the ¹ H NMR figure of orthoester OE-2 in the embodiment 2 of the present invention;

Fig. 3 is the ¹ H NMR figure of orthoester OE-3 in the embodiment 3 of the present invention;

Fig. 4 is the change trend diagram of mass loss of E-1-E-7 under different pHs in Example 5 of the present invention, and A-G in the figure represent E-1-E-7 respectively;

Fig. 5 is E-1-E-7 (A and B) and E-A-E-D (C and D) in the embodiment of the present invention 6 respectively to 3T3 and QSG cytotoxicity change graph;

Fig. 6 is the result figure of drug release in the phosphate buffer solution of pH 7.4, 6.5 and 5.0 respectively in the paclitaxel injection in embodiment 7 of the present invention;

Fig. 7 is a graph showing tumor inhibition results after subcutaneous injection of paclitaxel injection in tumor-bearing mice in Example 7 of the present invention;

Fig. 8 is a graph showing the drug release results of celecoxib injection in phosphate buffered saline solution with pH 7.4, 6.5 and 5.0 respectively in Example 8 of the present invention;

Figure 9 is a graph showing the results of expression levels of vascular endothelial expression factors, COX-2, and prostaglandin E2 in mice subcutaneously injected with celecoxib injection for seven days in Example 8 of the present invention; in the figure, A represents vascular endothelial expression factors, and B represents COX-2 , C represents prostaglandin E2;

Fig. 10 is a graph showing drug release results of insulin injections in phosphate buffer solutions of pH 7.4, 6.5 and 5.0 in Example 9 of the present invention;

Fig. 11 is a trend diagram of insulin level and blood sugar concentration in the rat diabetic model after subcutaneous injection of insulin injection in Example 9 of the present invention; in the figure, A represents the insulin level in the body, and B represents the blood sugar concentration;

Figure 12 is a graph showing the drug release results of Erbesa injection in phosphate buffered saline solution with pH 7.4, 6.5 and 5.0 in Example 10 of the present invention;

Fig. 13 is a trend diagram of blood drug concentration and blood pressure in the rat hypertensive model in Example 10 of the present invention after subcutaneous injection of irbesartan injection; in the figure, A represents the blood drug concentration, and B represents the average blood pressure;

Fig. 14 is a graph showing drug release results of ovalbumin injection in phosphate buffered saline solution with pH 7.4, 6.5 and 5.0 in Example 11 of the present invention;

Fig. 15 is a graph showing the results of IgG antibody concentration in vivo in mice after subcutaneous injection of ovalbumin injection in Example 11 of the present invention;

Figure 16 is a graph showing the drug release results of mepivacaine injection in phosphate buffer solutions with pH 7.4, 6.5 and 5.0 in Example 12 of the present invention.

Detailed ways

In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in 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 part of the present invention Examples, not all examples. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

The test materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

Those that do not indicate specific techniques or conditions in the examples can be carried out according to the techniques or conditions described in the documents in this field or according to the product instructions.

Example 1

Synthesis of ortho ester compound 4,4'-(oxybis(methylene))bis(2-methoxy-1,3-dioxolane)(OE-1)

Under nitrogen protection, diglycerol (16.6g, 0.1mol), trimethyl orthoformate (31.84g, 0.3mol) and p-toluenesulfonic acid (344.4mg, 0.002mol) were added to the reaction flask, and acetonitrile (150mL ) was dissolved and reacted overnight at room temperature. After the crude product was distilled off under reduced pressure to remove acetonitrile, ethyl acetate was added to dissolve it, extracted with saturated sodium carbonate solution, dried over anhydrous magnesium sulfate, ethyl acetate and excess trimethyl orthoformate were distilled off under reduced pressure to obtain a colorless oily product, The yield was 83%, as shown in FIG. 1 by ¹ H NMR.

Example 2

Synthesis of ortho ester compound 4,4'-(oxybis(methylene))bis(2-methoxy-4-methyl-1,3-dioxolane)(OE-2)

Under nitrogen protection, diglycerol (16.6g, 0.1mol), trimethyl orthoacetate (36.05g, 0.3mol) and p-toluenesulfonic acid (344.4mg, 0.002mol) were added to the reaction flask, and acetonitrile (150mL ) was dissolved and reacted overnight at room temperature. After the crude product was distilled off under reduced pressure to remove acetonitrile, ethyl acetate was added to dissolve it, extracted with saturated sodium carbonate solution, dried over anhydrous magnesium sulfate, ethyl acetate and excess trimethyl orthoformate were distilled off under reduced pressure to obtain a colorless oily product, The yield was 78%. ¹ H NMR is shown in FIG. 2 .

Example 3

Synthesis of ortho ester compound 4,4'-(oxybis(methylene))bis(4-ethyl-2-methoxy-1,3-dioxolane)(OE-3)

Under nitrogen protection, diglycerol (16.6g, 0.1mol), trimethyl orthopropionate (40.25g, 0.3mol) and p-toluenesulfonic acid (344.4mg, 0.002mol) were added to the reaction flask, and dichloro Methane (150 mL) was dissolved and reacted overnight at room temperature. The crude product was distilled under reduced pressure to remove acetonitrile, dissolved in ethyl acetate, extracted with saturated sodium carbonate solution, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove ethyl acetate and excess trimethyl orthoformate to obtain a colorless oily product. The yield was 81%, as shown in FIG. 3 by ¹ H NMR.

Example 4

Miscibility of OE-1 with polycaprolactone diol (Mn=530), polycaprolactone (Mn=2000), polyethylene glycol (Mn=500), polylactic acid (Mn=600), OE-3 preparation of

Under normal temperature and nitrogen atmosphere, OE-1 and polycaprolactone diol (Mn=530) are respectively in mass ratio 1:1, 1:3, 1:5, 1:7, 1:9, 1:11, 1 :13 weighed and put into a beaker, stirred and mixed for 30 minutes to obtain a miscible substance, which was named as E-1-E-7 respectively.

At 75°C and under negative pressure, OE-1 and polycaprolactone (Mn=2000), polyethylene glycol (Mn=500), polylactic acid (Mn=3000), and OE-3 were in mass ratio of 20:3, 30:1, 15:1, 1:4 were weighed into pear-shaped reaction flasks, stirred and mixed for 30 minutes to obtain miscibles, which were named E-A, E-B, E-C, and E-D respectively.

Example 5

Mass Loss Detection

Accurately weigh 0.5g of E-1—E-7 blends and transfer them to capped screw bottles, add 20 mL of phosphate buffer solution with pH 5.0, 6.5 and 7.4 into the bottles, let stand at 37°C, and Take out the threaded bottle at the time point, remove excess phosphate buffer in the bottle, weigh the remaining mass, and calculate the mass loss. The above operation was repeated three times, and the results are shown in Figure 4. On the one hand, the seven polymers have similar mass loss trends, and the mass loss accelerates as the acidity increases; on the other hand, as the hydrophobic environment around the orthoester bond increases , the mass loss rate slows down, and exhibits a regulated long-term degradation ability.

Example 6

Cytotoxicity Assay

Add mouse embryonic fibroblasts (3T3) and human hepatocytes (QSG) into 96-well cell culture plates, respectively, to ensure ¹⁰⁴ cells per well, culture overnight, remove the original medium, add 180 μL of fresh medium, and then Add 20 μL of E-1—E-7, EA—ED blends whose concentrations varied from 1 to 5000 mg/mL to each space. After 48 hours of co-cultivation, remove the original medium and add 180 μL of fresh medium and 20 μL MTT (5mg/mL), remove the medium after co-incubation for 4 hours, add 150 μL of DMSO, shake for 10 minutes, detect at a wavelength of 570nm, and measure the corresponding OD value with a microplate reader, according to the comparison with the control group The cell viability of each group was compared. The results are shown in Figure 5, the seven polymers did not cause cytotoxicity, indicating their good biocompatibility.

Example 7

Preparation, in vitro release test and evaluation of tumor inhibitory effect of paclitaxel as active substance in liquid sustained-release drug preparation

Preparation method of injection with paclitaxel as the active substance: under nitrogen protection, 800 mg of E-1 blend and 200 mg of paclitaxel were heated and miscible 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%.

Accurately weigh 0.5g of paclitaxel injection (E-1-PTX), transfer it to a screw bottle with a cap, add 50mL of 20mL phosphate buffer solution with a pH of 5.0, 6.5 and 7.4 into the bottle, let it stand at 37°C, and Take out the screw bottle at the time point, collect the phosphate buffer in the bottle, add an equal amount of fresh buffer and continue to stand still, then take 1mL of the old buffer to measure the paclitaxel concentration, and then calculate the release amount of paclitaxel. The above operation was repeated three times. As a result, as shown in Figure 6, the drug release of paclitaxel injection is zero-order release and shows an obvious long-acting sustained-release effect, and the drug release rate is positively correlated with the acidity of the buffer.

According to the prepared paclitaxel injection (E-1-PTX), the dose of paclitaxel content 30mg/kg was injected into different tumor-bearing mice by intratumoral injection, and then the tumor volume, tumor mass and Mouse body weight was recorded. The results are shown in Figure 7, paclitaxel injection (E-1-PTX) exhibits long-acting tumor suppressive ability and can significantly reduce toxic and side effects.

Example 8

Preparation, in vitro release test and evaluation of anti-inflammatory effect of celecoxib as active substance in liquid sustained-release drug preparation

Preparation method of injection with celecoxib as active agent: under nitrogen protection, use 20mL of absolute ethanol to mix 750mg E-D and 250mg of celecoxib, heat to dissolve at 40°C, distill under reduced pressure to remove absolute ethanol, and then cool to room temperature The celecoxib injection (E-D-CXB) was obtained, wherein the weight content of celecoxib was 25%, and the weight content of E-D was 75%.

Accurately weigh 0.5g of celecoxib injection (E-D-CXB), move it to a threaded bottle with a cap, add phosphate buffer solution with pH 5.0, 6.5 and 7.4 into the bottle, let stand at 37°C, and Take out the screw bottle at the time point, collect the phosphate buffer in the bottle, add an equal amount of fresh buffer and continue to stand still, then take 1mL of the old buffer to measure the concentration of celecoxib, and then calculate the release of celecoxib quantity. The above operation was repeated three times, and the results are shown in Figure 8. The drug release of celecoxib injection was zero-order release and showed an obvious long-term sustained-release effect. In addition, the drug release rate was positively correlated with the acidity of the buffer.

According to the prepared celecoxib injection (ED-CXB) to treat inflammation model mice with a dose of celecoxib content 20mg/kg, wherein celecoxib is administered in oral form, celecoxib injection (ED-CXB) -CXB) administered in the form of subcutaneous injection. After 7 days of administration, the expression levels of vascular endothelial growth factor, COX-2 and prostaglandin E ₂ were detected. As shown in Figure 9, celecoxib injection (ED-CXB) can significantly reduce the vascular endothelial The expression of growth factors, COX-2 and prostaglandin E ₂ showed obvious long-term anti-inflammatory effect.

Example 9

Preparation, in vitro release test and evaluation of hypoglycemic effect of new liquid sustained-release drug preparations with insulin as the active substance

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

Accurately weigh 0.5 g of insulin injection (E-B-INS), transfer it to a screw bottle with a cap, add 20 mL of phosphate buffer solution with pH 5.0, 6.5, and 7.4 into the bottle, let stand at 37°C, and Take out the screw bottle, collect the phosphate buffer solution in the bottle, add an equal amount of fresh buffer solution and continue to stand still, then take 1mL of the old buffer solution to measure its insulin concentration, and then calculate the release amount of insulin. The above operation was repeated three times. As shown in Figure 10, the drug release of the insulin injection was zero-order release and showed an obvious long-term sustained release effect. In addition, the drug release rate was positively correlated with the acidity of the buffer.

The prepared insulin injection (E-B-INS) was subcutaneously injected into different hyperglycemia model rats with a dose of 5 IU/kg of insulin, and the blood insulin concentration and blood sugar level were detected. The results are shown in FIG. 11 , the insulin injection (E-B-INS) can release insulin continuously in the body for a long time, and maintain the blood sugar of rats at a normal blood sugar level.

Example 10

Preparation, in vitro release test and evaluation of hypotensive effect of irbesartan as active substance in liquid sustained-release drug preparation

Preparation method of injection with irbesartan as active agent: mix 770mg of E-1 and 230mg of irbesartan, heat to 70°C under nitrogen atmosphere and stirring to dissolve, then cool 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%.

Accurately weigh 0.5g of irbesartan injection (E-1-Irbe), move it to a screw bottle with a cap, add 20mL of phosphate buffer solution with a pH of 5.0, 6.5 and 7.4 into the bottle, let it stand at 37°C, and Take out the screw bottle at the preset time point, collect the phosphate buffer in the bottle, add an equal amount of fresh buffer and continue to stand still, then take 1mL of the old buffer to measure its concentration of irbesartan, and then calculate the irbesartan concentration Tank release. The above operation was repeated three times. As shown in Figure 12, the drug release of irbesartan injection was zero-order release and showed an obvious long-term sustained release effect. In addition, the drug release rate was positively correlated with the acidity of the buffer.

Irbesartan and the prepared irbesartan injection (E-1-Irbe) were used to treat hypertension model rats with a dose of irbesartan content of 40 mg/kg, wherein irbesartan was administered orally , Irbesartan injection (E-1-Irbe) is administered in the form of subcutaneous injection, and the drug concentration in the blood is detected at the preset time point, and the blood pressure level is detected at the same time. The results are shown in Figure 13. Besartan can lower blood pressure, but its concentration drops rapidly, correspondingly the blood pressure of rats rises rapidly, while irbesartan injection can continuously release irbesartan in the body and maintain the blood pressure of rats at a normal level.

Example 11

Preparation of new preparations of liquid sustained-release drugs with ovalbumin as the active substance, and detection of antibody production effects

Preparation method of injection with ovalbumin as active agent: After mechanically mixing 950 mg of E-C and 50 mg of ovalbumin, dissolve under reduced pressure and stirring to obtain ovalbumin injection (E-C-Ova), wherein the weight of ovalbumin The content is 5%, and the weight content of E-C is 95%.

Accurately weigh 0.5g of ovalbumin injection (E-C-Ova), transfer it to a screw bottle with a cap, add 20mL of phosphate buffer solution with pH 5.0, 6.5 and 7.4 into the bottle, let stand at 37°C, and Take out the screw bottle at the time point, collect the phosphate buffer in the bottle, add an equal amount of fresh buffer and continue to stand still, then take 1mL of the old buffer to measure the concentration of ovalbumin, and then calculate the release amount of ovalbumin. The above operation was repeated three times. As shown in Figure 14, the drug release of ovalbumin injection was zero-order release and showed an obvious long-term sustained release effect. In addition, the drug release rate was positively correlated with the acidity of the buffer.

The ovalbumin injection and the prepared ovalbumin injection (E-C-Ova) were injected into different mice on the 1st day and the 15th day by subcutaneous injection at a dose of 50 mg/kg ovalbumin content, and the ovalbumin injection was detected. IgG concentration. The results are shown in Figure 15, ovalbumin can make mice produce certain antibodies, but its concentration drops rapidly, while ovalbumin injection (E-C-Ova) can continuously release ovalbumin in vivo, and keep the antibody of mice continuously. maintain at a high level to achieve a good immune effect.

Example 12

Preparation and evaluation of analgesic effect of mepivacaine as active substance in liquid sustained-release drug preparation

Preparation method of injection with mepivacaine as active agent: after mixing 550 mg of E-A and 450 mg of mepivacaine, heat to 45° C. to dissolve under nitrogen atmosphere and stirring, then cool to room temperature to obtain mepivacaine injection ( E-A-Mep), wherein the weight content of mepivacaine is 45%, and the weight content of E-A is 55%.

Accurately weigh 0.5g of mepivacaine injection (E-A-Mep), move it to a screw bottle with a cap, add 20mL of phosphate buffer solution with pH 5.0, 6.5 and 7.4 into the bottle, let it stand at 37°C, and Take out the screw bottle at the time point, collect the phosphate buffer in the bottle, add an equal amount of fresh buffer and continue to stand still, then take 1mL of the old buffer to measure the concentration of mepivacaine, and then calculate the concentration of mepivacaine amount released. The above operation was repeated three times. The results are shown in Figure 16, the drug release of mepivacaine injection is zero-order release and shows an obvious long-acting sustained-release effect, and the drug release rate is positively correlated with the acidity of the buffer.

The mepivacaine injection and the prepared mepivacaine injection (E-A-Mep) were subcutaneously injected into different pain model rats with a mepivacaine content of 200 mg/kg. Then record the time required for rats to achieve normal response to deep pain and electrical stimulation, and record the time required for rats to recover from motor weakness to normal. When half of the rats return to normal, the detection is stopped. The recorded results are shown in Table 1. The analgesic duration of mepivacaine injection (E-A-Mep) is significantly longer than that of mepivacaine alone, which can achieve a good therapeutic effect.

Table 1 is the treatment result of mepivacaine injection and mepivacaine alone

The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: it can still be described in the foregoing embodiments Modifications are made to the recorded technical solutions, or equivalent replacements are made to some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

An orthoester miscible pharmaceutical excipient, characterized in that: it is mainly obtained by mixing different orthoester compounds with each other in different proportions or orthoester compounds and biocompatible medical polymer materials in different proportions;

Shown in the chemical formula I of described orthoester compound:

wherein R represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl or phenyl.
The orthoester miscible pharmaceutical excipient according to claim 1, characterized in that: the ratio between the different orthoester compounds is 1:1000-1000:1, and the orthoester compound and biological The ratio of compatible medical polymer materials is 1:1000-1000:1.
The orthoester miscible pharmaceutical excipient according to claim 1, wherein the biocompatible medical polymer material comprises:

(i) Polycaprolactone

Wherein, m represents an integer value 2-100;

(ii) Polycaprolactone diol

Wherein, n represents an integer value 1-50;

(iii) Polylactic acid

where x represents an integer value 2-100;

(iv) polyethylene glycol

where y represents an integer value 2-150.
The orthoester miscible pharmaceutical excipient according to claim 1, characterized in that: the preparation method of the orthoester compound comprises the following steps: under nitrogen protection, diglycerol, trimethyl esters and catalysts are mixed according to the molar ratio of 1 : (2.2-5.0): (0.01-0.04) dissolved in the first organic solvent, and stirred at room temperature for 12-48 hours, then extracted with saturated sodium carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove excess trimethyl esters The starting material yields an ortho ester compound.
The orthoester miscible pharmaceutical excipient according to claim 4, wherein the first organic solvent includes acetonitrile, dichloromethane, tetrahydrofuran, and dioxane, and the trimethyl ester raw material includes orthoformic acid Trimethyl, trimethyl orthoacetate, trimethyl orthopropionate, trimethyl orthoisopropionate, trimethyl orthobutyrate, trimethyl orthobenzoate, the catalyst includes p-toluenesulfonic acid, p-toluene Pyridinium sulfonate.
The method for preparing the orthoester miscible pharmaceutical excipient as described in any one of claims 1-5, is characterized in that: comprising the following steps: combining different orthoester compounds or orthoester compounds with biocompatibility Medical polymer materials are miscible, and the miscibility method includes miscibility at 25-140°C under negative pressure or 25-140°C under nitrogen atmosphere conditions, or miscibility after dissolving with a second organic solvent, and reducing The organic solvent was removed under pressure.
The method for preparing orthoester miscible pharmaceutical excipients as claimed in claim 6, wherein the second organic solvent comprises tetrahydrofuran, methylene chloride, dioxane, ethanol, methanol, chloroform, acetone, Dimethyl sulfoxide, N,N-dimethylformamide.
A local sustained-release drug preparation, characterized in that: comprising the orthoester miscible pharmaceutical excipient and active substance according to any one of claims 1-5, the weight percentage of the active substance is 0.1-50 %, the weight percentage of the orthoester miscible pharmaceutical excipient is 50-99.9%.
The local sustained-release drug preparation according to claim 8, characterized in that: the active substance is selected from one of antineoplastic drugs, anti-inflammatory drugs, hypoglycemic drugs, hypotensive drugs, analgesic drugs, and protein vaccines. one or more species.
The local sustained-release drug preparation according to claim 9, wherein the antineoplastic drug includes paclitaxel, doxorubicin, gemcitabine, 5-fluorouracil, camptothecin, hydroxycamptothecin, cisplatin, carboplatin , PD-1, gefitinib, erlotinib, sorafenib, dasatinib.
The local sustained-release drug preparation according to claim 9, wherein the anti-inflammatory drugs include aspirin, diclofenac sodium, ibuprofen, flurbiprofen, ketoprofen, naproxen, indobufen , indomethacin, piroxicam, meloxicam, erecoxib, celecoxib, dexamethasone, hydrocortisone, prednisolone, methylprednisolone, triamcinolone acetonide, fluocinolone , fludrocortisone, beclomethasone.
The local sustained-release drug preparation according to claim 9, wherein the blood pressure-lowering drugs include thiazides, potassium-storing diuretics, aldosterone antagonists, loop diuretics, central antihypertensive drugs, ganglion blockers, etc. Blocking drugs, noradrenergic nerve ending blocking drugs, adrenergic receptor blocking drugs, angiotensin converting enzyme inhibitors, angiotensin Ⅱ receptor blocking drugs, renin inhibitors, dihydropyridines, Dihydropyridines and vasodilators.
The local sustained-release drug preparation according to claim 9, characterized in that: the analgesic drugs include receptor agonists, receptor partial agonists, opioid receptor antagonists and antipyretic analgesics.
The local sustained-release drug preparation according to claim 9, characterized in that: the protein vaccine comprises natural protein and chemically inactivated toxoid.