CN101816777A - Novel Boanmycin composition and preparation method thereof - Google Patents
Novel Boanmycin composition and preparation method thereof Download PDFInfo
- Publication number
- CN101816777A CN101816777A CN201010156908A CN201010156908A CN101816777A CN 101816777 A CN101816777 A CN 101816777A CN 201010156908 A CN201010156908 A CN 201010156908A CN 201010156908 A CN201010156908 A CN 201010156908A CN 101816777 A CN101816777 A CN 101816777A
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- boanmycin
- poloxamer
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- solution
- injection
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 108010052945 thanamycin Proteins 0.000 description 1
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Abstract
The invention relates to a novel Boanmycin composition and a preparation method thereof. In particular, the invention relates to a Boanmycin composition which comprises therapeutically effective dose of Boanmycin or pharmaceutically acceptable salt thereof, poloxamer, gelatinizing assistant, water, and optional osmoregulator and/or pH regulator; and the invention also relates to a preparation method of the composition, including pharmaceutical preparations of the composition and an instant injection needle, and applications of the composition in preparing medicaments for treating tumors and/or cancers. The composition of the invention has favorable behaviors in vivo and/or in vitro.
Description
Technical field
The present invention relates to a kind of compositions of novelty, particularly a kind of B1eomycin compositions of novelty and the preparation method of said composition.
Background technology
Malignant tumor is serious threat human life's a major disease, and its sickness rate home and abroad all is the trend that rises year by year.In recent years, antineoplastic agent is being kept the good momentum that increases fast always in the global range.
B1eomycin (Boanmycin) is the novel anti-tumor antibiotic with independent intellectual property right of Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences's initiative exploitation, its hydrochlorate was examined by National Drug Administration in 2004, obtained the first class national new drug certificate and produced certification.
B1eomycin is that wheel branch streptomycin Pingyang new variant (Streptomyces verticilus Var.Pingyangensis n.sp) produces, and belongs to bleomycin family.Experimental studies have found that, B1eomycin has stronger antitumor action, antitumor spectra is wide, except that to incidence, scale cancer, esophageal carcinoma, nasopharyngeal carcinoma, malignant lymphoma, breast carcinoma, choriocarcinoma effectively, also sickness rate height and hepatocarcinoma, colon cancer of not having active drug etc. there is good curative effect, strong to the lethal effect of hepatoma carcinoma cell than amycin (ADM) and mitomycin (MMC), to the suppression ratio of colon cancer HT-29 apparently higher than MMC and fluorouracil (5-FU).Route of administration many (intramuscular injection, intravenous injection, venous cannulations etc.) is not seen bone marrow inhibition, and lung toxicity is lower than other like product.
The route of administration of B1eomycin is more, as intramuscular injection, intravenous injection, venous cannulation etc.But clinical test results shows that after the hydrochlorate administered intramuscular of B1eomycin, medicine enters tissue rapidly, and 5min can record blood drug level, and the medicine in the blood plasma is two-compartment model and distributes t
1/2 αBe (14.036 ± 4.409) min, t
1/2 βBe (39.160 ± 5.599) min, average blood drug level 18.6min after medication reaches the peak, and mean concentration is 0.20 μ g/ml, is reduced to zero (＞0.01 μ g/ml) after 4 hours, and drug half-life is short, and removing speed is fast.
Therefore, this area still needs the promising new method that overcomes the above-mentioned defective of B1eomycin, particularly needs the novel composition that comprises the rich mycin of peace that can overcome the problems referred to above.
Summary of the invention
The objective of the invention is a kind of B1eomycin compositions of improving release behavior in the external and/or body of medicine, particularly can delay medicine rate of release in external and/or body, make medicine in vivo the half-life during medication prolong, improve curative effect, reduce untoward reaction.
The inventor is surprised to find, after making B1eomycin and specific gel rubber material make liquid composite, for example big under the temperature of body temperature in specific temperature range, congealing reaction can take place and form gel in this liquid composite, thereby can be, and then can overcome the unfavorable problem of behavior feature in the existing B1eomycin preparation body so that medicine discharges from this gel under controlled rate.The present invention is based on above-mentioned discovery and be accomplished.
Summary of the invention
First aspect present invention provides the B1eomycin compositions, and it comprises: the B1eomycin of treatment effective dose or its officinal salt, poloxamer, gelling adjuvant, water, and optional osmotic pressure regulator and/or pH regulator agent.
According to each B1eomycin compositions of first aspect present invention,, wherein comprise B1eomycin or its officinal salt of 0.01～2.0g in 100ml.In one embodiment, in 100ml, comprise B1eomycin or its officinal salt of 0.02～1.8g, 0.04～1.6g, 0.05～1.5g, 0.05～1.2g or 0.05～1.0g in the said composition.In one embodiment, in 100ml, comprise B1eomycin or its officinal salt of 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 in the said composition.In one embodiment, in 100ml, comprise B1eomycin or its officinal salt of 0.06～0.5g, 0.06～0.4g, 0.06～0.3g, 0.06～0.2g or 0.08～0.2g in the said composition.
According to each B1eomycin compositions of first aspect present invention,, wherein comprise the poloxamer of 10～30g in 100ml.In one embodiment, in 100ml, comprise the poloxamer of 12～28g, 13～27g, 14～26g, 15～25g or 18～23g in the said composition.In one embodiment, in 100ml, comprise the poloxamer of 10～28g, 10～27g, 10～26g or 10～25g in the said composition.In one embodiment, in 100ml, comprise the poloxamer of 12～30g, 14～30g, 16～30g or 18～30g in the said composition.
According to each B1eomycin compositions of first aspect present invention,, wherein comprise the gelling adjuvant of 0.1～5.0g in 100ml.In one embodiment, in 100ml, comprise the gelling adjuvant of 0.2～5.0g, 0.3～5.0g, 0.4～5.0g or 0.5～5.0g in the said composition.In one embodiment, in 100ml, comprise the gelling adjuvant of 0.2～4.5g, 0.2～4.0g, 0.2～3.5g or 0.2～3.0g in the said composition.In one embodiment, in 100ml, comprise the gelling adjuvant of 0.2～4.5g, 0.3～4.0g, 0.4～3.5g, 0.5～3.0g or 0.5～2.5g in the said composition.
According to each B1eomycin compositions of first aspect present invention,, wherein comprise the osmotic pressure regulator of 0～6.0g in 100ml.In one embodiment, the consumption of this osmotic pressure regulator can be different and can be different according to the different and used concrete osmotic pressure regulator of concrete prescription, but in general, its consumption final osmotic pressure of being enough to make compositions at about 0.5-2 of the normal osmotic pressure of human body doubly.
According to each B1eomycin compositions of first aspect present invention,, wherein comprise an amount of pH regulator agent in 100ml.In one embodiment, the consumption of this pH regulator agent can be different and can be different according to the different and used concrete pH regulator agent of concrete prescription, but in general, its consumption is enough to make the final pH value of compositions to be adjusted in the scope of pH4-9 (for example pH5-8, pH5.5-7.5, pH6-7.5).
According to each B1eomycin compositions of first aspect present invention,, wherein comprise in 100ml:
B1eomycin or its officinal salt 0.01～2.0g,
Gelling adjuvant 0.1～5.0g,
The pH regulator agent an amount of and
Water adds to 100ml.
According to each B1eomycin compositions of first aspect present invention,, wherein comprise in 100ml:
B1eomycin or its officinal salt 0.05～1.5g,
Poloxamer 12～28g,
Gelling adjuvant 0.2～4.5g,
The pH regulator agent an amount of and
Water adds to 100ml.
According to each B1eomycin compositions of first aspect present invention,, wherein comprise in 100ml:
B1eomycin or its officinal salt 0.08～1.2g,
Gelling adjuvant 0.3～4.0g,
The pH regulator agent an amount of and
Water adds to 100ml.
According to each B1eomycin compositions of first aspect present invention,, wherein comprise in 100ml:
B1eomycin or its officinal salt 0.1～1.0g,
Poloxamer 18～23g,
Gelling adjuvant 0.5～3.0g,
The pH regulator agent an amount of and
Water adds to 100ml.
According to each B1eomycin compositions of first aspect present invention, the officinal salt of wherein said B1eomycin is selected from: Boanmycin Hydrochloride, sulphuric acid B1eomycin, phosphoric acid B1eomycin, tartaric acid B1eomycin and citric acid B1eomycin, acetic acid B1eomycin, fumaric acid B1eomycin, maleic acid B1eomycin.In one embodiment, the officinal salt of described B1eomycin is a Boanmycin Hydrochloride.
According to each B1eomycin compositions of first aspect present invention, wherein said poloxamer is that one or more molecular weight ranges are 5000～20000 poloxamer.In one embodiment, described poloxamer is that one or more molecular weight ranges are 5000～18000,5000～15000,5000～12000,6000～20000,8000～20000,10000～20000,12000～20000,6000～18000,7000～15000 or 8000～12000 poloxamer.
According to each B1eomycin compositions of first aspect present invention, wherein said poloxamer is that one or more oxygen ethyls and oxygen propyl group proportion are (0.2～4): 1 poloxamer.In one embodiment, described poloxamer is that one or more oxygen ethyls and oxygen propyl group proportion are (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 each B1eomycin compositions of first aspect present invention, wherein said poloxamer is one or more poloxamers that are selected from following model: poloxamer P407 (being F127), poloxamer P188 (being F68).In one embodiment, described poloxamer is poloxamer P407 (being F127), poloxamer P188 (being F68) or this two combination with arbitrary proportion.In one embodiment, described poloxamer is poloxamer P188 (being F68) and poloxamer P407 (being F127) (0.01～0.5): the combination of 1 ratio.In one embodiment, described poloxamer is poloxamer P188 (being F68) and poloxamer P407 (being F127) (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): the combination of 1 ratio.
According to each B1eomycin compositions of first aspect present invention, wherein said gelling adjuvant is that one or more are selected from following material: propylene glycol, glycerol, Polyethylene Glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, sodium alginate and derivant thereof, arabic gum, tragcanth, guar gum, carbomer, phytohemagglutinin, hyaluronic acid, xanthan gum, chitosan, dextrin and derivant.In one embodiment, described gelling adjuvant is that one or more are selected from following material: hydroxypropyl emthylcellulose, methylcellulose, propylene glycol, Polyethylene Glycol.In one embodiment, described hydroxypropyl emthylcellulose is selected from: HPMC K4M, E4M, F4M, R15M.In the embodiment, described Polyethylene Glycol is the PEG of molecular weight 200-600.In one embodiment, described Polyethylene Glycol is selected from: PEG200, PEG300, PEG400, PEG600, PEG4000, PEG4000.
According to each B1eomycin compositions of first aspect present invention, wherein said B1eomycin or its officinal salt are Boanmycin Hydrochlorides, described poloxamer is poloxamer P407 (being F127), poloxamer P188 (being F68) or this two combination with arbitrary proportion, and the gelling adjuvant is that one or more are selected from following material: hydroxypropyl emthylcellulose, methylcellulose, propylene glycol, Polyethylene Glycol.
In each a particularly preferred embodiment of B1eomycin compositions of first aspect present invention,, wherein comprise the poloxamer P407 of 17～23g and the poloxamer P188 of 0～3g in 100ml.
In each a particularly preferred embodiment of B1eomycin compositions of first aspect present invention, in 100ml, wherein comprise: the gelling adjuvant of poloxamer P188, the 0.5～3.0g of poloxamer P407, the 0～3g of the B1eomycin of 0.1～1.0g or its officinal salt, 17～23g, the osmotic pressure regulator of 0～6.0g, an amount of pH regulator agent and add to the water of 100ml.
According to each B1eomycin compositions of first aspect present invention, wherein said osmotic pressure regulator is that one or more are selected from following material: mannitol, sorbitol, sodium chloride, glucose.
According to each B1eomycin compositions of first aspect present invention, wherein said pH regulator agent is that one or more are selected from following material: hydrochloric acid, sodium hydroxide, phosphoric acid and salt thereof, acetic acid and salt thereof, citric acid and salt thereof, boric acid and salt thereof and their aqueous solution.
According to each B1eomycin compositions of first aspect present invention, it is injectable pharmaceutical composition.In one embodiment, described compositions is can be by the compositions of intramuscular injection, intramuscular injection, subcutaneous injection, the injection of tumor body.
According to each B1eomycin compositions of first aspect present invention, it is transparent or substantial transparent, flowable liquid under 25 ± 0.5 ℃, and it is gelatinous semisolid under 37 ± 0.5 ℃.
According to each B1eomycin compositions of first aspect present invention, its prescription that comprises the embodiment of the invention is formed.
Second aspect present invention provides the preparation first aspect present invention each described method for compositions, and it may further comprise the steps:
I) take by weighing the gelling adjuvant, add suitable quantity of water, fully stir, make whole dissolvings;
Ii) take by weighing poloxamer, join step I) solution in, stir and/or leave standstill and make whole dissolvings;
Iii) B1eomycin or its pharmaceutical salts, optional osmotic pressure regulator are dissolved in the suitable quantity of water, stir and make its dissolving, through 0.45 μ m filtering with microporous membrane;
Iv) with step I filtrate and step I i ii)) solution merge, be 5.5～8.5 with the pH value of pH regulator agent regulator solution, add water to full dose, stir, leave standstill, obtain the liquid of transparent or substantially transparent, promptly.
Third aspect present invention provides a kind of pharmaceutical preparation of B1eomycin, and it comprises each described compositions of first aspect present invention, and optional pharmaceutically acceptable carrier or excipient.In one embodiment, described pharmaceutically acceptable carrier or excipient can be water for injection, sodium chloride injection, glucose injection etc.In one embodiment, described pharmaceutical preparation is injection.
Fourth aspect present invention provides a kind of instant entry needle of B1eomycin, and it comprises the syringe that comprises syringe needle, and is stored in each the described compositions of first aspect present invention in this syringe.In one embodiment, described instant entry needle is to preserve under aseptic condition.In one embodiment, described instant entry needle comprises B1eomycin or its officinal salt of single dose.
Fifth aspect present invention provides the purposes of each described compositions of first aspect present invention in the medicine of preparation treatment tumor and/or cancer.In one embodiment, described tumor and/or cancer are B1eomycin or medicable tumor of its officinal salt and/or cancer.In one embodiment, described tumor and/or cancer are selected from incidence cancer, scale cancer, esophageal carcinoma, nasopharyngeal carcinoma, malignant lymphoma, breast carcinoma, choriocarcinoma, hepatocarcinoma, colon cancer.
Sixth aspect present invention provides treatment tumor and/or method for cancer, and it comprises each the described compositions of first aspect present invention to experimenter's administering therapeutic effective dose.In one embodiment, described tumor and/or cancer are B1eomycin or medicable tumor of its officinal salt and/or cancer.In one embodiment, described tumor and/or cancer are selected from incidence cancer, scale cancer, esophageal carcinoma, nasopharyngeal carcinoma, malignant lymphoma, breast carcinoma, choriocarcinoma, hepatocarcinoma, colon cancer.
Seventh aspect present invention provides the compositions that can be used for treating tumor and/or cancer, and said composition has the feature of each described compositions of first aspect present invention.In one embodiment, described tumor and/or cancer are B1eomycin or medicable tumor of its officinal salt and/or cancer.In one embodiment, described tumor and/or cancer are selected from incidence cancer, scale cancer, esophageal carcinoma, nasopharyngeal carcinoma, malignant lymphoma, breast carcinoma, choriocarcinoma, hepatocarcinoma, colon cancer.
The feature that each had of either side of the present invention or this either side is equally applicable to each of other either side or this other either side.In the present invention, when for example, mentioning " first aspect present invention each ", should " each " be meant the arbitrary sub-aspect of first aspect present invention, when others are mentioned in a similar manner, also have identical meanings.
Detailed Description Of The Invention:
Be further described with characteristics to various aspects of the present invention below.
All documents that the present invention quoted from, their full content is incorporated this paper by reference into, and if the expressed implication of these documents and the present invention when inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this more detailed description and interpretation to be made in these terms and phrase, term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.
In the context of this article, when mentioning the percent (%) of material, except as otherwise noted, be meant certain material shared percent in certain system.For this system is under the liquid situation, and this percent (%) can be weight/volume (w/v) percent (for solute for solid time be preferred) or volume/volume (w/v) percent (for solute for liquid time be preferred).For this system is that this percent (%) is w/w (w/w) percent preferably under the solid-state situation.
With regard to compositions of the present invention, preferred situation is, " percent (%) " among the present invention is meant weight/volume (w/v) percentage ratio, and in the embodiment of a concrete compositions of the present invention, the weight/volume percent sum of active component and each adjuvant equals 100%; Perhaps carry out balance, for example form according to prescription is total with wherein a certain basic excipient, when preparation, adopt a kind of basic excipient for example water (for example water for injection) carry out balance (for example full weight amount or the full volumetric that adds to theoretical prescription with this water come balance).
As used herein, term " officinal salt " generally is meant on the physiology salt acceptably.
As used herein, term " gelling adjuvant " is meant can regulate gelation temperature, improves gel strength, regulates the material or the reagent of drug release.The present invention is surprisingly found out that, for active component B1eomycin of the present invention or its officinal salt, under situation about being used with gelling adjuvant of the present invention, (for example 0～30 ℃) is transparent or substantial transparent, flowable liquid to the solution that comprises poloxamer under the temperature of human temperature being lower than; And near human temperature, be gelatinous semisolid when (for example 37 ± 7 ℃) under the temperature, and have certain gel strength and slow releasing function at this moment.Make the present composition become a kind of particularly in-situ gel of gel sustained release performance, responsive to temperature type, that injectable is used that has.
As used herein, term " water " when particularly injectable is used compositions, typically refers to water for injection at the preparation present composition.
As used herein, term " comprises ", " comprising " etc., is meant a kind of open implication.For example, be meant except the material of being enumerated and contain the material that other is not enumerated describing " the comprising " of adopting when the present composition is formed.For example in the present composition, can also contain antibacterial or antiseptic etc.
In this article, when mentioning " B1eomycin or its officinal salt that wherein comprise 0.01～2.0g ", the amount of this 0.01～2.0g can be in the B1eomycin free alkali, also can be in its salt.Usually can be in the B1eomycin free alkali.
In this article, when mentioning " water adds to 100ml ", be meant with water to be base solvent, promptly water adds to the full dose of said composition, or water adds to final volume and carries out balance adjustment.
As used herein, term " instant entry needle " is meant a kind of entry needle of making up a prescription and can using at any time of need not that comprises syringe needle and syringe, divides the compositions of the first aspect present invention that doses is housed in the syringe wherein in advance.
As used herein, term " compositions " can exchange with " pharmaceutical composition " and use the two can have identical meanings.
Compositions provided by the invention can be used as situ-gel and uses.So-called situ-gel (in situ gel) is meant that a class can take place to change mutually at agents area immediately with after the solution state administration, is transformed by liquid state and forms a class preparation of crosslinked semi-solid gel non-chemically.Formation mechanism is to utilize macromolecular material to stimulate the response of (as temperature, ionic strength or pH etc.) to external world, makes polymer issue the reversible change of diffusing state estranged or conformation at physiological condition, finishes by the inversion of phases of solution state to the semi-solid gel state.This situ-gel by water-soluble high-molecular material preparation has highly hydrophilic three dimensional network structure and the favorable tissue compatibility, bioadhesive and unique solution-semi-solid gel property of transition, have concurrently preparation technology easy, use convenient, in agents area (as injection site, nasal mucosa, oral mucosa, eye mucosa, rectal mucosa and the vaginal mucosa etc.) holdup time advantage such as long and good slow release effect.
The injection in-situ gel preparation is the new focus of research that delays control release type injection field in recent years, it is that medicine and polymer are dissolved in the The suitable solvent, local injection, at medicine-feeding part, polymer solidifies under physiological condition and forms gel-type semi-solid medicament storage storehouse.Situ-gel has overcome common Emulsion, liposome, microsphere and micellar shortcoming, has the topical that can be used for diseased region, prolongs the release cycle, reduces dosage and adverse effect, avoids implant to operate on the relative advantage such as simple of misery, technology when implanting.
B1eomycin is prepared into the injection in-situ gel preparation, compares, have the advantage of normal injection agent with the normal injection agent of this medicine, good fluidity, easy to use, be injected into human body after, be subjected to the influence of human body temperature, form the semi-solid medicament storage storehouse of gel-type in local solidification, can prolong the release cycle, reduce dosage, reduce production cost, strengthen patient's compliance, improve, widen the clinical indication of this medicine simultaneously the tumor treatment effect.
Poloxamer (poloxamer) is a kind of gel rubber material of responsive to temperature type, by the block copolymer (ABA type) that poly(ethylene oxide) PEO (A) construction unit and poly(propylene oxide) PPO (B) construction unit are formed, can form heat-convertible gel after reaching finite concentration.The mechanism of poloxamer solution gelization is relevant with micellar crosslinking method, and when temperature surpassed the critical micell temperature, the dehydration of PPO chain caused micelle formation, rising along with temperature, micelle formation is even more important, when reaching a certain specified temp, is in contact with one another between micelle and no longer mobile.Therefore, intermicellar parcel may be poloxamer solution forms gel with the temperature rising a main cause with tangling.The poloxamer preparation can increase the holdup time of medicine at application site usually, thereby improves bioavailability and curative effect.
In the research in the early stage, the inventor finds, in the compositions of B1eomycin of the present invention, do not use auxiliary gellant simultaneously if use poloxamer separately, then when gelling, occur the non-biodegradation of gelling bad mechanical strength, corrosion fast (dissolving), PEO-PPO-PEO chain easily from the surface.Surprisingly, by auxiliary gellant and poloxamer are used in combination, can form the situ-gel system of function admirable, and because the various adjuvants in the said composition all are can absorb or biodegradable, this becomes possibility for this situ-gel system administrated by injection.Thereby, the situ-gel compositions that comprises B1eomycin that the present invention obtains is prolong drug release time effectively, thereby in vivo holdup time of prolong drug, improve bioavailability, improve curative effect, overcome the short shortcoming of retention time in the existing B1eomycin injection body.
Therefore, in one aspect, the invention provides is a kind of vivo medicine-feeding system of B1eomycin, i.e. in-situ gel preparation, specifically, the invention provides for example hydrochlorate injection temperature-sensitive situ-gel preparation and preparation method thereof of a kind of antitumor antibiotics B1eomycin or its officinal salt.
In one embodiment, compositions provided by the invention is a Boanmycin Hydrochloride injection temperature-sensitive situ-gel preparation, wherein comprise: 0.01～2.0% Boanmycin Hydrochloride, 10～30% poloxamers, 0.1～5.0% gelling adjuvant, 0～6.0% osmotic pressure regulator, the pH regulator agent is an amount of and add to 100% water for injection.
In one embodiment, in compositions provided by the invention, described poloxamer molecular weight ranges is 5000～20000, and oxygen ethyl and oxygen propyl group proportion are 4: 1～1: 4.
In one embodiment, in compositions provided by the invention, described poloxamer is poloxamer P407, poloxamer P188, or the mixture of the two.
In one embodiment, in compositions provided by the invention, described gelling adjuvant is propylene glycol, glycerol, Polyethylene Glycol (PEG), polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose, methylcellulose (MC), carboxymethyl cellulose, sodium alginate and derivant, arabic gum, tragcanth, guar gum, carbomer, phytohemagglutinin, hyaluronic acid, xanthan gum, chitosan, dextrin and derivant, one or more mixture.
In one embodiment, in compositions provided by the invention, described gelling adjuvant is preferably hydroxypropyl emthylcellulose, methylcellulose, propylene glycol, Polyethylene Glycol.
In one embodiment, in compositions provided by the invention, described osmotic pressure regulator is any one in mannitol, sorbitol, sodium chloride or the glucose.
In one embodiment, in compositions provided by the invention, described pH regulator agent is hydrochloric acid, sodium hydroxide, phosphoric acid and salt thereof, acetic acid and salt thereof, citric acid and salt thereof, boric acid and salt thereof, or their mixture.
In one embodiment, be prepared by a method comprising the following steps: take by weighing the gelling adjuvant in proportion, add water for injection, fully stir, be placed to whole dissolvings in compositions provided by the invention; Take by weighing poloxamer more in proportion, join in the above-mentioned solution, stirring makes and is partly dissolved, and is placed to whole dissolvings in cold compartment of refrigerator; Boanmycin Hydrochloride, osmotic pressure regulator are dissolved in the water for injection, stirring makes its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and above-mentioned solution are merged, pH value with pH regulator agent regulator solution is 5.5～8.5, adds to the full amount of water for injection, and stirs, leave standstill, obtain transparent or approaching transparent gel liquid.
In one embodiment, compositions provided by the invention (about 25 ℃,＜30 ℃) character at ambient temperature is transparent or approaching transparent liquid, has certain fluidity, is the semisolid of gel-type in human body temperature (about 37 ℃) character.
The invention provides a kind of Boanmycin Hydrochloride injection in-situ gel preparation, it forms dual system by the compound use of heat-sensitive gel substrate poloxamer and suitable macromolecular material, regulate its phase transition temperature between 30～37 ℃, be injected in human body or direct injection behind tumor locus, can make B1eomycin or its officinal salt for example hydrochlorate slowly discharge, prolong half-life improves bioavailability and reduces toxic and side effects.
The present invention also provide B1eomycin or its officinal salt for example the compositions of hydrochlorate be the preparation method of injection in-situ gel preparation.
In one embodiment, B1eomycin of the present invention or its officinal salt be the compositions injection situ-gel of hydrochlorate for example, wherein comprise: 0.01～2.0% Boanmycin Hydrochloride, 10～30% poloxamers, 0.1～5.0% gelling adjuvant, 0～6.0% osmotic pressure regulator, the pH regulator agent is an amount of and add to 100% water.
In one embodiment, B1eomycin compositions of the present invention, it after perhaps abundant balance, is transparent or substantial transparent, flowable liquid after placing the time of 10min or 20min under 25 ± 0.5 ℃; And it after perhaps abundant balance, is gelatinous semisolid after placing the time of 10min or 20min under 37 ± 0.5 ℃; After temperature reduces, can return to solution state from gel state again, this process has reversibility.
In one embodiment, B1eomycin of the present invention or its officinal salt be the compositions injection situ-gel of hydrochlorate for example, wherein the molecular weight ranges of used poloxamer is 5000～20000 in the present composition as heat-sensitive gel substrate, oxygen ethyl and oxygen propyl group proportion are 4: 1～1: 4, preferably poloxamer P407 (being F127), poloxamer P188 (being F68), or the two a certain proportion of mixture.
In one embodiment, B1eomycin of the present invention or its officinal salt be the compositions injection situ-gel of hydrochlorate for example, in order to regulate the rate of release of medicine, the action time of prolong drug, improve the rheological property of gel rubber system, added in the gel and be no more than 5% gelling adjuvant, as propylene glycol, glycerol, Polyethylene Glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, sodium alginate and derivant thereof, arabic gum, tragcanth, guar gum, carbomer, phytohemagglutinin, hyaluronic acid, xanthan gum, chitosan, dextrin and derivant etc., one or more mixture.The inventor finds that adopting hydroxypropyl emthylcellulose, methylcellulose, propylene glycol, Polyethylene Glycol etc. is preferred gelling adjuvant.
In one embodiment, osmotic pressure regulator of the present invention is any one in mannitol, sorbitol, sodium chloride, the glucose.
In one embodiment, pH regulator agent of the present invention is hydrochloric acid, sodium hydroxide, phosphoric acid and salt thereof, acetic acid and salt thereof, citric acid and salt thereof, boric acid and salt thereof, or their mixture, and the aqueous solution of these materials.
In one embodiment, B1eomycin of the present invention or its officinal salt be the compositions injection situ-gel of hydrochlorate for example, and its preparation method can comprise the steps:
(1) takes by weighing the gelling adjuvant in proportion, add water for injection, fully stir, be placed to whole dissolvings;
(2) take by weighing poloxamer more in proportion, join in the solution (1), stirring makes and is partly dissolved, and is placed to whole dissolvings in cold compartment of refrigerator;
(3) B1eomycin or its salt, osmotic pressure regulator are dissolved in the water for injection, stir and make its dissolving,,, stir filtrate and solution (2) merging through 0.45 μ m filtering with microporous membrane;
(4) pH value with pH regulator agent regulator solution is 5.5～8.5, adds to the full amount of water for injection, and stirs, and leaves standstill, and obtains transparent or approaches transparent gel solution.
The Boanmycin Hydrochloride injection situ-gel of the present invention's preparation has suitable phase transition temperature, be liquid condition at ambient temperature, form with solution makes things convenient for drug administration by injection, be easy to accurately control dosage, the advantage that had both had the normal injection agent, good fluidity, easy to use, injectable is in body local or be injected directly into tumor locus, is subjected to the influence of human body temperature, temperature changes gel into when being elevated near body temperature, form the semi-solid medicament storage storehouse of gel-type, compare with the normal injection agent of this medicine, can the significant prolongation release cycle, reduce untoward reaction, reduce dosage, reduce production costs, strengthen patient's compliance, raising is widened the clinical indication of this medicine to the tumor treatment effect.
The present composition be that particularly suitable uses by the mode of injecting for example intramuscular injection or intratumor injection.For the using dosage of the present composition, can use with reference to the dosage of existing B1eomycin injection, but preferably can suitably reduce dosage or can prolong dosing interval, this is quite favourable for the present composition.Certainly, concrete dosage range depends on the factor such as seriousness, route of administration, doctor's judgement of patient's size, the state of an illness.In general, in the preparation of a unit dose of the present invention, the amount that can contain B1eomycin or its salt is in the scope of 0.1～100mg, 0.5～80mg, 1～50mg or 1～25mg etc.
Description of drawings
Fig. 1 has shown the gelation temperature of variable concentrations poloxamer P407
Fig. 2 has shown the temperature-viscosity profile of different prescriptions
Fig. 3 has shown different prescription gelling structure performance plots
Fig. 4 has shown the scanning electron microscope picture of different prescriptions
Fig. 5 has shown the release profiles of bag filter method medicine
Fig. 6 has shown no film method for releasing drug release and gel corrosion curve (prescription 20%P407+1.2%P188+0.3%HPMC), n=3.
The specific embodiment
Can further describe the present invention by the following examples, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that are used in the test.Though for realizing that employed many materials of the object of the invention and operational approach are well known in the art, the present invention still does to describe in detail as far as possible at this.Test hereinafter in the example, as not specifying that described B1eomycin is meant its hydrochlorate, under identical experimental condition, other salt type also is expected to obtain similar results certainly, and this is that those skilled in the art understand easily.
The embodiment part
Embodiment 1: the present composition-P407/P188/ propylene glycol situ-gel system
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.1g
P407????????????????20g
P188????????????????????0.5g
Propylene glycol 2g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
According to prescription, take by weighing propylene glycol, adding water for injection is an amount of, fully stirs, and makes mix homogeneously, as solution I; Take by weighing P407 and P188 and join in the solution I, stirring makes and is partly dissolved, and places in cold compartment of refrigerator and spends the night, to all dissolvings, as solution II; Take by weighing Boanmycin Hydrochloride in an amount of water for injection, stir and make its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and solution II are merged, regulate pH value to 7.4, add to the full amount of water for injection with 1mol/L sodium hydroxide solution and/or 1mol/L phosphoric acid solution, stir, promptly.
Embodiment 2: the present composition-P407/P188/ propylene glycol/HPMC situ-gel system
System
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.1g
P407?????????????????????20g
P188?????????????????????0.8g
Propylene glycol 2g
HPMC?K4M?????????????????0.3g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
According to prescription, take by weighing propylene glycol, HPMC, adding water for injection is an amount of, fully stirs, and places, to whole dissolvings, as solution I; Take by weighing P407 and P188 and join in the solution I, stirring makes and is partly dissolved, and places in cold compartment of refrigerator and spends the night, to all dissolvings, as solution II; Take by weighing Boanmycin Hydrochloride in an amount of water for injection, stir and make its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and solution II are merged, with the 1mol/L sodium hydroxide solution and (or) the 1mol/L phosphoric acid solution regulates pH value to 7.4, add to the full amount of water for injection, stir, promptly.
Embodiment 3: the present composition-P407/P188/HPMC situ-gel system
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.1g
P407?????????????????????20g
P188?????????????????????1.2g
HPMC?K4M?????????????????0.3g
Sodium chloride 0.9g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
According to prescription, take by weighing HPMC, adding water for injection is an amount of, fully stirs, and places, to whole dissolvings, as solution I; Take by weighing P407 and P188 and join in the solution I, stirring makes and is partly dissolved, and places in cold compartment of refrigerator and spends the night, to all dissolvings, as solution II; Take by weighing Boanmycin Hydrochloride, sodium chloride in an amount of water for injection, stirring makes its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and solution II are merged, with the 1mol/L sodium hydroxide solution and (or) the 1mol/L phosphoric acid solution regulates pH value to 7.4, add to the full amount of water for injection, stir, promptly.
Embodiment 4: the present composition-P407/P188/PEG situ-gel system
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.1g
P407????????????????????20g
P188????????????????????0.5g
PEG400??????????????????1.0g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
According to prescription, take by weighing PEG400, adding water for injection is an amount of, fully stirs, and makes mix homogeneously, as solution I; Take by weighing P407 and P188 and join in the solution I, stirring makes and is partly dissolved, and places in cold compartment of refrigerator and spends the night, to all dissolvings, as solution II; Take by weighing Boanmycin Hydrochloride in an amount of water for injection, stir and make its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and solution II are merged, with the 1mol/L sodium hydroxide solution and (or) the 1mol/L phosphoric acid solution regulates pH value to 7.4, add to the full amount of water for injection, stir, promptly.
Embodiment 5: the present composition-P407/P188/PEG/MC situ-gel system
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.1g
P407????????????????????20g
P188????????????????????2.0g
PEG400??????????????????2.0g
Methylcellulose 0.5g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
According to prescription, take by weighing PEG400, methylcellulose (MC), adding water for injection is an amount of, fully stirs, and places, to whole dissolvings, as solution I; Take by weighing P407 and P188 and join in the solution I, stirring makes and is partly dissolved, and places in cold compartment of refrigerator and spends the night, to all dissolvings, as solution II; Take by weighing Boanmycin Hydrochloride in an amount of water for injection, stir and make its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and solution II are merged, with the 1mol/L sodium hydroxide solution and (or) the 1mol/L phosphoric acid solution regulates pH value to 7.4, add to the full amount of water for injection, stir, promptly.
Embodiment 6: the present composition-P407/P188/PEG/HPMC situ-gel system
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.1g
P407????????????????????20g
P188????????????????????1.5g
PEG400??????????????????0.5g
HPMC?F4M????????????????1.0g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
According to prescription, take by weighing PEG400, HPMC, adding water for injection is an amount of, fully stirs, and places, to whole dissolvings, as solution I; Take by weighing P407 and P188 and join in the solution I, stirring makes and is partly dissolved, and places in cold compartment of refrigerator and spends the night, to all dissolvings, as solution II; Take by weighing Boanmycin Hydrochloride in an amount of water for injection, stir and make its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and solution II are merged, with the 1mol/L sodium hydroxide solution and (or) the 1mol/L phosphoric acid solution regulates pH value to 7.4, add to the full amount of water for injection, stir, promptly.
Embodiment 7: the present composition-P407/PEG/HPMC situ-gel system
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.1g
P407?????????????????????20g
PEG400???????????????????2.0g
HPMC?R15M????????????????1.5g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
According to prescription, take by weighing PEG400, HPMC, adding water for injection is an amount of, fully stirs, and places, to whole dissolvings, as solution I; Take by weighing P407 and join in the solution I, stirring makes and is partly dissolved, and places in cold compartment of refrigerator and spends the night, to all dissolvings, as solution II; Take by weighing Boanmycin Hydrochloride in an amount of water for injection, stir and make its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and solution II are merged, with the 1mol/L sodium hydroxide and (or) the 1mol/L phosphoric acid solution regulates pH value to 7.4, add to the full amount of water for injection, stir, promptly.
Embodiment 8: the present composition
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.1g
P407???????????????????20g
P188???????????????????1.5g
HPMC?K4M???????????????0.5g
NaCl???????????????????0.9g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
Preparation process is with embodiment 3.
Embodiment 9: the present composition
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.1g
P407????????????????20g
P188????????????????2.0g
HPMC?K4M????????????0.8g
NaCl?????????????????????0.9g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
Preparation process is with embodiment 3.
Embodiment 10: the present composition
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.05g
P407???????????????????????18g
Propylene glycol 1.0g
MC?????????????????????????2.5g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
According to prescription, take by weighing MC, it is an amount of that propylene glycol adds water for injection, fully stirs, and places, to all dissolvings, as solution I; Take by weighing P407 and join in the solution I, stirring makes and is partly dissolved, and places in cold compartment of refrigerator and spends the night, to all dissolvings, as solution II; Take by weighing Boanmycin Hydrochloride in an amount of water for injection, stir and make its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and solution II are merged, with the 1mol/L sodium hydroxide solution and (or) the 1mol/L phosphoric acid solution regulates pH value to 7.4, add to the full amount of water for injection, stir, promptly.
Embodiment 11: the present composition
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.05g
P407????????????????????15g
MC??????????????????????3.5g
Sodium chloride 0.9g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
According to prescription, take by weighing MC, adding water for injection is an amount of, fully stirs, and places, to whole dissolvings, as solution I; Take by weighing P407 and join in the solution I, stirring makes and is partly dissolved, and places in cold compartment of refrigerator and spends the night, to all dissolvings, as solution II; Take by weighing Boanmycin Hydrochloride, sodium chloride in an amount of water for injection, stirring makes its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and solution II are merged, with the 1mol/L sodium hydroxide solution and (or) the 1mol/L phosphoric acid solution regulates pH value to 7.4, add to the full amount of water for injection, stir, promptly.
Embodiment 12: the present composition
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.03g
P407???????????????????????12g
Arabic gum 1.0g
Xanthan gum 3.0g
Sodium chloride 0.9g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
According to prescription, take by weighing arabic gum, xanthan gum, adding water for injection is an amount of, fully stirs, and places, to whole dissolvings, as solution I; Take by weighing P407 and join in the solution I, stirring makes and is partly dissolved, and places in cold compartment of refrigerator and spends the night, to all dissolvings, as solution II; Take by weighing Boanmycin Hydrochloride, sodium chloride in an amount of water for injection, stirring makes its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and solution II are merged, with the 1mol/L sodium hydroxide solution and (or) the 1mol/L phosphoric acid solution regulates pH value to 7.4, add to the full amount of water for injection, stir, promptly.
Embodiment 13: the present composition
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.01g
P407????????????????????10g
Xanthan gum 5.0g
Glucose 5.0g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
According to prescription, take by weighing xanthan gum, adding water for injection is an amount of, fully stirs, and places, to whole dissolvings, as solution I; Take by weighing P407 and join in the solution I, stirring makes and is partly dissolved, and places in cold compartment of refrigerator and spends the night, to all dissolvings, as solution II; Take by weighing Boanmycin Hydrochloride, glucose in an amount of water for injection, stirring makes its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and solution II are merged, with the 1mol/L sodium hydroxide solution and (or) the 1mol/L phosphoric acid solution regulates pH value to 7.4, add to the full amount of water for injection, stir, promptly.
Embodiment 14: the present composition
Composition prescription (by 100ml):
Boanmycin Hydrochloride 0.5g
P407?????????????????????22g
P188?????????????????????2.0g
HPMC?E4M?????????????????0.2g
Glucose 5.0g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
According to prescription, take by weighing HPMC K4M, adding water for injection is an amount of, fully stirs, and places, to whole dissolvings, as solution I; Take by weighing P407, P188 and join in the solution I, stirring makes and is partly dissolved, and places in cold compartment of refrigerator and spends the night, to all dissolvings, as solution II; Take by weighing Boanmycin Hydrochloride, glucose in an amount of water for injection, stirring makes its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and solution II are merged, with the 1mol/L sodium hydroxide solution and (or) the 1mol/L phosphoric acid solution regulates pH value to 7.4, add to the full amount of water for injection, stir, promptly.
Embodiment 15: the present composition
Composition prescription (by 100ml):
Boanmycin Hydrochloride 1.0g
P407??????????????????????25g
P188??????????????????????5g
HPMC?K4M??????????????????0.1g
Glucose 5g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
Preparation process is with embodiment 14
Embodiment 16: the present composition
Composition prescription (by 100ml):
Boanmycin Hydrochloride 1.5g
P407????????????????????28g
P188????????????????????2.0g
Arabic gum 3.0g
Glucose 5.0g
NaOH and/or the phosphoric acid of 1mol/L are an amount of
Water for injection is to 100ml
According to prescription, take by weighing arabic gum, adding water for injection is an amount of, fully stirs, and places, to whole dissolvings, as solution I; Take by weighing P407, P188 and join in the solution I, stirring makes and is partly dissolved, and places in cold compartment of refrigerator and spends the night, to all dissolvings, as solution II; Take by weighing Boanmycin Hydrochloride, glucose in an amount of water for injection, stirring makes its dissolving, through 0.45 μ m filtering with microporous membrane, filtrate and solution II are merged, with the 1mol/L sodium hydroxide solution and (or) the 1mol/L phosphoric acid solution regulates pH value to 7.4, add to the full amount of water for injection, stir, promptly.
Test routine part
Below investigate the various performances of situ-gel,, can system be optimized, the screening optimized prescription according to above index as gelation temperature, rheological properties, gelling matter structure performance, electron-microscope scanning, drug release characteristics etc. by the test example.
The phase transition temperature of test example 1, situ-gel is measured.
(1.5cm * 0.6cm) put into a small beaker places psychrolusia with small beaker, and thermometer is terminal to be immersed in the solution, opens electromagnetic agitation 100 commentaries on classics/min, the about 0.5 ℃/min of warming-in-water speed to get gel sample 10ml and lesser trochanter.Temperature when magnetic stir bar stops operating fully is gelation temperature, and each solution parallel assay 3 times is averaged.Prepare the P407 solution (seeing Table 1) of a series of concentration, measure gelation temperature, the results are shown in Figure 1.
As seen from Figure 1, the gelation temperature of P407 type situ-gel has concentration dependent.The P407 solution of low concentration is warmed up to 40 ℃ and does not occur the gelling phenomenon yet, and 19%P407 solution begins to occur the gelling phenomenon about 32 ℃, and along with the increase of P407 concentration, gelation temperature descends gradually.Usually adopt higher P407 concentration to prepare situ-gel guaranteeing it, but the high concentration gelation temperature is just low, has all brought problem and difficulty for preparation, storage and the use of situ-gel to the variations in temperature sensitivity.Therefore, need to add the gelation temperature of other adjuvants in the prescription, can also reach the adjusting gel strength simultaneously, increase adhesion, improve purposes such as drug release rate to obtain to suit.
Designing the prescription of different component different proportions, is index with the gelation temperature, carries out single factor and investigates, and filters out the have suitable gelation temperature prescription of (35 ℃ ± 2 ℃).Part test the results are shown in Table 1.
The part that table 1 screening obtains has the prescription (n=3) of suitable gelation temperature (35 ℃ ± 2 ℃)
| Prescription * | Gelation temperature ℃ |
| 1. 20%P407+2% propylene glycol+0.5%P188 | ??33.9±1.5 |
| 2. 20%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 |
* also comprise 0.1% Boanmycin Hydrochloride in each prescription, and by embodiment 1 prescription method preparation (comprising step and corresponding adjuvant).In addition, it is to be noted, though the gelation temperature of respectively writing out a prescription in the last table does not reach about 37 ℃ of the common body temperature of human body, but this does not influence them and realizes the object of the invention, because consider individual difference and physiological status, the temperature of human body also has a scope, must make the actual gelation temperature of prescription a little less than body temperature, when using clinically, can guarantee to present gelatinized after medicinal liquid under the room temperature is in being expelled to human body, and typical temperature also has a process that slowly rises, and visible above-mentioned gelation temperature is applicable to clinical practice.
Test example 2, the research of situ-gel rheological property.
With viscometer determining (DV-II+ digital display viscometer, Brookfield, USA).Utilize with the circulator bath of viscometer contact different prescription sample (seeing Table 1) is warming up to 37 ℃, 1 ℃/minute of programming rate, the viscosity of respectively writing out a prescription under the mensuration different temperatures from 20 ℃.Result of the test is seen Fig. 2.
By temperature-viscosity profile of Fig. 2 as seen, the change curve of each viscosity with temperature of writing out a prescription presents S shape.Below 30 ℃, each viscosity of writing out a prescription is less, presents liquid characteristic, and viscosity is along with the rising of temperature slowly increases, from the approximate horizontal line of figure, continuation rising along with temperature begins rapid rising in some critical temperature viscosity, and flowability significantly descends, hop appears, solution-gel conversion process takes place, change into gel after viscosity can show solid-state feature up to millions of centipoises.Afterwards, viscosity continues to increase by a small margin, may be the result that temperature raises and makes micelle tangle and aggravate, and the increase of viscosity with temperature tends to be steady.
Test example 3, the performance study of gelling matter structure
Adopt CT3 texture analyser (Brookfield, the U.S.) to analyze, location parameter is as follows: probe TA5, and anchor clamps TA-SBT, trigger point load 0.2g, test speed 0.5mm/s, return speed 0.5mm/s circulates 37 ℃ of temperature 1 time.
The gelling matter structure parameter of different prescriptions sees Table 2.Wherein, hardness: the positive peak-to-peak value of first compression cycle; Gel strength: the total positive peak area of compression; Viscosity: the negative peak area of compression, the complexity when the representative probe leaves from sample; Viscous force: the peak value that compresses negative peak for the first time.
The different prescription of table 2 gelling matter structure parameter
| Prescription * | Hardness g | Gel strength g * s | Viscosity g * s | Viscous force G |
| 1. 20%P407+2% propylene glycol+0.5%P188 | ??13.8 | ??194.1 | ??259.1 | ??14.5 |
| 2. 20%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 |
* also comprise 0.1% Boanmycin Hydrochloride in each prescription, and by embodiment 1 prescription method preparation (comprising step and corresponding adjuvant).
The texture characteristic figure of different prescriptions sees Fig. 3.
Experimental result shows that list is regulated the prescription of the gelling time of P407 with P188, and every numerical value such as the hardness after the gelling, intensity, viscosity and viscous force are minimum.Adding propylene glycol and HPMC can increase gel strength in the prescription, and along with the increase of bioadhesive high molecular polymer HPMC addition, agglomerative intensity and viscosity descend on the contrary to some extent, and this may be the result of HPMC and P188 comprehensive function, the two mutual restriction.As seen to obtain all suitable prescription of gelation temperature and gel strength, must will have the additives (as P188) of temperature rise mechanism and the additives (as HPMC) of temperature downward modulation mechanism and carry out rational proportion.
Test example 4, electron-microscope scanning
Adopt scanning electron microscope (S-4800, HITACHI, Japan) (each also comprises 0.1% Boanmycin Hydrochloride in writing out a prescription, and presses the preparation of embodiment 1 prescription method to observe each prescription, the corresponding adjuvant that comprises preparation process and use) three dimensional structure after the gelling the results are shown in Figure 4.
By the scanning electron microscope picture as seen, have the prescription that gel transforms character and after gelling, form three-dimensional network shape space structure.
The extracorporeal releasing test of test example 5, embodiment sample
1. bag filter method
Method: precision is got the 5.0mL situ-gel in homemade stripping cuvette, and the bottom adopts bag filter to seal, and carries out extracorporeal releasing experiment.Release medium is pH7.4 phosphate buffer 1 00ml, and circulating water temperature is controlled at (37.0 ± 0.1) ℃, and rotating speed is 100rmin-1, respectively at regular hour sampling 5mL, and in time replenishes the release medium of equitemperature and equivalent.The release solution via hole diameter 0.45 μ m membrane filtration that takes out is measured with the UV method.Calculate the cumulative release percentage rate.
The release of embodiment 1,2,3,9, Boanmycin Hydrochloride isosmotic solution (hydrochloric B1eomycin 1mg/ml) is investigated and be the results are shown in Figure 5.
As seen from Figure 5, the principal agent Boanmycin Hydrochloride can slowly discharge among the embodiment 1,2,3,9, and rate of release is considerably slower than the common isosmotic solution of this medicine, has significant slow releasing function.
2. there is not the film leaching
Method: precision is got the 10.0mL situ-gel and is placed the flat band plug glass tubing of having weighed in advance, this glass tubing placed 37 ℃ temperature control shaking table preheating 10min, make the solution complete gelation, the PBS that adds the pH7.4 of 37 ℃ of 5ml, as release medium, under the rotating speed of 50rpm, shake, at set intervals, inclining whole release medium, and the glass tubing outer wall is wiped clean, weigh and record, be reentered into then in the temperature control shaking table, replenish 37 ℃ release medium 5ml, so repeatable operation, until off-test, the example weight difference of adjacent time point promptly for this reason during gel corrosion amount.When investigating the gel corrosion, measure drug release rate.The release liquid that each dissolved corrosion test is obtained changes and all moves in the 25ml volumetric flask, is diluted to scale with the PBS of pH7.4, measures the trap value, calculates drug level, and calculating cumulative release percentage rate.
The no film stripping of embodiment 3 the results are shown in Figure 6.
No film leaching is simulated the human body environment, is easier to disclose in the possible body of situ-gel medicine than bag filter method discharge, and the vivo and vitro dependency is good.As seen from Figure 6, can extend to more than 12 hours the release time of Boanmycin Hydrochloride in the present composition, and corrosion is the principal element of control drug release.Gel is accumulated corrosion amount and drug accumulation release respectively the time is returned, present the good linear relation, be shown as the zero order kinetics feature.
The present composition of the preparation of each embodiment in " embodiment part " above, according to above "
Test routine part "The example of respectively testing test, all obtained gratifying result.For example, the compositions of each embodiment is measured according to " test example 1 ", begins to take place agglomerative temperature all between 32 to 37 ℃; Gelling matter structure performance and electron-microscope scanning and release in vitro result have all obtained and the top basically identical of measuring in the example as a result of respectively testing.
Though above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103169978A (en) * | 2013-04-03 | 2013-06-26 | 江苏省农业科学院 | Temperature control slow release injection for bird immune globulin as well as preparation method and application thereof |
| CN112516081A (en) * | 2020-12-16 | 2021-03-19 | 郑州百瑞动物药业有限公司 | Novel diclofenac injection and preparation method thereof |
| CN116115568A (en) * | 2021-11-12 | 2023-05-16 | 洛阳瑞华动物保健品有限公司 | A kind of preparation method of lincomycin hydrochloride soluble powder |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103169978A (en) * | 2013-04-03 | 2013-06-26 | 江苏省农业科学院 | Temperature control slow release injection for bird immune globulin as well as preparation method and application thereof |
| CN103169978B (en) * | 2013-04-03 | 2014-10-22 | 江苏省农业科学院 | Temperature control slow release injection for bird immune globulin as well as preparation method and application thereof |
| CN112516081A (en) * | 2020-12-16 | 2021-03-19 | 郑州百瑞动物药业有限公司 | Novel diclofenac injection and preparation method thereof |
| CN112516081B (en) * | 2020-12-16 | 2023-03-10 | 郑州百瑞动物药业有限公司 | Diclofenac injection and preparation method thereof |
| CN116115568A (en) * | 2021-11-12 | 2023-05-16 | 洛阳瑞华动物保健品有限公司 | A kind of preparation method of lincomycin hydrochloride soluble powder |
| CN116115568B (en) * | 2021-11-12 | 2025-08-26 | 洛阳瑞华动物保健品有限公司 | A preparation method of lincomycin hydrochloride soluble powder |
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