CN101023919A - Entity-tumor-resistant slow-release agent - Google Patents

Abstract

The present invention relates to an anti-tumor slow-release preparation. It is an anti-tumor slow-release injection formed from slow-release microsphere and solvent, in which the slow-release microsphere includes slow-release auxiliary material, angiogenesis inhibitor and glucocorticoid, its solvent contains suspension adjuvant. The angiogenesis inhibitor can be selected from vandetanib tipifarnib, sirolimus or lenalidomide, the glucocorticoid can be one selected from prednisone, prednisolone, methyl prednisolone, clobetasone, betamethasone, dexamethasone and triamcinolone or their combination, the slow-release auxiliary material is selected from sebacic acid copolymer, polyphosphate, polylactic acid and its mixture or copolymer, and the suspension adjuvant is selected from carboxymethylcellulose sodium, etc. Said preparation also can be made into implantation preparation.

Description

Sustained-release agent for resisting solid tumor

(I) technical field

The invention relates to a sustained release agent for resisting solid tumors, belonging to the technical field of medicaments. More particularly, it is a slow-release implantation agent and injection for resisting solid tumor. The anti-solid tumor sustained release agent can effectively inhibit or destroy tumor blood vessels and inhibit tumor neovascularization; the sustained-release implant for resisting the solid tumor also relates to the effects of effectively reducing tension, interstitial pressure and interstitial viscosity in the tumor, further improving the interstitial fluid conductivity of the sustained-release implant, and being beneficial to the effective diffusion of the drug into the solid tumor and in the tumor.

(II) background of the invention

The solid tumor is composed of tumor cells and tumor stroma, wherein blood vessels in the tumor stroma not only provide a scaffold and essential nutrients for the growth of the tumor cells, but also influence the penetration and diffusion of chemotherapeutic drugs around the tumor and in the tumor tissue, see Niti et al, "influence of the condition of extracellular stroma on drug operation in the solid tumor" [ Cancer research ] No. 60, No. 2497 and No. 503, 2000 (Netti PA, Cancer Res.2000, 60 (9): 2497 and No. 503).

The components of fibrin and collagen in blood vessels and connective tissues in tumor stroma and hyperproliferative tumor cells cause high interstitial pressure (interstitial pressure), high interstitial viscosity (interstitial viscosity), high tissue tension coefficient (tissue tension module) and low interstitial fluid conductivity (hydralic con) of solid tumors. These factors greatly limit the effective diffusion of drugs into solid tumors and within tumors, and thus constitute a major obstacle to tumor chemotherapy.

The local placement of the antitumor drug can better overcome the defects, not only can obviously improve the local drug concentration of the tumor, but also can obviously reduce the systemic toxic reaction. A number of in vitro and in vivo experiments have shown therapeutic efficacy against solid tumors, see Kongqing et al, "cisplatin placement in tumors plus systemic carmustine for treatment of rat brain tumors" [ J.Oncork.69, 76-82 ], 1998 (Kong Q et al, J Surg Oncol.1998 Oct; 69 (2): 76-82) ] and Kongqing et al, "cisplatin placement in tumors for cure of rat primary brain tumors" [ J.Oncork.64, 268-273 (1997) (Kong Q et al, JSURg Oncol.1997 Oct; 64: 268-273). See also Chinese patent (ZL 00111093.4; ZL 96115937.5; application Nos. 001111264, 001111272) and U.S. patent Nos. 6,376,525B 1; 5,651,986; 5,626,862).

However, the blood vessels in the tumor stroma are not sensitive to conventional chemotherapeutic drugs, often resulting in increased resistance of tumor cells to anticancer drugs, and local edema can cause many complications, with the result that treatment fails.

Disclosure of the invention

Aiming at the defects of the prior art, the invention provides a novel pharmaceutical composition, in particular to a sustained-release agent for resisting solid tumors. The anti-solid tumor sustained release preparation mainly comprises a sustained release implant and a sustained release injection, and can effectively inhibit or destroy tumor blood vessels and inhibit tumor neovascularization by local application; can inhibit tumor growth and increase the sensitivity of tumor cells to anticancer drugs; the anti-solid tumor sustained release agent can also reduce edema, effectively reduce tension, interstitial pressure and interstitial viscosity in the tumor, further improve interstitial fluid conductivity, and facilitate the effective diffusion of the drug into the solid tumor and in the tumor.

The anti-solid tumor slow release agent comprises anti-cancer active ingredients and pharmaceutic adjuvant, wherein the anti-cancer active ingredients are vascular inhibitor and/or glucocorticoid, the vascular inhibitor has the function of inhibiting the growth of tumor cells, can effectively inhibit or destroy the blood vessels of the tumor and can inhibit the formation of new blood vessels of the tumor, so that the tumor cells lose the sources of the stent and nutrient substances required by the growth, and the anti-solid tumor slow release agent can be used together with or independently from the glucocorticoid to obviously promote the penetration and diffusion of chemotherapeutic drugs into the tumor and the tumor periphery and the tumor tissues. The glucocorticoid can effectively reduce inflammatory edema, and further obviously promote the penetration and diffusion of chemotherapeutic drugs into tumors, around tumors and in tumor tissues.

The number of the medicinal auxiliary materials is more than hundreds, the medicinal auxiliary materials with slow release effect are not obvious, particularly, the medicine selected in the invention can be slowly released in a human body or an animal body within a certain time, and the selection of the specific slow release auxiliary materials and the slow release medicine can be determined only by a great deal of creative labor. Too slow release to achieve effective drug concentration and thus ineffective killing of tumor cells; if the release is too fast, a burst will be caused, which is likely to cause a general toxic reaction like a conventional injection. The related data, particularly the data of the release characteristics in animals, can be obtained through a large number of creative experiments in vivo and in vitro, can not be determined through limited experiments, and is non-obvious.

The vascular inhibitor is selected from one or a combination of the following: vandetanib (vandetiniib, ZD6474, Zactima), tipifarnib (tipifarnib), sirolimus (temsirolimus), lenalidomide (lenalidomide), and exetecan (dx-8951 f).

The above vascular inhibitors also include their salts, such as, but not limited to, sulfate, phosphate, hydrochloride, lactobionate, acetate, aspartate, nitrate, citrate, purine or pyrimidine salts, succinate, maleate, and the like.

The above-mentioned blood vessel inhibitor is preferably vandetanib, tipifarnib, sirolimus, lenalidomide and irinotecan.

The proportion of the angiogenesis inhibitor in the sustained release preparation is determined by specific conditions, and can be 0.1-50%, preferably 1-40%, and most preferably 5-30%.

When the effective anticancer component in the medicine is only glucocorticoid, the slow released anticancer implant is used mainly in raising the effect of neovascular inhibitor in other application routes or in raising the effect of radiotherapy or other treatment. When the effective anticancer component is a neovascular inhibitor, the application and the synergistic mode of the anticancer sustained-release agent are as follows:

(1) the slow release agent containing the angiogenesis inhibitor is locally injected, and the glucocorticoid is applied by other ways;

(2) local application of a slow release agent containing glucocorticoid and other ways of application of a neovascular inhibitor;

(3) a slow release agent containing a neovascularization inhibitor and a slow release injection containing glucocorticoid are locally applied; or

(4) A sustained release formulation comprising a neovascular inhibitor and a glucocorticoid is applied topically.

Sustained release formulations for topical application of anticancer agents are also useful for potentiation of radiation or other therapies. Other routes refer, but are not limited to, arterial, venous, intraperitoneal, subcutaneous, intraluminal administration.

The weight percentage of the anti-cancer active ingredient neovascular inhibitor and/or glucocorticoid in the drug sustained release agent is 0.5-60%, preferably 2-40%, and most preferably 5-30%. The weight ratio of the angiogenesis inhibitor to the glucocorticoid is 1-19: 1 to 1: 1-19, preferably 1-9: 1 to 1: 1-9.

A wide variety of materials that can alleviate localized edema are available for the purposes of the present invention. However, glucocorticoid-like drugs are selected and include, but are not limited to, cortisone (cortisone), hydrocortisone (hydrocortisone), hydrocortisone acetate (hydrocortisone acetate), hydrocortisone butyrate (hydrocortisone butyrate), Prednisone (Prednisone), prednisolone (Prednisone), Methylprednisolone (methylprednisone), Triamcinolone (Triamcinolone acetonide, Triamcinolone, Triamcinolone fludrolone, Triamcinolone, dexamethasone (desoxysone), betamethasone (Betemethasone), clobetasone butyrate (clobetamethasone butyrate), clobetasone propionate (Triamcinolone, Triamcinolone acetonide, triamcino, Desometasone valerate (betamethasone valerate), betamethasone dipropionate (betamethasone dipropionate), fluocinolone (flucinode), clobetasone (Halcinonide ), halomethasone (halomethasone), Beclomethasone Dipropionate (BDP), Budesonide (BUD) and fluticasone.

Glucocorticoids also include salts and esters that may be used, such as, but not limited to, acetic acid, butyric acid, sodium succinate, diacetate, phosphoric acid, propionic acid, hydrochloride or ester, sulfate, phosphate, hydrochloride, lactobionate, aspartate, nitrate, citrate, purine or pyrimidine salts, maleate, and the like.

The glucocorticoid medicaments are classified into low, medium and high efficiency according to the strength of the effect, generally thought that the low efficiency mainly comprises cortisone and hydrocortisone, and the daily dosage is about 1-50 mg; the intermediate effect mainly comprises prednisone, prednisolone, methylprednisolone and triamcinolone, and the daily dosage is 0.1-10 mg; the high efficiency mainly comprises betamethasone and dexamethasone, and the daily dose is 0.01-5 mg.

The invention is selected according to the clinical dosage, and the clinical dosage is divided into the following categories (1) low-efficiency category: including, but not limited to, cortisone, hydrocortisone acetate, prednisone; (2) the intermediate efficiency class: including, but not limited to, prednisolone, methylprednisolone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, triamcinolone acetonide, mometasone furoate, fluocinolone acetonide; (3) high-efficiency class: including, but not limited to, flumethasone pivalate, desatasone valerate, betamethasone dipropionate, clobetasone, halometasone, beclomethasone dipropionate, budesonide, fluticasone.

The dosage of the glucocorticoid medicaments is determined according to specific situations, and the daily dosage of low-efficiency medicaments is about 1-50mg when the glucocorticoid medicaments are used in a clinical system; the daily dosage of the intermediate effect is 0.1-10 mg; the daily dose of the composition is 0.01-5 mg. The amount of the present invention may be, but is not limited to, 0.1 to 10 times, preferably 0.1 to 5 times, the daily amount as mentioned above.

The proportion of the glucocorticoid in the sustained release agent is determined by the specific situation, but not limited to, 0.001% -50%, preferably 0.01% -30%, and most preferably 0.1% -20%.

The above glucocorticoids also include their salts such as, but not limited to, sulfate, phosphate, hydrochloride, lactobionate, acetate, aspartate, nitrate, citrate, purine or pyrimidine salts, succinate, maleate and the like.

The compositions of the invention may be prepared in a manner known per se, for example, by means of conventional mixing, dissolving, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The carrier includes various excipients and adjuvants. Suitable formulations may be prepared according to the chosen route of administration. Such as injection, oral administration, inhalation, suppository, patch, implant, etc. For transmucosal and transdermal administration, the use of penetrants appropriate to the permeation barrier in the formulation is generally known in the art.

Can be made into oral preparation in the form of tablet, pill, disintegrating agent, dragee, capsule, push-fit capsule, soft capsule, liquid, gel, syrup, slurry, suspension, etc.

Among the various formulations, long acting formulations are preferred, with topical application of long acting formulations being most preferred. The latter can be applied locally to the tumor by implantation (rectal, transmucosal, transdermal, enteral, intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections), with significantly reduced systemic toxicity while effectively achieving and maintaining local drug concentrations.

Administration is by topical means, e.g., by direct injection into a particular tissue, usually in the form of a depot or sustained release formulation.

Thus, the main form of the present invention is a sustained release agent including a sustained release implant and a sustained release injection.

One main form of the present invention is a sustained-release injection comprising:

(A) a sustained release microsphere comprising:

0.1-60% of anticancer active ingredient

Sustained release auxiliary materials 40-99.9%

0.0 to 30 percent of suspending agent

The above are weight percentages

And

(B) the solvent is common solvent or special solvent containing suspending agent.

Wherein,

the effective anticancer component is neovascular inhibitor and/or glucocorticoid;

the slow release auxiliary material is selected from one or the combination of the following materials:

a) polylactic acid;

b) copolymers of polyglycolic acid and glycolic acid;

c) polifeprosan;

d) polifeprosan in combination with polylactic acid or a copolymer of polyglycolic acid and glycolic acid;

e) a di-fatty acid and sebacic acid copolymer;

f) poly (erucic acid dimer-sebacic acid) copolymer:

g) poly (fumaric acid-sebacic acid) copolymer.

The suspending agent is selected from one or more of sodium carboxymethylcellulose, iodine glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80,

the viscosity of the suspending agent is 100cp-3000cp (at 20 ℃ -30 ℃).

The anticancer active ingredients in the sustained-release injection microsphere are preferably as follows, and the weight percentages are as follows:

(a) 2-40% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan; or

(b) 2-40% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan in combination with 0.01-20% of cortisone, hydrocortisone acetate, prednisone, prednisolone, methylprednisolone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, triamcinolone acetonide, mometasone furoate, fluocinolone acetonide, flumethasone pivalate, desomethasone valerate, betamethasone dipropionate, clobetasone, clobetamethasone, halomethasone, beclomethasone dipropionate, budesonide or fluticasone.

The sustained-release adjuvant can be various water-soluble or water-insoluble polymer, and preferably selected from p (BHET-EOP/TC, 80/20), p (BHET-EOP/TC, 50/50), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC, 80/20), p (BHDPT-EOP/TC, 50/50), p (CHDM-HOP), p (CHDM-EO)P), one or a combination of racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid/glycolic acid copolymer, polifeprosan, di-fatty acid and sebacic acid copolymer, poly (erucic acid dimer-sebacic acid), poly (fumaric acid-sebacic acid), ethylene vinyl acetate copolymer, polylactic acid, copolymer of polyglycolic acid and glycolic acid, xylitol, oligosaccharide, chondroitin, chitin, chitosan, poloxamer 188, poloxamer 407, hyaluronic acid, collagen, gelatin, poloxamer and albumin glue. Therein would

Qiazhi mansion barium capsule muscle

The most preferable sustained-release auxiliary materials in the sustained-release microspheres and the weight percentage thereof are as follows:

(1) 55-90% PLA;

(2) 50-90% PLGA;

(3) 50-85% of polifeprosan;

(4) 25-60% PLGA and 20-60% sebacic acid copolymerized or mixed;

(5) 30-90% of polifeprosan and 35-90% of PLA mixture;

(6) 40-95% of xylitol, oligosaccharide, chondroitin, chitin, chitosan, poloxamer 188, poloxamer 407, hyaluronic acid, collagen, gelatin, poloxamer or albumin glue; or

(7) 40-95% of racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycollic acid copolymer;

(8) 40-95% of p (BHET-EOP/TC, 80/20), p (BHET-EOP/TC, 50/50), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC, 80/20), p (BHDPT-EOP/TC, 50/50), p (CHDM-HOP) or p (CHDM-EOP); or

(9) 30-85% of p (DAPG-EOP) and 40-80% of sebacic acid.

In the combination, the total amount of different auxiliary materials is not more than 99%.

The molecular weight peak and the monomer ratio in the copolymer are as follows:

a) the peak value of the molecular weight of the polylactic acid is 10000-, 30000-, 300000-60000-, 60000-100000-or 100000-150000;

b) in the copolymer of polyglycolic acid and glycolic acid, the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50, and the peak value of molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;

c) in polifeprosan, the ratio of p-carboxyphenylpropane to sebacic acid is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;

d) in p (BHET-EOP/TC), the ratio of BHET-EOP to TC is 90-40: 10-60;

e) in p (BHDPT-EOP/TC), the ratio of BHDPT-EOP to TC is 90-40: 10-60;

f) the peak value of the molecular weight of p (DAPG-EOP) is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;

in various high molecular polymers, the molecular weight peak depends on different requirements, but is not limited to, 5000-; the monomer blending ratio is not limited to 10-90: 90-10, but is preferably 20-80: 80-20, more preferably 40-60: 60-40, and the polymer viscosity range IV (dl/g) is 0.1-0.8, more preferably 0.2-0.6, most preferably 0.2-0.5.

The sustained-release excipients used for preparing the sustained-release agent can be various water-soluble or water-insoluble polymer polymers, and one or the combination of polylactic acid (PLA), polyglycolic acid-glycolic acid copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, fatty acid dimer and sebacic acid copolymer (PFAD-SA), poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ] is preferred in various sustained-release excipients.

When polylactic acid (PLA), polyglycolic acid (PGA), a mixture of polylactic acid (PLA) and polyglycolic acid, and a copolymer of glycolic acid and hydroxycarboxylic acid (PLGA) are selected, the PLA and PLGA content is arbitrary, but is preferably 1 to 99% and 99 to 1% by weight. The molecular weight peak of polylactic acid may be, but is not limited to, 5000-; the molecular weight of polyglycolic acid may be, but is not limited to, 5000-; the polyhydroxy acids can be selected singly or in multiple ways. When selected alone, polylactic acid (PLA) or a copolymer of hydroxycarboxylic acid and glycolic acid (PLGA) is preferred, and the molecular weight of the copolymer may be, but is not limited to, 5000-; when more than one choice is selected, a polymer or a composite polymer or copolymer of different polymers is preferred, and a composite polymer or copolymer of polylactic acid or sebacic acid with different molecular weights is most preferred, such as, but not limited to, polylactic acid with a molecular weight of 10000 to 100000 mixed with polylactic acid with a molecular weight of 20000 to 150000, polylactic acid with a molecular weight of 10000 to 100000 mixed with PLGA with a molecular weight of 30000 to 80000, polylactic acid with a molecular weight of 20000 to 30000 mixed with sebacic acid, PLGA with a molecular weight of 30000 to 80000 mixed with sebacic acid.

Among the various polymers, preferred are polylactic acid, sebacic acid, and a mixture or copolymer of polylactic acid and sebacic acid, and the mixture or copolymer can be selected from, but not limited to, PLA, PLGA, a mixture of glycolic acid and hydroxycarboxylic acid, and a mixture or copolymer of sebacic acid and an aromatic polyanhydride or an aliphatic polyanhydride. The blending ratio of glycolic acid and hydroxycarboxylic acid is 10/90-90/10 (by weight), preferably 25/75-75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and hydroxycarboxylic acid in copolymerization are 10-90 wt% and 90-10 wt%, respectively. Representative of aromatic polyanhydrides are polifeprosan [ poly (1, 3-di (P-carboxyphenoxy) propane-sebacic acid) (P (CPP-SA)), di-fatty acid-sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], and poly (fumaric acid-sebacic acid) [ P (FA-SA) ], and the like. The content of p-carboxyphenoxy propane (p-CPP) and sebacic acid in copolymerization is 10-60 wt% and 20-90 wt%, respectively, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.

In addition to the above sustained-release excipients, other substances can be selected and used as described in detail in U.S. Pat. Nos. 4757128 (4857311; 4888176; 4789724) and "pharmaceutical excipients" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luoming and high-tech). In addition, Chinese patent (application No. 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S. patent No. 5,651,986) also list some pharmaceutical excipients, including fillers, solubilizers, absorption promoters, film-forming agents, gelling agents, pore-forming agents, excipients or retarders.

In order to adjust the drug release rate or change other characteristics of the present invention, the monomer component or molecular weight of the polymer can be changed, and the composition and ratio of the pharmaceutical excipients can be added or adjusted, and water-soluble low molecular compounds such as, but not limited to, various sugars or salts can be added. Wherein the sugar can be, but is not limited to, xylitol, oligosaccharide, (chondroitin sulfate), chitin, etc.; wherein the salt can be, but is not limited to, potassium salt, sodium salt, and the like; other pharmaceutical adjuvants such as, but not limited to, fillers, solubilizers, absorption enhancers, film-forming agents, gelling agents, pore-forming agents, excipients, or retarders may also be added.

In the slow release injection, the drug slow release system can be prepared into microspheres, submicron spheres, micro emulsion, nanospheres, granules or spherical pellets, and then the injection is prepared after the drug slow release system is mixed with an injection solvent. The suspension type sustained-release injection is preferably selected from various sustained-release injections, the suspension type sustained-release injection is a preparation obtained by suspending a drug sustained-release system containing an anti-cancer component in injection, the used sustained-release auxiliary material is one or the combination of the sustained-release auxiliary materials, and the used solvent is a common solvent or a special solvent containing a suspending agent. Common solvents are, but not limited to, distilled water, water for injection, physiological saline, absolute ethanol or buffers formulated with various salts. The suspending agent is intended to effectively suspend the microspheres containing the drug, thereby facilitating injection. For convenient injection, the suspending agent has viscosity of 100-3000 cp (at 20-30 deg C), preferably 1000-3000 cp (at 20-30 deg C), and most preferably 1500-3000 cp (at 20-30 deg C). The suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.

The content of the suspending agent in the common solvent depends on the characteristics of the suspending agent, and can be 0.1-30% according to the specific situation. Preferably, the suspending agent consists of:

A) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80; or

B) 5-20% of mannitol and 0.1-0.5% of Tween 80; or

C)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.

The preparation of the solvent depends on the kind of the solvent, and common solvents are commercially available or self-made, such as distilled water, water for injection, physiological saline, absolute ethanol or buffers prepared from various salts, but the preparation must strictly follow the relevant standards. The special solvent should be selected from the type and composition of suspending agent, the composition and properties of the drug suspended in the solvent, the sustained release microsphere (or microcapsule), and the required amount thereof, and the preparation method of the injection, for example, sodium carboxymethylcellulose (1.5%) + mannitol and/or sorbitol (15%) and/or tween 80 (0.1%) are dissolved in physiological saline to obtain the corresponding solvent with viscosity of 10-650 cp (at 20-30 deg.C).

The invention discovers that the key factor influencing the suspension and/or injection of the medicament and/or the sustained-release microspheres is the viscosity of the solvent, and the higher the viscosity is, the better the suspension effect is and the stronger the injectability is. This unexpected finding constitutes one of the main exponential features of the present invention. The viscosity of the solvent depends on the viscosity of the suspending agent, and the viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃). The viscosity of the solvent prepared according to the condition is 10cp-650cp (at 20-30 ℃), preferably 20cp-650cp (at 20-30 ℃), and most preferably 60cp-650cp (at 20-30 ℃).

The preparation of injection has several methods, one is that the slow release particles (A) whose suspending agent is '0' are directly mixed in special solvent to obtain correspondent slow release particle injection; the other is that the slow release particles (A) of which the suspending agent is not 0 are mixed in a special solvent or a common solvent to obtain the corresponding slow release particle injection; and the other one is that the slow release particles (A) are mixed in common dissolvent, then suspending agent is added and mixed evenly, and the corresponding slow release particle injection is obtained. Besides, the sustained-release particles (A) can be mixed in special solvent to prepare corresponding suspension, then the water in the suspension is removed by methods such as vacuum drying, and then the suspension is suspended by special solvent or common solvent to obtain the corresponding sustained-release particle injection. The above methods are merely illustrative and not restrictive of the invention. It is noted that the concentration of the suspended drug or the sustained release microspheres (or microcapsules) in the injection may be, but is not limited to, 10-400mg/ml, but is preferably 30-300mg/ml, and most preferably 50-200mg/ml, depending on the particular need. The viscosity of the injection is 50-1000 cp (at 20-30 deg C), preferably 100-1000 cp (at 20-30 deg C), and most preferably 200-650 cp (at 20-30 deg C). This viscosity is suitable for 18-22 gauge needles and specially made needles with larger (to 3 mm) inside diameters.

The method of preparation of the sustained release injection is arbitrary and can be prepared by several methods: such as, but not limited to, mixing, melting, dissolving, spray drying to prepare microspheres, dissolving in combination with freezing (drying) and pulverizing to form fine powders, liposome-encapsulating, and emulsifying. Among them, a dissolving method (i.e., solvent evaporation method), a drying method, a spray drying method and an emulsification method are preferable. The microspheres can be used for preparing the various sustained-release injections, and the method is arbitrary. The microspheres used may have a particle size in the range of 5-400um, preferably 10-300um, most preferably 20-200 um.

The microspheres can also be used for preparing other sustained-release injections, such as gel injections and block copolymer micelle injections. The block copolymer micelle is formed by a hydrophobic-hydrophilic block copolymer in an aqueous solution and has a spherical core-shell structure, wherein the hydrophobic block forms a core, and the hydrophilic block forms a shell. The drug-loaded micelle is injected into the body to achieve the purpose of controlling the release of the drug or targeting therapy. The drug carrier is any one of the above or the combination thereof. Of these, polyethylene glycol (PEG) having a molecular weight of 1000-15000 is preferable as the hydrophilic block of the micelle copolymer, and biodegradable polymers such as PLA, polylactide, polycaprolactone and copolymers thereof (molecular weight 1500-25000) are preferable as the hydrophobic block of the micelle copolymer. The block copolymer micelles may have a particle size in the range of 10 to 300um, preferably 20 to 200 um. The gel injection is prepared by dissolving biodegradable polymer (such as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer) in certain amphiphilic solvent, adding the medicine, mixing (or suspending) with the solvent to form gel with good fluidity, and can be injected around tumor or in tumor. Once injected, the amphiphilic solvent diffuses into the body fluid quickly, and the water in the body fluid permeates into the gel, so that the polymer is solidified and the drug is released slowly.

The sustained-release microspheres can also be used for preparing sustained-release implants, the used pharmaceutic adjuvant can be any one or more of the above pharmaceutic adjuvants, but the water-soluble high polymer is selected as the main choice, and the mixture or copolymer of polylactic acid, sebacic acid, and high polymer containing polylactic acid or sebacic acid is selected as the first choice among various high polymers, and the mixture and copolymer can be selected from, but are not limited to, PLA, PLGA, mixture of PLA and PLGA, mixture or copolymer of sebacic acid and aromatic polyanhydride or aliphatic polyanhydride, fatty acid dimer-sebacic acid [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ]. The blending ratio of polylactic acid (PLA) to polyglycolic acid is 10/90 to 90/10 (by weight), preferably 25/75 to 75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and lactic acid in copolymerization are respectively 10-90% and 90-10% by weight. The aromatic polyanhydride is represented by p-carboxyphenylpropane (p-CPP), the content of the p-carboxyphenylpropane (p-CPP) and sebacic acid in copolymerization is respectively 10-60% and 20-90% by weight, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.

Still another form of the anticancer drug sustained-release preparation of the present invention is that the anticancer drug sustained-release preparation is a sustained-release implant. The effective components of the anticancer implant can be uniformly packaged in the whole pharmaceutic adjuvant, and also can be packaged in the center of a carrier support or on the surface of the carrier support; the active principle can be released by direct diffusion and/or by degradation via polymers.

The slow release implant is characterized in that the slow release auxiliary material contains any one or more of the other auxiliary materials besides the high molecular polymer. The added pharmaceutic adjuvants are collectively called as additives. The additives can be classified into fillers, pore-forming agents, excipients, dispersants, isotonic agents, preservatives, retarding agents, solubilizers, absorption enhancers, film-forming agents, gelling agents, etc. according to their functions.

The main components of the sustained-release implant can be prepared into various dosage forms. Such as, but not limited to, capsules, sustained release formulations, implants, sustained release implants, and the like; in various shapes such as, but not limited to, granules, pills, tablets, powders, spheres, chunks, needles, rods, columns, and films. Among various dosage forms, slow release implants in vivo are preferred.

The optimal dosage form of the sustained-release implant is biocompatible, degradable and absorbable sustained-release implant, and can be prepared into various shapes and various dosage forms according to different clinical requirements. The packaging method and procedure for its main ingredients are described in detail in US patent (US5651986) and include several methods for preparing sustained release formulations: such as, but not limited to, (i) mixing a carrier support powder with a drug and then compressing into an implant, a so-called mixing process; (ii) melting the carrier support, mixing with the drug to be packaged, and then cooling the solid, the so-called melt process; (iii) dissolving the carrier support in a solvent, dissolving or dispersing the drug to be packaged in a polymer solution, and then evaporating the solvent and drying, the so-called dissolution method; (iv) spray drying; and (v) freeze-drying method.

The anticancer active ingredients of the sustained-release implant are preferably as follows, and the weight percentages are as follows:

(a) 2-40% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan; or

(b) 2-40% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan in combination with 0.01-20% of cortisone, hydrocortisone acetate, prednisone, prednisolone, methylprednisolone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, triamcinolone acetonide, mometasone furoate, fluocinolone acetonide, flumethasone pivalate, desomethasone valerate, betamethasone dipropionate, clobetasone, clobetamethasone, halomethasone, beclomethasone dipropionate, budesonide or fluticasone.

The sustained release excipient can be various water-soluble or water-insoluble polymer, which can be referred to as sustained release injection, and preferably selected from polylactic acid (PLA), polyglycolic acid-glycolic acid copolymer (PLGA), ethylene-vinyl acetate copolymer (EVAc), polifeprosan, fatty acid dimer and sebacic acid copolymer (PFAD-SA), poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], or their combination.

The route of administration depends on a variety of factors, and in order to achieve effective concentrations at the site of the primary or metastatic tumor, the drug may be administered by a variety of routes, such as subcutaneous, intraluminal (e.g., intraperitoneal, thoracic, and intravertebral), intratumoral, peritumoral injection or placement, selective arterial injection, intralymph node, and intramedulary injection. Selective arterial injection, intracavitary, intratumoral, peritumoral injection or placement is preferred. When the anticancer drug in the drug sustained-release microspheres is only a neovascular inhibitor or a synergist thereof (cytotoxic drug), the application and the synergy mode of the anticancer sustained-release implant are the same as those of a sustained-release injection.

The invention can be used for preparing pharmaceutical preparations for treating various tumors of human and animals, mainly sustained-release injections or sustained-release implants, wherein the tumors comprise primary or metastatic cancers or sarcomas or carcinosarcomas originated from brain, central nervous system, kidney, liver, gall bladder, head and neck, oral cavity, thyroid, skin, mucous membrane, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, mammary gland, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon and rectum.

The tumors of the organs can be of different pathological types, the tumors of the lymph nodes are Hodgkin lymphoma and non-Hodgkin lymphoma, the lung cancer comprises small cell lung cancer, non-small cell lung cancer and the like, and the brain tumor comprises glioma and the like. However, common tumors include solid tumors such as brain tumor, brain glioma, kidney cancer, liver cancer, gallbladder cancer, head and neck tumor, oral cancer, thyroid cancer, skin cancer, hemangioma, osteosarcoma, lymphoma, lung cancer, thymus cancer, esophageal cancer, stomach cancer, breast cancer, pancreatic cancer, retinoblastoma of eyes, nasopharyngeal cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, and testicular cancer.

The application and the synergy mode of the sustained-release implant are the same as those of an anticancer sustained-release injection, namely the combination of a locally-placed chemotherapy synergist and an anticancer medicament administrated by other routes, the combination of a locally-placed anticancer medicament and a chemotherapy synergist administrated by other routes, and the combination of a locally-placed anticancer medicament and a locally-placed chemotherapy synergist. Wherein the locally applied anticancer drug and the chemotherapeutic synergist can be produced, packaged, sold and used separately or jointly. The package refers to the loading process of the drug for the auxiliary materials and the internal and external package of the drug-containing sustained release agent for transportation and/or storage. Drug loading processes include, but are not limited to, weighing, dissolving, mixing, drying, shaping, coating, spraying, granulating, and the like.

The clinically applicable dose of the anticancer agent depends on the patient's condition and may be from 0.01 to 300mg/kg body weight, preferably 1 to 200mg/kg, most preferably 10 to 100 mg/kg. The hormone is used in an amount of one hundredth to one tenth of the amount

The sustained-release injection or the sustained-release implant prepared by the invention can also be added with other medicinal components, such as, but not limited to, antibiotics, analgesic drugs, anticoagulant drugs, hemostatic drugs and the like.

The technical process of the present invention is further described by the following examples. The following examples are intended to illustrate but not limit the scope of the invention. The present invention is not to be limited in scope by the illustrated embodiments, which are intended as individual illustrations of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are, of course, intended to be within the scope of the appended claims.

It should be understood, therefore, that the foregoing description focuses on certain specific embodiments of the invention and that equivalent alterations and substitutions made thereto are within the spirit and scope of the appended claims.

Example 1 comparison of local drug concentrations after different modes of application of neovascular inhibitor (vandetanib)

Using white rat as test object, 2X 10⁵Individual prostate tumor cells were injected subcutaneously into their quaternary costal regions and grouped after tumors grew to 1 cm in diameter. The dose of each group was 5mg/kg vandetanib. The results of measuring the content (%) of the medicament in the tumor at different times show that the local medicament concentration difference of the vandetanib applied in different modes is obvious, the local administration can obviously improve and effectively maintain the effective medicament concentration of the part where the tumor is located, and the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumor is the best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. This finding constitutes an important feature of the present invention. This is further confirmed by the following relevant tumor inhibition test.

Example 2 comparison of in vivo tumor-inhibiting action of different modes of application of neovascular inhibitor (tipifarnib)

Using white rat as test object, 2X 10⁵Individual brain tumor cells were injected subcutaneously into their quaternary costal regions and grouped after tumors grew to 0.5 cm diameter. The dose of each group was 1mg/kg tipifarnib. The volume of the tumor was measured on the 30 th day after the treatment, and the treatment effect was compared. The results show that the difference of the tumor inhibition effect of tipifarnib applied in different modes is obvious, the effective drug concentration of the tumor part can be obviously improved and effectively maintained by local administration, and the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumor is the best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. Not only has good curative effect, but also has little toxic and side effect.

Example 3 in vivo tumor-inhibiting action of neovascular inhibitor and glucocorticoid (sustained-release injection)

Using white rat as test object, 2X 10⁵Individual pancreatic cancer tumor cells were injected subcutaneously into the quaternary costal region and divided into the following 10 groups 14 days after tumor growth (see table 1). The first group was the control, and groups 2 to 10 were the treatment groups, and the drug was injected intratumorally. The dosage of the angiogenesis inhibitor is 7.5mg/kg, and the dosage of the glucocorticoid is 2.5 mg/kg. Tumor volume was measured on day 20 after treatment and the effect was compared (see table 1).

TABLE 1

Test set (n)	Is treated by	Tumor volume (cm)3)	P value
				1(6)	Control	62±10
2(6)	Glucocorticoids	40±5.0	＜0.05
				3(6)	Vandetanib	40±2.2	＜0.01
4(6)	Tipifarnib	48±4.4	＜0.01
				5(6)	Sirolimus	46±4.2	＜0.01
6(6)	Lenalidomide	48±3.6	＜0.01
				7(6)	Glucocorticoid + vandetanib	14±2.0	＜0.001
8(6)	Glucocorticoid + tipifarnib	22±3.0	＜0.001
				9(6)	Glucocorticoid + sirolimus	18±2.2	＜0.001
10(6)	Glucocorticoid + lenalidomide	20±2.0	＜0.001

The results show that the angiogenesis inhibitor (vandetanib, tipifarnib, sirolimus, lenalidomide) and the glucocorticoid (dexamethasone) have obvious inhibition effect on the growth of various tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being jointly applied. This finding constitutes a further important feature of the present invention.

Example 4 tumor inhibition by neovascular inhibitor and glucocorticoid (sustained Release injection)

Using white rat as test object, 2X 10⁵Tumor cells (including pancreatic cancer-PC, brain tumor-C6, gastric cancer (SA), bone tumor (BC), breast cancer (BA), liver cancer (LH), thyroid cancer (PAT)) were subcutaneously injected into the quaternary pleural region, and the tumor was divided into the following 7 groups (see Table 2) after 14 days of tumor growth. The medicine is injected intratumorally. Therapeutic efficacy (see table 2). The dosage of the angiogenesis inhibitor is 2.5mg/kg, and the dosage of the glucocorticoid is 7.5 mg/kg. The size of tumor volume was measured on day 20 after the treatment, and the treatment effect was compared using the tumor growth inhibition (%) as an index (see table 2).

TABLE 2

Tumor cell	Glucocorticoids	Vandetanib	Tipifarnib	Ixatecan	Glucocorticoid + vandetanib	Glucocorticoid + tipifarnib	Glucocorticoid + exatecan
								PC	50％	46％	48％	56％	78％	78％	84％
C6	40％	52％	58％	44％	64％	80％	82％
								SA	42％	40％	22％	42％	68％	86％	80％
BC	38％	44％	26％	38％	80％	80％	68％
								BA	54％	42％	52％	26％	78％	76％	78％
LH	48％	50％	22％	38％	70％	86％	80％
								PAT	50％	48％	46％	48％	72％	80％	84％

The results show that the glucocorticoid (dexamethasone) and the neovascular inhibitor (vandetanib, tipifarnib and ixatecan) have obvious inhibition effect on the growth of a plurality of tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being jointly applied.

Example 5 tumor inhibition by neovascular inhibitor and glucocorticoid (sustained Release injection)

Using white rat as test object, 2X 10⁵One lung cancer cell was injected subcutaneously into the quaternary costal region, and the tumor was divided into the following 10 groups 14 days after growth (see table 3). The first group was the control, and groups 2 to 10 were the treatment groups, with the sustained release implant placed intratumorally. The dosage of the angiogenesis inhibitor is 2.5mg/kg, and the dosage of the glucocorticoid is 10 mg/kg. Tumor volume was measured on day 20 after treatment and the treatment effect was compared (see table 3).

TABLE 3

Test set (n)	Is treated by	Tumor volume (cm)3)	P value
				1(6)	Control	62±10
2(6)	Glucocorticoids	46±8.0	＜0.05
				3(6)	Vandetanib	40±6.0	＜0.01
4(6)	Glucocorticoid + vandetanib	22±4.2	＜0.001
				5(6)	Tipifarnib	36±6.2	＜0.01
6(6)	Glucocorticoid + tipifarnib	28±4.8	＜0.001
				7(6)	Lenalidomide	38±6.8	＜0.01
8(6)	Glucocorticoid + lenalidomide	28±5.4	＜0.001
				9(6)	Ixatecan	40±8.0	＜0.01
10(6)	Glucocorticoid + exatecan	26±6.0	＜0.001

The results show that the used angiogenesis inhibitors (vandetanib, tipifarnib, lenalidomide and ixotecan) and the glucocorticoid (betamethasone) have obvious inhibition effects on the growth of various tumor cells when being singly applied at the concentration, and can show obvious synergistic effects when being jointly applied. This finding constitutes a further important feature of the present invention.

Example 6 tumor inhibition by neovascular inhibitor and glucocorticoid (sustained Release injection)

Using white rat as test object, 2X 10⁵One prostate tumor cell was injected subcutaneously into the quaternary costal region and 14 days after tumor growth was divided into negative control (blank), single drug treatment group (neovascular inhibitor or glucocorticoid) and combination treatment group (neovascular inhibitor and glucocorticoid). The medicine is injected intratumorally. The dosage of the angiogenesis inhibitor is 12.5mg/kg, and the dosage of the glucocorticoid is 2.5 mg/kg. The volume of the tumor was measured on the 20 th day after the treatment, and the therapeutic effect was compared using the tumor growth inhibition rate as an index. The results show that the used neovascular inhibitors (vandetanib, tipifarnib, lenalidomide and ixatecan) and glucocorticoids (methylprednisolone) have obvious inhibition effects on the growth of various tumor cells when being singly applied at the concentration, and can show obvious synergistic effects when being jointly applied.

Example 7 tumor inhibition by neovascular inhibitor and glucocorticoid (sustained Release injection)

Using white rat as test object, 2X 10⁵The ovarian cancer tumor cells are injected subcutaneously into the costal region of the patient, and the tumor cells are divided into a negative control (blank), a single-drug treatment group and a combined treatment group after the tumor grows for 14 days. The medicine is injected intratumorally. The dosage of the angiogenesis inhibitor is 5mg/kg, and the dosage of the glucocorticoid is 15 mg/kg. The volume of the tumor was measured on the 20 th day after the treatment, and the therapeutic effect was compared using the tumor growth inhibition rate as an index. The results show that the used angiogenesis inhibitors (vandetanib, tipifarnib, sirolimus, lenalidomide and ixatecan) and the glucocorticoid (triamcinolone acetonide) have obvious inhibition effect on the growth of a plurality of tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being jointly applied. This finding constitutes a further important feature of the present invention.

EXAMPLE 8 tumor-inhibiting action of neovascular inhibitor and glucocorticoid (sustained-release implant)

Using white rat as test object, 2X 10⁵Each breast tumor cell was injected subcutaneously into the costal region of the patient, and the tumor was divided into a negative control (blank), a single drug treatment group, and a combination treatment group 14 days after the tumor had grown. The sustained release implant is placed intratumorally. The dosage of the angiogenesis inhibitor is 15mg/kg, and the dosage of the glucocorticoid is 2.5 mg/kg. The volume of the tumor was measured on the 20 th day after the treatment, and the therapeutic effect was compared using the tumor growth inhibition rate as an index. The results show that the used angiogenesis inhibitors (vandetanib, tipifarnib, sirolimus, lenalidomide and ixatecan) and the glucocorticoid (triamcinolone acetonide) have obvious inhibition effect on the growth of a plurality of tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being jointly applied. This finding constitutes a further important feature of the present invention.

Example 9 tumor inhibition by neovascular inhibitor and glucocorticoid (sustained Release injection)

The tumor inhibition effect of glucocorticoid (slow release injection) is determined by the method described in example 7, and the result shows that glucocorticoid (dexamethasone) can remarkably enhance the tumor inhibition effect of vandetanib, tipifarnib, sirolimus, lenalidomide and exetecan on pancreatic cancer, prostate cancer and rectal cancer, and the synergistic effect is 50-60% (P < 0.01).

In conclusion, the neovascular inhibitor and/or the glucocorticoid used have obvious inhibition effect on the growth of various tumor cells when being used alone, and can show obvious synergistic effect when being used together. Therefore, the active ingredient of the invention is any one of the neovascularization inhibitors or the glucocorticoids or the combination of any one of the neovascularization inhibitors and the glucocorticoids. The medicine containing the above effective components can be made into sustained release microsphere, and further made into sustained release injection and implant, wherein suspension injection formed by combining with special solvent containing suspending agent is preferred.

The sustained-release injection or sustained-release implant can be further explained by the following embodiments. The above examples and the following examples are only for further illustration of the present invention and are not intended to limit the contents and uses thereof in any way.

Example 10.

80mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, 1mg of prednisolone and 19mg of vandetanib are added after the mixture is dissolved and mixed evenly, and the microspheres for injection containing 1% of prednisolone and 19% of vandetanib are prepared by a spray drying method after the mixture is shaken again and evenly. Then suspending the microspheres in physiological saline containing 15 percent of mannitol to prepare the corresponding suspension type sustained-release injection with the viscosity of 220-460 cp (at 20-30 ℃). The slow release injection has the release time of 30-35 days in-vitro physiological saline and the release time of about 30 days under the skin of a mouse.

Example 11.

The steps of the method for processing the sustained-release injection are the same as the example 10, but the difference is that the polifeprosan is 50: 50, and the anticancer active ingredients and the weight percentage thereof are as follows:

(a) 2-40% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan; or

(b) 2-40% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan in combination with 0.01-20% of cortisone, hydrocortisone acetate, prednisone, prednisolone, methylprednisolone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, triamcinolone acetonide, mometasone furoate, fluocinolone acetonide, flumethasone pivalate, desomethasone valerate, betamethasone dipropionate, clobetasone, clobetamethasone, halomethasone, beclomethasone dipropionate, budesonide or fluticasone.

Example 12.

70mg of polylactic acid (PLGA, 75: 25) with the molecular weight peak value of 15000-30000 is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 5mg of dexamethasone and 25mg of tipifarnib are added, the mixture is shaken up again and dried in vacuum to remove the organic solvent. The dried drug-containing solid composition is frozen and crushed into micro powder containing 5 percent of dexamethasone and 25 percent of tipifarnib, and then the micro powder is suspended in physiological saline containing 1.5 percent of sodium carboxymethylcellulose to prepare the corresponding suspension type sustained-release injection with the viscosity of 300cp to 400cp (at the temperature of 20 ℃ to 30 ℃). The slow release injection has the release time of 30-35 days in-vitro physiological saline and the release time of about 30 days under the skin of a mouse.

Example 13

The steps of the method for processing the sustained-release injection are the same as the example 12, but the difference is that the effective anticancer components contained in the polylactic acid (PLGA, 50: 50) with the molecular weight peak of 35000-50000 and the weight percentage thereof are as follows:

(a) 5-20% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan; or

(b) 5-20% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan in combination with 1-10% of cortisone, hydrocortisone acetate, prednisone, prednisolone, methylprednisolone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, triamcinolone acetonide, mometasone furoate, fluocinolone acetonide, flumethasone pivalate, desbetamethasone valerate, betamethasone dipropionate, clobetasone, clobetamethasone, beclomethasone, halomethasone, beclomethasone dipropionate, budesonide or fluticasone.

Example 14.

70mg of polylactic acid (PLA) with the molecular weight peak value of 15000-30000 is put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 5mg of triamcinolone acetonide and 25mg of sirolimus are added, the mixture is shaken again and then spray drying is carried out to prepare the microspheres for injection containing 5% of triamcinolone acetonide and 25% of sirolimus. Then suspending the microspheres in injection containing 5-15% sorbitol to obtain corresponding suspension type sustained release injection with viscosity of 100-200 cp (at 20-30 deg.C). The slow release injection has the release time in vitro physiological saline of 25-35 days and the release time under the skin of a mouse of about 30 days.

Example 15.

The procedure of the method for preparing the sustained-release injection is the same as that of example 14, except that the molecular weight peak of polylactic acid is 30000-50000, and the anticancer active ingredient is:

(a) 10-30% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan; or

(b) 5-10% of vandetanib, tipifarnib, sirolimus, lenalidomide or exatecan in combination with 1-10% of methylprednisolone, clobetasol butyrate, hydrocortisone butyrate, dexamethasone, betamethasone or triamcinolone acetonide.

Example 16.

30mg of polifeprosan (20: 80) and 50mg of polylactic acid (PLA) with the molecular weight peak value of 15000-30000 are put into a container, 100 ml of dichloromethane is added, after the materials are dissolved and mixed evenly, 10mg of Vandetave and 10mg of dexamethasone are added, after the materials are shaken again evenly, the spray drying method is used for preparing the microspheres for injection containing 10 percent of Vandetave and 10 percent of dexamethasone. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose and 0.5 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection with the viscosity of 80-150 cp (at the temperature of 20-25 ℃). The slow release injection has the release time in vitro physiological saline of 30-35 days and the release time under the skin of a mouse of about 40 days.

Example 17.

The process steps for preparing the sustained-release injection are the same as the example 16, but the differences are that the polifeprosan is 50: 50, the molecular weight peak value of the polylactic acid is 30000-50000, and the anticancer active ingredients are: a combination of 10-20% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan with 5-20% of dexamethasone, betamethasone or triamcinolone acetonide.

Example 18

70mg of copolymer of difatty acid and sebacic acid (PFAD-SA, 20: 80) is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 15mg of vandetanib and 15mg of dexamethasone are added, after the mixture is shaken up again, the microspheres for injection containing 15% of vandetanib and 15% of dexamethasone are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose, 15 percent of sorbitol and 0.2 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection with the viscosity of 560cp to 640cp (at the temperature of 20 ℃ to 30 ℃). The slow release injection has the release time of 20-25 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.

Example 19

The steps of the method for processing the sustained-release injection are the same as those of the example 18, but the difference is that the used auxiliary material is poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], and the anticancer active ingredients are as follows: a combination of 5% of vandetanib, tipifarnib, sirolimus, lenalidomide or exatecan with 5-10% of dexamethasone, betamethasone or triamcinolone acetonide.

Example 20

70mg of poly (fumaric acid-sebacic acid) [ P (FA-SA) ] copolymer is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and uniformly mixed, 10mg of tipifarnib and 20mg of betamethasone are added, and after the mixture is uniformly shaken again, microspheres for injection containing 10% of tipifarnib and 20% of betamethasone are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The sustained-release implant has the drug release time of 20-25 days in-vitro physiological saline and the drug release time of about 25 days under the skin of a mouse.

Example 21

The procedure of processing into a sustained-release implant was the same as in example 20, except that the anticancer active ingredient contained therein was:

(a) 15% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan; or

(b) A combination of 10% of vandetanib, tipifarnib, sirolimus, lenalidomide or exatecan with 5% of methylprednisolone, clobetasol butyrate, hydrocortisone butyrate, dexamethasone, betamethasone or triamcinolone acetonide.

Example 22

60mg of p (BHET-EOP/TC) (50: 50) with the molecular weight peak value of 15000-35000 is placed into a container, 100 ml of dichloromethane is added, 20mg of sirolimus and 20mg of dexamethasone are added after the uniform dissolution, the mixture is shaken again and then spray drying is carried out to prepare the microspheres for injection containing 20% of sirolimus and 20% of dexamethasone. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 20-35 days in vitro physiological saline and 35-40 days under the skin of a mouse.

Example 23

The procedure of processing into sustained release implant was the same as in example 22, except that p (LAEG-EOP) (50: 50), which contains anticancer active ingredients:

(a) 15% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan; or

(b) A combination of 15% of vandetanib, tipifarnib, sirolimus, lenalidomide or exatecan with 5% of methylprednisolone, clobetasol butyrate, hydrocortisone butyrate, dexamethasone, betamethasone or triamcinolone acetonide.

Example 24.

80mg of p (DAPG-EOP) (50: 50) with a molecular weight peak of 15000-35000 was placed in a container, 100 ml of dichloromethane was added, after dissolving and mixing uniformly, 10mg of betamethasone and 10mg of lenalidomide were added, shaking again uniformly and vacuum-dried to remove the organic solvent. The dried drug-containing solid composition is frozen and crushed into micro powder containing 10 percent of betamethasone and 10 percent of lenalidomide, and then the micro powder is suspended in physiological saline containing 1.5 percent of sodium carboxymethylcellulose to prepare the corresponding suspension type sustained-release injection with the viscosity of 220cp-260cp (at the temperature of 25 ℃ -30 ℃). The slow release injection has the release time of 18-25 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.

Example 25

The steps of the method for processing the sustained-release injection are the same as the example 24, but the difference is that the used auxiliary material is p (BHDPT-EOP/TC), the anticancer active ingredients and the weight percentage thereof are as follows:

(a) 25% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan; or

(b) A combination of 20% of vandetanib, tipifarnib, sirolimus, lenalidomide or exatecan with 5% of methylprednisolone, dexamethasone, betamethasone or triamcinolone acetonide.

Example 26.

70mg of p (DAPG-EOP) (20: 80) with a molecular weight peak of 30000-50000 is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 15mg of irinotecan and 15mg of triamcinolone acetonide are added, shaking uniformly again and vacuum drying is carried out to remove the organic solvent. The dried drug-containing solid composition is frozen and crushed into micro powder containing 15 percent of ixotecan and 15 percent of triamcinolone acetonide, and then the micro powder is suspended in physiological saline containing 1.5 percent of sodium carboxymethylcellulose to prepare the corresponding suspension type sustained-release injection with the viscosity of 380cp-460cp (at the temperature of 25 ℃ -30 ℃). The slow release injection has the release time of 18-25 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.

Example 27.

The steps of the method for processing the sustained-release injection are the same as the example 26, but the difference is that the anticancer active ingredients and the weight percentage thereof are as follows:

(a) 35% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan; or

(b) A combination of 25% of vandetanib, tipifarnib, sirolimus, lenalidomide or exatecan with 15% of methylprednisolone, dexamethasone, betamethasone or triamcinolone acetonide.

Example 28

The procedure of processing into sustained release preparation is the same as that of examples 1-27, except that the sustained release excipient is one or a combination of the following:

a) polylactic acid (PLA) with a molecular weight peak of 10000-;

b) a copolymer (PLGA) of polyglycolic acid and glycolic acid, wherein the ratio of the polyglycolic acid to the glycolic acid is 50-95: 50-50, and the peak value of the molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;

c) PLGA and polifeprosan are copolymerized or mixed;

d) polifeprosan, p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) at a ratio of 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;

e) di-fatty acid and sebacic acid copolymer (PFAD-SA);

f) poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ];

g) poly (fumaric-sebacic acid) [ P (FA-SA) ];

h) xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin, poloxamer or albumin glue;

i) racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer;

j) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP)) or p (CHDM-EOP); or

k) p (DAPG-EOP) is copolymerized or mixed with sebacic acid.

In the combination, the total amount of different auxiliary materials is not more than 99 percent;

example 29

The procedure for preparing a sustained release injection is the same as in examples 1 to 28, except that the suspending agent used is one or a combination of the following:

a) 0.5-3.0% carboxymethylcellulose (sodium);

b) 5-15% mannitol;

c) 5-15% sorbitol;

d) 0.1-1.5% of surface active substances;

e) 0.1-0.5% tween 20.

Example 30

The procedure of processing into sustained release injection is the same as in examples 1 to 29, except that the anticancer active ingredient is:

(a) 2-40% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan; or

(b) 2-40% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan in combination with 0.01-20% of cortisone, hydrocortisone acetate, prednisone, prednisolone, methylprednisolone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, triamcinolone acetonide, mometasone furoate, fluocinolone acetonide, flumethasone pivalate, desomethasone valerate, betamethasone dipropionate, clobetasone, clobetamethasone, halomethasone, beclomethasone dipropionate, budesonide or fluticasone.

The above examples are intended to illustrate, but not limit, the application of the invention.

The invention is disclosed and claimed.

Claims (10)

1. The slow released preparation for resisting solid tumor features that the effective component of the slow released preparation is neovascular inhibitor or the combination of neovascular inhibitor and glucocorticoid, and the weight ratio of the glucocorticoid to the neovascular inhibitor in the slow released preparation is 1-19 to 1-1 to 1-19.

2. The sustained-release preparation according to claim 1, wherein the sustained-release preparation is a sustained-release injection or a sustained-release implant.

3. The sustained-release injection for treating solid tumor according to claim 1, wherein the sustained-release injection comprises:

(A) a sustained release microsphere comprising:

0.1-60% of anticancer active ingredient

Sustained release auxiliary materials 40-99.9%

0.0 to 30 percent of suspending agent

The above are weight percentages

And

(B) the solvent is common solvent or special solvent containing suspending agent.

Wherein,

the anticancer active component is a neovascular inhibitor or a combination of the neovascular inhibitor and glucocorticoid.

The slow release auxiliary material is selected from one or the combination of the following materials:

(1)PLA；

(2)PLGA；

(3) polifeprosan;

(4) PLGA and polifeprosan are copolymerized or mixed;

(5) polifeprosan and PLA mixture;

(6) xylitol, oligosaccharide, chondroitin, chitin, chitosan, poloxamer 188, poloxamer 407, hyaluronic acid, collagen, gelatin, poloxamer or albumin glue;

(7) racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer;

(8) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP); or

(9) p (DAPG-EOP) is copolymerized or mixed with sebacic acid.

In the combination, the total amount of different auxiliary materials is not more than 99 percent;

the suspending agent is selected from one or more of sodium carboxymethylcellulose, iodine glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80,

the viscosity of the suspending agent is 100cp-3000cp (at 20 ℃ -30 ℃).

4. The sustained-release agent for anti-solid tumor according to claim 1, wherein the angiogenesis inhibitor is selected from one of vandetanib, tipifarnib, sirolimus, lenalidomide, and irinotecan or the combination thereof.

5. The sustained-release agent for anti-solid tumor according to claim 1, wherein the glucocorticoid is selected from one or a combination of cortisone, hydrocortisone acetate, prednisone, prednisolone, methylprednisolone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, triamcinolone acetonide, mometasone furoate, fluocinolone acetonide, flumethasone pivalate, desometasone valerate, betamethasone dipropionate, clobetasone, beclomethasone, halometasone, beclomethasone dipropionate, budesonide, fluticasone.

6. The sustained-release preparation according to claim 1, wherein the sustained-release preparation comprises the following active anticancer components in percentage by weight:

(a) 2-40% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan; or

(b) 2-40% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan in combination with 0.01-20% of cortisone, hydrocortisone acetate, prednisone, prednisolone, methylprednisolone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, triamcinolone acetonide, mometasone furoate, fluocinolone acetonide, flumethasone pivalate, desomethasone valerate, betamethasone dipropionate, clobetasone, clobetamethasone, halomethasone, beclomethasone dipropionate, budesonide or fluticasone.

7. The sustained-release preparation according to claim 2, wherein the sustained-release excipient comprises

a) The peak value of the molecular weight of the polylactic acid is 10000-, 30000-, 300000-60000-, 60000-100000-or 100000-150000;

b) in the copolymer of polyglycolic acid and glycolic acid, the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50, and the peak value of molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;

c) in polifeprosan, the ratio of p-carboxyphenylpropane to sebacic acid is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40.

8. The sustained-release injection for treating solid tumor according to claim 2, wherein the suspending agent is one or a combination of the following:

a) 0.5-3.0% carboxymethylcellulose (sodium);

b) 5-15% mannitol;

c) 5-15% sorbitol;

d) 0.1-1.5% of surface active substances;

e) 0.1-0.5% tween 20;

f) (iodine) glycerol, dimethicone, propylene glycol or carbomer;

g) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;

h) 5-20% of mannitol and 0.1-0.5% of Tween 80; or

i)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.

9. The sustained-release anticancer implant according to claim 2, characterized in that the sustained-release excipients are selected from one or a combination of the following:

(1) 55-90% of PLA, and the peak value of molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;

(2) 50-90% of PLGA, the proportion of polyglycolic acid and glycolic acid is 50-95: 50-50, and the peak value of molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;

(3) 50-85% of polifeprosan, p-carboxyphenylpropane and sebacic acid are 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;

(4) 25-60% PLGA and 30-60% sebacic acid copolymerized or mixed;

(5) 30-60% of polifeprosan and 35-60% of PLA mixture;

(6) 40-95% of xylitol, oligosaccharide, chondroitin, chitin, chitosan, poloxamer 188, poloxamer 407, hyaluronic acid, collagen, gelatin, poloxamer or albumin glue; or

(7) 40-95% of racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycollic acid copolymer;

(8) 40-95% of p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP); or

(9) 30-65% of p (DAPG-EOP) and 40-70% of sebacic acid.

In the combination, the total amount of different auxiliary materials is not more than 99 percent;

the anticancer active components and the weight percentage are as follows:

(a) 2-40% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan; or

(b) 2-40% of vandetanib, tipifarnib, sirolimus, lenalidomide or ixatecan in combination with 0.01-20% of cortisone, hydrocortisone acetate, prednisone, prednisolone, methylprednisolone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, triamcinolone acetonide, mometasone furoate, fluocinolone acetonide, flumethasone pivalate, desomethasone valerate, betamethasone dipropionate, clobetasone, clobetamethasone, halomethasone, beclomethasone dipropionate, budesonide or fluticasone.

10. The sustained-release agent for treating solid tumor according to claim 1, wherein the solid tumor is primary or secondary cancer, sarcoma or carcinosarcoma derived from brain, central nervous system, kidney, liver, gallbladder, head and neck, oral cavity, thyroid, skin, mucosa, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, breast, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon or rectum of human or animal