CN101816777B - Novel Boanmycin composition and preparation method thereof - Google Patents

Abstract

The present invention relates to a novel boanmycin composition and a preparation method thereof. Specifically, the present invention relates to a boanmycin composition comprising: a therapeutically effective amount of boanmycin or a pharmaceutically acceptable salt thereof, a poloxamer, a gelling aid, water, and optionally Osmotic pressure regulator and/or pH regulator. The present invention also relates to a method for preparing the composition, a pharmaceutical preparation and a ready-to-use injection needle containing the composition, and the use of the composition in preparing a medicament for treating tumors and/or cancers. Excellent in vivo and/or in vitro behavior of the compositions of the invention.

Description

Novel boanmycin composition and its preparation method

technical field

The present invention relates to a novel composition, in particular to a novel boanmycin composition and a preparation method of the composition.

Background technique

Malignant tumor is a major disease that seriously threatens human life, and its incidence is increasing year by year both at home and abroad. In recent years, antineoplastic drugs have maintained a good momentum of rapid growth worldwide.

Boanmycin is a new anti-tumor antibiotic with independent intellectual property rights first developed by the Institute of Pharmaceutical Biotechnology, Chinese Academy of Medical Sciences. Its hydrochloride has been approved by the State Drug Administration in 2004, and has obtained a national first-class new drug Certificates and production approvals.

Boanmycin is produced by Streptomyces verticilus Var.Pingyangensis n.sp and belongs to the bleomycin family. Experimental studies have found that Boanmycin has a strong anti-tumor effect and a broad anti-tumor spectrum. In addition to being effective against head and neck cancer, squamous cell carcinoma, esophageal cancer, nasopharyngeal cancer, malignant lymphoma, breast cancer, and choriocarcinoma, it is also effective against It has a good curative effect on liver cancer and colon cancer with high incidence and no effective drugs, and its killing effect on liver cancer cells is stronger than that of doxorubicin (ADM) and mitomycin (MMC), and it can inhibit colon cancer HT-29 The rate was significantly higher than that of MMC and fluorouracil (5-FU). There are many routes of administration (intramuscular injection, intravenous injection, venous cannulation, etc.), no bone marrow suppression effect is seen, and the pulmonary toxicity is lower than that of other similar products.

There are many routes of administration of Boanmycin, such as intramuscular injection, intravenous injection, and intravenous catheterization. However, the results of clinical trials show that after intramuscular injection of boanmycin hydrochloride, the drug quickly enters the tissue, and the blood drug concentration can be measured within 5 minutes. The drug in the plasma is distributed in a two-compartment model, and t _1/2α is ( 14.036±4.409)min, t _1/2β is (39.160±5.599)min, the average plasma concentration reaches the peak at 18.6min after administration, the average concentration is 0.20μg/ml, and drops to zero after 4 hours (>0.01μg/ml ml), the drug has a short half-life and a fast clearance.

Therefore, there is still a need in the art for a new method to overcome the above-mentioned defects of boanmycin, especially a novel composition comprising ampomycin that can overcome the above-mentioned problems.

Contents of the invention

The object of the present invention is a boanmycin composition that can improve the release behavior of the drug in vitro and/or in vivo, especially can delay the release rate of the drug in vitro and/or in vivo, so that the half-life of the drug in the body can be prolonged, and the drug can be improved. curative effect and reduce adverse reactions.

The present inventors have surprisingly found that after making boanmycin and a specific gel material into a solution composition, the solution composition can coagulate in a specific temperature range, such as about at the temperature of the body temperature of the human body to form Gel, so that the drug can be released from the gel at a controlled rate, and then can overcome the problem of unsatisfactory behavior characteristics of the existing boanmycin preparations in vivo. The present invention has been accomplished based on the above findings.

Summary of the invention

The first aspect of the present invention provides a boanmycin composition, which comprises: a therapeutically effective amount of boanmycin or a pharmaceutically acceptable salt thereof, a poloxamer, a gelling aid, water, and optionally an osmotic pressure regulator agents and/or pH adjusters.

The boanmycin composition according to any one of the first aspect of the present invention, based on 100ml, contains 0.01-2.0g of boanmycin or a pharmaceutically acceptable salt thereof. In one embodiment, based on 100ml, the composition contains 0.02-1.8g, 0.04-1.6g, 0.05-1.5g, 0.05-1.2g, or 0.05-1.0g of boanmycin or its pharmaceutically acceptable Salt. In one embodiment, based on 100ml, the composition comprises 0.05-1.0g, 0.06-1.0g, 0.07-1.0g, 0.08-1.0g, 0.09-1.0g, or 0.1-1.0g of boanmycin or a pharmaceutically acceptable salt thereof. In one embodiment, based on 100ml, the composition contains 0.06-0.5g, 0.06-0.4g, 0.06-0.3g, 0.06-0.2g, or 0.08-0.2g of boanmycin or its pharmaceutically acceptable Salt.

According to any one of the first aspect of the present invention, the boanmycin composition contains 10-30 g of poloxamer in 100 ml. In one embodiment, based on 100 ml, the composition comprises 12-28 g, 13-27 g, 14-26 g, 15-25 g, or 18-23 g of poloxamer. In one embodiment, based on 100 ml, the composition comprises 10-28 g, 10-27 g, 10-26 g, or 10-25 g of poloxamer. In one embodiment, based on 100 ml, the composition comprises 12-30 g, 14-30 g, 16-30 g, or 18-30 g of poloxamer.

The boanmycin composition according to any one of the first aspect of the present invention contains 0.1-5.0 g of a gelling aid in 100 ml. In one embodiment, based on 100 ml, the composition contains 0.2-5.0 g, 0.3-5.0 g, 0.4-5.0 g, or 0.5-5.0 g of the gelling aid. In one embodiment, based on 100ml, the composition contains 0.2-4.5g, 0.2-4.0g, 0.2-3.5g, or 0.2-3.0g of the gelling aid. In one embodiment, based on 100ml, the composition contains 0.2-4.5g, 0.3-4.0g, 0.4-3.5g, 0.5-3.0g, or 0.5-2.5g of the gelling aid.

The boanmycin composition according to any one of the first aspect of the present invention contains 0-6.0 g of osmotic pressure regulator in 100 ml. In one embodiment, the amount of the osmotic pressure regulator can vary depending on the specific formulation and the specific osmotic pressure regulator used, but generally speaking, the amount is sufficient to make the final osmotic pressure of the composition in the human body. About 0.5-2 times the normal osmotic pressure.

The boanmycin composition according to any one of the first aspect of the present invention contains an appropriate amount of pH regulator in 100ml. In one embodiment, the amount of the pH adjusting agent used can vary depending on the specific formulation and the specific pH adjusting agent used, but generally speaking, the amount is sufficient to adjust the final pH value of the composition to pH 4- 9 (eg pH5-8, pH5.5-7.5, pH6-7.5).

The boanmycin composition according to any one of the first aspect of the present invention, in 100ml, comprises:

Boanmycin or its pharmaceutically acceptable salt 0.01～2.0g,

Poloxamer 10～30g,

Gelling auxiliary agent 0.1～5.0g,

Osmotic pressure regulator 0～6.0g,

pH regulators in appropriate quantities, and

Add water to 100ml.

The boanmycin composition according to any one of the first aspect of the present invention, in 100ml, comprises:

Boanmycin or its pharmaceutically acceptable salt 0.05～1.5g,

Poloxamer 12～28g,

Gelling auxiliary agent 0.2～4.5g,

Osmotic pressure regulator 0～6.0g,

pH regulators in appropriate quantities, and

Add water to 100ml.

The boanmycin composition according to any one of the first aspect of the present invention, in 100ml, comprises:

Boanmycin or its pharmaceutically acceptable salt 0.08～1.2g,

Poloxamer 15～25g,

Gelling auxiliary agent 0.3～4.0g,

Osmotic pressure regulator 0～6.0g,

pH regulators in appropriate quantities, and

Add water to 100ml.

The boanmycin composition according to any one of the first aspect of the present invention, in 100ml, comprises:

Boanmycin or its pharmaceutically acceptable salt 0.1～1.0g,

Poloxamer 18～23g,

Gelling auxiliary agent 0.5～3.0g,

Osmotic pressure regulator 0～6.0g,

pH regulators in appropriate quantities, and

Add water to 100ml.

According to the boanmycin composition according to any one of the first aspect of the present invention, wherein the pharmaceutically acceptable salt of boanmycin is selected from the group consisting of: boanmycin hydrochloride, boanmycin sulfate, boanmycin phosphate, Boanmycin tartrate and Boanmycin citrate, Boanmycin acetate, Boanmycin fumarate, Boanmycin maleate. In one embodiment, the pharmaceutically acceptable salt of boanmycin is boanmycin hydrochloride.

The boanmycin composition according to any one of the first aspect of the present invention, wherein the poloxamer is one or more poloxamers with a molecular weight ranging from 5,000 to 20,000. In one embodiment, the poloxamer is one or more molecular weight ranges of 5000-18000, 5000-15000, 5000-12000, 6000-20000, 8000-20000, 10000-20000, 12000-20000, 6000 ~18000, 7000~15000, or 8000~12000 poloxamers.

The boanmycin composition according to any one of the first aspect of the present invention, wherein the poloxamer is one or more poloxamers with a ratio of oxyethyl to oxypropyl ranging from (0.2 to 4): 1 sham. In one embodiment, the poloxamer is one or more oxyethyl to oxypropyl ratios in the range of (0.25-4):1, (0.5-4):1, (0.75-4): 1. (1~4): 1, (0.25~3.5): 1, (0.25~3.0): 1, (0.25~2.5): 1, (0.25~2): 1, (0.3~3.5): 1, (0.4-3.0):1, (0.5-2.5):1, (0.5-2):1, or (0.5-1.5):1 poloxamer.

According to the boanmycin composition according to any one of the first aspect of the present invention, wherein the poloxamer is one or more poloxamers selected from the following models: poloxamer P407 (ie F127), Poloxamer P188 (ie F68). In one embodiment, the poloxamer is poloxamer P407 (ie F127), poloxamer P188 (ie F68), or a combination of the two in any ratio. In one embodiment, the poloxamer is a combination of poloxamer P188 (ie F68) and poloxamer P407 (ie F127) in a ratio (0.01-0.5):1. In one embodiment, the poloxamer is (0.015～0.4):1, (0.02～0.2):1, ( 0.02-0.15):1, (0.02-0.1):1, or (0.025-0.1):1 ratio combination.

According to the boanmycin composition according to any one of the first aspect of the present invention, wherein the gelling aid is one or more substances selected from the group consisting of propylene glycol, glycerin, polyethylene glycol, polyvinylpyrrolidone, polyvinylpyrrolidone, Vinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, sodium alginate and its derivatives, acacia gum, tragacanth gum, guar gum, carba Pom, lectin, hyaluronic acid, xanthan gum, chitosan, dextrin and derivatives. In one embodiment, the gelling aid is one or more substances selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, propylene glycol, polyethylene glycol. In one embodiment, the hydroxypropyl methylcellulose is selected from: HPMC K4M, E4M, F4M, R15M. In one embodiment, the polyethylene glycol is PEG with a molecular weight of 200-600. In one embodiment, the polyethylene glycol is selected from: PEG200, PEG300, PEG400, PEG600, PEG4000, PEG4000.

The boanmycin composition according to any one of the first aspect of the present invention, wherein the boanmycin or a pharmaceutically acceptable salt thereof is boanmycin hydrochloride, and the poloxamer is poloxamer P407 ( i.e. F127), poloxamer P188 (i.e. F68), or a combination of the two in any proportion, the gelling aid is one or more substances selected from the following: hydroxypropylmethylcellulose, methyl Cellulose, Propylene Glycol, Polyethylene Glycol.

In a particularly preferred embodiment of the boanmycin composition according to any one of the first aspect of the present invention, 100ml contains 17-23g of poloxamer P407 and 0-3g of poloxamer P188 .

In a particularly preferred embodiment of the boanmycin composition according to any one of the first aspect of the present invention, in 100ml, it contains: 0.1-1.0 g of boanmycin or a pharmaceutically acceptable salt thereof, 17- 23g of poloxamer P407, 0-3g of poloxamer P188, 0.5-3.0g of gelling aid, 0-6.0g of osmotic pressure regulator, appropriate amount of pH regulator, and water added to 100ml .

The boanmycin composition according to any one of the first aspect of the present invention, wherein the osmotic pressure regulator is one or more substances selected from the following: mannitol, sorbitol, sodium chloride, and glucose.

The boanmycin composition according to any one of the first aspect of the present invention, wherein the pH regulator is one or more substances selected from the group consisting of hydrochloric acid, sodium hydroxide, phosphoric acid and its salts, acetic acid and its salts , citric acid and its salts, boric acid and its salts, and their aqueous solutions.

The boanmycin composition according to any one of the first aspect of the present invention is an injectable pharmaceutical composition. In one embodiment, the composition is a composition that can be injected intramuscularly, intramuscularly, subcutaneously, or into tumors.

The boanmycin composition according to any one of the first aspect of the present invention, which is a transparent or substantially transparent, flowable liquid at 25±0.5°C, and which is gel-like at 37±0.5°C semi-solid.

The boanmycin composition according to any one of the first aspect of the present invention, which comprises the prescription composition of the embodiment of the present invention.

The second aspect of the present invention provides a method for preparing any one of the compositions of the first aspect of the present invention, comprising the following steps:

i) Weigh the gelling aid, add an appropriate amount of water, and stir fully to dissolve all;

ii) Weighing the poloxamer, adding it to the solution in step i), stirring and/or standing to dissolve it completely;

iii) dissolving boanmycin or its pharmaceutically acceptable salt, and an optional osmotic pressure regulator in an appropriate amount of water, stirring to dissolve, and filtering through a 0.45 μm microporous membrane;

iv) Combine the filtrate of step iii) with the solution of step ii), adjust the pH value of the solution to 5.5-8.5 with a pH regulator, add water to the full amount, stir evenly, and let stand to obtain a transparent or basically transparent liquid, namely .

The third aspect of the present invention provides a pharmaceutical preparation of boanmycin, which comprises the composition described in any one of the first aspect of the present invention, and optionally a pharmaceutically acceptable carrier or excipient. In one embodiment, the pharmaceutically acceptable carrier or excipient may be water for injection, sodium chloride injection, glucose injection and the like. In one embodiment, the pharmaceutical formulation is an injection.

The fourth aspect of the present invention provides a ready-to-use injection needle for boanmycin, which comprises a syringe containing a needle, and the composition according to any one of the first aspect of the present invention stored in the syringe. In one embodiment, the ready-to-use injectable needle is kept sterile. In one embodiment, the ready-to-use injectable needle comprises a single dose of boanmycin or a pharmaceutically acceptable salt thereof.

The fifth aspect of the present invention provides the use of the composition described in any one of the first aspect of the present invention in the preparation of a drug for treating tumor and/or cancer. In one embodiment, the tumor and/or cancer is a tumor and/or cancer treatable by boanmycin or a pharmaceutically acceptable salt thereof. In one embodiment, the tumor and/or cancer is selected from head and neck cancer, squamous cell carcinoma, esophageal cancer, nasopharyngeal cancer, malignant lymphoma, breast cancer, choriocarcinoma, liver cancer, and colon cancer.

The sixth aspect of the present invention provides a method for treating tumor and/or cancer, which comprises administering a therapeutically effective amount of the composition of any one of the first aspect of the present invention to a subject. In one embodiment, the tumor and/or cancer is a tumor and/or cancer treatable by boanmycin or a pharmaceutically acceptable salt thereof. In one embodiment, the tumor and/or cancer is selected from head and neck cancer, squamous cell carcinoma, esophageal cancer, nasopharyngeal cancer, malignant lymphoma, breast cancer, choriocarcinoma, liver cancer, and colon cancer.

The seventh aspect of the present invention provides a composition useful for treating tumors and/or cancers, and the composition has the characteristics of any one of the compositions in the first aspect of the present invention. In one embodiment, the tumor and/or cancer is a tumor and/or cancer treatable by boanmycin or a pharmaceutically acceptable salt thereof. In one embodiment, the tumor and/or cancer is selected from head and neck cancer, squamous cell carcinoma, esophageal cancer, nasopharyngeal cancer, malignant lymphoma, breast cancer, choriocarcinoma, liver cancer, and colon cancer.

Any aspect of the present invention or any feature of any one aspect of the present invention is also applicable to any other aspect or any one of the other aspects. In the present invention, for example, when referring to "any one of the first aspect of the present invention", the "any one" refers to any sub-aspect of the first aspect of the present invention, and when other aspects are mentioned in a similar manner, it also refers to have the same meaning.

Detailed description of the invention:

Various aspects and features of the present invention are further described below.

All the documents cited in the present invention are incorporated herein by reference in their entirety, and if the meaning expressed in these documents is inconsistent with the present invention, the expression of the present invention shall prevail. In addition, various terms and phrases used in the present invention have common meanings known to those skilled in the art. Even so, the present invention still hopes to make a more detailed description and explanation of these terms and phrases here. The terms and phrases mentioned are as follows: If there is any inconsistency with the known meaning, the meaning expressed in the present invention shall prevail.

In the context of this article, when referring to the percentage (%) of a substance, unless otherwise specified, it refers to the percentage of a certain substance in a certain system. Where the system is liquid, the percentage (%) may be a weight/volume (w/v) percentage (preferred for solutes that are solid) or a volume/volume (w/v) percentage (for solutes that are liquid is preferred). For the case where the system is solid, the percentage (%) is preferably a weight/weight (w/w) percentage.

As far as the compositions of the present invention are concerned, it is preferred that "percentage (%)" in the present invention refers to weight/volume (w/v) percentages, and in a specific composition embodiment of the present invention, The sum of the weight/volume percentages of the active ingredient and each auxiliary material is equal to 100%; or it is balanced with one of the basic excipients, for example, according to the total composition of the prescription, a basic excipient such as water is used during preparation (such as injection Balanced with water) (for example by adding the water to the full weight or full volume of the theoretical prescription).

As used herein, the term "pharmaceutically acceptable salt" generally refers to a physiologically acceptable salt.

As used herein, the term "gelation aid" refers to a substance or agent capable of adjusting gelation temperature, improving gelation strength, and regulating drug release. The present invention has surprisingly found that, for the active ingredient boanmycin of the present invention or a pharmaceutically acceptable salt thereof, when used in conjunction with the gelling aid of the present invention, the solution containing poloxamer is less than It is a transparent or substantially transparent, flowable liquid at human body temperature (for example, 0 to 30°C); it is a gelatinous semi-solid at a temperature near human body temperature (for example, 37±7°C), and At this time, it has a certain gel strength and sustained release effect. The composition of the present invention becomes a kind of sustained-release, temperature-sensitive, injectable gel, especially an in-situ gel.

As used herein, the term "water" generally refers to water for injection when preparing the composition of the present invention, especially the injectable composition.

As used herein, the terms "comprising", "comprising", etc., refer to an open meaning. For example, "comprising" used when describing the composition of the composition of the present invention means that other unlisted substances may be contained in addition to the listed substances. For example, the composition of the present invention may further contain a bacteriostat or a preservative.

In this article, when referring to "contains 0.01-2.0 g of Boanmycin or its pharmaceutically acceptable salt", the amount of 0.01-2.0 g can be calculated as Boanmycin free base or its salt . Usually it can be calculated as boanmycin free base.

In this article, when "water is added to 100ml", it means that water is used as the base solvent, that is, water is added to the entire amount of the composition, or water is added to the final volume for balance adjustment.

As used herein, the term "ready-to-use injection needle" refers to an injection needle comprising a needle and a syringe ready for use without dispensing, the barrel of which has been pre-filled with a certain dose of the first aspect of the present invention. combination.

As used herein, the term "composition" may be used interchangeably with "pharmaceutical composition" and both may have the same meaning.

The composition provided by the invention can be used as an in-situ gel. The so-called in situ gel (in situ gel) refers to a class of preparations that can undergo a phase transition at the site of administration immediately after administration in a solution state, and form a non-chemically cross-linked semi-solid gel from a liquid state. The formation mechanism is to use the response of polymer materials to external stimuli (such as temperature, ionic strength or pH, etc.), so that the polymer undergoes a reversible change in the dispersed state or conformation under physiological conditions, and completes the transformation from the solution state to the semi-solid gel state. phase inversion. This in situ gel prepared from water-soluble polymer materials has a highly hydrophilic three-dimensional network structure, good tissue compatibility, bioadhesion, and unique solution-semi-solid gel transition properties. It has the advantages of simple process, convenient application, long residence time at the drug site (such as injection site, nasal mucosa, oral mucosa, eye mucosa, rectal mucosa and vaginal mucosa, etc.), and good sustained-release effect.

In situ gel preparation for injection is a new research hotspot in the field of sustained and controlled release injections in recent years. It dissolves drugs and polymers in a suitable solvent and injects them locally. At the administration site, the polymer solidifies under physiological conditions. And form a gel-type semi-solid drug depot. The in situ gel overcomes the disadvantages of common emulsions, liposomes, microspheres and micelles, and can be used for local administration of lesions, prolonging the release period, reducing dosage and adverse drug reactions, and avoiding surgery on implants Pain during implantation, relatively simple process and other advantages.

Boanmycin is prepared into an in situ gel preparation for injection. Compared with the common injection of the drug, it has the advantages of common injections, good fluidity, and convenient use. After being injected into the human body, it is affected by the temperature of the human body. Solidification to form a gel-type semi-solid drug storage can prolong the drug release period, reduce the dosage, reduce production costs, enhance patient compliance, improve the therapeutic effect on tumors, and at the same time broaden the clinical indications of the drug.

Poloxamer is a temperature-sensitive gel material, which is a block copolymer (ABA) composed of polyethylene oxide PEO (A) structural units and polypropylene oxide PPO (B) structural units. type), and can form a thermoreversible gel after reaching a certain concentration. The mechanism of poloxamer solution gelation is related to the cross-linking mode of micelles. When the temperature exceeds the critical micelle temperature, the dehydration of PPO chains leads to the formation of micelles. As the temperature increases, the micellization is more important. , when a certain temperature is reached, the micelles contact each other and stop moving. Therefore, the encapsulation and entanglement among micelles may be the main reason for the gel formation of poloxamer solution with increasing temperature. Poloxamer formulations generally increase the residence time of the drug at the site of application, thereby improving bioavailability and efficacy.

In the initial research, the inventors found that, in the composition of the present invention, if poloxamer is used alone without using auxiliary gelling agent simultaneously, the mechanical strength of gelation will easily appear during gelation. Poor, rapid erosion (ie dissolution from the surface), abiotic degradation of the PEO-PPO-PEO chains. Surprisingly, by combining auxiliary gelling agents with poloxamers, an in situ gel system with excellent performance can be formed, and since the various excipients in the composition are absorbable or biodegradable , which makes it possible for the in situ gel system to be administered by injection. Thus, the in situ gel composition containing boanmycin obtained by the present invention can effectively prolong the release time of the drug, thereby prolonging the residence time of the drug in the body, improving the bioavailability, and improving the curative effect, overcoming the existing boanmycin Shortcomings of injections in vivo retention time.

Therefore, in one aspect, the present invention provides an in vivo drug delivery system of boanmycin, i.e. in-situ gel formulation, specifically, the present invention provides an antitumor antibiotic boanmycin or its equivalent A temperature-sensitive in-situ gel formulation for injection of pharmaceutically acceptable salts such as hydrochloride and a preparation method thereof.

In one embodiment, the composition provided by the present invention is a temperature-sensitive in-situ gel preparation for boanmycin hydrochloride injection, which comprises: 0.01-2.0% boanmycin hydrochloride, 10-30% poloxamer, 0.1-5.0% gelling aid, 0-6.0% osmotic pressure regulator, appropriate amount of pH regulator, and water for injection added to 100%.

In one embodiment, in the composition provided by the present invention, the molecular weight of the poloxamer ranges from 5000 to 20000, and the ratio of oxyethyl to oxypropyl ranges from 4:1 to 1:4.

In one embodiment, in the composition provided by the present invention, the poloxamer is poloxamer P407, poloxamer P188, or a mixture of the two.

In one embodiment, in the composition provided by the invention, the gelling aid is propylene glycol, glycerin, polyethylene glycol (PEG), polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl methylcellulose ( HPMC), hydroxypropyl cellulose, methyl cellulose (MC), carboxymethyl cellulose, sodium alginate and its derivatives, acacia gum, tragacanth gum, guar gum, carbomer, plant agglutinate Xanthan gum, hyaluronic acid, chitosan, dextrin and derivatives, one or a mixture of several.

In one embodiment, in the composition provided by the present invention, the gelling aid is preferably hydroxypropylmethylcellulose, methylcellulose, propylene glycol, polyethylene glycol.

In one embodiment, in the composition provided by the present invention, the osmotic pressure regulator is any one of mannitol, sorbitol, sodium chloride, or glucose.

In one embodiment, in the composition provided by the present invention, the pH regulator is hydrochloric acid, sodium hydroxide, phosphoric acid and its salts, acetic acid and its salts, citric acid and its salts, boric acid and its salts, or their mixtures.

In one embodiment, the composition provided by the present invention is prepared by a method comprising the following steps: weighing the gelling aid in proportion, adding water for injection, fully stirring, and standing until it is completely dissolved; Add loxamer to the above solution, stir to dissolve part of it, and place it in the refrigerator until it is completely dissolved; dissolve boanmycin hydrochloride and osmotic pressure regulator in water for injection, stir to dissolve, and Filter through a microporous membrane, combine the filtrate with the above solution, adjust the pH value of the solution to 5.5-8.5 with a pH regulator, add water for injection to the full amount, stir evenly, and stand still to obtain a transparent or nearly transparent gel liquid.

In one embodiment, the composition provided by the present invention is a transparent or near-transparent liquid at room temperature (about 25°C, <30°C) and has a certain fluidity. Gel-type semi-solid.

The invention provides an in situ gel preparation for boanmycin hydrochloride injection, which forms a dual system through the combined use of a heat-sensitive gel matrix poloxamer and a suitable polymer material, and adjusts its phase transition temperature at 30-30 After being injected into the human body or directly into the tumor site at a temperature of 37°C, Boanmycin or its pharmaceutically acceptable salts such as hydrochloride can be released slowly, prolonging the half-life, improving bioavailability and reducing side effects.

The present invention also provides a preparation method of the composition of boanmycin or its pharmaceutically acceptable salt such as hydrochloride, that is, the in situ gel preparation for injection.

In one embodiment, the in situ gel for injection of the composition of boanmycin or its pharmaceutically acceptable salt such as hydrochloride of the present invention comprises: 0.01-2.0% boanmycin hydrochloride, 10-30% Poloxamer, 0.1-5.0% gelling aid, 0-6.0% osmotic pressure regulator, appropriate amount of pH regulator, and water added to 100%.

In one embodiment, the boanmycin composition of the present invention is a transparent or substantially transparent, flowable liquid after it is placed at 25±0.5°C for 10 minutes or 20 minutes, or after it is fully equilibrated; and After standing at 37±0.5°C for 10min or 20min, or after fully equilibrating, it becomes a gel-like semi-solid; when the temperature is lowered, it can return from the gel state to the solution state, and this process is reversible.

In one embodiment, the composition of Boanmycin or its pharmaceutically acceptable salt such as hydrochloride of the present invention is an in situ gel for injection, wherein the porol used in the composition of the present invention as a thermosensitive gel matrix The molecular weight range of shamer is 5000～20000, the ratio range of oxyethyl group to oxypropyl group is 4:1～1:4, preferably poloxamer P407 (ie F127), poloxamer P188 (ie F68) , or a mixture of the two in certain proportions.

In one embodiment, the composition of boanmycin or its pharmaceutically acceptable salt such as hydrochloride of the present invention is an in-situ gel for injection, in order to adjust the release rate of the drug, prolong the action time of the drug, and improve the gel system The rheological properties, the gel has added no more than 5% gelling aids, such as propylene glycol, glycerin, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl Cellulose, methylcellulose, carboxymethylcellulose, sodium alginate and its derivatives, acacia gum, tragacanth gum, guar gum, carbomer, plant lectin, hyaluronic acid, xanthan gum , chitosan, dextrin and derivatives, etc., one or a mixture of several. The present inventors found that the use of hydroxypropylmethylcellulose, methylcellulose, propylene glycol, polyethylene glycol, etc. is a preferred gelling aid.

In one embodiment, the osmotic pressure regulator of the present invention is any one of mannitol, sorbitol, sodium chloride, and glucose.

In one embodiment, the pH regulator of the present invention is hydrochloric acid, sodium hydroxide, phosphoric acid and salts thereof, acetic acid and salts thereof, citric acid and salts thereof, boric acid and salts thereof, or mixtures thereof, and these Aqueous solutions of substances.

In one embodiment, the composition of boanmycin or its pharmaceutically acceptable salt such as hydrochloride of the present invention is an in situ gel for injection, and its preparation method may include the following steps:

(1) Weigh the gelling aid in proportion, add water for injection, fully stir, and place until completely dissolved;

(2) Weigh the poloxamer in proportion again, add it to the solution (1), stir to partially dissolve it, and place it in the refrigerator until it is completely dissolved;

(3) dissolving boanmycin or its salt and osmotic pressure regulator in water for injection, stirring to dissolve, filtering through a 0.45 μm microporous membrane, merging the filtrate with the solution (2), and stirring evenly;

(4) Use a pH regulator to adjust the pH of the solution to 5.5-8.5, add water for injection to the full amount, stir evenly, and let stand to obtain a transparent or nearly transparent gel solution.

The boanmycin hydrochloride in situ gel for injection prepared by the present invention has a suitable phase transition temperature, is in a liquid state at room temperature, is convenient for injection administration in the form of a solution, and is easy to accurately control dosage, and has the advantages of ordinary injections , good fluidity, easy to use, can be injected into the local part of the human body or directly into the tumor site, affected by the temperature of the human body, when the temperature rises to close to body temperature, it will transform into a gel, forming a gel-type semi-solid drug storage, and Compared with ordinary injections of the drug, it can significantly prolong the release cycle, reduce adverse reactions, reduce dosage, reduce production costs, enhance patient compliance, improve the therapeutic effect on tumors, and broaden the clinical indications of the drug.

The composition of the present invention is particularly suitable for use by injection such as intramuscular injection or intratumoral injection. For the dosage of the composition of the present invention, reference can be made to the dosage of the existing Boanmycin injection, but preferably the dosage can be appropriately reduced or the dosing interval can be extended, which is quite advantageous for the composition of the present invention. Of course, the specific dose range depends on factors such as the size of the patient, the severity of the condition, the route of administration, and the judgment of the doctor. Generally speaking, in the preparation of a unit dose of the present invention, the amount of boanmycin or its salt can be contained in the range of 0.1-100 mg, 0.5-80 mg, 1-50 mg, or 1-25 mg, etc.

Description of drawings

Figure 1 shows the gelation temperature of different concentrations of poloxamer P407

Figure 2 shows the temperature-viscosity curves for different formulations

Figure 3 shows the texture properties of gels with different formulations

Figure 4 shows the SEM images of different formulations

Figure 5 shows the release profile of the dialysis bag drug

Figure 6 shows the drug release and gel erosion curves of the filmless release method (prescription 20% P407+1.2% P188+0.3% HPMC), n=3.

Detailed ways

The present invention can be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art can understand that various changes and modifications can be made in the present invention without departing from the spirit and scope of the present invention.

The present invention provides general and/or specific descriptions of the materials and test methods used in the tests. While many of the materials and methods of manipulation which are employed for the purposes of the invention are well known in the art, the invention has been described here in as much detail as possible. In the following test examples, if not specifically stated, the described Boanmycin refers to its hydrochloride. Of course, under the same test conditions, other salt forms are also expected to obtain similar results, which is easy for those skilled in the art. understand.

Example part

Embodiment 1: Composition of the present invention-P407/P188/propylene glycol in situ gel system

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.1g

P407 20g

P188 0.5g

Propylene glycol 2g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

According to the prescription, weigh propylene glycol, add an appropriate amount of water for injection, stir well to make the mixture uniform, and use it as solution I; weigh P407 and P188 and add it to solution I, stir to dissolve part of it, and place it in the refrigerator overnight until completely dissolved , as solution II; weigh boanmycin hydrochloride in an appropriate amount of water for injection, stir to dissolve it, filter through a 0.45 μm microporous membrane, combine the filtrate with solution II, and use 1mol/L sodium hydroxide solution and/or 1mol/L phosphoric acid solution to adjust the pH value to 7.4, add water for injection to the full amount, stir evenly, and obtain.

Embodiment 2: Composition of the present invention-P407/P188/propylene glycol/HPMC in situ gel system system

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.1g

P407 20g

P188 0.8g

Propylene glycol 2g

HPMC K4M 0.3g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

According to the prescription, weigh propylene glycol and HPMC, add an appropriate amount of water for injection, stir well, place until completely dissolved, and use it as solution I; weigh P407 and P188 and add them to solution I, stir to partially dissolve, and place in the refrigerator overnight , until completely dissolved, as solution II; weigh boanmycin hydrochloride in an appropriate amount of water for injection, stir to dissolve it, filter through a 0.45 μm microporous membrane, combine the filtrate with solution II, and add 1mol/L sodium hydroxide solution and (or) 1mol/L phosphoric acid solution to adjust the pH value to 7.4, add water for injection to the full amount, stir evenly, and obtain.

Embodiment 3: Composition of the present invention-P407/P188/HPMC in situ gel system

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.1g

P407 20g

P188 1.2g

HPMC K4M 0.3g

Sodium chloride 0.9g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

According to the prescription, weigh HPMC, add an appropriate amount of water for injection, stir well, place it until it is completely dissolved, and use it as solution I; weigh P407 and P188 and add it to solution I, stir to dissolve part of it, and place it in the refrigerator overnight. Dissolve them all as solution II; weigh boanmycin hydrochloride and sodium chloride in an appropriate amount of water for injection, stir to dissolve, filter through a 0.45 μm microporous membrane, combine the filtrate with solution II, and add 1mol/L hydrogen Sodium oxide solution and (or) 1mol/L phosphoric acid solution to adjust the pH value to 7.4, add water for injection to the full amount, and stir evenly to obtain.

Embodiment 4: Composition of the present invention-P407/P188/PEG in situ gel system

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.1g

P407 20g

P188 0.5g

PEG400 1.0g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

According to the prescription, weigh PEG400, add an appropriate amount of water for injection, stir well to make the mixture uniform, and use it as solution I; weigh P407 and P188 and add them to solution I, stir to dissolve part of it, and place it in the refrigerator overnight until completely dissolved , as solution II; take boanmycin hydrochloride in an appropriate amount of water for injection, stir to dissolve it, filter through a 0.45 μm microporous membrane, combine the filtrate with solution II, and use 1mol/L sodium hydroxide solution and (or ) 1mol/L phosphoric acid solution to adjust the pH value to 7.4, add water for injection to the full amount, stir evenly, and obtain.

Embodiment 5: Composition of the present invention-P407/P188/PEG/MC in situ gel system

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.1g

P407 20g

P188 2.0g

PEG400 2.0g

Methylcellulose 0.5g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

According to the prescription, weigh PEG400 and methyl cellulose (MC), add an appropriate amount of water for injection, fully stir, place until completely dissolved, and use it as solution I; weigh P407 and P188 and add them to solution I, stir to partially dissolve, and then Put it in the refrigerator overnight until it is completely dissolved, and use it as solution II; weigh boanmycin hydrochloride in an appropriate amount of water for injection, stir to dissolve, filter through a 0.45 μm microporous membrane, combine the filtrate with solution II, and use 1mol/L sodium hydroxide solution and (or) 1mol/L phosphoric acid solution to adjust the pH value to 7.4, add water for injection to the full amount, and stir evenly to obtain the product.

Embodiment 6: Composition of the present invention-P407/P188/PEG/HPMC in situ gel system

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.1g

P407 20g

P188 1.5g

PEG400 0.5g

HPMC F4M 1.0g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

According to the prescription, weigh PEG400 and HPMC, add an appropriate amount of water for injection, stir well, place until completely dissolved, and use it as solution I; weigh P407 and P188 and add them to solution I, stir to partially dissolve, and place in the refrigerator overnight , until completely dissolved, as solution II; weigh boanmycin hydrochloride in an appropriate amount of water for injection, stir to dissolve it, filter through a 0.45 μm microporous membrane, combine the filtrate with solution II, and add 1mol/L sodium hydroxide solution and (or) 1mol/L phosphoric acid solution to adjust the pH value to 7.4, add water for injection to the full amount, stir evenly, and obtain.

Embodiment 7: Composition of the present invention-P407/PEG/HPMC in situ gel system

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.1g

P407 20g

PEG400 2.0g

HPMC R15M 1.5g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

According to the prescription, weigh PEG400 and HPMC, add an appropriate amount of water for injection, stir fully, place until completely dissolved, and use it as solution I; weigh P407 and add it to solution I, stir to dissolve part of it, and place it in the refrigerator overnight. All dissolved as solution II; take boanmycin hydrochloride in an appropriate amount of water for injection, stir to dissolve it, filter through a 0.45 μm microporous membrane, combine the filtrate with solution II, and use 1mol/L sodium hydroxide and ( Or) adjust the pH value to 7.4 with 1mol/L phosphoric acid solution, add water for injection to the full amount, and stir evenly to obtain.

Example 8: Compositions of the invention

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.1g

P407 20g

P188 1.5g

HPMC K4M 0.5g

NaCl 0.9g

1mol/L NaOH and/or phosphoric acid Appropriate amount

Water for injection up to 100ml

The preparation process is the same as in Example 3.

Example 9: Compositions of the invention

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.1g

P407 20g

P188 2.0g

HPMC K4M 0.8g

NaCl 0.9g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

The preparation process is the same as in Example 3.

Example 10: Compositions of the invention

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.05g

P407 18g

Propylene glycol 1.0g

MC 2.5g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

According to the prescription, weigh MC, add an appropriate amount of water for injection to propylene glycol, stir well, place it until it is completely dissolved, and use it as solution I; weigh P407 and add it to solution I, stir to dissolve part of it, and place it in the refrigerator overnight to completely dissolve Dissolve as solution II; take boanmycin hydrochloride in an appropriate amount of water for injection, stir to dissolve it, filter through a 0.45 μm microporous membrane, combine the filtrate with solution II, and use 1mol/L sodium hydroxide solution and ( Or) adjust the pH value to 7.4 with 1mol/L phosphoric acid solution, add water for injection to the full amount, and stir evenly to obtain.

Example 11: Compositions of the Invention

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.05g

P407 15g

MC 3.5g

Sodium chloride 0.9g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

According to the prescription, weigh MC, add an appropriate amount of water for injection, stir well, place it until it is completely dissolved, and use it as solution I; weigh P407 and add it to solution I, stir to dissolve part of it, and place it in the refrigerator overnight until it is completely dissolved , as solution II; weigh boanmycin hydrochloride and sodium chloride in an appropriate amount of water for injection, stir to dissolve them, filter through a 0.45 μm microporous membrane, combine the filtrate with solution II, and use 1mol/L sodium hydroxide solution and (or) 1mol/L phosphoric acid solution to adjust the pH value to 7.4, add water for injection to the full amount, stir evenly, and obtain.

Example 12: Compositions of the Invention

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.03g

P407 12g

Gum Arabic 1.0g

Xanthan gum 3.0g

Sodium chloride 0.9g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

According to the prescription, weigh Arabic gum and xanthan gum, add an appropriate amount of water for injection, stir fully, place until completely dissolved, and use it as solution I; weigh P407 and add it to solution I, stir to partially dissolve, and place in the refrigerator Overnight, until completely dissolved, as solution II; weigh boanmycin hydrochloride and sodium chloride in an appropriate amount of water for injection, stir to dissolve, filter through a 0.45 μm microporous membrane, combine the filtrate with solution II, and use 1mol /L sodium hydroxide solution and (or) 1mol/L phosphoric acid solution to adjust the pH value to 7.4, add water for injection to the full amount, and stir evenly to obtain.

Example 13: Compositions of the Invention

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.01g

P407 10g

Xanthan gum 5.0g

Glucose 5.0g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

According to the prescription, weigh xanthan gum, add an appropriate amount of water for injection, stir fully, place until it is completely dissolved, and use it as solution I; weigh P407 and add it to solution I, stir to dissolve part of it, and place it in the refrigerator overnight. Dissolve them all as solution II; weigh boanmycin hydrochloride and glucose in an appropriate amount of water for injection, stir to dissolve them, filter through a 0.45 μm microporous membrane, combine the filtrate with solution II, and dissolve with 1mol/L sodium hydroxide solution and (or) 1mol/L phosphoric acid solution to adjust the pH value to 7.4, add water for injection to the full amount, stir evenly, and obtain.

Example 14: Compositions of the Invention

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 0.5g

P407 22g

P188 2.0g

HPMC E4M 0.2g

Glucose 5.0g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

According to the prescription, weigh HPMC K4M, add an appropriate amount of water for injection, fully stir, place until it is completely dissolved, and use it as solution I; weigh P407 and P188 and add them to solution I, stir to partially dissolve, and place in the refrigerator overnight. until completely dissolved, as solution II; weigh boanmycin hydrochloride and glucose in an appropriate amount of water for injection, stir to dissolve, filter through a 0.45 μm microporous membrane, combine the filtrate with solution II, and oxidize with 1mol/L hydrogen Sodium solution and (or) 1mol/L phosphoric acid solution to adjust the pH value to 7.4, add water for injection to the full amount, and stir evenly to obtain.

Example 15: Compositions of the Invention

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 1.0g

P407 25g

P188 5g

HPMC K4M 0.1g

Glucose 5g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

The preparation process is the same as in Example 14

Example 16: Compositions of the Invention

Composition prescription (according to 100ml):

Boanmycin Hydrochloride 1.5g

P407 28g

P188 2.0g

Gum Arabic 3.0g

Glucose 5.0g

Appropriate amount of 1mol/L NaOH and/or phosphoric acid

Water for injection up to 100ml

According to the prescription, take gum arabic, add an appropriate amount of water for injection, fully stir, place until it is completely dissolved, and use it as solution I; weigh P407 and P188 and add them to solution I, stir to partially dissolve, and place in the refrigerator overnight. until completely dissolved, as solution II; weigh boanmycin hydrochloride and glucose in an appropriate amount of water for injection, stir to dissolve, filter through a 0.45 μm microporous membrane, combine the filtrate with solution II, and oxidize with 1mol/L hydrogen Sodium solution and (or) 1mol/L phosphoric acid solution to adjust the pH value to 7.4, add water for injection to the full amount, and stir evenly to obtain.

Test case part

The following test examples are used to investigate various properties of in-situ gels, such as gelation temperature, rheological properties, gelation texture properties, electron microscope scanning, drug release properties, etc., and the system can be optimized and screened for optimization based on the above indicators. prescription.

Test Example 1. Determination of phase transition temperature of in-situ gel.

Take 10ml of the gel sample and a small rotor (1.5cm×0.6cm) into a small beaker, place the small beaker in a cold water bath, immerse the end of the thermometer in the solution, turn on the electromagnetic stirring at 100 rpm, and the temperature rise rate of the water bath is about 0.5 °C/min. The temperature at which the magnetic stirrer completely stops rotating is the gelation temperature, and each solution is measured in parallel three times, and the average value is taken. A series of concentrations of P407 solutions (see Table 1) were prepared, and the gelation temperature was measured. The results are shown in Figure 1.

It can be seen from Figure 1 that the gelation temperature of P407 in situ gel is concentration-dependent. The lower concentration of P407 solution did not gel when the temperature was raised to 40°C, but the 19% P407 solution began to gel at about 32°C, and the gelation temperature gradually decreased with the increase of P407 concentration. Usually a higher concentration of P407 is used to prepare in situ gels to ensure that they are sensitive to temperature changes, but the gelation temperature at high concentrations is low, which brings problems and difficulties to the preparation, storage and use of in situ gels. Therefore, other excipients need to be added to the prescription to obtain a suitable gelation temperature, and at the same time, it can also achieve the purpose of adjusting gelation strength, increasing adhesion, and improving drug release.

Formulas with different proportions of different components were designed, and the gelation temperature was used as an index to conduct a single-factor investigation to screen out the formulations with a suitable gelation temperature (35°C±2°C). Some test results are shown in Table 1.

Table 1 Screened some prescriptions with suitable gelling temperature (35°C±2°C) (n=3)

Prescription* Gelation temperature ℃ ①20% P407+2% Propylene Glycol+0.5% P188 33.9±1.5 ②20%P407+2%Propylene Glycol+0.8%P188+0.3%HPMC 33.3±0.7 ③20%P407+1.0%P188 35.3±1.6 ④20%P407+1.2%P188+0.3%HPMC 34.9±1.4 ⑤20%P407+1.5%P188+0.5%HPMC 34.6±1.6 ⑥20%P407+2.0%P188+0.8%HPMC 35.3±1.4

* Each prescription also contains 0.1% Boanmycin hydrochloride, and is prepared according to the prescription method of Example 1 (including steps and corresponding auxiliary materials). In addition, it should be pointed out that although the gelation temperature of each prescription in the above table has not reached about 37°C of the normal body temperature of the human body, this does not affect their realization of the purpose of the present invention, because considering individual differences and physiological states, the human body The temperature also has a range. The actual gelling temperature of the prescription must be slightly lower than the body temperature of the human body. When used clinically, it can ensure that the liquid medicine at normal temperature is in a gelled state after being injected into the human body, and usually the temperature also has a slow rate. It can be seen that the above gelation temperature is suitable for clinical practice.

Test Example 2. Research on rheological properties of in-situ gel.

Measured with a viscometer (DV-II+digital display viscometer, Brookfield, USA). Using a circulating water bath in contact with the viscometer, different formulation samples (see Table 1) were heated from 20°C to 37°C at a heating rate of 1°C/min, and the viscosity of each formulation at different temperatures was measured. The test results are shown in Figure 2.

It can be seen from the temperature-viscosity curve diagram in Figure 2 that the variation curve of the viscosity of each prescription with temperature presents an S-shape. Below 30°C, the viscosity of each prescription is small, showing liquid characteristics. The viscosity increases slowly with the increase of temperature, which is similar to a flat line from the figure. As the temperature continues to increase, the viscosity at a certain critical temperature It began to rise sharply, the fluidity decreased significantly, a sudden jump occurred, and a solution-gel transition process occurred. After conversion into a gel, the viscosity can be as high as several million centipoise, showing solid-state characteristics. After that, the viscosity continued to increase slightly, which may be the result of the entanglement of micelles intensified by the increase of temperature, and the viscosity tended to be stable with the increase of temperature.

Test Example 3, Research on Gelled Texture Properties

CT3 texture analyzer (Brookfield, USA) was used for analysis, and the measurement parameters were as follows: probe TA5, fixture TA-SBT, trigger point load 0.2g, test speed 0.5mm/s, return speed 0.5mm/s, cycle 1 time, The temperature is 37°C.

The gel texture parameters of different formulations are shown in Table 2. Among them, hardness: the positive peak value of the first compression cycle; gel strength: the total positive peak area of compression; viscosity: the negative peak area of compression, representing the difficulty of the probe leaving the sample; viscous force: the first Second compresses the peak of the negative peak.

Table 2 Gelling texture parameters of different formulations

prescription* Hardness g Gel strength g×s Viscous g×s Viscous force G ①20% P407+2% Propylene Glycol+0.5% P188 13.8 194.1 259.1 14.5 ②20%P407+2%Propylene Glycol+0.8%P188+0.3%HPMC 14.9 178.2 157.8 10.9 ③20%P407+1.0%P188 12.0 133.3 113.0 8.5 ④20%P407+1.2%P188+0.3%HPMC 19.8 265.9 196.5 13.1 ⑤20%P407+1.5%P188+0.5%HPMC 18.7 258.0 216.9 15.7 ⑥20%P407+2.0%P188+0.8%HPMC 17.3 253.4 193.5 11.6

* Each prescription also contains 0.1% Boanmycin hydrochloride, and is prepared according to the prescription method of Example 1 (including steps and corresponding auxiliary materials).

The texture properties of different formulations are shown in Figure 3.

The experimental results show that the formula that only uses P188 to adjust the gelation time of P407 has the lowest values of hardness, strength, viscosity and viscous force after gelation. Adding propylene glycol and HPMC to the prescription can increase the gel strength. With the increase of the bioadhesive polymer HPMC, the gel strength and viscosity decrease. This may be due to the combined effect of HPMC and P188. As a result, the two restrict each other. It can be seen that in order to obtain a prescription with suitable gelation temperature and gelation strength, the additives with temperature-up mechanism (such as P188) and the additives with temperature-down mechanism (such as HPMC) must be properly proportioned.

Test example 4, scanning electron microscope

Adopt scanning electron microscope (S-4800, HITACHI, Japan) to observe each prescription (also comprise 0.1% boanmycin hydrochloride in each prescription, and prepare according to the prescription method of Example 1, including preparation steps and corresponding auxiliary materials used) The three-dimensional structure after coagulation is shown in Figure 4.

It can be seen from the scanning electron microscope pictures that the prescription with gel transformation properties forms a three-dimensional network-like spatial structure after gelation.

Test example 5, the in vitro release test of embodiment sample

① Dialysis bag method

Method: 5.0 mL of in situ gel was precisely taken in a homemade dissolution cuvette, and the bottom was sealed with a dialysis bag, and the in vitro release test was carried out. The release medium is 100ml of pH7.4 phosphate buffer solution, the circulating water temperature is controlled at (37.0±0.1)°C, and the rotation speed is 100r·min-1, 5mL samples are taken at a certain time, and the same temperature and the same amount of release medium are replenished in time . The release solution taken out was filtered through a filter membrane with a pore size of 0.45 μm, and measured by UV method. Calculate the percent cumulative release.

Example 1, 2, 3, 9, the results of investigation on the release of Boanmycin hydrochloride isotonic solution (containing Boanmycin hydrochloride 1mg/ml) are shown in FIG. 5 .

It can be seen from Figure 5 that the main drug Boanmycin hydrochloride in Examples 1, 2, 3, and 9 can be released slowly, and the release rate is obviously slower than that of the common isotonic solution of the drug, which has a significant sustained-release effect.

②Membraneless dissolution method

Method: Precisely take 10.0mL of in-situ gel and place it in a pre-weighed flat-bottomed glass tube with a stopper, place the glass tube in a temperature-controlled shaker at 37°C for 10 minutes to preheat the solution to completely gel, add 5ml PBS with a pH of 7.4 at 37°C was used as the release medium and shaken at a speed of 50 rpm. Every once in a while, pour out all the release medium, wipe the outer wall of the glass tube, weigh and record, and then put it back into the temperature-controlled shaker. In the bed, 5ml of release medium at 37°C was added, and the operation was repeated until the end of the test. The difference in weight of samples at adjacent time points was the amount of gel erosion during this period. Drug release was measured while investigating gel erosion. Transfer all the release solution obtained in each erosion test to a 25ml volumetric flask, dilute to the mark with PBS of pH 7.4, measure the absorbance value, calculate the drug concentration, and calculate the cumulative release percentage.

The membrane-free dissolution results of Example 3 are shown in Figure 6.

The membraneless dissolution method simulates the human environment, and it is easier to reveal the possible release of in situ gel drugs than the dialysis bag method, and the correlation between in vivo and in vitro is good. It can be seen from Fig. 6 that the release time of boanmycin hydrochloride in the composition of the present invention can be extended to more than 12 hours, and erosion is the main factor controlling drug release. Regression of cumulative gel erosion amount and drug cumulative release rate against time respectively showed a good linear relationship, showing zero-order kinetic characteristics.

The compositions of the present invention prepared in the examples in the above "Example Section" were tested according to the test examples in the above " Test Example Section" , and satisfactory results were obtained. For example, the composition of each embodiment is determined according to "Test Example 1", and the temperature at which gelation begins to occur is between 32°C and 37°C; The results of the measurements in the examples are basically the same.

Although the present invention has been described in detail with general descriptions and specific embodiments above, it is obvious to those skilled in the art that some modifications or improvements can be made on the basis of the present invention. Therefore, the modifications or improvements made on the basis of not departing from the spirit of the present invention all belong to the protection scope of the present invention.

Claims (10)

1. Boanmycin composition, which comprises: 0.01-2.0g/100ml boanmycin or its pharmaceutically acceptable salt, 10-30g/100ml poloxamer, 0.1-5.0g/100ml gelling Adjuvant, water, and pH regulator; and, wherein said boanmycin or its pharmaceutically acceptable salt is boanmycin hydrochloride, and said poloxamer is poloxamer P407, poloxamer Combination of both P188 and P188 at a ratio of 1:0.025-0.1, the gelling aid is one or more substances selected from the following: propylene glycol, hydroxypropyl methylcellulose. 2. The boanmycin composition according to claim 1, further comprising an osmotic pressure regulator. 3. The boanmycin composition according to claim 1, which contains 0-6.0 g of osmotic pressure regulator in 100 ml. 4. The boanmycin composition according to claim 1, in 100ml, comprising: Boanmycin Hydrochloride 0.01～2.0g, Poloxamer 10～30g, Gelling aid 0.1～5.0g, Osmotic pressure regulator 0～6.0g, pH adjuster qs, and Add water to 100ml. 5. The boanmycin composition according to any one of claims 1 to 4, which is a clear or substantially clear, flowable liquid at 25±0.5°C and which is a gel at 37±0.5°C semi-solid. 6. The method for preparing the boanmycin composition of any one of claims 1 to 4, comprising the steps of: i) Weigh the gelling aid, add an appropriate amount of water, and stir fully to dissolve all; ii) Weighing the poloxamer, adding it to the solution in step i), stirring and/or standing to dissolve it completely; iii) Dissolving Boanmycin or its pharmaceutically acceptable salt in an appropriate amount of water, when the Boanmycin composition contains an osmotic pressure regulator, dissolve the osmotic pressure regulator in water, and stir to dissolve it , filtered through a 0.45μm microporous membrane; iv) Combine the filtrate of step iii) with the solution of step ii), adjust the pH value of the solution to 5.5-8.5 with a pH regulator, add water to the full amount, stir evenly, and let stand to obtain a transparent or basically transparent liquid, namely . 7. A pharmaceutical preparation of boanmycin, which comprises the boanmycin composition according to any one of claims 1 to 4, and optionally a pharmaceutically acceptable carrier or excipient. 8. A ready-to-use injection needle of boanmycin, comprising a syringe containing a needle, and the boanmycin composition according to any one of claims 1 to 4 stored in the syringe. 9. Use of the boanmycin composition according to any one of claims 1 to 4 in the preparation of medicaments for treating tumors. 10. Use of the boanmycin composition according to any one of claims 1 to 4 in the preparation of a medicament for treating cancer.

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