CN1889929B - Excipients in drug delivery vehicles - Google Patents
Excipients in drug delivery vehicles Download PDFInfo
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- CN1889929B CN1889929B CN200480035672.0A CN200480035672A CN1889929B CN 1889929 B CN1889929 B CN 1889929B CN 200480035672 A CN200480035672 A CN 200480035672A CN 1889929 B CN1889929 B CN 1889929B
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Abstract
Injectable depot gel compositions and kits that provide an excipient for modulating a release rate and stabilizing beneficial agents are provided. Methods of administering and preparing such systems are also provided. The gel compositions comprise biodegradable, bioerodible polymers and water-immiscible solvents in amounts effective to plasticize the polymers and form gels with the polymers. Suitable excipients include pH modifiers, reducing agents, and antioxidants.
Description
The cross reference of related application
The application requires the U.S. Provisional Application No.60/519 submitted on November 14th, 2003, the U.S. Patent application No.10/. that on November 10th, 972 and 2004 submits to ... ... interests, be referenced herein by reference.
Invention field
The present invention relates generally to depot compositions and the test kit of sustained release, they provide the sustained release of beneficiating ingredient.The present invention also relates to prepare and give the method for described compositions.
Background of invention
Biodegradable polymer is used for many years in medical applications.The device example be comprised of Biodegradable polymer comprises stitching thread, surgery folder, medical nail, implant and drug delivery system.These Biodegradable polymers of great majority are based on Acetic acid, hydroxy-, bimol. cyclic ester, lactide, caprolactone and copolymer thereof.
Injectable implant adopts and dissolves in very much or relatively solvent/the plasticizer of aqueous body fluid with the Biodegradable polymer preparation, to promote polymer, at the rapid of implant site, solidifies, and promotes that medicine spreads from implant.When implant is placed in body neutralization and is exposed to aqueous body fluid, it is a serious problem that water adopts the polymeric implants of water-soluble solvent to divide a word with a hyphen at the end of a line rapidly to this class.Moisture picked-up rapidly often causes implant to have the inhomogeneous loose structure of size and shape.Usually, surperficial aperture presents finger sample pore structure, extends in from implant surface to implant and reaches 1/3rd millimeters or more, and this class finger sample hole makes implant surface open to environment for use.It is less that inner aperture is tending towards, and the fluid be present in environment for use is not accessible.Moisture picked-up feature often causes the release of beneficiating ingredient out of control rapidly, shows as the initial rapidly release of beneficiating ingredient from polymer formulations, " prominent the releasing " of the beneficiating ingredient that is equivalent to discharge from implant.The prominent major part that often causes beneficiating ingredient, if not all released discharges, for example a few hours or 1-2 days within the very short time.A kind of like this effect may be unacceptable, particularly at needs, control in those environment of sending, beneficiating ingredient sending in a controlled manner namely, last two weeks above or reach one month or even reach 1 year, perhaps existing therein narrow treatment window and excessive beneficiating ingredient to discharge may cause in those environment of adverse consequences the curee, or be necessary therein to simulate beneficiating ingredient, such as hormone etc. in curee's body abiogenous every day curve those environment in.
Therefore, when implanting this class device, finger sample hole allows very fast aqueous body fluid picked-up to enter implant inside, and the significant quantity beneficiating ingredient dissolves immediately and rapidly subsequently, and the without hindrance environment for use that diffuses into of beneficiating ingredient, produce burst effect as discussed above.
In addition, moisture picked-up rapidly may cause too early polymer precipitation, so that produces the implant of sclerosis or have the implant of sclerosis crust.The inner aperture that contains beneficiating ingredient is cut off with body fluid and contacts with a lot of inner spaces, may be not in the inapparent time (" lag time ") cause the release of beneficiating ingredient significantly to reduce.From the viewpoint of the controlled, sustained release of beneficiating ingredient is provided to the curee, be unwanted this lag time.Then viewed is prominent the releasing that beneficiating ingredient discharges at short notice soon after implantation, wherein do not have or beneficiating ingredient d/d lag time seldom, subsequently beneficiating ingredient continue send (the supposition beneficiating ingredient also has and remains after prominent releasing), until the supply of beneficiating ingredient exhausts.
Various control beneficiating ingredients are prominent to be released and regulates and controls to send and the existing description of the method that makes its stabilisation.Following patent United States Patent(USP) Nos. 6,468,961; 6,331,311; 6,130,200; 5,990,194; 5,780,044; 5,733,950; 5,656,297; 5,654,010; 4,985,404 and 4,853,218 and PCT communique WO 98/27962 it is believed that be the representative, be referenced herein by reference.Although obtain certain success, but these methods are still not exclusively satisfactory with regard to the beneficiating ingredient of in a large number implanted thing effectively being sent.
The impact that the initial burst release of medicine and release rate profile can be subject to several factors, for example the water miscibilty of the molecular weight of the ratio of polymer and solvent, polymer, solvent and the character of drug particle.But, reach required rate of release and may be subject in some cases the rotten inhibition of beneficiating ingredient.In addition, when polymeric matrices is caught beneficiating ingredient, the be released in polymeric matrix of beneficiating ingredient from polymeric matrix inside starts before significantly degraded may be mainly what to spread-to control, cause it may is not desirable release rate profile.
The problem of using some Biodegradable polymers to face in drug delivery system is the degraded of polymer, causes for example accumulation of sour by-product in delivery system.The environment that gained contains polymer degradation products may damage beneficiating ingredient, for example protein, peptide and small-molecule drug.
Using another problem that some implantable systems face is the existence from free radical and/or the peroxide of body fluid.The normal foreign body reaction of for example implantable drug delivery system is also caused to the generation of free radical and peroxide.Therefore, free radical and peroxide may diffuse into implanted drug delivery system, and beneficiating ingredient is harmful to.
As a result, beneficiating ingredient is subject to the impact of some factors apt to deteriorate, reduces thus the general validity of dosage form, because the beneficiating ingredient of not all wanting can be for curee's treatment.
Still be starved of such drug delivery system, they can make to be exposed to due to the existence of depolymerization and/or unwanted free radical or peroxide the beneficiating ingredient stabilisation of harmful microenvironment.In addition, still need to regulate and control the release of beneficiating ingredient from drug delivery system, to reach required rate of release.
Summary of the invention
The invention provides Injectable depot gel combination and test kit, they go through the persistent period releasing beneficial composition of short persistent period and prolongation.The method that gives and prepare this based composition also is provided.Compositions according to the present invention comprises gel vehicle, dissolves or is dispersed in beneficiating ingredient and the excipient in this gel vehicle.Gel vehicle comprises not miscibilty solvent of bioerosion, biocompatible polymer and water, and content is for plasticized polymer and to generate gel with polymer be effective.In some situation, form solvent and water and do not use together with the miscibilty solvent.The present composition is used excipient regulation and control release profiles and makes the beneficiating ingredient stabilisation.For example, some excipient can be offset the effect of depolymerization.Other excipient can be offset the effect from peroxide and/or the free radical of body fluid.
Comprise according to the embodiment of the present invention the Injectable depot gel combination that continues to send beneficiating ingredient, comprise: gel vehicle, comprise not miscibilty solvent of bioerosion, biocompatible polymer and water, content is for plasticized polymer and to generate with it gel be effective; Dissolve or be dispersed in the beneficiating ingredient in this gel vehicle; Regulation and control rate of release and the excipient that makes the beneficiating ingredient stabilisation; Wherein continue to send occur in about twenty four hours after administration to approximately between 12 months during.
Although applicable excipient has a lot, example comprises pH modifier, reducing agent and antioxidant.Embodiments of the present invention can be used the combination of single excipient or excipient.
PH modifier class excipient includes but not limited to inorganic salt, for example zinc carbonate, magnesium carbonate, calcium carbonate, magnesium hydroxide, calcium hydrogen phosphate, calcium acetate, calcium hydroxide, calcium lactate, calcium maleate, calcium oleate, calcium oxalate, calcium phosphate, magnesium acetate, magnesium hydrogen phosphate, magnesium phosphate, magnesium lactate, maleic acid magnesium, magnesium oleate, magnesium oxalate, zinc acetate, phosphoric acid hydrogen zinc, zinc phosphate, zinc lactate, MALEIC ACID, ZINC SALT, zinc oleate, zinc oxalate and their combination.Reducing agent class excipient can be cysteine or methionine.Antioxidant as excipient can be selected from lower group: d-α tocopherol acetate, the d1-alpha tocopherol, Vitamin C acyl cetylate, butylation hydroxyl anidole, ascorbic acid, butylatedhydroxyanisole, the butylation hydroxyquinone, BHA, Hydroxycoumarin, Yoshinox BHT, cephalm, ethyl gallate, propyl gallate, the gallate monooctyl ester, the gallate lauryl, nipasol, trihydroxy butyl rophenone, xylenol, DI-tert-butylphenol compounds, vitamin E, lecithin, ethanolamine and their combination.
About excipient, compositions of the present invention can comprise approximately 0.01% and approximately between 50%, by weight; Approximately 0.05% and approximately between 40%, by weight; Perhaps approximately 0.1% and approximately between 30%, by weight.In addition, the ratio between excipient and beneficiating ingredient can be at approximately 0.1: 99.9 and approximately between 99: 1, and preferably, this ratio was at approximately 1: 99 and approximately between 60: 40.
The water of the present invention not water miscibilty of miscibilty solvent can be to be less than or equal to approximately 7 % by weight under 25 ℃.In addition, compositions can not moisture miscibilty be greater than the solvent of 7 % by weight under 25 ℃.Solvent can be selected from lower group: the rudimentary aralkyl ester of the lower alkyl esters of aromatic alcohol, aryl acid, aryl acid; The lower alkyl esters of aryl ketones, aralkyl ketone, lower alkyl ketone, citric acid and their combination.Other can be used for solvent of the present invention benzylalcohol, benzoic acid benzyl ester, ethyl benzoate and glyceryl triacetate.
Some embodiments of the present invention comprise the composition solvent that is selected from lower group: glyceryl triacetate, diacetin, tributyorin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, tributyl 2-acetylcitrate, triethyl group glyceride, triethyl phosphate, diethyl phthalate, diethyl tartrate., mineral oil, polybutene, silicone fluid, glycerol, ethylene glycol, Polyethylene Glycol, capryl alcohol, ethyl lactate, propylene glycol, Allyl carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, METHYLPYRROLIDONE, 2-Pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, butanone, dimethyl formamide, dimethyl sulfoxide, oxolane, caprolactam, decyl methyl sulfoxide, oleic acid, Azone and their combination.
Can be selected from lower group according to polymer used in the present invention: polyactide, PGA, poly-(caprolactone), polyanhydride, polyamine, polyesteramide, poe, the Ju diethyleno dioxide ketone, polyacetals, polyketals, Merlon, poly phosphate, polyester, the poly terephthalic acid butene esters, poly-orthocarbonic ester, polyphosphazene, succinate, poly-(malic acid), poly-(aminoacid), polyvinylpyrrolidone, Polyethylene Glycol, poly-hydroxylated cellulose, polysaccharide, chitin, chitosan, hyaluronic acid and their copolymer, terpolymer and mixture.Can use lactide acid polymer in the present invention, preferably the copolymer (PLGA) of lactic acid and glycolic, comprise poly-(D, L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester) and poly-(L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester).In some embodiments, the weight average molecular weight of PLGA polymer approximately 3,000 to approximately between 120,000, the monomer ratio of lactic acid and glycolic approximately 50: 50 to approximately between 100: 0.Also can use caprolactone polymer in the present invention.
Other embodiments of the present invention comprise approximately 5 % by weight and approximately between 90 % by weight, about 25 % by weight and approximately between 80 % by weight or approximately 35 % by weight and the approximately polymer between 75 % by weight.In the ratio of polymer and solvent, some ratios can be at approximately 5: 95 and approximately between 90: 10, and other ratios can be approximately between 20: 80 and 80: 20, and other ratios can be at approximately 30: 70 and approximately between 75: 25.
According to the present invention, compositions can further comprise at least one following ingredients: emulsifying agent, pore former, dissolubility adjusting control agent and penetrating agent for anesthetis.
About beneficiating ingredient, compositions can comprise approximately 0.1% to approximately 50%, approximately 0.5% to approximately 40% or approximately 1% to about 30% beneficiating ingredient, by weight.The mean diameter of beneficiating ingredient can be less than approximately 250 μ m, approximately between 5 μ m and 250 μ m, at about 20 μ m and approximately between 125 μ m or at about 38 μ m and approximately between 63 μ m.
Beneficiating ingredient can be selected from lower group: protein, peptide, medicine and their combination.For example, when beneficiating ingredient comprises protein, this protein can be selected from lower group: human growth hormone, Intederon Alpha-2a, Interferon Alpha-2b, EPO, methionine-human growth hormone, go-phenylalanine human growth hormone, synonym interferon and their combination.When beneficiating ingredient comprises medicine, this medicine can be bupivacaine or paclitaxel.Peptide class beneficiating ingredient can comprise leuprolide or Desmopressin.
In one embodiment of the invention, provide preparation to go through about twenty four hours to approximately within 12 months, to the curee, continuing to send the method for the Injectable depot gel combination of beneficiating ingredient, the method comprises: the water of mixed biologic aggressivity, biocompatible polymer and effective plasticising amount is the miscibilty solvent not, generates gel vehicle; Mix beneficiating ingredient in this gel vehicle; To mixing the excipient of regulation and control rate of release in this gel vehicle; With make this beneficiating ingredient stabilisation, wherein the effect of depolymerization is offset in the existence of this excipient.The method can further be included in to premixing excipient and beneficiating ingredient before admixed excipients in gel vehicle and beneficiating ingredient.On the other hand, the method can further comprise to gel vehicle and loads separately excipient and beneficiating ingredient.Described excipient can dissolve or be dispersed in gel vehicle.
In other embodiments of the present invention, provide preparation to go through about twenty four hours to approximately within 12 months, to the curee, continuing to send the method for the Injectable depot gel combination of beneficiating ingredient, the method comprises: the water of mixed biologic aggressivity, biocompatible polymer and effective plasticising amount is the miscibilty solvent not, generates gel vehicle; Mix beneficiating ingredient in this gel vehicle; To mixing the excipient of regulation and control rate of release in this gel vehicle; With make this beneficiating ingredient stabilisation, wherein the existence of this excipient offset the peroxide see in body fluid or free radical or this two.
Another embodiment of the invention comprises the extremely approximately method of the Injectable depot compositions of 12 months sustained release beneficiating ingredients of about twenty four hours of going through, comprise and give a kind of compositions, said composition comprises: gel vehicle, the water that comprises bioerosion, biocompatible polymer and effective plasticising amount is the miscibilty solvent not, generates gel vehicle; Dissolve or be dispersed in the beneficiating ingredient in this gel vehicle; Regulation and control rate of release and the excipient that makes this beneficiating ingredient stabilisation.Compositions can give once.On the other hand, compositions can give repeatedly.Compositions can part or systemic delivery.In addition, compositions can be delivered to a plurality of positions on the curee.
Another embodiment of the invention comprises that continuing to send beneficiating ingredient reaches after administration about twenty four hours to the about administration test kit of 12 months, this test kit comprises: gel vehicle, comprise not miscibilty solvent of bioerosion, biocompatible polymer and water, content is for this polymer of plasticising and to generate with it gel be effective; Dissolve or be dispersed in the beneficiating ingredient in this gel vehicle; The excipient of regulation and control rate of release, wherein this excipient makes this beneficiating ingredient stabilisation by the effect of offsetting depolymerization; With optional one or more following ingredients: emulsifying agent; Pore former; The optional anesthetis dissolubility adjusting control agent associated with this beneficiating ingredient; And penetrating agent; Wherein at least optional anesthetis associated with this dissolubility adjusting control agent keeps and separated from solvent, until anesthetis is in curee's administration.
Another embodiment of the invention comprises that continuing to send beneficiating ingredient reaches after administration about twenty four hours to the about administration test kit of 12 months, this test kit comprises: gel vehicle, comprise not miscibilty solvent of bioerosion, biocompatible polymer and water, content is for this polymer of plasticising and to generate with it gel be effective; Dissolve or be dispersed in the beneficiating ingredient in this gel vehicle; The excipient of regulation and control rate of release, wherein this excipient makes this beneficiating ingredient stabilisation by the effect of offsetting depolymerization; With optional one or more following ingredients: emulsifying agent; Pore former; The optional anesthetis dissolubility adjusting control agent associated with this beneficiating ingredient; And penetrating agent; Wherein at least optional anesthetis associated with this dissolubility adjusting control agent keeps and separated from solvent, until anesthetis is in curee's administration.
See disclosing of this paper, these and other embodiments will easily be understood by those of ordinary skills.
Brief description of drawings
After reading following detailed description and accompanying drawing as described below, above and other object of the present invention, feature and advantage are by easier to understand.
Fig. 1 sets forth from the interior release profiles of the body of depot formulations of the present invention (preparation 1-2) gained bupivacaine alkali.
Fig. 2 sets forth from the interior release profiles of the body of depot formulations of the present invention (preparation 3-5) gained bupivacaine hydrochloride.
Fig. 3 sets forth from the interior release profiles of the body of depot formulations of the present invention (preparation 6-8) gained hGH.
Describe in detail
Have been found that in some system, can make beneficiating ingredient stabilisation and their release of regulation and control of Injectable depot compositions under the existence of excipient.
Compositions of the present invention is used excipient to offset effect and the regulation and control release profiles of depolymerization.Although applicable excipient has a lot, but example comprises pH modifier and antioxidant, for example reducing agent and free radical scavenger.
PH modifier includes but not limited to inorganic and organic salt, comprises zinc carbonate, magnesium carbonate, calcium carbonate, magnesium hydroxide, calcium hydrogen phosphate, calcium acetate, calcium hydroxide, calcium lactate, calcium maleate, calcium oleate, calcium oxalate, calcium phosphate, magnesium acetate, magnesium hydrogen phosphate, magnesium phosphate, magnesium lactate, maleic acid magnesium, magnesium oleate, magnesium oxalate, zinc acetate, phosphoric acid hydrogen zinc, zinc phosphate, zinc lactate, MALEIC ACID, ZINC SALT, zinc oleate, zinc oxalate and their combination.Reducing agent includes but not limited to cysteine or methionine.Antioxidant includes but not limited to d-α tocopherol acetate, the d1-alpha tocopherol, Vitamin C acyl cetylate, butylation hydroxyl anidole, ascorbic acid, butylatedhydroxyanisole, the butylation hydroxyquinone, BHA, Hydroxycoumarin, Yoshinox BHT, cephalm, ethyl gallate, propyl gallate, the gallate monooctyl ester, the gallate lauryl, nipasol, trihydroxy butyl rophenone, xylenol, DI-tert-butylphenol compounds, vitamin E, lecithin and ethanolamine.
The present invention for compositions comprise those that mix excipient; inorganic salt for example; for example magnesium carbonate or zinc carbonate; their local pH in can (1) balance depot formulations; avoid the impact of after depolymerization, hanging down pH with the protection beneficiating ingredient, and (2) regulate and control release rate profile by dynamic creation microcellular structure in polymer.Due to the alkalescence of more selected inorganic salts, can the local acid pH of balance in bank microenvironment due to depolymerization.Therefore can protect beneficiating ingredient, especially protein, peptide and medicine are avoided the adverse effect of low pH.In addition, do not plan to be subject to theoretical institute to limit, think that the white space that former cause salt occupies is by the dynamic creation microcellular structure when the particle of excipient, for example inorganic salt leaves polymeric matrices because dissolving in water.The size of aperture and density may be subject to the control of raw material and loading level.Thereby required release profiles can be programmable.
And then a lot of small-molecule drugs exist with multi-form, this depends on the pH of the environment that medicine exposes.For example, small-molecule drug can possess positive charge under low pH, under higher pH, possesses negative charge, under middle pH, there is no electric charge.Therefore, by changing local pH, can easily determine hydrophilic-hydrophobic matter and the dissolubility of medicine in substrate of medicine.Thereby, can regulate and control the initial burst of beneficiating ingredient from bank and discharge and release rate profile.The release rate profile of known activity composition from bank can highly depend on the hydrophilic-hydrophobic matter of medicine.Because the hydrophilic-hydrophobic matter of medicine can easily depend on its chemical species and depend under many circumstances local pH, method of the present invention may not need to add the dissolubility of any other preparation raw material with regulating medicine in the drug particle preparation, thereby makes pharmaceutical preparation simpler.
For example, and then a lot of small-molecule drugs contain when peroxide or free radical exist the functional group to the Oxidation sensitivity, amine, hydroxyl.When oxidized, medicine may be lost the active of them and/or cause some unwanted side effect.By mixing antioxidant; such as but not limited to reducing agent or free radical scavenger; can protect the integrity of medicine to avoid the two attack of peroxide or free radical or this, they diffuse into gel vehicle from body fluid, or are produced by the normal foreign body reaction institute to implant.In addition, do not plan to be subject to theoretical institute to limit, think that the white space that former cause excipient occupies is by the dynamic creation microcellular structure when the dispersant liquid drop of the particle of excipient, for example solid reductant, antioxidant and free radical scavenger or excipient, for example solid reductant, antioxidant and free radical scavenger leaves polymeric matrices because of diffusion.The size of aperture and density may be subject to the control of raw material and loading level.Thereby required release profiles can be programmable.
Bioactive ingredients, such as protein, peptide, monoclonal antibody etc., when peroxide or free radical exist, to Oxidation, be generally responsive.When oxidized, bioactive ingredients may be lost the active of them and/or cause some unwanted side effect, for example immunoreation.By mixing reducing agent, antioxidant or free radical scavenger; can protect the integrity of composition to avoid the attack of peroxide and/or free radical; they diffuse into gel vehicle from body fluid, or are produced by the normal foreign body reaction to implant.In addition, do not plan to be subject to theoretical institute to limit, think that the white space that former cause excipient occupies is by the dynamic creation microcellular structure when the dispersant liquid drop of the particle of excipient, for example solid reductant, antioxidant and free radical scavenger or excipient, for example solid reductant, antioxidant and free radical scavenger leaves polymeric matrices because of diffusion.The size of aperture and density may be subject to the control of raw material and loading level.Thereby required release profiles can be programmable.
Compositions according to the present invention is mixed excipient, for example antioxidant, reducing agent and/or free radical scavenger, their free radical and peroxide that for example targeting diffuses into gel vehicle or produced by the normal foreign body reaction to implant from body fluid.
For example can carry out like this to mixing excipient in gel vehicle, directly mix or the premixing excipient in drug particle during the drug particle formulated.On the other hand, can in gel vehicle, load separately excipient and medicine.Excipient as the beneficiating ingredient, can dissolve or be dispersed in gel vehicle.
Definition
Describing and claimed when of the present invention, will be according to following definition use following term.
Singulative " one ", " a kind of " and " being somebody's turn to do " comprise plural indicant, and context separately has except clear and definite instruction.Thereby for example, the appellation of " a kind of solvent " is comprised to single solvent and the mixture of two or more different solvents, the appellation of " a kind of anesthetis " is comprised to single anesthetis and two or more different narcotic combinations, etc.
Appellation to " effect of depolymerization " means to decompose by Biodegradable polymer those by-products that produce without limitation.This class by-product can comprise sour by-product, and for example lactic acid and glycolic, for example, when being used PLGA.In addition, by-products such as oxide, peroxide and free radical also may exist.Therefore, the appellation of " counteracting degradation effect " is meaned and prevents by-product infringement beneficiating ingredient.For example, the excipient that comprises salt can the neutralizing acid by-product.The excipient that comprises reducing agent suppresses peroxide, same, and polyphenoils prevents oxide degraded beneficiating ingredient.
To the appellation of " peroxide or free radical or this two " mean without limitation to be present in body fluid, those peroxide and/or free radical that may be harmful to beneficiating ingredient.For example, the normal foreign body reaction of for example implant generated to free radical and the peroxide that may enter implant and degraded beneficiating ingredient.Other peroxide and free radical are the results of normal body function, also still harmful to beneficiating ingredient.
Term " excipient " means in preparation except beneficiating ingredient or for any useful composition the raw material that generates gel vehicle.Can be used for regulating and controlling rate of release and make the excipient of beneficiating ingredient stabilisation comprise pH modifier, reducing agent, antioxidant and free radical scavenger.
Term " AUC " means the area under curee's in vivoassay curve obtained, from the compositions Implantation Time to time " t " measurement curee implanting in the plasma concentration of beneficiating ingredient, the time is mapped.Time t will be equivalent to the Delivery time section of beneficiating ingredient to the curee.
Term " prominent release index " means that about the particular composition for the beneficiating ingredient systemic delivery following (i) is divided by (ii) gained quotient: (i) according to compositions, implant very first time section is calculated after the curee the AUC hourage (t divided by very first time section
1); (ii) AUC calculated according to the Delivery time of beneficiating ingredient is divided by the hourage (t of total Delivery time
2).For example, prominent 24 hours the time to release index be following (i) divided by (ii) gained quotient: (i) according to compositions, implant AUC that the front twenty four hours after the curee calculates divided by numeral 24; (ii) AUC calculated according to the Delivery time of beneficiating ingredient is divided by the hourage of total Delivery time.
Wording " is dissolved or disperses " and planning to contain all means of setting up beneficiating ingredient and/or the existence of excipient in gel combination, comprises dissolving, dispersion, suspension etc.
Term " whole body " about beneficiating ingredient to the curee send or administration means that beneficiating ingredient is detectable on significant level in curee's blood plasma, in biology.
Term " part " about beneficiating ingredient to the curee send or administration means that beneficiating ingredient is delivered to curee's localization position, but in curee's blood plasma, in biology, on significant level, be not detectable.
Term " gel vehicle " be illustrated in do not have beneficiating ingredient under the compositions that generated by the mixture of polymer and solvent.
Term " short-term " or " short persistent period " are used interchangeably, mean to occur the time period that beneficiating ingredient discharges from bank gel combination of the present invention, generally will be equal to or less than two weeks, preferably approximately 24 hours to approximately 2 weeks, preferably approximately 10 days or shorter, preferably approximately 7 days or shorter, more preferably from about 3 days to approximately 7 days.
Term " for a long time " or " persistent period of prolongation " mean the time period that beneficiating ingredient discharges from implant of the present invention occurs, and will be generally approximately one week or longer, and preferably approximately 30 days or longer, more preferably 1 year.
Term " initial burst " means that about particular composition of the present invention following (i) is divided by (ii) gained quotient: (i) in the implantation weight that beneficiating ingredient discharges from compositions in predetermined initial time section afterwards; (ii) remain the beneficiating ingredient total amount of sending from implanted compositions.Self-evident, initial burst can be different because of shape and the surface area of implant.Therefore, the percentage ratio relevant with initial burst described herein and prominent release index and be intended for use the compositions of testing in the mode of assign group compound from standard syringe.
Term " dissolubility adjusting control agent " means a kind of like this composition about beneficiating ingredient, and it will change the dissolubility of beneficiating ingredient with respect to polymer solvent or water, is different from the beneficiating ingredient dissolubility under this adjusting control agent not.Adjusting control agent can improve or reduce the dissolubility of beneficiating ingredient in solvent or water.But, in the situation that beneficiating ingredient is high water soluble, the dissolubility adjusting control agent will be generally the composition that reduces the dissolubility of beneficiating ingredient in water.The effect of beneficiating ingredient dissolubility adjusting control agent may from dissolubility adjusting control agent and solvent or with the interaction of beneficiating ingredient itself, for example generate coordination compound, or this two.For this purpose, when dissolubility adjusting control agent and beneficiating ingredient " association ", all these classes interact or nucleus formation all likely occurs.Can be at mixed dissolution degree adjusting control agent and beneficiating ingredient before viscogel is combined, or can before adding beneficiating ingredient, join in viscogel, depend on the circumstances.
Term " curee " and " patient " mean animals or humans about the administration of the present composition.
Due to all solvents at least all will be on certain very limited degree on molecular level water soluble (namely with water can mix), term used herein " can not mix " mean by weight 7% or following, preferably 5% or following solvent be water soluble or can mix with water.For purpose disclosed herein, the solubility values of solvent in water is considered to be under 25 ℃ to be measured.Owing to generally acknowledging that the solubility values report may always not carried out under the same conditions, this paper may not be absolute as the limit of the dissolubility with water can mix or water-soluble percentage by weight is quoted, and is the part of a kind of scope or the upper limit.For example, if the upper solubility limit of solvent in water is cited as " 7 % by weight " in this article, and do not provide further the restriction of solvent, reported so that solvent " glyceryl triacetate " that water solubility is the every 100ml water of 7.17 gram was deemed to be included in 7% limit.Water solubility limit used herein is less than 7 % by weight and does not comprise that solvent glyceryl triacetate or water solubility are equal to or greater than the solvent of glyceryl triacetate.
Term " bioerosion " means the material that decomposes gradually on the spot, dissolves, is hydrolyzed and/or corrode.Generally speaking, " bioerosion " polymer herein is hydrolyzable and main by the hydrolysis polymer of bioerosion on the spot.
Polymer of the present invention, solvent and other compositions must be " biocompatibility "; Namely they must not cause stimulation, inflammation or necrosis to environment for use.Environment for use is fluid environment, can comprise in human or animal's subcutaneous, intramuscular, blood vessel in (high/low flow), myocardium inside and outside film, tumor or part in brain, wound site, joint space or body cavity closely.
Term used herein " alkyl " means saturated hydrocarbyl group, usually only must not contain 1 to about 30 carbon atoms, such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, octyl group, decyl etc., and cycloalkyl, such as cyclopenta, cyclohexyl etc.Generally speaking, but be not still inevitably, alkyl herein contains 1 to about 12 carbon atoms.Term " low alkyl group " means 1 to 6 carbon atom, the preferred alkyl of 1 to 4 carbon atom." alkyl of replacement " means the alkyl replaced by one or more substituent groups, and term " contains heteroatomic alkyl " and " assorted alkyl " means the alkyl that wherein at least one carbon atom is replaced by hetero atom.If not indication is separately arranged, term " alkyl " and " low alkyl group " comprise straight chain, side chain, ring-type, do not replace, replace and/or contain heteroatomic alkyl or low alkyl group.
Term used herein " aryl " unless otherwise specified, means aromatic substituent, contain single aromatic ring or a plurality ofly condense together, covalently bound or be connected in the aromatic ring of public group, for example methylene or ethylidene part.Preferred aryl contains an aromatic ring or two aromatic rings that condense or connect, such as phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamines, benzophenone etc., and most preferred aryl is monocycle." aryl of replacement " means the aryl moiety replaced by one or more substituent groups, and term " contains heteroatomic aryl " and " heteroaryl " means the aryl that wherein at least one carbon atom is replaced by hetero atom.Unless otherwise directed, term " aryl " comprises the aryl of heteroaryl, replacement and the heteroaryl of replacement.
Term " aralkyl " means the alkyl replaced by aryl, and wherein alkyl and aryl are as defined above.Term " heteroarylalkyl " means the alkyl replaced by heteroaryl.Unless otherwise directed, term " aralkyl " comprises aralkyl and the unsubstituted aralkyl of heteroarylalkyl and replacement.Generally speaking, the term of this paper " aralkyl " means the low alkyl group of aryl-replacement, the low alkyl group of preferred phenyl-replacement, such as benzyl, phenethyl, 1-phenyl propyl, 2-phenyl propyl etc.
I. Injectable depot compositions
Contrary with former polymer class Injectable depot, bank of the present invention is used a kind of excipient, and it regulates and controls rate of release, and makes the beneficiating ingredient stabilisation by the effect of offsetting depolymerization.Can before to the curee, injecting bank, generate for sending for a long time the Injectable depot compositions of beneficiating ingredient, be viscogel.The viscogel carrier disperses beneficiating ingredient, so that suitable delivery curves to be provided, comprises that, along with beneficiating ingredient discharges from bank, the initial burst of beneficiating ingredient is lower.
Usually, from the pre-filled standard subcutaneous injections device that beneficiating ingredient-viscogel compositions arranged, inject viscogel, generate bank.When being injected, skin and subcutaneous tissue often preferably utilize the syringe needle (minimum diameter) of minimum dimension to be injected, to reduce curee's discomfort.Need reach higher needle injection gel by 16guage, preferred 20gauge and higher, more preferably 22gauge and higher, and then more preferably 24gauge reaches higher.With regard to the high viscosity gel, namely viscosity is approximately 200 to moor or larger gels, and the syringe from syringe needle in the 20-30gauge scope, the injection force of distribution gel may be very high, so that very difficult or quite impossible when manual the injection.Meanwhile, the high viscosity of gel is after injection and between allotment period, to keep the integrity of bank required, also is conducive to the required suspension feature of beneficiating ingredient in gel.
Bank gel combination described herein shows the viscosity reduced when being subject to shearing force.The degree reduced is the function of the polydispersity of the molecular weight of the shear rate of gel when being subject to shearing force, polymer and polymeric matrix on the part degree.When removing shearing force, the viscosity recovery of bank gel combination to be subject to viscosity before shearing force or near.Therefore, the bank gel combination can be subject to shearing force when injection from syringe, and this can temporarily reduce the viscosity during injection process.When completing injection process, remove shearing force, gel reverts to the state before approaching very much.
Excipient
As discussed above, can be used for regulating and controlling rate of release and the excipient of beneficiating ingredient stabilisation is comprised in preparation except beneficiating ingredient or for any useful composition the raw material that generates gel vehicle.Can be used for regulating and controlling rate of release and make the excipient of beneficiating ingredient stabilisation for example comprise pH modifier, reducing agent, antioxidant and free radical scavenger.
PH modifier includes but not limited to inorganic and organic salt, comprises zinc carbonate, magnesium carbonate, calcium carbonate, magnesium hydroxide, calcium hydrogen phosphate, calcium acetate, calcium hydroxide, calcium lactate, calcium maleate, calcium oleate, calcium oxalate, calcium phosphate, magnesium acetate, magnesium hydrogen phosphate, magnesium phosphate, magnesium lactate, maleic acid magnesium, magnesium oleate, magnesium oxalate, zinc acetate, phosphoric acid hydrogen zinc, zinc phosphate, zinc lactate, MALEIC ACID, ZINC SALT, zinc oleate, zinc oxalate and their combination.Reducing agent includes but not limited to cysteine or methionine.Antioxidant includes but not limited to d-α tocopherol acetate, the d1-alpha tocopherol, Vitamin C acyl cetylate, butylation hydroxyl anidole, ascorbic acid, butylatedhydroxyanisole, the butylation hydroxyquinone, BHA, Hydroxycoumarin, Yoshinox BHT, cephalm, ethyl gallate, propyl gallate, the gallate monooctyl ester, the gallate lauryl, nipasol, trihydroxy butyl rophenone, xylenol, DI-tert-butylphenol compounds, vitamin E, lecithin and ethanolamine.
Bioerosion, biocompatible polymer
The polymer that can be used for the inventive method and compositions is bioerosion, that is to say that they are hydrolyzed gradually in the aqueous fluids of patient body, dissolving, physical erosion or otherwise disintegrate.Generally speaking, bioerosion occurs as hydrolysis or the result of physical erosion in polymer, but main bioerosion process normally is hydrolyzed.
This base polymer includes but not limited to polyactide, PGA, poly-(caprolactone), polyanhydride, polyamine, polyurethane, polyesteramide, poe, the Ju diethyleno dioxide ketone, polyacetals, polyketals, Merlon, poly phosphate, polyoxaester, poly-orthocarbonic ester, polyphosphazene, succinate, poly-(malic acid), poly-(aminoacid), polyvinylpyrrolidone, Polyethylene Glycol, poly-hydroxylated cellulose, chitin, chitosan, hyaluronic acid and their copolymer, terpolymer and mixture.
At present preferred polymer is polyactide, lactide acid polymer namely, it may be only to take lactic acid as basis, or may be based on the copolymer of lactic acid and glycolic, and can comprise a small amount of other comonomers, the favourable outcome that can substantial effect can not reach according to the present invention.Term used herein " lactic acid " comprises isomer Pfansteihl, D-ALPHA-Hydroxypropionic acid, DL-LACTIC ACID and lactide, and term " glycolic " comprises Acetic acid, hydroxy-, bimol. cyclic ester.Most preferably the PLG copolymer, generally be called as " PLGA ".The lactic acid of polymer/glycolic monomer ratio can be from approximately 100: 0 to approximately 15: 85, and preferably approximately 75: 25 to approximately 30: 70, more preferably from about 60: 40 to approximately 40: 60, the lactic acid of the copolymer be particularly useful/glycolic monomer ratio was approximately 50: 50.
As U.S. Patent No. 5,242, shown in 910, polymer can be according to U.S. Patent No. 4,443, prepared by 340 instruction.Select as an alternative, can be directly prepared from the mixture of lactic acid or lactic acid and glycolic (contain or do not have further comonomer) by lactide acid polymer, according to U.S. Patent No. 5,310, and 865 described instructions.The content of all these patents all is referenced herein by reference.Applicable lactide acid polymer is commercially available.For example, molecular weight is 8,000,10,000,30,000 and 100,50: 50 lactic acid of 000: ethanol copolymer can be from Boehringer Ingelheim (Petersburg, VA), MedisorbTechnologies International L.P. (Cincinatti, OH) and BirminghamPolymers, Inc. (Birmingham, AL) obtain, as described below.
Applicable polymer includes but not limited to gather (D, L-lactide-altogether-glycolide) (PLGA), and 50: 50DL-PLG, intrinsic viscosity 0.15 (PLGA-BPI, Birmingham Polymers, Inc., Birmingham, AL), 50: 50
RG502 (PLGA RG 502), poly-(D, L-lactide)
L104, PLA-L104, code no.33007, Poly (D, L-lactide-altogether-glycolide) 50: 50
RG502, code no.0000366, poly-(D, L-lactide-altogether-glycolide) 50: 50
RG502H, PLGA-502H, code no.260187, poly-(D, L-lactide-altogether-glycolide) 50: 50
RG503, PLGA-503, code no.0080765, poly-(D, L-lactide-altogether-glycolide) 50: 50
RG755, PLGA-755, code no.95037, poly-L-lactide MW 2,000 (
L 206,
L 207,
L 209,
L 214); Poly-D, the L-lactide (
R 104,
R 202,
R 203,
R 206,
R 207,
R 208); Poly-L-lactide-altogether-D, L-lactide 90: 10 (
LR 209); Poly-D-L-lactide-altogether-glycolide 75: 25 (
RG 752,
RG 756); Poly-D, L-lactide-altogether-glycolide 85: 15 (
RG 858); Poly-L-lactide-altogether-carbonic acid trimethylene ester 70: 30 (
LT 706); The Ju diethyleno dioxide ketone (
X 210) (BoehringerIngelheim Chemicals, Inc., Petersburg, VA); DL-lactide/glycolide 100: 0 (
Polymer 100 DL High,
Polymer 100DL Low); DL-lactide/glycolide 85/15 (
Polymer 8515 DL High,
Polymer 8515 DL Low); DL-lactide/glycolide 75/25 (
Polymer 7525 DL High,
Polymer 7525 DL Low); DL-lactide/glycolide 65/35 (
Polymer 6535 DL, High,
Polymer 6535 DL Low); DL-lactide/glycolide 54/46 (
Polymer 5050 DL High,
Polymer 5050 DL Low); DL-lactide/glycolide 54/46 (
Polymer 5050 DL 2A (3),
Polymer 5050 DL 3A (3),
Polymer 5050 DL4A (3)) (Medisorb Teclmologies International L.P., Cincinnati, OH); Poly-D, L-lactide-altogether-glycolide 50: 50; Poly-D, L-lactide-altogether-glycolide 65: 35; Poly-D, L-lactide-altogether-glycolide 75: 25; Poly-D, L-lactide-altogether-glycolide 85: 15; Poly-DL-lactide; Poly-L-lactide; PGA; Poly-epsilon-caprolactone; Poly-DL-lactide-altogether-caprolactone 25: 75; With poly-DL-lactide-altogether-caprolactone 75: 25 (Birmingham Polymers, Inc., Birmingham, AL).
Biocompatibility, the content of bioerosion polymer in gel combination account for approximately 5 to approximately 90% of viscogel weight, preferably approximately 25 to approximately 80%, usually approximately 35 to approximately 75%, the biocompatible polymer that viscogel comprises combined amount and be less than the solvent of 7wt.% 25 ℃ of lower water miscibilties.
To add solvent to polymer by following amount, so that implantable or injectable viscogel to be provided.
Solvent
Injectable depot compositions of the present invention, except bioerosion polymer, excipient and beneficiating ingredient, can also contain the solvent that is less than 7wt.% 25 ℃ of lower water miscibilties.Solvent must be biocompatibility, should generate gel, preferred viscogel with polymer, and the limiting moisture picked-up enters implant.Applicable solvent will limit the picked-up of implant to moisture basically, and as mentioned above, can take water not miscibilty be feature, namely water solubility or miscibilty are 7 % by weight at the most.Preferably, the water solubility of aromatic alcohol is 5wt.% or following, more preferably 3wt.% or following, and then more preferably 1wt.% or following.Most preferably, the water solubility of aromatic alcohol is equal to or less than 0.5 % by weight.In a preferred embodiment, solvent is selected from ester, aromatic ketone and their mixture of aromatic alcohol, aromatic acid.
Water miscibilty measuring as follows: water (1-5g) is placed in to the transparent vessel tared, controls approximately 25 ℃ of temperature, weigh, drip candidate's solvent.Make solution rotating, be separated with observation.As if when reaching saturation point, this depends on the observation be separated, and solution is placed and spent the night, second day reexamines.If it is saturated that solution remains, this depends on the observation be separated, and measures so the percentage ratio (w/w) of the solvent added.Otherwise add more solvent, repeat this process.The gross weight of the solvent added, divided by the final weight of solvent/water mixture, is measured dissolubility or miscibilty.When using solvent mixture, before being added to the water premixing they.
Except water, not the miscibilty solvent, compositions can also comprise one or more other miscibilty solvents (" composition solvent "), as long as the other solvent of this class is not low-grade alkane alcohol arbitrarily.And composition solvent that can mix compatible with basic solvent can have higher water miscibilty, and the gained mixture still can show moisture is absorbed to the remarkable restriction that enters implant.This class mixture will be called as " composition solvent mixture ".Useful composition solvent mixture can show the water solubility that is greater than basic solvent itself, usually in 0.1 % by weight until and comprise between 50 % by weight, preferably until and comprise 30 % by weight, most preferably until and comprise 10 % by weight, can detrimentally not affect the moisture picked-up inhibitory action showed by implant of the present invention.
Can be used on the composition solvent formed in solvent mixture is those solvents that can mix with basic solvent or solvent mixture, include but not limited to glyceryl triacetate, diacetin, tributyorin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, tributyl 2-acetylcitrate, triethyl group glyceride, triethyl phosphate, diethyl phthalate, diethyl tartrate., mineral oil, polybutene, silicone fluid, glycerol, ethylene glycol, Polyethylene Glycol, capryl alcohol, ethyl lactate, propylene glycol, Allyl carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, METHYLPYRROLIDONE, 2-Pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, butanone, dimethyl formamide, dimethyl sulfoxide, oxolane, caprolactam, decyl methyl sulfoxide, oleic acid, Azone and their mixture.
Solvent or solvent mixture can dissolve polymers, generate viscogel, can before discharging, keep the beneficiating ingredient particle to dissolve or disperse, and separate with environment for use.Compositions of the present invention provides has the low prominent implant of releasing index.The moisture picked-up is subject to solvent or forms the control of solvent mixture, its solubilising or plasticized polymer, but the limiting moisture picked-up enters implant basically.
The content of solvent or solvent mixture accounts for approximately 95 to approximately 5% of viscogel weight usually, and preferably approximately 75 to approximately 15%, most preferably from about 65% to approximately 20%.In especially preferred embodiment, solvent is selected from aromatic alcohol, benzoic low alkyl group and aralkyl ester.At present, most preferred solvent is the mixture of mixture, BB and ethanol of benzoic acid benzyl ester (BB), benzylalcohol (BA), ethyl benzoate (EB), BB and BA and the mixture of BB and EB.
The ratio of polymer and solvent comprises approximately 5: 95 and approximately between 90: 10, preferably at approximately 20: 80 and approximately between 80: 20, more preferably at approximately 30: 70 and approximately between 75: 25.
Beneficiating ingredient
Beneficiating ingredient can be physiology or pharmacological active substance arbitrarily, alternatively with pharmaceutically acceptable carrier and the combination of composition in addition, such as antioxidant, stabilizing agent, penetration enhancers etc., they can not adversely affect the favourable outcome that can be reached by the present invention basically.Beneficiating ingredient can be any such composition, their known human or animal bodies that is delivered to, and preferential water soluble rather than polymer-dissolubility solvent.These compositions comprise ingredient, medicine, vitamin, nutrient etc.Comprise low molecular weight compound, protein, peptide, genetic stocks, nutrient, vitamin, food additive, sexual organ's antibacterial, fertility inhibitor and fertility promoter at the component type that meets this requirement.
The ingredient that can be sent by the present invention comprises and acts on following medicine: peripheral nervous, adrenoreceptor, cholinoceptor, skeletal muscle, cardiovascular system, smooth muscle, blood circulation, joint part, neural effector junction, endocrine and Hormone system, immune system, reproductive system, skeletal system, autacoid system, nutrition and Excretory system, histamine system and central nervous system.Applicable composition for example can be selected from protein, enzyme, hormone, polynucleotide, nucleoprotein, polysaccharide, glycoprotein, lipoprotein, polypeptide, steroid, analgesic, local anesthetic, antibiotic, chemotherapeutics, immunosuppressant, antiinflammatory (comprising anti-inflammatory corticosteroid), antiproliferative, antimitotic agent, angiogenic agent, major tranquilizer, central nervous system (CNS) agent, anticoagulant, the fibrin distintegrant, somatomedin, antibody, medicament for the eyes, metabolite with these kinds, analog (comprising analog synthetic and that replace), derivant (comprising the covalent conjugates with manner known in the art and other macromolecular aggregation conjugate/fusions and nothing to do with chemical part), fragment, and purification, separate, restructuring and chemosynthesis version.
The exemplary drugs that can be sent by the present composition includes but not limited to bupivacaine, buprenorphine, the ethionic acid prochlorperazine, ferrous sulfate, aminocaproic acid, mecamylamine hydrochloride, procaine amide hydrochloride, amfetamine sulfate, methamphetamine hydrochloride, hydrochloric acid benzamphetamine, isoproterenol sulfate, phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, the bromine scopolamine, isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, the cholic acid theophylline, cefalexin hydrochloride, diphenidol, meclozine hydrochloride, the maleic acid prochlorperazine, phenoxybenzamine, thiethylperazine dimaleate, anisindione, diphenadione, cardilate, digoxin, isoflurophate, acetazolamide, methazolamide, bendroflumethiazide, chloropromaide, tolazamide, chlormadinone, phenaglycodol, allopurinol, aluminium aspirin, methotrexate, acetyl sulfisoxazole, erythromycin, hydrocortisone, the acetic acid hydrocortisone, the acetic acid cortisone, dexamethasone and derivant thereof (for example betamethasone), triamcinolone, methyltestosterone, testosterone, the 17-S-estradiol, ethinylestradiol, ethinylestradiol 3-methyl ether, prednisolone, acetic acid 17 Alpha-hydroxy progesterone, 19-is nor--progesterone, norgestrel, norethindrone, the alkynes nordinone, norethiederone, progesterone, norgesterone, Norethynodrel, aspirin, indometacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, sorbide nitrate, Propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, cefalexin, erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine, diltiazem
, milrinone, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenufen, fluprofen, tolmetin, alclofenac, mefenamic acid, flufenamic acid, difuinal, nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine, lisinopril, enalapril, enalaprilat, captopril, ramipril, famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil, chlorine nitrogen
, diazepam, amitriptyline, imipramine, paliperidone, resperidone, octreotide, alendronic Acid, α-4, β-7 receptor antagonist leukosite and infliximab (Remicade).
The further example of beneficiating ingredient is protein and peptide, and they include but not limited to bone morphogenetic protein, insulin, colchicine, glucagon, thyrotropin, parathyroid gland and pituitary hormone, calcitonin, feritin, prolactin antagonist, thyroliberin, parent's thyroxin, follicle-stimulating hormone, chorionic gonadotropin, gonadotropin-releasing hormone, bovine growth hormone, pig growth hormone, oxytocin, vassopressin, GRF, somatostatin, lypressin, Pancreozymin, lutropin, LHRH, LHRH agonist and antagonist, leuprolide, interferon (Intederon Alpha-2a for example, Interferon Alpha-2b and synonym interferon), interleukin, growth hormone (for example human growth hormone and derivant thereof, for example methionine-human growth hormone and go-phenylalanine human growth hormone, parathyroid hormone, bovine growth hormone and pig growth hormone), fertility inhibitor (for example prostaglandin), fertility promoter, somatomedin (epidermal growth factor (EGF) for example, platelet derived growth factor (PDGF), fibroblast growth factor (FGF), transforminggrowthfactor-α (TGF-α), transforming growth factor-beta (TGF-β), erythropoietin (EPO), insulin like growth factor-1 (IGF-I), insulin like growth factor-1 I (IGF-II), il-1, interleukin-2, interleukin-6, interleukin-8, tumor necrosis factor-alpha (TNF-α), tumor necrosis factor-β (TNF-β), interferon-' alpha ' (INF-α), interferon-beta (INF-β), interferon-γ (INF-γ), interferon-ω (INF-ω), colony stimulating factor (CGF), the vascular cell growth factor (VEGF), thrombopoietin (TPO), stroma cell derivative factor (SDF), placental growth factor (P1GF), hepatocyte growth factor (HGF), granulocyte macrophage colony stimulating factor (GM-CSF), neuroglia derives close neural factor (GDNF), granulocyte colony-stimulating factor (G-CSF), parent's ciliary nerves factor (CNTF), skeletal growth factor, transforming growth factor), bone morphogenetic protein (BMP), thrombin, human pancreas's releasing factor, the pharmaceutically acceptable salt of the analog of these compounds and derivant and these compounds or their analog or derivant.
The present invention also can be used for chemotherapeutics, for the topical application of these compositions, to avoid or to reduce systemic side effects.The gel of the present invention that contains chemotherapeutics can enter tumor tissues by direct injection, for chemotherapeutics go through a period of time continue send.In some cases, particularly, after the excision of tumor, gel can directly be implanted in the gained cavity, or can be used as coating and be applied to the residue tissue.In the situation that implanted gel after operation likely adopts the gel with viscosity higher, because they needn't be through the syringe needle of minor diameter.The representative chemotherapeutics that can be sent according to practice of the present invention for example comprises and suppresses oncogene translation or carboplatin, cisplatin, paclitaxel, BCNU, vincristine, camptothecine, etoposide, cytokine, ribozyme, interferon, oligonucleotide and the oligonucleotide sequence of transcribing, above-mentioned functional deriv and known chemotherapeutics, for example U.S. Patent No. 5,651,986 described those.The application be particularly useful for the water solublity chemotherapeutics continue send, for example cisplatin and carboplatin, and the soluble derivative of paclitaxel.Those features that the present invention minimizes burst effect are particularly conducive to the administration of all kinds water solublity beneficiating ingredient, but particularly clinically useful and effectively but may there are those compounds of adverse side effect.
On the degree of above not mentioning, also can use above-mentioned U.S. Patent No. 5,242,910 described beneficiating ingredients.A kind of definite advantage of the present invention is raw material, for example protein that is difficult to microencapsulation or is processed into microsphere, take lysozyme as example, with the cDNA and the DNA that are incorporated in virus and non-virus carrier, can be incorporated in compositions of the present invention, can not degrade because being exposed to the high temperature and the degeneration solvent that often are present in other process technologies.
Beneficiating ingredient preferably is incorporated into from the viscogel of polymer and solvent generation, is the form of particle, and mean diameter is generally and is less than 250 microns, approximately 5 to approximately 250 microns, and preferably approximately 20 to approximately 125 microns is often 38 to 68 microns.
In order to generate suspension or the dispersion of beneficiating ingredient particle the viscogel from polymer and solvent generation, can under environmental condition, utilize the low shear of any conventional, for example Ross double-planet formula mixer.In such a way, can realize effective distribution of beneficiating ingredient, basically non-degradable beneficiating ingredient.
Beneficiating ingredient dissolves or the amount in compositions of being dispersed in accounts for 0.1% to approximately 50% of polymeric blends, solvent and beneficiating ingredient gross weight usually, and preferably approximately 1% to approximately 30%, more preferably from about 2% to approximately 20%, often 2 to 10%.According to the content of beneficiating ingredient in compositions, can obtain different release profiles and the prominent index of releasing.More specifically, with regard to given polymer and solvent, the amount by regulating these components and the amount of beneficiating ingredient, can obtain and depend on the release profiles that depolymerization spreads from compositions more than beneficiating ingredient, and vice versa.In this, under lower beneficiating ingredient LOADING RATES, the general release profiles that obtains the reflection depolymerization, wherein rate of release increased along with the time.Under higher LOADING RATES, the general release profiles caused by the beneficiating ingredient diffusion that obtains, wherein rate of release reduced along with the time.Under middle LOADING RATES, obtain the release profiles of combination, so that if necessary, can reach the rate of release of substantial constant.For prominent releasing minimized, the LOADING RATES of beneficiating ingredient be whole gel combinations, namely polymer, solvent and beneficiating ingredient weight 30% or below be preferred, LOADING RATES be 20% or below be preferred.
By regulating rate of release and the LOADING RATES of beneficiating ingredient, the treatment effectiveness that provides beneficiating ingredient to go through the lasting delivery phase of expection is sent.Preferably, beneficiating ingredient will exist with such concentration in polymer gel, and they are more than the water saturation concentration of beneficiating ingredient, with the medicine storage that provides beneficiating ingredient therefrom to distribute.Although the rate of release of beneficiating ingredient depends on specific environment, the beneficiating ingredient that for example will give, but rate of release can be approximately 0.1 micro-g/day to about 10 mg/day, preferably approximately 1 micro-g/day to about 5 mg/day, more preferably from about 10 micro-g/days to about 1 mg/day, lasts approximately 24 hours to approximately 360 days, preferably 24 hours to approximately 180 days, more preferably 24 hours to approximately 120 days, often 3 days to approximately 90 days.And then, by regulating the amount of the bank gel of injecting, can regulate the dosage of beneficiating ingredient.If need to send, can send larger amount in shorter time.Generally speaking, if larger prominent releasing can be tolerated, so higher rate of release is possible.Gel combination by the situation of Operation in or be used as the situation of " leaving over " bank while being treated at the same time the operation of morbid state or another kind of disease, the more high dose normally given while likely being provided at the injection implant.And then, by regulating the volume of the gel of implanting or the injectable gel of injecting, can control the dosage of beneficiating ingredient.Preferably, this system discharges 40 % by weight or following beneficiating ingredient in being present in viscogel after implanting the curee in first 24 hours.More preferably, after implantation, in first 24 hours, will discharge 30 % by weight or following beneficiating ingredient, the compositions of implanting prominent release index be 12 or below, preferably 8 or below.
Optional other components
Can there be other components in gel combination, need or for compositions provides the character of use as long as have, for example Polyethylene Glycol, hygroscopic agent, stabilizing agent, pore former, thixotropic agent and other.When compositions is included in solvable in aqueous environments or unsettled peptide or protein, may need to comprise the dissolubility adjusting control agent in compositions by height, can be for example stabilizing agent.Various adjusting control agents are described in United States Patent(USP) Nos. 5,654, and in 010 and 5,656,297, its disclosure is referenced herein by reference.For example, in the situation that hGH preferably includes a certain amount of divalent metal salt, preferred zinc.Can coordinate with beneficiating ingredient or associate provides this class adjusting control agent and the stabilizing agent example of stabilisation or regulation and control release effects to comprise metal cation, preferred bivalence, in compositions, with following form, exist: magnesium carbonate, zinc carbonate, calcium carbonate, magnesium acetate, magnesium sulfate, zinc acetate, zinc sulfate, zinc chloride, magnesium chloride, magnesium oxide, magnesium hydroxide, other antacids etc.The amount of this constituents used will depend on the attribute of the coordination compound generated between beneficiating ingredient and this composition, if any, or the attribute of association.The mol ratio of dissolubility adjusting control agent or stabilizing agent and beneficiating ingredient can adopt approximately 100: 1 to 1: 1 usually, preferably 10: 1 to 1: 1.
Pore former comprises biocompatible materials, and they dissolve, disperse or degrade when contacting with body fluid, produces hole or passage in polymeric matrix.Usually, can use by convention organic and inorganic material as pore former, they have water-soluble sugar (such as sucrose, glucose), water soluble salt (such as sodium chloride, sodium phosphate, potassium chloride and sodium carbonate), water-soluble solvent (such as METHYLPYRROLIDONE and Polyethylene Glycol) and water-soluble polymer (such as carboxymethyl cellulose, hydroxypropyl cellulose etc.).The content of this class material can account for approximately 0.1% to approximately 100% of polymer weight, but usually will be less than 50% of polymer weight, more typically less than 10-20%.
Thixotropic agent comprises gives the composition of polymer gel with thixotropic nature, such as low-grade alkane alcohol (such as ethanol, isopropyl alcohol) etc.Self-evident, thixotropic agent of the present invention can not form simple diluent or polymer solvent, only by each concentration of component that reduces compositions, reduces viscosity.The use of conventional diluent can reduce viscosity, but also can cause above-mentioned burst effect when the compositions of injection process dilution.On the contrary, Injectable depot compositions of the present invention, through preparation, can be avoided burst effect by selecting thixotropic agent, once so that injection enters space, thixotropic agent only has inappreciable impact to the releasing properties of primal system.Preferably, this system discharges 40 % by weight or following beneficiating ingredient in being present in viscogel after implanting the curee in first 24 hours.More preferably, after implantation, in first 24 hours, will discharge 30 % by weight or following beneficiating ingredient, the compositions of implanting prominent release index be 12 or below, preferably 8 or below.
II. application and administration
The means of administration of implant is not limited to injection, but this mode of sending may be often preferred.If implant will be as leaving over the product administration, it can adapt to the body cavity of the rear existence of having performed the operation, or flowable gel can be brushed or spread upon on remnant tissue or bone.This class application can allow to load the beneficiating ingredient higher than the concentration usually existed with Injectable composition in gel.
In order further to understand various aspects of the present invention, according to the following example, obtain the described result of aforementioned figures.
Embodiment
Below the some embodiment that implement the specific embodiment of the present invention.These embodiment only, for explanation, do not plan to limit the scope of the invention by any way.
Embodiment 1
Bank gel prepared product
Be prepared as follows the gel vehicle be used in the Injectable depot compositions.Glass container is placed on Mettler PJ3000 top carrying balance.Being weighed into poly-(PLG) (PLGA) to glass container, is 50: 50 DL-PLG, and intrinsic viscosity is 0.15 (PLGA-BPI, Birmingham Polymers, Inc., Birmingham, AL), and 50: 50
RG502 (PLGA RG502).Tare to the glass container that contains polymer, add corresponding solvent.The percentage ratio of various polymer/solvent combination is described in table 1 below.Polymer/solvent mixture is stirred under 250 ± 50rpm to (IKA electricity agitator, IKH-Werke GmbH and Co., Stanfen, Germany) about 5-10 minute, obtain the viscous paste sample material that contains polymer particle.To contain the seal of vessel of polymer/solvent mixture, the temperature control calorstat that is placed in balance to 37 ℃ reaches 1 to 4 day, the intermittent stirring, and this depends on the ratio of solvent and polymer type and solvent and polymer.Take out polymer/solvent mixture from calorstat when presenting the amber homogeneous solution of clarification.Then, mixture is placed in to baking oven (65 ℃) and reaches 30 minutes.Notice that taking out rear PLGA from baking oven is dissolved in mixture.
Utilize following solvent or solvent mixture and following polymers to prepare other bank gel vehicle: benzoic acid benzyl ester (BB), benzylalcohol (BA), ethyl benzoate (EB), BB/BA, BB/ ethanol, BB/EB; Poly-(D, L-lactide)
L104, PLA-L104, code no.33007, poly-(D, L-lactide-altogether-glycolide) 50: 50
RG502, code no.0000366, poly-(D, L-lactide-altogether-glycolide) 50: 50
RG502H, PLGA-502H, code no.260187, poly-(D, L-lactide-altogether-glycolide) 50: 50
RG503, PLGA-503, code no.0080765, poly-(D, L-lactide-altogether-glycolide) 50: 50
RG755, PLGA-755, code no.95037, poly-L-lactide MW 2,000 (
L 206,
L 207,
L 209,
L214); Poly-D, the L-lactide (
R 104,
R 202,
R203,
R 206,
R 207,
R 208); Poly-L-lactide-altogether-D, L-lactide 90: 10 (
LR 209); Poly-D-L-lactide-altogether-glycolide 75: 25 (
RG 752,
RG 756); Poly-D, L-lactide-altogether-glycolide 85: 15 (
RG 858); Poly-L-lactide-altogether-carbonic acid trimethylene ester 70: 30 (
LT 706); The Ju diethyleno dioxide ketone (
X 210) (Boehringer Ingelheim Chemicals, Inc., Petersburg, VA); DL-lactide/glycolide 100: 0 (
Polymer 100 DL High,
Polymer 100 DL Low); DL-lactide/glycolide 85/15 (
Polymer8515 DL High,
Polymer 8515 DL Low); DL-lactide/glycolide 75/25 (
Polymer 7525 DL High,
Polymer 7525DL Low); DL-lactide/glycolide 65/35 (
Polymer 6535 DL High,
Polymer 6535 DL Low); DL-lactide/glycolide 54/46 (
Polymer 5050 DL High,
Polymer 5050 DL Low); With DL-lactide/glycolide 54/46 (
Polymer 5050 DL 2A (3),
Polymer 5050 DL 3A (3),
Polymer 5050 DL4A (3)) (Medisorb Technologies International L.P., Cincinnati, OH); With poly-D, L-lactide-altogether-glycolide 50: 50; Poly-D, L-lactide-altogether-glycolide 65: 35; Poly-D, L-lactide-altogether-glycolide 75: 25; Poly-D, L-lactide-altogether-glycolide 85: 15; Poly-DL-lactide; Poly-L-lactide; PGA; Poly-epsilon-caprolactone; Poly-DL-lactide-altogether-caprolactone 25: 75; With poly-DL-lactide-altogether-caprolactone 75: 25 (BirminghamPolymers, Inc., Birmingham, AL).
Embodiment 2
Bupivacaine alkali prepared product
Bupivacaine hydrochloride (Sigma-Aldrich Corporation, St.Louis, MO) is dissolved in to deionization (DI) water, and concentration is 40mg/ml (saturated).The sodium hydroxide (1N solution) that adds amount of calculation to this solution, the pH to 10 of adjusting final mixture, to be settled out BP alkali.Precipitated product is filtered, further use DI water washing at least three times.By precipitated product in about 40 ℃ of vacuum dry 24 hours.
Embodiment 3
Bupivacaine particle prepared product
Following bupivacaine alkali and the hydrochlorate that uses bupivacaine hydrochloride (Sigma-Aldrich Corporation, St.Louis, MO) or prepare according to embodiment 2 prepares the bupivacaine drug particle.Grinding bupivacaine, then utilize 3 " stainless steel sift sieves.Typical scope comprises 25 μ m to 38 μ m, 38 μ m to 63 μ m and 63 μ m to 125 μ m.
HGH/Zn complex preparation thing
Utilize concentrated/dialysis to select the diafiltration instrument, hGH aqueous solution (5mg/ml) (BresaGenCorporation, Adelaide, Australia) is concentrated into to 10mg/ml.To wash with the TRIS (pH 7.6) of 5 times of volumes through the hGH solution of diafiltration, further in 5mM TRIS buffer, be concentrated into the 40mg/ml solution of hGH.Add the solution of 27.2mM zinc (from zinc acetate) in 5mM TRIS buffer of equal portions, obtain final mixture, zinc: the mol ratio of hGH is 15: 1.Make this mixture coordinate about 1 hour under 4 ℃.Then this coordination compound is precooled to-70 ℃, utilizes the lyophilizing of Durastop μ P lyophil apparatus according to the following lyophilization cycle
Embodiment 5
The particle of hGH/Zn complex preparation thing
The different particles of prepared lyophilizing hGH/Zn complex preparation hGH/Zn coordination compound from embodiment 4, do not have compacting or process compacting: 1) utilize the Waring blender to grind the hGH/Zn coordination compound through lyophilizing, do not suppress.Collect the particle between 120 orders (125 μ m) and 400 orders (38 μ m).2) will be transferred to through the hGH/Zn coordination compound of lyophilizing the circular compacting of 13mm punch die, under 5 tons of pressure, compacting is 5 minutes, forms granule.Utilize Waring blender abrasive grains.Collect the particle between 120 orders (125 μ m) and 400 orders (38 μ m).
Embodiment 6
Zinc carbonate particle prepared product
Utilize 3 " stainless steel sift, by 38 μ m, sieve, retain 15 μ m, prepare zinc carbonate zinc hydroxide hydrate (ZnCO
32Zn (OH)
2XH
2O) particle of (Aldrich, Milwaukee, WI, USA), size is 15-38 μ m.
Embodiment 7
Medicine loads
The particle of as above preparation is joined in gel vehicle, and consumption is the 10-30 % by weight, and manual fusion, until dry powder is fully moistening.Then utilize the Caframo mechanical agitator with square-most advanced and sophisticated metal spoon to mix the light yellow particle/gel mixture of abundant fusion emulsus by routine.The gained preparation is as described in table 1,2 and 3.
Table 1
| Preparation | PLGA RG 502 a (wt％) | Benzoic acid benzyl ester (wt%) | Bupivacaine alkali (wt%) | ZnCO 3(wt％) |
| 1 | 45 | 45 | 10 | 0 |
| 2 | 43.5 | 43.5 | 10 | 3 |
aPLGA RG 502，MW＝16,000
Table 2
| Preparation | LMW PLGA a (wt％) | Benzylalcohol (wt%) | Bupivacaine HCl (wt%) | ZnCO 3(wt％) |
| 3 | 67.5 | 22.5 | 10 | 0 |
| 4 | 65.2 | 21.8 | 10 | 3 |
| 5 | 63.0 | 21 | 10 | 6 |
aLow-molecular-weight (LMW, MW=10,000) PLGA with carboxyl terminal
The common loading of bupivacaine and zinc carbonate
By embodiment 3, the prepared zinc carbonate particle of prepared drug particle and embodiment 6 is by the predetermined ratio premixing, in process as described in Example 7, the particles mixture of medicine and zinc carbonate joined to gel vehicle.The gained preparation is as described in table 1 and 2.
Embodiment 9
The common loading of hGH/Zn coordination compound particle and zinc carbonate
By embodiment 5, the prepared zinc carbonate particle of prepared hGH/Zn coordination compound particle and embodiment 6 joins separately in gel vehicle by predetermined ratio, is mixing the particle of hGH/Zn coordination compound and zinc carbonate in process in gel vehicle as described in Example 7.The gained preparation is as described in Table 3.
Table 3
| Preparation | PLGA RG502 a (wt％) | Benzoic acid benzyl ester (wt%) | HGH/Zn coordination compound (wt%) | ZnCO 3(wt％) |
| 6 | 45.0 | 45.0 | 10 b | 0 |
| 7 | 45.0 | 45.0 | 10 c | 0 |
| 8 | 43.5 | 43.5 | 10 c | 3 |
aPLGA RG 502，MW＝16,000；
bCompacting does not in advance prepare hGH/Zn coordination compound particle;
cThrough the hGH/Zn of compacting preparation in advance coordination compound particle.
Research in the bupivacaine body
Follow open scheme and carry out research (4 or 5 every group) in the rat body, to be determined at the bupivacaine blood plasma level of bupivacaine after via implant system whole body of the present invention administration.Bank gel bupivacaine preparation is loaded in the 0.5cc disposable syringe of customization.To syringe, disposable 18gauge syringe needle is installed, is utilized circulation to bathe and be heated to 37 ℃.Bank gel bupivacaine preparation is expelled in rat, by fixed time interval (1 hour, 4 hours and the 1st, 2,5,7,9,14,21 and 28 days) blood drawing, utilizes LC/MS to analyze bupivacaine.
Fig. 1 sets forth from the interior release profiles of the various long-term representative bupivacaine alkali rat bodies that system for, depot formulations (about 1 month) obtains, comprise of the present invention those.There is no ZnCO
3The common depot formulations (preparation 1) loaded shows biphase release profiles, that is to say in the first stage (<1-2 week), rate of release reduces (control of mainly being spread) along with the time, and, in the latter half (1-2 is after week), discharge and become steadily or increase (due to depolymerization and diffusion) along with the time.ZnCO is arranged
3The common depot formulations (preparation 2) loaded does not show typical biphase release profiles, and after initial burst discharges, release profiles more steadily (approaches and there is no ZnCO
3Preparation 1), replace of short duration release duration.This discovery clearly proves, to depot formulations, adds ZnCO
3Can become release rate profile to approach the zero order release rate curve from typical two facies patterns, and the regulation and control release duration.
Surprising is by ZnCO is arranged
3The shown rate of release of the common depot formulations (preparation 2) loaded is faster than there is no ZnCO
3The common preparation (preparation 1) loaded.Usually, in alkaline environment (pH>7.0), the expection bupivacaine keeps its alkali form, because its hydrophobicity will show slowly, discharges.But as shown in preparation 2, under the existence of weak base, ZnCO for example
3(pKa>7), rate of release is faster than there is no weak base, and what to bupivacaine by the hydrophilic state, show is similar.
Fig. 2 sets forth from the interior release profiles of the various short-terms representative hydrochloric acid bupivacaine rat body that system for, depot formulations (2 weeks at the most) obtains, comprise of the present invention those.There is no ZnCO
3The common depot formulations (preparation 3) loaded shows the release that medicine reduces in time, shows to be mainly the release profiles of DIFFUSION CONTROLLED.But, ZnCO is arranged
3The common depot formulations (preparation 4 and 5) loaded with there is no ZnCO
3The common preparation (preparation 3) loaded is compared prominent releases that performance reduced and release profiles (approaching zero level) more stably, shows to add ZnCO to depot formulations
3Also can change the release rate profile of short-term bank.
Embodiment 11
Research in the hGH body
Follow open scheme and carry out research in the rat body, to be determined at the hGH serum levels of hGH after via implant system whole body of the present invention administration.Bank gel hGH preparation is loaded in the 0.5cc disposable syringe of customization.To syringe, disposable 18gauge 1 is installed " syringe needle, utilize circulation to bathe and be heated to 37 ℃.Bank gel hGH preparation is expelled in Immunosuppreessed rats, at injection latter 1 hour, 4 hours, the 1st, 2,4,7,10,14,21 and 28 days collection blood serum samples.Before analysis, all blood serum sample is stored under 4 ℃.Utilize the complete hGH content of radioimmunoassay (RIA) analytic sample.Make rat euthanasia when research finishes, carry out rough clinical observation, fetch bank, carry out the integrity observation.
Fig. 3 sets forth release profiles in representative human growth hormone (hGH) the rat body obtained from various depot compositions, comprise of the present invention those.ZnCO is arranged
3The common depot formulations (preparation 8) loaded with there is no ZnCO
3The common preparation (preparation 6 and 7) loaded is compared and is tending towards having release rate profile and shorter release duration more stably, as the bupivacaine in Fig. 1.This further shows to add ZnCO to depot formulations as described herein
3Also can change protein release rate curve and regulation and control release duration.
The particle prepared product of reducing agent
Utilizing 3 " stainless steel sift sieves by 38 μ m, retains 15 μ m, prepares the particle of reducing agent methionine (Sigma, St.Louis, MO, USA), and size is 15-38 μ m.
Embodiment 13
Load hGH and methionine and body build-in test in bank
The reducing agent methionine that adds embodiment 12 to gel vehicle, consumption is the 0.1-20 % by weight, manual fusion, until dry powder is fully moistening.Then utilize the Caframo mechanical agitator with square-most advanced and sophisticated metal spoon to mix the light yellow particle/gel mixture of abundant fusion emulsus by routine.Load therapeutic agent to gel vehicle, for example protein, resemble hGH, or micromolecule, for example bupivacaine.The ratio of methionine and therapeutic agent approximately 0.1: 99.9 to approximately between 70: 30.Carry out the body build-in test, to generate release rate profile.
Embodiment 14
The particle prepared product of antioxidant
Utilizing 3 " stainless steel sift sieves by 38 μ m, retains 15 μ m, prepares the particle of antioxidant vitamin E acid succinate (Sigma, St.Louis, MO, USA), and size is 15-38 μ m.
Embodiment 15
Medicine loads and the body build-in test
The antioxidant vitamin E that adds embodiment 14 to gel vehicle, consumption is the 0.1-20 % by weight, manual fusion, until dry powder is fully moistening.Then utilize the Caframo mechanical agitator with square-most advanced and sophisticated metal spoon to mix the light yellow particle/gel mixture of abundant fusion emulsus by routine.When the content of vitamin E is very low (approximately 0.1 to approximately between 5 % by weight), it is dissolved in gel vehicle.Load therapeutic agent to gel vehicle, for example protein, resemble hGH, or micromolecule, for example bupivacaine.The ratio of vitamin E and therapeutic agent approximately 0.1: 99.9 to approximately between 70: 30.Carry out the body build-in test, to generate release rate profile.
Claims (35)
1. continue to send the Injectable depot gel combination of beneficiating ingredient, comprise:
Gel vehicle, the bioerosion that comprises 5 % by weight to 90 % by weight, biocompatible polymer and water is the miscibilty solvent not, the copolymer that wherein said polymer is lactic acid and glycolic (PLGA), and wherein said solvent is selected from lower group: aromatic alcohol, benzoic lower alkyl esters and benzoic rudimentary aralkyl ester, the water miscibilty of described solvent is less than or equal to 7 % by weight under 25 ℃, and the ratio of wherein said polymer and described solvent is between 5: 95 and 90: 10;
Dissolve or be dispersed in the beneficiating ingredient of 0.1 % by weight to 50 % by weight in this gel vehicle, this beneficiating ingredient is bupivacaine or human growth hormone; With
The excipient of 0.01 % by weight to 50 % by weight of regulation and control rate of release, this excipient is cysteine or methionine, wherein this excipient makes this beneficiating ingredient stabilisation by the effect of offsetting depolymerization;
Wherein after administration, twenty four hours to ten continued to send between two months.
2. the compositions of claim 1, the excipient that comprises 0.05 % by weight to 40 % by weight.
3. the compositions of claim 2, the excipient that comprises 0.1 % by weight to 30 % by weight.
4. the compositions of claim 1, the ratio between wherein said excipient and this beneficiating ingredient is between 0.1: 99.9 and 99: 1.
5. the compositions of claim 4, wherein said ratio is between 1: 99 and 60: 40.
6. the compositions of claim 1, the not moisture miscibilty of wherein said compositions is greater than the solvent of 7 % by weight under 25 ℃.
7. the compositions of claim 1, wherein said solvent is benzylalcohol.
8. the compositions of claim 1, wherein said solvent is benzoic acid benzyl ester.
9. the compositions of claim 1, wherein said solvent is ethyl benzoate.
10. the compositions of claim 1, wherein said solvent is to be selected from the composition solvent of lower group: glyceryl triacetate, diacetin, tributyorin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, tributyl 2-acetylcitrate, triethyl group glyceride, triethyl phosphate, diethyl phthalate, diethyl tartrate., mineral oil, polybutene, silicone fluid, glycerol, ethylene glycol, Polyethylene Glycol, capryl alcohol, ethyl lactate, propylene glycol, Allyl carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, METHYLPYRROLIDONE, 2-Pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, butanone, dimethyl formamide, dimethyl sulfoxide, oxolane, caprolactam, decyl methyl sulfoxide, oleic acid, Azone and their combination.
11. the compositions of claim 1, the weight average molecular weight of wherein said polymer is between 3,000 to 120,000, and the lactic acid of this copolymer and the monomer ratio of glycolic are between 50: 50 to 100: 0.
12. the compositions of claim 1, wherein said polymer is poly-(PLG).
13. the compositions of claim 1, wherein said polymer is poly-(L-lactide-co-glycolide).
14. the compositions of claim 1, the polymer that comprises 25 % by weight to 80 % by weight.
15. the compositions of claim 14, the polymer that comprises 35 % by weight to 75 % by weight.
16. the compositions of claim 1, the beneficiating ingredient that wherein said compositions comprises 0.5 % by weight to 40 % by weight.
17. the compositions of claim 16, the beneficiating ingredient that wherein said compositions comprises 1 % by weight to 30 % by weight.
18. the compositions of claim 1, the ratio of wherein said polymer and this solvent is between 20: 80 and 80: 20.
19. the compositions of claim 18, the ratio of wherein said polymer and this solvent is between 30: 70 and 75: 25.
20. the compositions of claim 1 further comprises at least one following ingredients: emulsifying agent, pore former, dissolubility adjusting control agent and penetrating agent for anesthetis.
21. the compositions of claim 1, wherein said beneficiating ingredient comprises the particle that mean diameter is less than 250 μ m.
22. the compositions of claim 21, wherein said mean diameter is between 5 μ m and 250 μ m.
23. the compositions of claim 22, wherein said mean diameter is between 20 μ m and 125 μ m.
24. the compositions of claim 23, wherein said mean diameter is between 38 μ m and 63 μ m.
25. the method that twenty four hours to ten two months continues to send the Injectable depot gel combination of beneficiating ingredient to the curee is gone through in preparation, comprising:
Bioerosion, biocompatible polymer and the water that mixes 5 % by weight to 90 % by weight is the miscibilty solvent not, the copolymer that wherein said polymer is lactic acid and glycolic (PLGA), and wherein said solvent is selected from lower group: aromatic alcohol, benzoic lower alkyl esters and benzoic rudimentary aralkyl ester, the water miscibilty of described solvent is less than or equal to 7 % by weight under 25 ℃, the ratio of wherein said polymer and described solvent, between 5: 95 and 90: 10, generates gel vehicle;
To dissolving or disperse the beneficiating ingredient of 0.1 % by weight to 50 % by weight, this beneficiating ingredient in this gel vehicle, be bupivacaine or human growth hormone; With
To the excipient of 0.01 % by weight to 50 % by weight of mixing the regulation and control rate of release in this gel vehicle, described excipient is cysteine or methionine;
Wherein the effect of depolymerization is offset in the existence of this excipient.
26. the method for claim 25, further be included in to premixing excipient and beneficiating ingredient before admixed excipients in gel vehicle and beneficiating ingredient.
27. the method for claim 25, further comprise to gel vehicle and load separately excipient and beneficiating ingredient.
28. the method for claim 25, wherein said excipient is dissolve or be dispersed in this gel vehicle.
29. the method for claim 25, further comprise excipient and the beneficiating ingredient of loading ratio between 0.1: 99.9 and 99: 1.
30. the method for claim 25, wherein said ratio is between 1: 99 and 60: 40.
31. the method for claim 25, the not moisture miscibilty of wherein said compositions is greater than the solvent of 7 % by weight under 25 ℃.
32. the method for claim 25, the weight average molecular weight of wherein said polymer is between 3,000 to 120,000, and the lactic acid of this copolymer and the monomer ratio of glycolic are between 100: 0 to 15: 85.
33. the method for claim 25, wherein said polymer is poly-(PLG).
34. the method for claim 25, wherein said polymer is poly-(L-lactide-co-glycolide).
Reach twenty four hours to the ten administration test kit of two months after administration 35. continue to send beneficiating ingredient, this test kit comprises:
Gel vehicle, the bioerosion that comprises 5 % by weight to 90 % by weight, biocompatible polymer and water is the miscibilty solvent not, the copolymer that wherein said polymer is lactic acid and glycolic (PLGA), and wherein said solvent is selected from lower group: aromatic alcohol, benzoic lower alkyl esters and benzoic rudimentary aralkyl ester, the water miscibilty of described solvent is less than or equal to 7 % by weight under 25 ℃, and the ratio of wherein said polymer and described solvent is between 5: 95 and 90: 10;
Dissolve or be dispersed in the beneficiating ingredient of 0.1 % by weight to 50 % by weight in this gel vehicle, this beneficiating ingredient is bupivacaine or human growth hormone;
Regulation and control rate of release and the excipient that makes 0.01 % by weight to 50 % by weight of this beneficiating ingredient stabilisation, described excipient is cysteine or methionine; With
Optional one or more following ingredients: emulsifying agent; Pore former; The optional anesthetis dissolubility adjusting control agent associated with this beneficiating ingredient; And penetrating agent;
Wherein at least optional anesthetis associated with this dissolubility adjusting control agent keeps and separated from solvent, until anesthetis is in curee's administration.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51997203P | 2003-11-14 | 2003-11-14 | |
| US60/519,972 | 2003-11-14 | ||
| US10/985,116 | 2004-11-10 | ||
| US10/985,116 US20050281879A1 (en) | 2003-11-14 | 2004-11-10 | Excipients in drug delivery vehicles |
| PCT/US2004/037606 WO2005048989A1 (en) | 2003-11-14 | 2004-11-12 | Excipients in drug delivery vehicles |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1889929A CN1889929A (en) | 2007-01-03 |
| CN1889929B true CN1889929B (en) | 2013-04-10 |
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|---|---|---|---|
| CN200480035672.0A Expired - Fee Related CN1889929B (en) | 2003-11-14 | 2004-11-12 | Excipients in drug delivery vehicles |
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| ZA (1) | ZA200604884B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5801012A (en) * | 1996-09-17 | 1998-09-01 | Northwestern University | Methods and compositions for generating angiostatin |
| US6130200A (en) * | 1996-12-20 | 2000-10-10 | Alza Corporation | Gel composition and methods |
-
2004
- 2004-11-12 CN CN200480035672.0A patent/CN1889929B/en not_active Expired - Fee Related
-
2006
- 2006-06-13 ZA ZA200604884A patent/ZA200604884B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5801012A (en) * | 1996-09-17 | 1998-09-01 | Northwestern University | Methods and compositions for generating angiostatin |
| US6130200A (en) * | 1996-12-20 | 2000-10-10 | Alza Corporation | Gel composition and methods |
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| Publication number | Publication date |
|---|---|
| ZA200604884B (en) | 2007-11-28 |
| CN1889929A (en) | 2007-01-03 |
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