CN1889929B - Excipients in drug delivery vehicles - Google Patents

Abstract

The present invention provides injectable depot gel compositions and kits that provide release rate modifying excipients that stabilize beneficial agents. Methods of administering and preparing such systems are also provided. The gel composition comprises a biodegradable, bioerodible polymer and a water immiscible solvent in an amount effective to plasticize the polymer and form a gel with the polymer. Suitable excipients include pH modifiers, reducing agents and antioxidants.

Description

Translated fromChinese

药物递送媒介物中的赋形剂Excipients in Drug Delivery Vehicles

相关申请的交叉参考Cross References to Related Applications

本申请要求2003年11月14日提交的美国临时申请No.60/519,972和2004年11月10日提交的美国专利申请No.10/.，...，...的利益，引用在此作为参考。This application claims the benefit of U.S. Provisional Application No. 60/519,972, filed November 14, 2003, and U.S. Patent Application No. 10/., ..., ..., filed November 10, 2004, incorporated herein by reference Reference.

发明领域field of invention

本发明一般涉及持续释放的储库组合物和试剂盒，它们提供有益成分的持续释放。本发明也涉及制备和给予所述组合物的方法。The present invention generally relates to sustained release depot compositions and kits which provide sustained release of beneficial ingredients. The invention also relates to methods of making and administering said compositions.

发明背景Background of the invention

生物降解性聚合物在医药应用中已经使用多年。由生物降解性聚合物组成的装置实例包括缝合线、外科夹、医用钉、植入物和药物递送系统。大多数这些生物降解性聚合物基于乙交酯、交酯、己内酯及其共聚物。Biodegradable polymers have been used in medical applications for many years. Examples of devices composed of biodegradable polymers include sutures, surgical clips, medical staples, implants, and drug delivery systems. Most of these biodegradable polymers are based on glycolide, lactide, caprolactone and their copolymers.

可注射植入物用生物降解性聚合物制剂采用非常或相对可溶于水性体液的溶剂/增塑剂，以促进聚合物在植入部位的迅速固化，促进药物从植入物中扩散。当植入物被置于机体中和暴露于水性体液时，水向这类采用水溶性溶剂的聚合植入物迅速移行是一个严重的问题。迅速的水分摄取经常导致植入物具有大小与形状不均匀的多孔结构。通常，表面小孔呈现手指样孔结构，从植入物表面至植入物内延伸长达三分之一毫米或者更多，这类手指样孔使植入物表面对使用环境开放。内部小孔趋于更小，存在于使用环境中的流体不易接近。迅速的水分摄取特征经常导致有益成分的释放失控，表现为有益成分从聚合物制剂中的初始迅速释放，相当于从植入物中释放的有益成分的“突释”。突释经常导致有益成分的大部分、如果不是全部的话，在非常短的时间内释放，例如数小时或1-2天。这样一种效应可能是不可接受的，特别是在需要控制递送的那些环境中，也就是有益成分以受控方式的递送，历时两周以上或长达一个月或者甚至长达一年，或者在其中存在狭窄治疗窗和过量有益成分释放可能对受治疗者导致不良后果的那些环境中，或者在其中有必要模拟有益成分、例如激素等在受治疗者体内自然发生的每日曲线的那些环境中。Biodegradable polymer formulations for injectable implants employ solvents/plasticizers that are very or relatively soluble in aqueous body fluids to facilitate rapid solidification of the polymer at the implant site and facilitate drug diffusion from the implant. Rapid migration of water into such polymeric implants employing water-soluble solvents is a serious problem when the implant is placed in the body and exposed to aqueous body fluids. Rapid water uptake often results in implants with porous structures that are not uniform in size and shape. Typically, the surface pores exhibit a finger-like pore structure extending up to one-third of a millimeter or more from the implant surface into the implant. Such finger-like pores open the implant surface to the environment of use. Internal pores tend to be smaller and less accessible to fluids present in the environment of use. The rapid water uptake profile often leads to an uncontrolled release of the beneficial ingredient, manifested by an initial rapid release of the beneficial ingredient from the polymer formulation, equivalent to a "burst release" of the beneficial ingredient released from the implant. Burst release often results in the release of most, if not all, of the beneficial ingredient within a very short period of time, such as hours or 1-2 days. Such an effect may be unacceptable, particularly in those settings where controlled delivery is required, that is, the delivery of beneficial ingredients in a controlled manner, over two weeks or up to a month or even up to a year, or in In those settings where there is a narrow therapeutic window and excessive release of the beneficial agent could lead to adverse consequences for the subject, or where it is necessary to mimic the daily profile of a beneficial agent, such as a hormone, that naturally occurs in the subject .

因此，在植入这类装置时，手指样孔允许非常迅速的水性体液摄取进入植入物内部，随后显著量有益成分立即和迅速溶解，有益成分无阻扩散进入使用环境，产生如上所讨论的突释效应。Thus, upon implantation of such devices, the finger-like pores allow very rapid uptake of aqueous body fluids into the interior of the implant, followed by immediate and rapid dissolution of a significant amount of the beneficial ingredient, and unimpeded diffusion of the beneficial ingredient into the environment of use, creating the abrupt change discussed above. release effect.

此外，迅速的水分摄取可能导致过早的聚合物沉淀，以致产生硬化的植入物或者具有硬化外皮的植入物。含有有益成分的内部小孔和很多内部空间被切断与体液接触，可能在并非不显著的时间内(“滞后时间”)导致有益成分的释放显著减少。从向受治疗者提供有益成分的受控持续释放的观点来看，该滞后时间是不需要的。然后所观察到的是在植入术后不久有益成分在短时间内释放的突释，其中没有或很少有益成分被释放的滞后时间，和随后有益成分的继续递送(假定有益成分在突释之后还有剩余)，直至有益成分的供应耗尽。Furthermore, rapid water uptake may lead to premature polymer precipitation, resulting in hardened implants or implants with hardened skin. The internal pores and much of the internal space containing the beneficial ingredient are cut off from contact with body fluids, possibly for a not insignificant amount of time ("lag time") resulting in a significantly reduced release of the beneficial ingredient. This lag time is undesirable from the standpoint of providing controlled sustained release of the beneficial ingredient to the subject. What is then observed is a burst release of the beneficial ingredient over a short period of time shortly after implantation, with a lag time in which no or little beneficial ingredient is released, and subsequent continued delivery of the beneficial ingredient (assuming the beneficial ingredient was released during the burst release). There are leftovers after that) until the supply of beneficial ingredients is depleted.

各种控制有益成分突释和调控递送与使其稳定化的方法已有描述。下列专利美国专利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和4,853,218和PCT公报WO 98/27962据信是代表，引用在此作为参考。尽管取得一定的成功，不过这些方法就大量将被植入物有效递送的有益成分而言尚不完全令人满意。Various methods of controlling the burst release and modulating delivery and stabilization of beneficial ingredients have been described. The following patents, U.S. Patent Nos. 6,468,961; 6,331,311; 6,130,200; 5,990,194; 5,780,044; 5,733,950; Despite some success, these approaches have not been entirely satisfactory in terms of the amount of beneficial ingredient that will be effectively delivered by the implant.

药物的初始突释释放和释放速率曲线可以受到很多因素的影响，例如聚合物与溶剂的比例、聚合物的分子量、溶剂的水可混性和药物粒子的性质。不过，达到所需的释放速率在有些情况下可能受到有益成分变质的抑制。此外，在聚合基质捕获有益成分时，有益成分从聚合物基质内部中的释放在聚合物基质开始显著降解之前可能主要是扩散-控制的，引起可能不是可取的释放速率曲线。The initial burst release and release rate profile of a drug can be influenced by many factors, such as the ratio of polymer to solvent, the molecular weight of the polymer, the water miscibility of the solvent, and the properties of the drug particles. However, achieving the desired release rate may in some cases be inhibited by the deterioration of the beneficial ingredient. Furthermore, when the polymeric matrix entraps the beneficial ingredient, the release of the beneficial ingredient from the interior of the polymeric matrix may be primarily diffusion-controlled before the polymeric matrix begins to degrade significantly, resulting in a release rate profile that may not be desirable.

在药物递送系统中使用一些生物降解性聚合物所面临的问题是聚合物的降解，导致例如酸副产物在递送系统内的累积。所得含有聚合物降解产物的环境可能损害有益成分，例如蛋白质、肽和小分子药物。A problem faced with the use of some biodegradable polymers in drug delivery systems is the degradation of the polymer, resulting in the accumulation of eg acid by-products within the delivery system. The resulting environment containing polymer degradation products can damage beneficial ingredients such as proteins, peptides and small molecule drugs.

使用一些可植入系统所面临的另一个问题是来自体液的自由基和/或过氧化物的存在。对例如可植入药物递送系统的正常外来机体反应也导致自由基和过氧化物的生成。因此，自由基和过氧化物可能扩散进入所植入的药物递送系统，对有益成分是有害的。Another problem faced with the use of some implantable systems is the presence of free radicals and/or peroxides from body fluids. The normal body response to foreign substances such as implantable drug delivery systems also leads to the generation of free radicals and peroxides. Therefore, free radicals and peroxides may diffuse into the implanted drug delivery system and be detrimental to the beneficial ingredients.

结果，有益成分受若干因素的影响容易变质，由此降低剂型的总有效性，因为并非全部想要的有益成分可以用于受治疗者的治疗。As a result, beneficial ingredients are susceptible to deterioration by several factors, thereby reducing the overall effectiveness of the dosage form, since not all of the desired beneficial ingredients are available for the treatment of a subject.

仍然非常需要这样的药物递送系统，它们能够使由于聚合物降解和/或不需要的自由基或过氧化物的存在而暴露于有害微环境的有益成分稳定化。此外，仍然需要调控有益成分从药物递送系统中的释放，以达到所需的释放速率。There remains a great need for drug delivery systems that can stabilize beneficial ingredients that are exposed to harmful microenvironments due to polymer degradation and/or the presence of unwanted free radicals or peroxides. Furthermore, there is still a need to modulate the release of beneficial ingredients from drug delivery systems to achieve the desired release rate.

发明概述Summary of the invention

本发明提供可注射储库凝胶组合物和试剂盒，它们历经短的持续时间和延长的持续时间释放有益成分。也提供给予和制备这类组合物的方法。根据本发明的组合物包括凝胶媒介物、溶解或分散在该凝胶媒介物中的有益成分、和赋形剂。凝胶媒介物包含生物侵蚀性、生物相容性聚合物和水不可混性溶剂，含量对增塑聚合物和与聚合物生成凝胶而言是有效的。在有些情形中，组成溶剂是与水不可混性溶剂一起使用的。本发明组合物使用赋形剂调控释放曲线和使有益成分稳定化。例如，有些赋形剂能够抵消聚合物降解的效应。其他赋形剂能够抵消来自体液的过氧化物和/或自由基的效应。The present invention provides injectable depot gel compositions and kits that release beneficial ingredients over short and extended durations. Methods of administering and preparing such compositions are also provided. Compositions according to the invention comprise a gel vehicle, a benefit ingredient dissolved or dispersed in the gel vehicle, and excipients. The gel vehicle comprises a bioerodible, biocompatible polymer and a water-immiscible solvent in an amount effective to plasticize the polymer and form a gel with the polymer. In some cases, the constituent solvents are used together with water-immiscible solvents. The compositions of the present invention use excipients to modify the release profile and stabilize the beneficial ingredient. For example, some excipients can counteract the effects of polymer degradation. Other excipients are able to counteract the effects of peroxides and/or free radicals from body fluids.

根据本发明的实施方式包括持续递送有益成分的可注射储库凝胶组合物，包含：凝胶媒介物，包含生物侵蚀性、生物相容性聚合物和水不可混性溶剂，含量对增塑聚合物和与之生成凝胶而言是有效的；溶解或分散在该凝胶媒介物中的有益成分；调控释放速率和使有益成分稳定化的赋形剂；其中持续递送发生在给药后约二十四小时至约十二个月之间的期间。An injectable depot gel composition according to an embodiment of the invention comprising a sustained delivery of a beneficial agent comprising: a gel vehicle comprising a bioerodible, biocompatible polymer and a water-immiscible solvent in an amount sufficient for plasticizing effective in terms of polymers and gels formed therewith; beneficial ingredients dissolved or dispersed in the gel vehicle; excipients that modulate the rate of release and stabilize the beneficial ingredients; wherein sustained delivery occurs after administration A period of between about twenty-four hours and about twelve months.

尽管适合的赋形剂有很多，实例包括pH改性剂、还原剂和抗氧化剂。本发明的实施方式可以使用单一的赋形剂或赋形剂的组合。While suitable excipients are numerous, examples include pH modifiers, reducing agents and antioxidants. Embodiments of the invention may use a single excipient or a combination of excipients.

pH改性剂类赋形剂包括但不限于无机盐，例如碳酸锌、碳酸镁、碳酸钙、氢氧化镁、磷酸氢钙、乙酸钙、氢氧化钙、乳酸钙、马来酸钙、油酸钙、草酸钙、磷酸钙、乙酸镁、磷酸氢镁、磷酸镁、乳酸镁、马来酸镁、油酸镁、草酸镁、乙酸锌、磷酸氢锌、磷酸锌、乳酸锌、马来酸锌、油酸锌、草酸锌和它们的组合。还原剂类赋形剂可以是半胱氨酸或甲硫氨酸。用作赋形剂的抗氧化剂可以选自下组：d-α乙酸生育酚、d1-α生育酚、抗坏血酰棕榈酸酯、丁基化羟基anidole、抗坏血酸、丁基化羟基茴香醚、丁基化羟基醌、丁羟基茴香醚、羟基香豆素、丁基化羟基甲苯、cephalm、棓酸乙酯、棓酸丙酯、棓酸辛酯、棓酸月桂酯、羟基苯甲酸丙酯、三羟基丁基rophenone、二甲基苯酚、二叔丁基苯酚、维生素E、卵磷脂、乙醇胺和它们的组合。pH modifier excipients include but are not limited to inorganic salts such as zinc carbonate, magnesium carbonate, calcium carbonate, magnesium hydroxide, calcium hydrogen phosphate, calcium acetate, calcium hydroxide, calcium lactate, calcium maleate, oleic acid Calcium, calcium oxalate, calcium phosphate, magnesium acetate, magnesium hydrogen phosphate, magnesium phosphate, magnesium lactate, magnesium maleate, magnesium oleate, magnesium oxalate, zinc acetate, zinc hydrogen phosphate, zinc phosphate, zinc lactate, zinc maleate , zinc oleate, zinc oxalate, and combinations thereof. The reducing agent excipient may be cysteine or methionine. Antioxidants used as excipients may be selected from the group consisting of d-alpha tocopheryl acetate, d1-alpha tocopherol, ascorbyl palmitate, butylated hydroxyanidole, ascorbic acid, butylated hydroxyanisole, Butylated Hydroxyquinone, Butylated Hydroxyanisole, Hydroxycoumarin, Butylated Hydroxytoluene, Cephalm, Ethyl Gallate, Propyl Gallate, Octyl Gallate, Lauryl Gallate, Propyl Hydroxybenzoate, Tris Hydroxybutyl rophenone, dimethylphenol, di-tert-butylphenol, vitamin E, lecithin, ethanolamine, and combinations thereof.

关于赋形剂，本发明的组合物可以包含约0.01％与约50％之间，按重量计；约0.05％与约40％之间，按重量计；或者约0.1％与约30％之间，按重量计。另外，赋形剂与有益成分之间的比例可以在约0.1∶99.9与约99∶1之间，优选地，该比例在约1∶99与约60∶40之间。With respect to excipients, the compositions of the present invention may comprise between about 0.01% and about 50% by weight; between about 0.05% and about 40% by weight; or between about 0.1% and about 30% , by weight. Additionally, the ratio of excipient to benefit ingredient may be between about 0.1:99.9 and about 99:1, preferably, the ratio is between about 1:99 and about 60:40.

本发明的水不可混性溶剂的水可混性可以是在25℃下小于或等于约7重量％。此外，组合物可以不含水可混性在25℃下大于7重量％的溶剂。溶剂可以选自下组：芳族醇、芳基酸的低级烷基酯、芳基酸的低级芳烷基酯；芳基酮、芳烷基酮、低级烷基酮、柠檬酸的低级烷基酯和它们的组合。其他可用于本发明的溶剂有苄醇、苯甲酸苄基酯、苯甲酸乙酯和三醋精。The water-miscibility of the water-immiscible solvents of the present invention can be less than or equal to about 7% by weight at 25°C. Additionally, the composition may be free of solvents having a water miscibility of greater than 7% by weight at 25°C. The solvent may be selected from the group consisting of aromatic alcohols, lower alkyl esters of arylic acids, lower aralkyl esters of arylic acids; aryl ketones, aralkyl ketones, lower alkyl ketones, lower alkyl citric acids Esters and their combinations. Other solvents that can be used in the present invention are benzyl alcohol, benzyl benzoate, ethyl benzoate and triacetin.

本发明的一些实施方式包含选自下组的组成溶剂：三醋精、二醋精、三丁精、柠檬酸三乙酯、柠檬酸三丁酯、乙酰柠檬酸三乙酯、乙酰柠檬酸三丁酯、三乙基甘油酯、磷酸三乙酯、邻苯二甲酸二乙酯、酒石酸二乙酯、矿物油、聚丁烯、硅酮液、甘油、乙二醇、聚乙二醇、辛醇、乳酸乙酯、丙二醇、碳酸丙烯酯、碳酸乙烯酯、丁内酯、氧化乙烯、氧化丙烯、N-甲基-2-吡咯烷酮、2-吡咯烷酮、甘油缩甲醛、乙酸甲酯、乙酸乙酯、甲乙酮、二甲基甲酰胺、二甲基亚砜、四氢呋喃、己内酰胺、癸基甲基亚砜、油酸、1-十二烷基氮杂环庚烷-2-酮和它们的组合。Some embodiments of the present invention comprise a constituent solvent selected from the group consisting of triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl triacetate Butyl ester, triethylglyceride, triethyl phosphate, diethyl phthalate, diethyl tartrate, mineral oil, polybutene, silicone fluid, glycerin, ethylene glycol, polyethylene glycol, caprylyl Alcohol, ethyl lactate, propylene glycol, propylene carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, N-methyl-2-pyrrolidone, 2-pyrrolidone, glycerin formal, methyl acetate, ethyl acetate , methyl ethyl ketone, dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, oleic acid, 1-dodecylazepan-2-one, and combinations thereof.

按照本发明所使用的聚合物可以选自下组：聚交酯、聚乙交酯、聚(己内酯)、聚酐、聚胺、聚酯酰胺、聚原酸酯、聚二噁烷酮、聚缩醛、聚缩酮、聚碳酸酯、聚磷酸酯、聚酯、聚对苯二甲酸丁烯酯、聚原碳酸酯、聚磷腈、琥珀酸酯、聚(苹果酸)、聚(氨基酸)、聚乙烯吡咯烷酮、聚乙二醇、聚羟基纤维素、多糖、壳多糖、壳聚糖、透明质酸和它们的共聚物、三元共聚物和混合物。在本发明中可以使用乳酸类聚合物，优选乳酸与乙醇酸的共聚物(PLGA)，包括聚(D，L-交酯-共-乙交酯)和聚(L-交酯-共-乙交酯)。在一些实施方式中，PLGA聚合物的重均分子量在约3,000至约120,000之间，乳酸与乙醇酸的单体比例在约50∶50至约100∶0之间。在本发明中也可以使用己内酯类聚合物。The polymers used according to the invention may be selected from the group consisting of polylactides, polyglycolides, poly(caprolactones), polyanhydrides, polyamines, polyesteramides, polyorthoesters, polydioxanones , polyacetal, polyketal, polycarbonate, polyphosphate, polyester, polybutylene terephthalate, polyorthocarbonate, polyphosphazene, succinate, poly(malic acid), poly( amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polysaccharides, chitin, chitosan, hyaluronic acid and their copolymers, terpolymers and mixtures. Lactic acid polymers may be used in the present invention, preferably copolymers of lactic acid and glycolic acid (PLGA), including poly(D,L-lactide-co-glycolide) and poly(L-lactide-co-glycolide) lactide). In some embodiments, the PLGA polymer has a weight average molecular weight between about 3,000 and about 120,000 and a monomer ratio of lactic acid to glycolic acid between about 50:50 and about 100:0. Caprolactone polymers may also be used in the present invention.

本发明的其他实施方式包含约5重量％与约90重量％之间、约25重量％与约80重量％之间或者约35重量％与约75重量％之间的聚合物。以聚合物与溶剂的比例计，一些比例可以在约5∶95与约90∶10之间，另一些比例可以在约20∶80与80∶20之间，其他比例可以在约30∶70与约75∶25之间。Other embodiments of the invention comprise between about 5% and about 90% by weight, between about 25% and about 80% by weight, or between about 35% and about 75% by weight polymer. Based on the ratio of polymer to solvent, some ratios can be between about 5:95 and about 90:10, other ratios can be between about 20:80 and 80:20, and other ratios can be between about 30:70 and Between about 75:25.

按照本发明，组合物可以进一步包含至少一种下列成分：乳化剂、成孔剂、麻醉剂用溶解度调控剂和渗透剂。According to the present invention, the composition may further comprise at least one of the following components: an emulsifier, a pore former, a solubility modifier for an anesthetic, and a penetrant.

关于有益成分，组合物可以包含约0.1％至约50％、约0.5％至约40％或者约1％至约30％的有益成分，按重量计。有益成分的平均粒径可以小于约250μm、在约5μm与250μm之间、在约20μm与约125μm之间或者在约38μm与约63μm之间。With regard to benefit ingredients, the composition may comprise from about 0.1% to about 50%, from about 0.5% to about 40%, or from about 1% to about 30%, by weight, of the benefit ingredient. The benefit ingredient may have an average particle size of less than about 250 μm, between about 5 μm and 250 μm, between about 20 μm and about 125 μm, or between about 38 μm and about 63 μm.

有益成分可以选自下组：蛋白质、肽、药物和它们的组合。例如，当有益成分包含蛋白质时，该蛋白质可以选自下组：人生长激素、干扰素α-2a、干扰素α-2b、EPO、甲硫氨酸-人生长激素、去-苯丙氨酸人生长激素、同义干扰素和它们的组合。当有益成分包含药物时，该药物可以是布比卡因或紫杉醇。肽类有益成分可以包括leuprolide或去氨加压素。The beneficial ingredient may be selected from the group consisting of proteins, peptides, drugs and combinations thereof. For example, when the beneficial ingredient comprises a protein, the protein may be selected from the group consisting of human growth hormone, interferon alpha-2a, interferon alpha-2b, EPO, methionine-human growth hormone, des-phenylalanine Human growth hormone, synonymous interferon, and combinations thereof. When the beneficial ingredient comprises a drug, the drug may be bupivacaine or paclitaxel. Peptide beneficial ingredients may include leuprolide or desmopressin.

在本发明的一种实施方式中，提供制备历经约二十四小时至约十二个月向受治疗者持续递送有益成分的可注射储库凝胶组合物的方法，该方法包含：混合生物侵蚀性、生物相容性聚合物与有效增塑量的水不可混性溶剂，生成凝胶媒介物；向该凝胶媒介物中混合有益成分；向该凝胶媒介物中混合调控释放速率的赋形剂；和使该有益成分稳定化，其中该赋形剂的存在抵消聚合物降解的效应。该方法可以进一步包含在向凝胶媒介物中混合赋形剂和有益成分之前预混合赋形剂与有益成分。另一方面，该方法可以进一步包含向凝胶媒介物单独加载赋形剂和有益成分。所述赋形剂可以溶解或分散在凝胶媒介物中。In one embodiment of the invention, there is provided a method of preparing an injectable depot gel composition for sustained delivery of a beneficial agent to a subject over a period of about twenty-four hours to about twelve months, the method comprising: mixing biological an aggressive, biocompatible polymer and an effective plasticizing amount of a water-immiscible solvent to form a gel vehicle; admixing a beneficial ingredient to the gel vehicle; mixing a release rate-modulating agent into the gel vehicle an excipient; and stabilizing the benefit ingredient, wherein the presence of the excipient counteracts the effect of polymer degradation. The method may further comprise premixing the excipient and the benefit ingredient prior to mixing the excipient and the benefit ingredient into the gel vehicle. In another aspect, the method can further comprise separately loading the gel vehicle with excipients and benefit ingredients. The excipients can be dissolved or dispersed in the gel vehicle.

在本发明的其他实施方式中，提供制备历经约二十四小时至约十二个月向受治疗者持续递送有益成分的可注射储库凝胶组合物的方法，该方法包含：混合生物侵蚀性、生物相容性聚合物与有效增塑量的水不可混性溶剂，生成凝胶媒介物；向该凝胶媒介物中混合有益成分；向该凝胶媒介物中混合调控释放速率的赋形剂；和使该有益成分稳定化，其中该赋形剂的存在抵消见于体液中的过氧化物或自由基或者此二者。In other embodiments of the present invention, there is provided a method of preparing an injectable depot gel composition for sustained delivery of a beneficial agent to a subject over a period of about twenty-four hours to about twelve months, the method comprising: mixing bioerodible a non-toxic, biocompatible polymer and an effective plasticizing amount of a water-immiscible solvent to form a gel vehicle; admixing a beneficial ingredient into the gel vehicle; mixing an endower that modifies the release rate into the gel vehicle excipient; and stabilizing the beneficial ingredient, wherein the presence of the excipient counteracts peroxides or free radicals or both found in bodily fluids.

本发明的另一种实施方式包括给予历经约二十四小时至约十二个月持续释放有益成分的可注射储库组合物的方法，包含给予一种组合物，该组合物包含：凝胶媒介物，包含生物侵蚀性、生物相容性聚合物和有效增塑量的水不可混性溶剂，生成凝胶媒介物；溶解或分散在该凝胶媒介物中的有益成分；调控释放速率和使该有益成分稳定化的赋形剂。组合物可以给予一次。另一方面，组合物可以反复给予。组合物可以局部或全身递送。另外，组合物可以递送至受治疗者上的多个部位。Another embodiment of the present invention includes a method of administering an injectable depot composition for sustained release of a beneficial agent over a period of about twenty-four hours to about twelve months, comprising administering a composition comprising: a gel A vehicle comprising a bioerodible, biocompatible polymer and an effective plasticizing amount of a water-immiscible solvent to produce a gel vehicle; a beneficial ingredient dissolved or dispersed in the gel vehicle; controlled release rate and Excipients that stabilize the beneficial ingredient. The composition can be administered once. In another aspect, the compositions can be administered repeatedly. Compositions can be delivered locally or systemically. Additionally, the compositions can be delivered to multiple sites on the subject.

本发明的另一种实施方式包括持续递送有益成分达给药后约二十四小时至约十二个月的给药试剂盒，该试剂盒包含：凝胶媒介物，包含生物侵蚀性、生物相容性聚合物和水不可混性溶剂，含量对增塑该聚合物和与之生成凝胶而言是有效的；溶解或分散在该凝胶媒介物中的有益成分；调控释放速率的赋形剂，其中该赋形剂通过抵消聚合物降解的效应使该有益成分稳定化；和可选的一种或多种下列成分：乳化剂；成孔剂；可选与该有益成分缔合的麻醉剂用溶解度调控剂；和渗透剂；其中至少可选与该溶解度调控剂缔合的麻醉剂保持与溶剂分离，直至麻醉剂对受治疗者给药之时。Another embodiment of the present invention includes a dosing kit for sustained delivery of a beneficial agent for about twenty-four hours to about twelve months after administration, the kit comprising: a gel vehicle comprising a bioerodible, biological Compatible polymers and water-immiscible solvents in amounts effective to plasticize and form gels with the polymers; beneficial ingredients to dissolve or disperse in the gel vehicle; excipient, wherein the excipient stabilizes the benefit ingredient by counteracting the effect of polymer degradation; and optionally one or more of the following: an emulsifier; a pore former; a solubility modulating agent for an anesthetic; and an osmotic agent; wherein at least the anesthetic optionally associated with the solubility modulating agent remains separated from the solvent until the time the anesthetic is administered to the subject.

本发明的另一种实施方式包括持续递送有益成分达给药后约二十四小时至约十二个月的给药试剂盒，该试剂盒包含：凝胶媒介物，包含生物侵蚀性、生物相容性聚合物和水不可混性溶剂，含量对增塑该聚合物和与之生成凝胶而言是有效的；溶解或分散在该凝胶媒介物中的有益成分；调控释放速率的赋形剂，其中该赋形剂通过抵消聚合物降解的效应使该有益成分稳定化；和可选的一种或多种下列成分：乳化剂；成孔剂；可选与该有益成分缔合的麻醉剂用溶解度调控剂；和渗透剂；其中至少可选与该溶解度调控剂缔合的麻醉剂保持与溶剂分离，直至麻醉剂对受治疗者给药之时。Another embodiment of the present invention includes a dosing kit for sustained delivery of a beneficial agent for about twenty-four hours to about twelve months after administration, the kit comprising: a gel vehicle comprising a bioerodible, biological Compatible polymers and water-immiscible solvents in amounts effective to plasticize and form gels with the polymers; beneficial ingredients to dissolve or disperse in the gel vehicle; excipient, wherein the excipient stabilizes the benefit ingredient by counteracting the effect of polymer degradation; and optionally one or more of the following: an emulsifier; a pore former; a solubility modulating agent for an anesthetic; and an osmotic agent; wherein at least the anesthetic optionally associated with the solubility modulating agent remains separated from the solvent until the time the anesthetic is administered to the subject.

见于本文的公开，这些和其他实施方式将容易为本领域普通技术人员所领会。These and other embodiments will be readily apparent to those of ordinary skill in the art in view of the disclosure herein.

附图的简要说明Brief description of the drawings

在阅读下列详细说明以及如下所述附图之后，本发明的上述和其他客体、特征和优点将更加容易理解。The above and other objects, features and advantages of the present invention will be more readily understood after reading the following detailed description and accompanying drawings described below.

图1阐述从本发明储库制剂(制剂1-2)所得布比卡因碱的体内释放曲线。Figure 1 illustrates the in vivo release profile of bupivacaine base obtained from a depot formulation according to the invention (Formulation 1-2).

图2阐述从本发明储库制剂(制剂3-5)所得盐酸布比卡因的体内释放曲线。Figure 2 illustrates the in vivo release profiles of bupivacaine hydrochloride obtained from depot formulations of the invention (formulations 3-5).

图3阐述从本发明储库制剂(制剂6-8)所得hGH的体内释放曲线。Figure 3 illustrates the in vivo release profiles of hGH from depot formulations of the invention (Formulations 6-8).

详细说明Detailed description

已经发现，在某些系统中，在赋形剂的存在下可以使可注射储库组合物的有益成分稳定化和调控它们的释放。It has been found that, in certain systems, the beneficial ingredients of the injectable depot compositions can be stabilized and their release modulated in the presence of the excipient.

本发明的组合物使用赋形剂抵消聚合物降解的效应和调控释放曲线。尽管适合的赋形剂有很多，不过实例包括pH改性剂和抗氧化剂，例如还原剂和自由基清除剂。The compositions of the invention use excipients to counteract the effects of polymer degradation and to modulate the release profile. While suitable excipients are numerous, examples include pH modifiers and antioxidants such as reducing agents and free radical scavengers.

pH改性剂包括但不限于无机和有机盐，包括碳酸锌、碳酸镁、碳酸钙、氢氧化镁、磷酸氢钙、乙酸钙、氢氧化钙、乳酸钙、马来酸钙、油酸钙、草酸钙、磷酸钙、乙酸镁、磷酸氢镁、磷酸镁、乳酸镁、马来酸镁、油酸镁、草酸镁、乙酸锌、磷酸氢锌、磷酸锌、乳酸锌、马来酸锌、油酸锌、草酸锌和它们的组合。还原剂包括但不限于半胱氨酸或甲硫氨酸。抗氧化剂包括但不限于d-α乙酸生育酚、d1-α生育酚、抗坏血酰棕榈酸酯、丁基化羟基anidole、抗坏血酸、丁基化羟基茴香醚、丁基化羟基醌、丁羟基茴香醚、羟基香豆素、丁基化羟基甲苯、cephalm、棓酸乙酯、棓酸丙酯、棓酸辛酯、棓酸月桂酯、羟基苯甲酸丙酯、三羟基丁基rophenone、二甲基苯酚、二叔丁基苯酚、维生素E、卵磷脂和乙醇胺。pH modifiers include, but are not limited to, inorganic and organic salts, including 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, magnesium maleate, magnesium oleate, magnesium oxalate, zinc acetate, zinc hydrogen phosphate, zinc phosphate, zinc lactate, zinc maleate, oil Zinc acid, zinc oxalate and combinations thereof. Reducing agents include, but are not limited to, cysteine or methionine. Antioxidants include, but are not limited to, d-alpha tocopheryl acetate, d1-alpha tocopherol, ascorbyl palmitate, butylated hydroxyanidole, ascorbic acid, butylated hydroxyanisole, butylated hydroxyquinone, butylated hydroxyquinone, butylated hydroxyanisole Anisole, Hydroxycoumarin, Butylated Hydroxytoluene, Cephalm, Ethyl Gallate, Propyl Gallate, Octyl Gallate, Lauryl Gallate, Propyl Hydroxybenzoate, Trihydroxybutyl Rophenone, Dimethyl Phenol, di-tert-butylphenol, vitamin E, lecithin and ethanolamine.

本发明所针对的组合物包括掺入赋形剂的那些，例如无机盐，例如碳酸镁或碳酸锌，它们能够(1)平衡储库制剂内的局部pH，以保护有益成分免受聚合物降解后低pH的影响，和(2)通过在聚合物中动态创建微孔结构来调控释放速率曲线。由于所选择的一些无机盐的弱碱性，能够平衡由聚合物降解所致储库微环境中的局部酸性pH。因此能够保护有益成分、尤其蛋白质、肽和药物免受低pH的有害影响。另外，不打算受理论所限，认为当赋形剂、例如无机盐的粒子因在水中溶解而离开聚合基质时，原来由盐占据的空白空间将动态地创建微孔结构。小孔的大小和密度可能受到原料和加载水平的控制。因而，所需的释放曲线可以是可编程的。Compositions contemplated by the present invention include those incorporating excipients, such as inorganic salts, such as magnesium carbonate or zinc carbonate, which are able to (1) balance the local pH within the depot formulation to protect the beneficial ingredients from polymer degradation and (2) modulating the release rate profile by dynamically creating a microporous structure in the polymer. Due to the weak basicity of some selected inorganic salts, it is possible to balance the local acidic pH in the reservoir microenvironment caused by polymer degradation. Beneficial ingredients, especially proteins, peptides and pharmaceuticals can thus be protected from the deleterious effects of low pH. Additionally, without intending to be bound by theory, it is believed that when particles of excipients, such as inorganic salts, leave the polymeric matrix due to dissolution in water, the empty spaces previously occupied by the salts will dynamically create a microporous structure. The size and density of pores may be controlled by the feedstock and loading level. Thus, the desired release profile can be programmable.

进而，很多小分子药物是以不同形式存在的，这依赖于药物所暴露的环境的pH。例如，小分子药物可以在低pH下具备正电荷，在较高pH下具备负电荷，在中间pH下没有电荷。因此，通过改变局部pH，可以容易地决定药物的亲水-疏水性质和药物在基质中的溶解度。因而，可以调控有益成分从储库中的初始突释释放和释放速率曲线。已知活性成分从储库中的释放速率曲线可以高度依赖于药物的亲水-疏水性质。由于药物的亲水-疏水性质可以容易地取决于它的化学形式和在很多情况下取决于局部pH，本发明的方法可能不需要在药物粒子制剂中加入任何另外的配制原料以调控药物的溶解度，从而使药物制剂更加简单。Furthermore, many small molecule drugs exist in different forms, depending on the pH of the environment to which the drug is exposed. For example, a small molecule drug can have a positive charge at low pH, a negative charge at higher pH, and no charge at intermediate pH. Therefore, by changing the local pH, the hydrophilic-hydrophobic properties of the drug and the solubility of the drug in the matrix can be easily determined. Thus, the initial burst release and release rate profile of the beneficial ingredient from the depot can be tuned. It is known that the release rate profile of an active ingredient from a depot can be highly dependent on the hydrophilic-hydrophobic nature of the drug. Since the hydrophilic-hydrophobic nature of a drug can readily depend on its chemical form and, in many cases, on the local pH, the methods of the present invention may not require the addition of any additional formulation materials in the drug particle formulation to regulate the solubility of the drug. , so that the pharmaceutical preparation is simpler.

进而，很多小分子药物含有当过氧化物或自由基存在时对氧化作用敏感的官能团，例如胺、羟基。当被氧化时，药物可能丧失它们的活性和/或导致一些不需要的副作用。通过掺入抗氧化剂，例如但不限于还原剂或自由基清除剂，能够保护药物的完整性免受过氧化物或自由基或者此二者的攻击，它们从体液中扩散进入凝胶媒介物，或者由对植入物的正常外来机体反应所产生。另外，不打算受理论所限，认为当赋形剂、例如固体还原剂、抗氧化剂和自由基清除剂的粒子或者赋形剂、例如固体还原剂、抗氧化剂和自由基清除剂的分散液滴因扩散而离开聚合基质时，原来由赋形剂占据的空白空间将动态地创建微孔结构。小孔的大小和密度可能受到原料和加载水平的控制。因而，所需的释放曲线可以是可编程的。Furthermore, many small molecule drugs contain functional groups such as amines, hydroxyls that are sensitive to oxidation in the presence of peroxides or free radicals. When oxidized, drugs may lose their activity and/or cause some unwanted side effects. By incorporating antioxidants, such as but not limited to reducing agents or free radical scavengers, the integrity of the drug can be protected from attack by peroxides or free radicals, or both, which diffuse from body fluids into the gel vehicle, Or produced by the normal foreign body's response to the implant. Additionally, without intending to be bound by theory, it is believed that when particles of excipients such as solid reducing agents, antioxidants and radical scavengers or dispersed droplets of excipients such as solid reducing agents, antioxidants and radical scavengers When leaving the polymeric matrix by diffusion, the empty space previously occupied by the excipient will dynamically create a microporous structure. The size and density of pores may be controlled by the feedstock and loading level. Thus, the desired release profile can be programmable.

生物活性成分、例如蛋白质、肽、单克隆抗体等一般当过氧化物或自由基存在时对氧化作用是敏感的。当被氧化时，生物活性成分可能丧失它们的活性和/或导致一些不需要的副作用，例如免疫反应。通过掺入还原剂、抗氧化剂或自由基清除剂，能够保护成分的完整性免受过氧化物和/或自由基的攻击，它们从体液中扩散进入凝胶媒介物，或者由对植入物的正常外来机体反应所产生。另外，不打算受理论所限，认为当赋形剂、例如固体还原剂、抗氧化剂和自由基清除剂的粒子或者赋形剂、例如固体还原剂、抗氧化剂和自由基清除剂的分散液滴因扩散而离开聚合基质时，原来由赋形剂占据的空白空间将动态地创建微孔结构。小孔的大小和密度可能受到原料和加载水平的控制。因而，所需的释放曲线可以是可编程的。Biologically active ingredients such as proteins, peptides, monoclonal antibodies, etc. are generally sensitive to oxidation in the presence of peroxides or free radicals. When oxidized, bioactive ingredients may lose their activity and/or cause some unwanted side effects, such as immune reactions. By incorporation of reducing agents, antioxidants or free radical scavengers, the integrity of the ingredients can be protected from attack by peroxides and/or free radicals that diffuse from body fluids into the gel vehicle, or by the implant produced by the normal body response to foreign substances. Additionally, without intending to be bound by theory, it is believed that when particles of excipients such as solid reducing agents, antioxidants and radical scavengers or dispersed droplets of excipients such as solid reducing agents, antioxidants and radical scavengers When leaving the polymeric matrix by diffusion, the empty space previously occupied by the excipient will dynamically create a microporous structure. The size and density of pores may be controlled by the feedstock and loading level. Thus, the desired release profile can be programmable.

根据本发明的组合物掺入赋形剂，例如抗氧化剂、还原剂和/或自由基清除剂，它们例如靶向从体液中扩散进入凝胶媒介物或者由对植入物的正常外来机体反应所产生的自由基和过氧化物。Compositions according to the invention incorporate excipients, such as antioxidants, reducing agents and/or free radical scavengers, which are targeted, for example, for diffusion from body fluids into the gel vehicle or by normal foreign body reactions to the implant. free radicals and peroxides.

向凝胶媒介物中掺入赋形剂例如可以这样进行，在药物粒子配制加工期间向药物粒子中直接掺入或者预混合赋形剂。另一方面，可以向凝胶媒介物中单独加载赋形剂和药物。赋形剂象有益成分一样，可以溶解或分散在凝胶媒介物中。The incorporation of excipients into the gel vehicle can be performed, for example, by directly incorporating or premixing the excipients into the drug particles during the drug particle formulation process. On the other hand, excipients and drug can be loaded separately into the gel vehicle. Excipients, like beneficial ingredients, can be dissolved or dispersed in the gel vehicle.

定义definition

在描述和要求保护本发明时，将按照下列定义使用下列术语。In describing and claiming the present invention, the following terminology will be used in accordance with the following definitions.

单数形式“一个”、“一种”和“该”包括复数指示物，上下文另有明确指令除外。因而例如，对“一种溶剂”的称谓包括单一的溶剂以及两种或多种不同溶剂的混合物，对“一种麻醉剂”的称谓包括单一的麻醉剂以及两种或多种不同麻醉剂的组合，等等。The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a solvent" includes a single solvent as well as a mixture of two or more different solvents, reference to "an anesthetic" includes a single anesthetic as well as a combination of two or more different anesthetics, etc. wait.

对“聚合物降解的效应”的称谓非限制性地表示由生物降解性聚合物分解所产生的那些副产物。这类副产物可以包括酸副产物，例如乳酸和乙醇酸，例如在使用PLGA时。另外，诸如氧化物、过氧化物和自由基等副产物也是可能存在的。因此，对“抵消降解效应”的称谓意味着防止副产物损害有益成分。例如，包含盐的赋形剂能够中和酸副产物。包含还原剂的赋形剂抑制过氧化物，同样，抗氧化物防止氧化物降解有益成分。The designation "effects of polymer degradation" denotes, without limitation, those by-products produced by the decomposition of biodegradable polymers. Such by-products may include acid by-products such as lactic acid and glycolic acid, for example when PLGA is used. In addition, by-products such as oxides, peroxides and free radicals may also be present. Therefore, the title of "counteracting degradation effects" means preventing by-products from damaging beneficial ingredients. For example, excipients comprising salts can neutralize acid by-products. Excipients containing reducing agents inhibit peroxides, and likewise, antioxidants prevent oxidation from degrading the beneficial ingredient.

对“过氧化物或自由基或者此二者”的称谓非限制性地表示存在于体液中、可能对有益成分有害的那些过氧化物和/或自由基。例如，对例如植入物的正常外来机体反应生成可能进入植入物和降解有益成分的自由基和过氧化物。其他过氧化物和自由基是正常机体功能的结果，也仍然对有益成分有害。References to "peroxides or free radicals or both" are meant without limitation to those peroxides and/or free radicals present in bodily fluids that may be detrimental to the benefit ingredient. For example, normal body reactions to foreign substances such as implants generate free radicals and peroxides that can enter the implant and degrade the beneficial ingredients. Other peroxides and free radicals are a result of normal body function and can still be harmful to the beneficial ingredients.

术语“赋形剂”表示制剂中除有益成分或用于生成凝胶媒介物的原料以外任何有用的成分。可用于调控释放速率和使有益成分稳定化的赋形剂包括pH改性剂、还原剂、抗氧化剂和自由基清除剂。The term "excipient" means any useful ingredient in a formulation other than a beneficial ingredient or a raw material used to form a gel vehicle. Excipients that can be used to modify the rate of release and stabilize the beneficial ingredient include pH modifiers, reducing agents, antioxidants and free radical scavengers.

术语“AUC”表示受治疗者体内测定所得曲线下的面积，从组合物植入时间到植入后时间“t”测量受治疗者中有益成分的血浆浓度，对时间作图。时间t将相当于有益成分向受治疗者的递送时间段。The term "AUC" means the area under the curve determined in vivo in a subject, measuring the plasma concentration of the beneficial ingredient in the subject from the time of implantation of the composition to time "t" post-implantation, plotted against time. The time t will correspond to the delivery period of the beneficial ingredient to the subject.

术语“突释指数”关于用于有益成分全身递送的特定组合物表示下列(i)除以(ii)所得商值：(i)根据组合物植入受治疗者后第一时间段计算的AUC除以第一时间段的小时数(t₁)；(ii)根据有益成分的递送时间计算的AUC除以总递送时间的小时数(t₂)。例如，24小时时的突释指数是下列(i)除以(ii)所得商值：(i)根据组合物植入受治疗者后的前二十四小时计算的AUC除以数字24；(ii)根据有益成分的递送时间计算的AUC除以总递送时间的小时数。The term "Burst Release Index" means, with respect to a particular composition for systemic delivery of a benefit ingredient, the quotient obtained by dividing (i) by (ii): (i) the AUC calculated from the first time period after implantation of the composition into a subject Divide by the hours of the first time period (t₁ ); (ii) AUC calculated from the delivery time of the beneficial ingredient divided by the total delivery time in hours (t₂ ). For example, the Burst Index at 24 hours is the quotient of (i) divided by (ii): (i) AUC calculated from the first twenty-four hours after implantation of the composition in a subject divided by thenumber 24; ( ii) AUC calculated from the delivery time of the beneficial ingredient divided by the total delivery time in hours.

措辞“溶解或分散”打算涵盖所有建立有益成分和/或赋形剂在凝胶组合物中的存在的手段，包括溶解、分散、悬浮等。The phrase "dissolve or disperse" is intended to cover all means of establishing the presence of the benefit ingredient and/or excipient in the gel composition, including dissolving, dispersing, suspending, and the like.

术语“全身”关于有益成分向受治疗者的递送或给药意味着有益成分在受治疗者的血浆中、在生物学显著水平上是可检测的。The term "systemic" with respect to delivery or administration of a beneficial agent to a subject means that the beneficial agent is detectable at biologically significant levels in the blood plasma of the subject.

术语“局部”关于有益成分向受治疗者的递送或给药意味着有益成分被递送至受治疗者的局限化部位，但是在受治疗者的血浆中、在生物学显著水平上不是可检测的。The term "topical" with respect to delivery or administration of a beneficial ingredient to a subject means that the beneficial ingredient is delivered to a localized site in the subject, but is not detectable at a biologically significant level in the blood plasma of the subject .

术语“凝胶媒介物”表示在没有有益成分的存在下由聚合物和溶剂的混合物所生成的组合物。The term "gel vehicle" means a composition resulting from a mixture of a polymer and a solvent in the absence of a benefit ingredient.

术语“短期”或“短的持续时间”是可互换使用的，表示发生有益成分从本发明储库凝胶组合物中释放的时间段，一般将等于或小于两周，优选约24小时至约2周，优选约10天或更短，优选约7天或更短，更优选约3天至约7天。The terms "short term" or "short duration" are used interchangeably to denote the period of time over which release of the benefit ingredient from the depot gel composition of the present invention occurs, which will generally be equal to or less than two weeks, preferably about 24 hours to About 2 weeks, preferably about 10 days or less, preferably about 7 days or less, more preferably about 3 days to about 7 days.

术语“长期”或“延长的持续时间”表示发生有益成分从本发明植入物中释放的时间段，一般将为约一周或更长，优选约30天或更长，更优选一年。The term "long-term" or "extended duration" means the period of time over which release of the beneficial agent from the implant of the present invention occurs, which will generally be about a week or longer, preferably about 30 days or longer, more preferably a year.

术语“初始突释”关于本发明的特定组合物表示下列(i)除以(ii)所得商值：(i)在植入后预定初始时间段中有益成分从组合物中释放的重量；(ii)有待从所植入的组合物中递送的有益成分总量。不言而喻，初始突释可以因植入物的形状和表面积而异。因此，与本文所述初始突释有关的百分比和突释指数打算用于以从标准注射器中分配组合物的方式测试的组合物。The term "initial burst release" means, with respect to a particular composition of the present invention, the quotient of (i) divided by (ii): (i) the weight of the beneficial ingredient released from the composition over a predetermined initial period of time after implantation; ( ii) The total amount of benefit ingredient to be delivered from the implanted composition. It goes without saying that the initial burst release may vary depending on the shape and surface area of the implant. Accordingly, the percentages and burst indices described herein relating to initial burst release are intended for compositions tested in such a way that the compositions are dispensed from a standard syringe.

术语“溶解度调控剂”关于有益成分表示这样一种成分，它将改变有益成分相对于聚合物溶剂或水的溶解度，不同于在没有该调控剂存在下的有益成分溶解度。调控剂可以提高或降低有益成分在溶剂或水中的溶解度。不过，在有益成分是高度水溶性的情况下，溶解度调控剂一般将是降低有益成分在水中的溶解度的成分。有益成分溶解度调控剂的效应可能来自溶解度调控剂与溶剂或者与有益成分本身的相互作用，例如生成配合物，或者此二者。出于此目的，在溶解度调控剂与有益成分“缔合”时，所有这类相互作用或生成作用都有可能发生。可以在与粘性凝胶结合之前混合溶解度调控剂与有益成分，或者可以在加入有益成分之前加入到粘性凝胶中，视情况而定。The term "solubility modulator" with respect to a benefit ingredient means an ingredient that will alter the solubility of the benefit ingredient with respect to the polymer solvent or water from the solubility of the benefit ingredient in the absence of the modulator. Modulators can increase or decrease the solubility of beneficial ingredients in solvents or water. However, where the beneficial ingredient is highly water soluble, the solubility modulating agent will generally be an ingredient that reduces the solubility of the beneficial ingredient in water. The effect of the benefit ingredient solubility modulating agent may result from the interaction of the solubility modulating agent with the solvent or with the benefit ingredient itself, such as forming a complex, or both. For this purpose, it is possible for all such interactions or generative effects to occur when the solubility modifier is "associated" with the benefit ingredient. The solubility modifying agent can be mixed with the benefit ingredient prior to combining with the adhesive gel, or can be added to the adhesive gel prior to adding the benefit ingredient, as appropriate.

术语“受治疗者”和“患者”关于本发明组合物的给药表示动物或人类。The terms "subject" and "patient" refer to animals or humans in relation to the administration of the compositions of the present invention.

由于所有溶剂至少在分子水平上都将在一定的非常有限的程度上可溶于水(也就是与水可混的)，本文所用的术语“不可混的”意味着按重量计7％或以下、优选5％或以下的溶剂是可溶于水或者与水可混的。出于本文公开的目的，溶剂在水中的溶解度值被认为是在25℃下测定的。由于公认所报道的溶解度值可能不总是在相同条件下进行的，本文作为与水可混或可溶于水的重量百分比所引用的溶解度限可能不是绝对的，为一种范围或上限的一部分。例如，如果溶剂在水中的溶解度上限在本文中被引用为“7重量％”，并且没有提供进一步对溶剂的限制，那么报道过水溶解度为7.17克每100ml水的溶剂“三醋精”被视为包括在7％的限度内。本文所用的水溶解度限小于7重量％不包括溶剂三醋精或者水溶解度等于或大于三醋精的溶剂。Since all solvents will be soluble in water (i.e. water-miscible) to some very limited extent at least at the molecular level, the term "immiscible" as used herein means 7% by weight or less , preferably 5% or less of the solvent is water soluble or miscible. For the purposes of this disclosure, solubility values of solvents in water are considered to be determined at 25°C. Since it is recognized that reported solubility values may not always be performed under the same conditions, solubility limits quoted herein as weight percent miscible with or soluble in water may not be absolute and are part of a range or upper limit . For example, if the upper limit of a solvent's solubility in water is cited herein as "7% by weight" and no further restrictions on the solvent are provided, then the solvent "triacetin" with a reported water solubility of 7.17 grams per 100 ml of water is considered To be included within the 7% limit. As used herein, the water solubility limit of less than 7% by weight excludes the solvent triacetin or solvents having a water solubility equal to or greater than triacetin.

术语“生物侵蚀性”表示就地逐渐分解、溶解、水解和/或侵蚀的材料。一般而言，本文中的“生物侵蚀性”聚合物是可水解的和主要通过水解作用就地生物侵蚀的聚合物。The term "bioerodible" means a material that gradually decomposes, dissolves, hydrolyzes and/or erodes in situ. Generally, "bioerodible" polymers herein are polymers that are hydrolyzable and bioerode in situ primarily by hydrolysis.

本发明的聚合物、溶剂和其他成分必须是“生物相容性”的；也就是它们必须不对使用环境导致刺激作用、炎症或坏死。使用环境是流体环境，可以包含人或动物的皮下、肌内、血管内(高/低流量)、心肌内、外膜、肿瘤内或大脑内部分、伤口部位、紧密的关节空间或体腔。The polymers, solvents and other components of the invention must be "biocompatible"; that is, they must not cause irritation, inflammation or necrosis in the environment of use. The environment of use is a fluid environment that can include subcutaneous, intramuscular, intravascular (high/low flow), intramyocardial, epicardial, intratumoral or intracerebral parts, wound sites, tight joint spaces or body cavities of humans or animals.

本文所用的术语“烷基”表示饱和的烃基团，通常不过不必需含有1至约30个碳原子，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、辛基、癸基等，以及环烷基，例如环戊基、环己基等。一般而言，不过仍然不是必然地，本文中的烷基含有1至约12个碳原子。术语“低级烷基”表示1至6个碳原子、优选1至4个碳原子的烷基。“取代的烷基”表示被一个或多个取代基取代的烷基，术语“含有杂原子的烷基”和“杂烷基”表示其中至少一个碳原子被杂原子代替的烷基。如果不是另有指示，术语“烷基”和“低级烷基”包括直链、支链、环状、未取代、取代和/或含有杂原子的烷基或低级烷基。The term "alkyl" as used herein denotes a saturated hydrocarbon group, usually but not necessarily containing from 1 to about 30 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, octyl, decyl, etc., and cycloalkyl groups such as cyclopentyl, cyclohexyl, etc. Generally, though still not necessarily, the alkyl groups herein contain from 1 to about 12 carbon atoms. The term "lower alkyl" means an alkyl group of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. "Substituted alkyl" means an alkyl group substituted with one or more substituents, and the terms "heteroatom-containing alkyl" and "heteroalkyl" mean an alkyl group in which at least one carbon atom is replaced by a heteroatom. If not otherwise indicated, the terms "alkyl" and "lower alkyl" include linear, branched, cyclic, unsubstituted, substituted and/or heteroatom-containing alkyl or lower alkyl.

本文所用的术语“芳基”除非另有指定，表示芳族取代基，含有单一的芳族环或者多个稠合在一起、共价连接或连接于公共基团、例如亚甲基或亚乙基部分的芳族环。优选的芳基含有一个芳族环或者两个稠合或连接的芳族环，例如苯基、萘基、联苯、二苯醚、二苯胺、二苯酮等，最优选的芳基是单环的。“取代的芳基”表示被一个或多个取代基取代的芳基部分，术语“含有杂原子的芳基”和“杂芳基”表示其中至少一个碳原子被杂原子代替的芳基。除非另有指示，术语“芳基”包括杂芳基、取代的芳基和取代的杂芳基。As used herein, unless otherwise specified, the term "aryl" denotes an aromatic substituent, containing a single aromatic ring or multiple aromatic rings fused together, covalently linked or linked to a common group, such as methylene or ethylene The aromatic ring of the base part. Preferred aryl groups contain one aromatic ring or two fused or linked aromatic rings, such as phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, benzophenone, etc., and the most preferred aryl groups are mono ring. "Substituted aryl" means an aryl moiety substituted with one or more substituents, and the terms "heteroatom-containing aryl" and "heteroaryl" mean an aryl group in which at least one carbon atom is replaced by a heteroatom. Unless otherwise indicated, the term "aryl" includes heteroaryl, substituted aryl and substituted heteroaryl.

术语“芳烷基”表示被芳基取代的烷基，其中烷基和芳基是如上所定义的。术语“杂芳烷基”表示被杂芳基取代的烷基。除非另有指示，术语“芳烷基”包括杂芳烷基和取代的芳烷基以及未取代的芳烷基。一般而言，本文的术语“芳烷基”表示芳基-取代的低级烷基，优选苯基-取代的低级烷基，例如苄基、苯乙基、1-苯基丙基、2-苯基丙基等。The term "aralkyl" denotes an alkyl group substituted by an aryl group, wherein alkyl and aryl are as defined above. The term "heteroaralkyl" means an alkyl group substituted with a heteroaryl group. Unless otherwise indicated, the term "aralkyl" includes heteroaralkyl and substituted aralkyl as well as unsubstituted aralkyl. In general, the term "aralkyl" herein denotes aryl-substituted lower alkyl, preferably phenyl-substituted lower alkyl, such as benzyl, phenethyl, 1-phenylpropyl, 2-phenyl Propyl etc.

I.可注射储库组合物I. Injectable Depot Compositions

与以前的聚合物类可注射储库相反，本发明的储库使用一种赋形剂，它调控释放速率，以及通过抵消聚合物降解的效应使有益成分稳定化。可以在向受治疗者注射储库之前生成用于长时间递送有益成分的可注射储库组合物，为粘性凝胶。粘性凝胶载体分散有益成分，以提供适当的递送曲线，包括随着有益成分从储库中释放，有益成分的初始突释较低。In contrast to previous polymer-based injectable depots, the depots of the present invention use an excipient that modulates the rate of release and stabilizes the beneficial ingredient by counteracting the effects of polymer degradation. The injectable depot composition for prolonged delivery of the beneficial agent can be formed as a viscous gel prior to injecting the depot into the subject. The viscous gel vehicle disperses the benefit ingredient to provide an appropriate delivery profile, including a low initial burst of the benefit ingredient as it is released from the depot.

通常，从预填充有有益成分-粘性凝胶组合物的标准皮下注射器中注射粘性凝胶，生成储库。在对皮肤和皮下组织进行注射时经常优选的是利用最小尺寸的针头(即最小直径)进行注射，以减少受治疗者的不适。需要能够通过16guage及更高的针头注射凝胶，优选20gauge及更高，更优选22gauge及更高，进而更优选24gauge及更高。就高度粘性凝胶而言，也就是粘度为约200泊或更大的凝胶，从针头在20-30gauge范围内的注射器中分配凝胶的注射力可能很高，以致在手工进行注射时很困难或者相当不可能。与此同时，凝胶的高粘度是在注射后和分配期间保持储库的完整性所需的，也有利于有益成分在凝胶中的所需悬浮特征。Typically, the depot is created by injecting the viscous gel from a standard hypodermic syringe pre-filled with the beneficial ingredient-viscous gel composition. When injecting into the skin and subcutaneous tissue it is often preferred to inject with the smallest size needle (ie, smallest diameter) to reduce discomfort to the subject. It is desirable to be able to inject the gel through a needle of 16 gauge and higher, preferably 20 gauge and higher, more preferably 22 gauge and higher, still more preferably 24 gauge and higher. In the case of highly viscous gels, that is, gels with a viscosity of about 200 poise or greater, the injection force to dispense the gel from a syringe with a needle in the 20-30 gauge range can be so high that it is difficult to perform the injection manually. Difficult or quite impossible. At the same time, the high viscosity of the gel, which is required to maintain the integrity of the depot after injection and during dispensing, also facilitates the desired suspension characteristics of the beneficial ingredients in the gel.

本文所述储库凝胶组合物在受到剪切力时表现降低了的粘度。降低的程度在部分程度上是凝胶在受到剪切力时的剪切率、聚合物的分子量和聚合物基质的多分散性的函数。当除去剪切力时，储库凝胶组合物的粘度恢复至受到剪切力之前的粘度或附近。因此，储库凝胶组合物在从注射器中注射时可以受到剪切力，这会暂时降低注射过程期间的粘度。当完成注射过程时，除去剪切力，凝胶恢复为非常接近以前的状态。The depot gel compositions described herein exhibit reduced viscosity when subjected to shear forces. The degree of reduction is, in part, a function of the shear rate at which the gel is subjected to shear, the molecular weight of the polymer, and the polydispersity of the polymer matrix. When the shear force is removed, the viscosity of the depot gel composition returns to or near the viscosity prior to being subjected to the shear force. Thus, the depot gel composition can be subjected to shear forces when injected from a syringe, which temporarily reduces the viscosity during the injection process. When the injection process is complete, the shear force is removed and the gel returns to a very close to its previous state.

赋形剂excipient

正如上文所讨论的，可用于调控释放速率和使有益成分稳定化的赋形剂包括制剂中除有益成分或用于生成凝胶媒介物的原料以外任何有用的成分。可用于调控释放速率和使有益成分稳定化的赋形剂例如包括pH改性剂、还原剂、抗氧化剂和自由基清除剂。As discussed above, excipients that can be used to modify the rate of release and stabilize the beneficial ingredient include any useful ingredient in the formulation other than the beneficial ingredient or the raw material used to generate the gel vehicle. Excipients that can be used to modify the rate of release and stabilize the beneficial ingredient include, for example, pH modifiers, reducing agents, antioxidants and free radical scavengers.

pH改性剂包括但不限于无机和有机盐，包括碳酸锌、碳酸镁、碳酸钙、氢氧化镁、磷酸氢钙、乙酸钙、氢氧化钙、乳酸钙、马来酸钙、油酸钙、草酸钙、磷酸钙、乙酸镁、磷酸氢镁、磷酸镁、乳酸镁、马来酸镁、油酸镁、草酸镁、乙酸锌、磷酸氢锌、磷酸锌、乳酸锌、马来酸锌、油酸锌、草酸锌和它们的组合。还原剂包括但不限于半胱氨酸或甲硫氨酸。抗氧化剂包括但不限于d-α乙酸生育酚、d1-α生育酚、抗坏血酰棕榈酸酯、丁基化羟基anidole、抗坏血酸、丁基化羟基茴香醚、丁基化羟基醌、丁羟基茴香醚、羟基香豆素、丁基化羟基甲苯、cephalm、棓酸乙酯、棓酸丙酯、棓酸辛酯、棓酸月桂酯、羟基苯甲酸丙酯、三羟基丁基rophenone、二甲基苯酚、二叔丁基苯酚、维生素E、卵磷脂和乙醇胺。pH modifiers include, but are not limited to, inorganic and organic salts, including 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, magnesium maleate, magnesium oleate, magnesium oxalate, zinc acetate, zinc hydrogen phosphate, zinc phosphate, zinc lactate, zinc maleate, oil Zinc acid, zinc oxalate and combinations thereof. Reducing agents include, but are not limited to, cysteine or methionine. Antioxidants include, but are not limited to, d-alpha tocopheryl acetate, d1-alpha tocopherol, ascorbyl palmitate, butylated hydroxyanidole, ascorbic acid, butylated hydroxyanisole, butylated hydroxyquinone, butylated hydroxyquinone, butylated hydroxyanisole Anisole, Hydroxycoumarin, Butylated Hydroxytoluene, Cephalm, Ethyl Gallate, Propyl Gallate, Octyl Gallate, Lauryl Gallate, Propyl Hydroxybenzoate, Trihydroxybutyl Rophenone, Dimethyl Phenol, di-tert-butylphenol, vitamin E, lecithin and ethanolamine.

生物侵蚀性、生物相容性聚合物Bioerodible, Biocompatible Polymers

可用于本发明方法和组合物的聚合物是生物侵蚀性的，也就是说它们在患者身体的水性流体内逐渐水解、溶解、物理侵蚀或以其他方式崩解。一般而言，聚合物作为水解或物理侵蚀的结果而发生生物侵蚀，不过主要的生物侵蚀过程通常是水解。Polymers useful in the methods and compositions of the present invention are bioerodible, that is, they gradually hydrolyze, dissolve, physically erode or otherwise disintegrate within the aqueous fluids of the patient's body. In general, polymers bioerode as a result of hydrolysis or physical erosion, although the predominant bioerosion process is usually hydrolysis.

这类聚合物包括但不限于聚交酯、聚乙交酯、聚(己内酯)、聚酐、聚胺、聚氨酯、聚酯酰胺、聚原酸酯、聚二噁烷酮、聚缩醛、聚缩酮、聚碳酸酯、聚磷酸酯、polyoxaester、聚原碳酸酯、聚磷腈、琥珀酸酯、聚(苹果酸)、聚(氨基酸)、聚乙烯吡咯烷酮、聚乙二醇、聚羟基纤维素、壳多糖、壳聚糖、透明质酸和它们的共聚物、三元共聚物和混合物。Such polymers include, but are not limited to, polylactides, polyglycolides, poly(caprolactones), polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals , polyketal, polycarbonate, polyphosphate, polyoxaester, polyorthocarbonate, polyphosphazene, succinate, poly(malic acid), poly(amino acid), polyvinylpyrrolidone, polyethylene glycol, polyhydroxy Cellulose, chitin, chitosan, hyaluronic acid and their copolymers, terpolymers and blends.

目前优选的聚合物是聚交酯，也就是乳酸类聚合物，它可能是仅以乳酸为基础的，或者可能是基于乳酸和乙醇酸的共聚物，并且可以包括少量其他共聚单体，不会实质性影响按照本发明所能达到的有利结果。本文所用的术语“乳酸”包括异构体L-乳酸、D-乳酸、DL-乳酸和丙交酯，而术语“乙醇酸”包括乙交酯。最优选的是聚(丙交酯-共-乙交酯)共聚物，普遍被称为“PLGA”。聚合物的乳酸/乙醇酸单体比例可以从约100∶0至约15∶85，优选约75∶25至约30∶70，更优选约60∶40至约40∶60，尤其有用的共聚物的乳酸/乙醇酸单体比例为约50∶50。The presently preferred polymer is polylactide, a lactic acid polymer, which may be based on lactic acid alone, or may be based on a copolymer of lactic and glycolic acids and may include small amounts of other comonomers without Substantially affect the advantageous results achievable according to the invention. As used herein, the term "lactic acid" includes the isomers L-lactic acid, D-lactic acid, DL-lactic acid and lactide, while the term "glycolic acid" includes glycolide. Most preferred is poly(lactide-co-glycolide) copolymer, commonly known as "PLGA". The polymer may have a lactic acid/glycolic acid monomer ratio of from about 100:0 to about 15:85, preferably from about 75:25 to about 30:70, more preferably from about 60:40 to about 40:60, especially useful copolymers The ratio of lactic acid/glycolic acid monomers is about 50:50.

如美国专利No.5,242,910所示，聚合物可以按照美国专利No.4,443,340的教导加以制备。作为替代选择，乳酸类聚合物可以直接从乳酸或者乳酸与乙醇酸的混合物(含有或没有进一步的共聚单体)制备，按照美国专利No.5,310,865所述教导。所有这些专利的内容都引用在此作为参考。适合的乳酸类聚合物是商业上可获得的。例如，分子量为8,000、10,000、30,000和100,000的50∶50乳酸∶乙醇酸共聚物可从Boehringer Ingelheim(Petersburg，VA)、MedisorbTechnologies International L.P.(Cincinatti，OH)和BirminghamPolymers，Inc.(Birmingham，AL)获得，如下所述。As shown in US Patent No. 5,242,910, polymers can be prepared following the teachings of US Patent No. 4,443,340. Alternatively, lactic acid based polymers can be prepared directly from lactic acid or a mixture of lactic acid and glycolic acid, with or without further comonomers, as taught in US Patent No. 5,310,865. The contents of all of these patents are incorporated herein by reference. Suitable lactic acid polymers are commercially available. For example, 50:50 lactic acid:glycolic acid copolymers with molecular weights of 8,000, 10,000, 30,000, and 100,000 are available from Boehringer Ingelheim (Petersburg, VA), Medisorb Technologies International L.P. (Cincinatti, OH), and Birmingham Polymers, Inc. (Birmingham, AL). , as described below.

适合的聚合物包括但不限于聚(D，L-交酯-共-乙交酯)(PLGA)，50∶50DL-PLG，固有粘度0.15(PLGA-BPI，Birmingham Polymers，Inc.，Birmingham，AL)，50∶50

RG502(PLGA RG 502)，聚(D，L-交酯)L104，PLA-L104，code no.33007，Poly(D，L-交酯-共-乙交酯)50∶50

RG502，code no.0000366，聚(D，L-交酯-共-乙交酯)50∶50RG502H，PLGA-502H，code no.260187，聚(D，L-交酯-共-乙交酯)50∶50

RG503，PLGA-503，code no.0080765，聚(D，L-交酯-共-乙交酯)50∶50

RG755，PLGA-755，code no.95037，聚L-交酯MW 2,000(L 206，L 207，L 209，L 214)；聚D，L-交酯(

R 104，R 202，R 203，R 206，

R 207，

R 208)；聚L-交酯-共-D，L-交酯90∶10(LR 209)；聚D-L-交酯-共-乙交酯75∶25(

RG 752，RG 756)；聚D，L-交酯-共-乙交酯85∶15(RG 858)；聚L-交酯-共-碳酸三亚甲基酯70∶30(

LT 706)；聚二噁烷酮(

X 210)(BoehringerIngelheim Chemicals，Inc.，Petersburg，VA)；DL-交酯/乙交酯100∶0(

Polymer 100 DL High，

Polymer 100DL Low)；DL-交酯/乙交酯85/15(Polymer 8515 DL High，

Polymer 8515 DL Low)；DL-交酯/乙交酯75/25(Polymer 7525 DL High，

Polymer 7525 DL Low)；DL-交酯/乙交酯65/35(

Polymer 6535 DL，High，Polymer 6535 DL Low)；DL-交酯/乙交酯54/46(Polymer 5050 DL High，Polymer 5050 DL Low)；DL-交酯/乙交酯54/46(Polymer 5050 DL 2A(3)，Polymer 5050 DL 3A(3)，Polymer 5050 DL4A(3))(Medisorb Teclmologies International L.P.，Cincinnati，OH)；聚D，L-交酯-共-乙交酯50∶50；聚D，L-交酯-共-乙交酯65∶35；聚D，L-交酯-共-乙交酯75∶25；聚D，L-交酯-共-乙交酯85∶15；聚DL-交酯；聚L-交酯；聚乙交酯；聚ε-己内酯；聚DL-交酯-共-己内酯25∶75；和聚DL-交酯-共-己内酯75∶25(Birmingham Polymers，Inc.，Birmingham，AL)。Suitable polymers include, but are not limited to, poly(D,L-lactide-co-glycolide) (PLGA), 50:50 DL-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-co-glycolide) 50:50

RG502, code no.0000366, poly(D,L-lactide-co-glycolide) 50:50 RG502H, PLGA-502H, code no.260187, poly(D,L-lactide-co-glycolide) 50:50

RG503, PLGA-503, code no.0080765, poly(D,L-lactide-co-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, L-lactide (

R 104, R 202, R 203, R 206,

R 207,

R 208); Poly L-lactide-co-D, L-lactide 90:10 ( LR 209); poly DL-lactide-co-glycolide 75:25 (

RG 752, RG 756); poly D, L-lactide-co-glycolide 85:15 ( RG 858); Poly L-lactide-co-trimethylene carbonate 70:30 (

LT 706); polydioxanone (

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 LP, Cincinnati, OH); poly D,L-lactide-co-glycolide 50:50; poly D,L-lactide-co-glycolide 65: 35; Poly D,L-lactide-co-glycolide 75:25; Poly D,L-lactide-co-glycolide 85:15; Poly DL-lactide; Poly L-lactide; Polyethylene Lactide; polyε-caprolactone; polyDL-lactide-co-caprolactone 25:75; and polyDL-lactide-co-caprolactone 75:25 (Birmingham Polymers, Inc., Birmingham, AL ).

生物相容性、生物侵蚀性聚合物在凝胶组合物中的含量占粘性凝胶重量的约5至约90％，优选约25至约80％，通常约35至约75％，粘性凝胶包含组合量的生物相容性聚合物和在25℃下水可混性小于7wt.％的溶剂。Biocompatible, bioerodible polymer accounts for about 5 to about 90% by weight of viscous gel in the gel composition, preferably about 25 to about 80%, usually about 35 to about 75%, viscous gel A combined amount of a biocompatible polymer and a solvent having a water miscibility of less than 7 wt.% at 25°C is included.

将按下述量向聚合物加入溶剂，以提供可植入或可注射的粘性凝胶。Solvent will be added to the polymer in the amounts stated below to provide an implantable or injectable viscous gel.

溶剂solvent

本发明的可注射储库组合物除了生物侵蚀性聚合物、赋形剂和有益成分以外，还可以含有在25℃下水可混性小于7wt.％的溶剂。溶剂必须是生物相容性的，应当与聚合物生成凝胶、优选粘性凝胶，并且限制水分摄取进入植入物。适合的溶剂将基本上限制植入物对水分的摄取，并且如上所述，可以以水不可混性为特征，也就是水溶解度或可混性为至多7重量％。优选地，芳族醇的水溶解度为5wt.％或以下，更优选3wt.％或以下，进而更优选1wt.％或以下。最优选地，芳族醇的水溶解度等于或小于0.5重量％。在优选的实施方式中，溶剂选自芳族醇、芳族酸的酯、芳族酮和它们的混合物。The injectable depot compositions of the present invention may contain, in addition to bioerodible polymers, excipients and benefit ingredients, solvents with a water miscibility of less than 7 wt.% at 25°C. The solvent must be biocompatible, should form a gel, preferably a viscous gel, with the polymer, and limit water uptake into the implant. A suitable solvent will substantially limit the uptake of water by the implant and, as noted above, may be characterized by water immiscibility, ie a water solubility or miscibility of at most 7% by weight. Preferably, the water solubility of the aromatic alcohol is 5 wt.% or less, more preferably 3 wt.% or less, even more preferably 1 wt.% or less. Most preferably, the aromatic alcohol has a water solubility equal to or less than 0.5% by weight. In a preferred embodiment, the solvent is selected from aromatic alcohols, esters of aromatic acids, aromatic ketones and mixtures thereof.

水可混性可以如下实验测定：将水(1-5g)置于称皮重的透明容器中，控制温度约25℃，称重，滴加候选溶剂。使溶液旋转，以观察相分离。当似乎达到饱和点时，这取决于相分离的观察，将溶液放置过夜，第二天重新检查。如果溶液仍然是饱和的，这取决于相分离的观察，那么测定所加入的溶剂的百分比(w/w)。否则加入更多的溶剂，重复该过程。所加入的溶剂的总重量除以溶剂/水混合物的最终重量，测定溶解度或可混性。在使用溶剂混合物时，在加入到水中之前预混合它们。Water miscibility can be determined by the following experiment: put water (1-5 g) in a tared transparent container, control the temperature at about 25° C., weigh, and add the candidate solvent dropwise. The solution was swirled to observe phase separation. When the saturation point appears to be reached, depending on the observation of phase separation, the solution is left overnight and rechecked the next day. If the solution was still saturated, depending on the observation of phase separation, the percentage (w/w) of solvent added was determined. Otherwise add more solvent and repeat the process. Solubility or miscibility is determined by dividing the total weight of solvent added by the final weight of the solvent/water mixture. When using solvent mixtures, premix them before adding to water.

除了水不可混性溶剂以外，组合物还可以包括一种或多种另外的可混性溶剂(“组成溶剂”)，只要任意这类另外的溶剂不是低级烷醇。与基本溶剂相容和可混的组成溶剂可以具有更高的水可混性，所得混合物仍然可以表现对水分摄取进入植入物的显著限制作用。这类混合物将被称为“组成溶剂混合物”。有用的组成溶剂混合物可以表现大于基本溶剂本身的水溶解度，通常在0.1重量％直至且包括50重量％之间，优选直至且包括30重量％，最优选直至且包括10重量％，不会有害地影响由本发明植入物所表现的水分摄取抑制作用。In addition to the water-immiscible solvent, the composition may also include one or more additional miscible solvents ("constituent solvents"), so long as any such additional solvents are not lower alkanols. The constituent solvents that are compatible and miscible with the base solvent can have higher water miscibility, and the resulting mixture can still exhibit significant restriction of water uptake into the implant. Such mixtures will be referred to as "constituent solvent mixtures". Useful constituent solvent mixtures may exhibit water solubility greater than that of the base solvent itself, typically between 0.1 wt. % up to and including 50 wt. %, preferably up to and including 30 wt. %, most preferably up to and including 10 wt. Affects the water uptake inhibition exhibited by the implants of the invention.

可用在组成溶剂混合物中的组成溶剂是与基本溶剂或溶剂混合物可混的那些溶剂，包括但不限于三醋精、二醋精、三丁精、柠檬酸三乙酯、柠檬酸三丁酯、乙酰柠檬酸三乙酯、乙酰柠檬酸三丁酯、三乙基甘油酯、磷酸三乙酯、邻苯二甲酸二乙酯、酒石酸二乙酯、矿物油、聚丁烯、硅酮液、甘油、乙二醇、聚乙二醇、辛醇、乳酸乙酯、丙二醇、碳酸丙烯酯、碳酸乙烯酯、丁内酯、氧化乙烯、氧化丙烯、N-甲基-2-吡咯烷酮、2-吡咯烷酮、甘油缩甲醛、乙酸甲酯、乙酸乙酯、甲乙酮、二甲基甲酰胺、二甲基亚砜、四氢呋喃、己内酰胺、癸基甲基亚砜、油酸、1-十二烷基氮杂环庚烷-2-酮和它们的混合物。The constituent solvents that may be used in the constituent solvent mixtures are those solvents that are miscible with the base solvent or solvent mixture, including but not limited to triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, Acetyl Triethyl Citrate, Acetyl Tributyl Citrate, Triethyl Glyceride, Triethyl Phosphate, Diethyl Phthalate, Diethyl Tartrate, Mineral Oil, Polybutene, Silicone Fluid, Glycerin , ethylene glycol, polyethylene glycol, octanol, ethyl lactate, propylene glycol, propylene carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, N-methyl-2-pyrrolidone, 2-pyrrolidone, Glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, oleic acid, 1-dodecylazepane Alkan-2-ones and mixtures thereof.

溶剂或溶剂混合物能够溶解聚合物，生成粘性凝胶，可以在释放之前保持有益成分粒子溶解或分散，并且与使用环境分离。本发明的组合物提供具有低突释指数的植入物。水分摄取受到溶剂或组成溶剂混合物的控制，它增溶或增塑聚合物，但是基本上限制水分摄取进入植入物。The solvent or solvent mixture is capable of dissolving the polymer to form a viscous gel that can keep the benefit ingredient particles dissolved or dispersed until released and separated from the environment of use. The compositions of the present invention provide implants with a low burst index. Water uptake is controlled by the solvent or constituent solvent mixture, which solubilizes or plasticizes the polymer, but substantially limits water uptake into the implant.

溶剂或溶剂混合物的含量通常占粘性凝胶重量的约95至约5％，优选约75至约15％，最优选约65％至约20％。在尤其优选的实施方式中，溶剂选自芳族醇、苯甲酸的低级烷基与芳烷基酯。目前，最优选的溶剂是苯甲酸苄基酯(BB)、苄醇(BA)、苯甲酸乙酯(EB)、BB与BA的混合物、BB与乙醇的混合物和BB与EB的混合物。The solvent or solvent mixture generally comprises from about 95% to about 5%, preferably from about 75% to about 15%, most preferably from about 65% to about 20%, by weight of the viscous gel. In an especially preferred embodiment, the solvent is selected from aromatic alcohols, lower alkyl and aralkyl esters of benzoic acid. Currently, the most preferred solvents are benzyl benzoate (BB), benzyl alcohol (BA), ethyl benzoate (EB), mixtures of BB and BA, mixtures of BB and ethanol, and mixtures of BB and EB.

聚合物与溶剂的比例包括约5∶95与约90∶10之间，优选在约20∶80与约80∶20之间，更优选在约30∶70与约75∶25之间。The ratio of polymer to solvent comprises between about 5:95 and about 90:10, preferably between about 20:80 and about 80:20, more preferably between about 30:70 and about 75:25.

有益成分Beneficial ingredients

有益成分可以是任意的生理或药理活性物质，可选地与药学上可接受的载体和另外成分的组合，例如抗氧化剂、稳定剂、渗透增强剂等，它们基本上不会不利地影响可以由本发明达到的有利结果。有益成分可以是任意这样的成分，它们已知递送至人或动物体，并且优先可溶于水而不是聚合物-溶解性溶剂。这些成分包括药物成分、药品、维生素、营养素等。在满足这种要求的成分类型中包括低分子量化合物、蛋白质、肽、遗传材料、营养素、维生素、食品添加剂、性器官杀菌剂、生育抑制剂和生育促进剂。The beneficial ingredient can be any physiologically or pharmacologically active substance, optionally in combination with a pharmaceutically acceptable carrier and additional ingredients, such as antioxidants, stabilizers, penetration enhancers, etc., which do not substantially adversely affect the Advantageous results achieved by the invention. The benefit ingredient can be any ingredient known for delivery to the human or animal body and which is preferentially soluble in water rather than polymer-soluble solvents. These ingredients include pharmaceutical ingredients, medicines, vitamins, nutrients, etc. Among the types of ingredients meeting this requirement are low molecular weight compounds, proteins, peptides, genetic material, nutrients, vitamins, food additives, sex organ bactericides, fertility suppressants and fertility promoters.

可以由本发明递送的药物成分包括作用于如下的药物：外周神经、肾上腺素能受体、胆碱能受体、骨骼肌、心血管系统、平滑肌、血液循环系统、关节部位、神经效应器接合部位、内分泌与激素系统、免疫系统、生殖系统、骨骼系统、自体有效物质系统、营养与排泄系统、组胺系统和中枢神经系统。适合的成分例如可以选自蛋白质、酶、激素、多核苷酸、核蛋白、多糖、糖蛋白、脂蛋白、多肽、类固醇、止痛剂、局部麻醉剂、抗生素、化疗剂、免疫抑制剂、抗炎剂(包括抗炎性皮质类固醇)、抗增殖剂、抗有丝分裂剂、血管生成剂、抗精神病剂、中枢神经系统(CNS)剂、抗凝血剂、纤维蛋白分解剂、生长因子、抗体、眼药、和这些品种的代谢产物、类似物(包括合成和取代的类似物)、衍生物(包括以本领域已知的方式与其他大分子的聚集性缀合物/融合物和与无关化学部分的共价缀合物)、片段、和纯化、分离、重组与化学合成版本。Drug components that may be delivered by the present invention include drugs that act on peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscle, cardiovascular system, smooth muscle, circulatory system, joint sites, neural effector junction sites , endocrine and hormone system, immune system, reproductive system, skeletal system, autologous effective substance system, nutrition and excretion system, histamine system and central nervous system. Suitable ingredients may for example be selected from proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotics, chemotherapeutics, immunosuppressants, anti-inflammatory agents (including anti-inflammatory corticosteroids), antiproliferative agents, antimitotic agents, angiogenic agents, antipsychotic agents, central nervous system (CNS) agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ophthalmic agents , and metabolites of these species, analogs (including synthetic and substituted analogs), derivatives (including aggregated conjugates/fusions with other macromolecules and combinations with unrelated chemical moieties in a manner known in the art covalent conjugates), fragments, and purified, isolated, recombinant, and chemically synthesized versions.

可以由本发明组合物递送的药物实例包括但不限于布比卡因、丁丙诺啡、乙二磺酸普鲁氯嗪、硫酸亚铁、氨基己酸、盐酸美加明、盐酸普鲁卡因酰胺、硫酸苯丙胺、盐酸脱氧麻黄碱、盐酸benzamphetamine、硫酸异丙肾上腺素、盐酸芬美曲嗪、氯贝胆碱、氯醋甲胆碱、盐酸毛果芸香碱、硫酸阿托品、溴东莨菪碱、异丙碘铵、曲地氯铵、盐酸苯乙双胍、盐酸哌醋甲酯、胆酸茶碱、盐酸头孢氨苄、地芬尼多、盐酸美克洛嗪、马来酸普鲁氯嗪、苯氧苄胺、马来酸硫乙拉嗪、茴茚二酮、二苯茚酮、赤藓醇四硝酸酯、地高辛、异氟磷、乙酰唑胺、醋甲唑胺、苄氟噻嗪、chloropromaide、妥拉磺脲、氯地孕酮、非那二醇、别嘌醇、阿司匹林铝、甲氨蝶呤、乙酰磺胺异噁唑、红霉素、氢化可的松、乙酸氢化皮质酮、乙酸可的松、地塞米松及其衍生物(例如倍他米松)、曲安西龙、甲基睾酮、睾酮、17-S-雌二醇、乙炔雌二醇、乙炔雌二醇3-甲基醚、泼尼松龙、乙酸17α-羟基孕酮、19-去甲-孕酮、炔诺孕酮、炔诺酮、炔诺甾酮、norethiederone、孕酮、诺孕酮、异炔诺酮、阿司匹林、消炎痛、萘普生、非诺洛芬、舒林酸、吲哚洛芬、硝酸甘油、硝酸异山梨酯、普萘洛尔、噻吗洛尔、阿替洛尔、阿普洛尔、西咪替丁、可乐定、丙咪嗪、左旋多巴、氯丙嗪、甲基多巴、二羟基苯丙氨酸、茶碱、葡萄糖酸钙、酮洛芬、布洛芬、头孢氨苄、红霉素、氟哌啶醇、佐美酸、乳酸亚铁、长春蔓胺、地西泮、苯氧苄胺、地尔硫

、米力农、mandol、quanbenz、氢氯噻嗪、雷尼替丁、氟比洛芬、fenufen、氟洛芬、托美丁、阿氯芬酸、甲芬那酸、氟芬那酸、difuinal、尼莫地平、尼群地平、尼索地平、尼卡地平、非洛地平、利多氟嗪、噻帕米、戈洛帕米、氨氯地平、米氟嗪、赖诺普利、依那普利、依那普利拉、卡托普利、雷米普利、法莫替丁、尼扎替丁、硫糖铝、依汀替丁、tetratolol、米诺地尔、氯氮

、地西泮、阿米替林、丙咪嗪、paliperidone、resperidone、奥曲肽、阿仑膦酸、α-4，β-7受体拮抗剂leukosite和infliximab(Remicade)。Examples of drugs that may be delivered by the compositions of the present invention include, but are not limited to, bupivacaine, buprenorphine, prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, mecamylamine hydrochloride, procainamide hydrochloride , amphetamine sulfate, methamphetamine hydrochloride, benzamphetamine hydrochloride, isoproterenol sulfate, fenmetrazine hydrochloride, bacholine, methacholine, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropyl ammonium iodide, koji Desammonium chloride, phenformin hydrochloride, methylphenidate hydrochloride, theophylline cholate, cephalexin hydrochloride, difenidol, meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, malay Thiethylperazine, Anindone, Dipheninone, Erythritol Tetranitrate, Digoxin, Isoflurphos, Acetazolamide, Methazolamide, Benzoflumethiazide, Chloropromaide, Tolasulfone Urea, chlormadinone, phenadiol, allopurinol, aluminum aspirin, methotrexate, acesulfamexazole, erythromycin, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, Semethasone and its derivatives (eg, betamethasone), triamcinolone, methyltestosterone, testosterone, 17-S-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone , 17α-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel, norethindrone, norethindrone, norethiederone, progesterone, norgestrel, norethindrone, aspirin, indomethacin, naphthalene Proxan, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol, aprenolol, cimetidine, Clonidine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, fluoride Piperidinol, zomeacin, ferrous lactate, vincamine, diazepam, phenoxybenzamine, diltiazem

, milrinone, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenufen, fluprofen, tolmetin, aclofenac, mefenamic acid, flufenamic acid, difuinal, nemo Dipine, nitrendipine, nisoldipine, nicardipine, felodipine, lidoflurazine, tiapamil, golopamil, amlodipine, mefluzine, lisinopril, enalapril, Naprilat, captopril, ramipril, famotidine, nizatidine, sucralfate, ettinidine, tetratolol, minoxidil, chlordiazepoxide

, diazepam, amitriptyline, imipramine, paliperidone, resperidone, octreotide, alendronate, alpha-4, beta-7 receptor antagonist leukosite and infliximab (Remicade).

有益成分的进一步实例是蛋白质和肽，它们包括但不限于骨形态发生蛋白、胰岛素、秋水仙碱、高血糖素、甲状腺刺激激素、甲状旁腺与垂体激素、降钙素、肾素、催乳激素、促肾上腺皮质激素、亲甲状腺激素、卵泡刺激激素、绒膜促性腺素、促性腺素释放激素、牛生长激素、猪生长激素、催产素、后叶加压素、GRF、促生长素抑制素、赖氨加压素、促胰酶素、黄体化激素、LHRH、LHRH激动剂与拮抗剂、leuprolide、干扰素(例如干扰素α-2a、干扰素α-2b和同义干扰素)、白介素、生长激素(例如人生长激素及其衍生物，例如甲硫氨酸-人生长激素和去-苯丙氨酸人生长激素，甲状旁腺激素、牛生长激素和猪生长激素)、生育抑制剂(例如前列腺素)、生育促进剂、生长因子(例如表皮生长因子(EGF)、血小板衍生生长因子(PDGF)、成纤维细胞生长因子(FGF)、转化生长因子-α(TGF-α)、转化生长因子-β(TGF-β)、红细胞生成素(EPO)、胰岛素样生长因子-I(IGF-I)、胰岛素样生长因子-II(IGF-II)、白介素-1、白介素-2、白介素-6、白介素-8、肿瘤坏死因子-α(TNF-α)、肿瘤坏死因子-β(TNF-β)、干扰素-α(INF-α)、干扰素-β(INF-β)、干扰素-γ(INF-γ)、干扰素-ω(INF-ω)、集落刺激因子(CGF)、血管细胞生长因子(VEGF)、血栓生成素(TPO)、基质细胞衍生因子(SDF)、胎盘生长因子(P1GF)、肝细胞生长因子(HGF)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、神经胶质衍生亲神经因子(GDNF)、粒细胞集落刺激因子(G-CSF)、亲睫状神经因子(CNTF)、骨生长因子、转化生长因子)、骨形态发生蛋白(BMP)、凝血因子、人胰腺激素释放因子、这些化合物的类似物与衍生物和这些化合物或者它们的类似物或衍生物的药学上可接受的盐。Further examples of beneficial ingredients are proteins and peptides which include but are not limited to bone morphogenetic protein, insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, renin, prolactin , corticotropin, thyrotropin, follicle-stimulating hormone, chorionic gonadotropin, gonadotropin-releasing hormone, bovine somatotropin, porcine somatotropin, oxytocin, vasopressin, GRF, somatostatin , lysinopressin, trypsin, luteinizing hormone, LHRH, LHRH agonists and antagonists, leuprolide, interferons (such as interferon alpha-2a, interferon alpha-2b, and synonymous interferon), interleukins , growth hormone (such as human growth hormone and its derivatives, such as methionine-human growth hormone and des-phenylalanine human growth hormone, parathyroid hormone, bovine growth hormone and porcine growth hormone), fertility inhibitors (such as prostaglandins), fertility promoters, growth factors (such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), transforming growth factor-α (TGF-α), transforming Growth Factor-β (TGF-β), Erythropoietin (EPO), Insulin-like Growth Factor-I (IGF-I), Insulin-like Growth Factor-II (IGF-II), Interleukin-1, Interleukin-2, Interleukin -6, interleukin-8, tumor necrosis factor-α (TNF-α), tumor necrosis factor-β (TNF-β), interferon-α (INF-α), interferon-β (INF-β), interference In-gamma (INF-gamma), interferon-omega (INF-omega), colony-stimulating factor (CGF), vascular cell growth factor (VEGF), thrombopoietin (TPO), stromal cell-derived factor (SDF), placenta Growth factor (P1GF), hepatocyte growth factor (HGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), glial-derived neurotropic factor (GDNF), granulocyte-colony-stimulating factor (G-CSF), Ciliary neurotropic factor (CNTF), bone growth factor, transforming growth factor), bone morphogenetic protein (BMP), blood coagulation factor, human pancreatic hormone releasing factor, analogs and derivatives of these compounds and these compounds or their analogs Pharmaceutically acceptable salts of substances or derivatives.

本发明也可用于化疗剂，用于这些成分的局部应用，以避免或减少全身副作用。含有化疗剂的本发明凝胶可以直接注射进入肿瘤组织，用于化疗剂历经一段时间的持续递送。在有些情况下，特别是在肿瘤的切除术后，凝胶可以直接植入所得空腔内，或者可以作为包衣涂于剩余组织上。在手术后植入凝胶的情况下，有可能采用具有较高粘度的凝胶，因为它们不必穿过小直径的针头。可以按照本发明的实践加以递送的代表性化疗剂例如包括抑制肿瘤基因翻译或转录的卡铂、顺铂、紫杉醇、BCNU、长春新碱、喜树碱、依托泊苷、细胞因子、核糖酶、干扰素、寡核苷酸与寡核苷酸序列、上述的功能衍生物和公知的化疗剂，例如美国专利No.5,651,986所述那些。本申请特别可用于水溶性化疗剂的持续递送，例如顺铂和卡铂，和紫杉醇的水溶性衍生物。本发明最小化突释效应的那些特征特别有利于所有种类水溶性有益成分的给药，但是特别是临床上有用且有效但是可能具有不良副作用的那些化合物。The present invention is also applicable to chemotherapeutic agents for topical application of these components to avoid or reduce systemic side effects. Gels of the invention containing chemotherapeutic agents can be injected directly into tumor tissue for sustained delivery of the chemotherapeutic agent over a period of time. In some cases, particularly following tumor resection, the gel can be implanted directly into the resulting cavity, or it can be applied as a coating on the remaining tissue. In the case of gel implants after surgery, it is possible to use gels with higher viscosity since they do not have to be passed through small diameter needles. Representative chemotherapeutic agents that can be delivered in accordance with the practice of the invention include, for example, carboplatin, cisplatin, paclitaxel, BCNU, vincristine, camptothecin, etoposide, cytokines, ribozymes, Interferons, oligonucleotides and oligonucleotide sequences, functional derivatives of the above, and known chemotherapeutic agents, such as those described in US Patent No. 5,651,986. The present application is particularly useful for sustained delivery of water-soluble chemotherapeutic agents, such as cisplatin and carboplatin, and water-soluble derivatives of paclitaxel. Those features of the present invention that minimize burst effects are particularly advantageous for the administration of all classes of water-soluble beneficial ingredients, but especially those compounds that are clinically useful and effective but may have adverse side effects.

在上文没有提到的程度上，也可以使用上述美国专利No.5,242,910所述的有益成分。本发明的一种确切优点是难以微囊包封或加工成微球的原料、例如蛋白质，以溶菌酶为例，和掺入到病毒与非病毒载体中的cDNA和DNA，能够掺入到本发明的组合物中，不会因暴露于经常存在于其他加工技术中的高温和变性性溶剂而降解。To an extent not mentioned above, the benefit ingredients described in the aforementioned US Patent No. 5,242,910 may also be used. A definite advantage of the present invention is that materials that are difficult to microencapsulate or process into microspheres, such as proteins, lysozyme for example, and cDNA and DNA incorporated into viral and non-viral vectors, can be incorporated into the present invention. In the composition of the invention, it is not degraded by exposure to high temperatures and denaturing solvents often present in other processing techniques.

有益成分优选地被掺入到从聚合物和溶剂生成的粘性凝胶中，为粒子的形式，平均粒径通常为小于250微米、约5至约250微米，优选约20至约125微米，经常为38至68微米。The benefit ingredient is preferably incorporated into a viscous gel generated from the polymer and solvent, in the form of particles, typically having an average particle size of less than 250 microns, from about 5 to about 250 microns, preferably from about 20 to about 125 microns, often 38 to 68 microns.

为了在从聚合物和溶剂生成的粘性凝胶中生成有益成分粒子的悬液或分散体，可以在环境条件下利用任意常规的低剪切装置，例如Ross双行星式混合机。按这种方式，能够实现有益成分的有效分布，基本上不会降解有益成分。To generate a suspension or dispersion of benefit ingredient particles in the viscous gel formed from the polymer and solvent, any conventional low shear apparatus, such as a Ross double planetary mixer, can be utilized under ambient conditions. In this manner, effective distribution of the beneficial ingredient can be achieved without substantial degradation of the beneficial ingredient.

有益成分溶解或分散在组合物中的量通常占聚合物混合物、溶剂和有益成分总重量的0.1％至约50％，优选约1％至约30％，更优选约2％至约20％，经常2至10％。根据组合物中有益成分的含量，可以获得不同的释放曲线和突释指数。更具体地，就给定的聚合物和溶剂而言，通过调节这些组分的量和有益成分的量，可以获得依赖于聚合物降解多于有益成分从组合物中扩散的释放曲线，反之亦然。在这一点上，在较低的有益成分加载率下，一般获得反映聚合物降解的释放曲线，其中释放速率随着时间而增加。在较高的加载率下，一般获得由有益成分扩散所导致的释放曲线，其中释放速率随着时间而降低。在中间加载率下，获得组合的释放曲线，以便如果需要的话，可以达到基本上恒定的释放速率。为了使突释最小化，有益成分的加载率为全部凝胶组合物、也就是聚合物、溶剂和有益成分重量的30％或以下是优选的，加载率为20％或以下是更优选的。The benefit ingredient is generally dissolved or dispersed in the composition in an amount ranging from 0.1% to about 50%, preferably from about 1% to about 30%, more preferably from about 2% to about 20%, based on the total weight of the polymer mixture, solvent and benefit ingredient, Often 2 to 10%. Depending on the amount of beneficial ingredients in the composition, different release profiles and burst indices can be obtained. More specifically, for a given polymer and solvent, by adjusting the amounts of these components and the amount of the benefit ingredient, it is possible to obtain a release profile that is more dependent on the degradation of the polymer than the diffusion of the benefit ingredient from the composition, and vice versa. Of course. In this regard, at lower benefit ingredient loading rates, a release profile reflecting polymer degradation is generally obtained, wherein the rate of release increases with time. At higher loading rates, a release profile due to diffusion of the beneficial ingredient is generally obtained, wherein the rate of release decreases with time. At intermediate loading rates, a combined release profile is obtained so that, if desired, a substantially constant release rate can be achieved. In order to minimize burst release, a loading rate of 30% or less of the weight of the total gel composition, ie, polymer, solvent and benefit ingredient, of the benefit ingredient is preferred, and a loading rate of 20% or less is more preferred.

通过调节有益成分的释放速率和加载率，将提供有益成分历经预期持续递送阶段的治疗有效性递送。优选地，有益成分将在聚合物凝胶中以这样的浓度存在，它们在有益成分的水饱和浓度以上，以提供有益成分从中分配的药物储备。尽管有益成分的释放速率依赖于特定的环境，例如所要给予的有益成分，不过释放速率可以是约0.1微克/天至约10毫克/天，优选约1微克/天至约5毫克/天，更优选约10微克/天至约1毫克/天，历时约24小时至约360天，优选24小时至约180天，更优选24小时至约120天，经常3天至约90天。进而，通过调节所注射的储库凝胶的量，可以调节有益成分的剂量。如果需要在更短时间内发生递送，可以递送更大的量。一般而言，如果更大的突释能够被耐受，那么更高的释放速率是可能的。在凝胶组合物被手术植入的情形中或者在同时进行治疗疾病状态或另一种病症的手术时被用作“遗留”储库的情形中，有可能提供在注射植入物时正常给予的更高剂量。进而，通过调节所植入的凝胶或所注射的可注射凝胶的体积，可以控制有益成分的剂量。优选地，该系统在植入受治疗者后前24小时内释放40重量％或以下的存在于粘性凝胶中的有益成分。更优选地，在植入后前24小时内将释放30重量％或以下的有益成分，所植入的组合物的突释指数为12或以下，优选8或以下。By modulating the release rate and loading rate of the beneficial ingredient, therapeutically effective delivery of the beneficial ingredient through the desired sustained delivery phase will be provided. Preferably, the beneficial ingredient will be present in the polymer gel at a concentration above the water saturation concentration of the beneficial ingredient to provide a drug reservoir from which the beneficial ingredient will dispense. Although the release rate of the beneficial ingredient depends on the particular circumstances, such as the beneficial ingredient to be administered, the release rate may be from about 0.1 microgram/day to about 10 mg/day, preferably from about 1 microgram/day to about 5 mg/day, more preferably Preferably about 10 micrograms/day to about 1 mg/day for about 24 hours to about 360 days, preferably 24 hours to about 180 days, more preferably 24 hours to about 120 days, often 3 days to about 90 days. In turn, by adjusting the amount of depot gel injected, the dosage of the beneficial ingredient can be adjusted. Larger amounts can be delivered if delivery is desired to occur in a shorter period of time. In general, higher release rates are possible if a larger burst release can be tolerated. In the case where the gel composition is surgically implanted or is used as a "leftover" depot while concurrently performing surgery to treat a disease state or another condition, it is possible to provide higher doses. Furthermore, by adjusting the volume of gel implanted or injectable gel injected, the dosage of beneficial ingredients can be controlled. Preferably, the system releases 40% by weight or less of the beneficial ingredient present in the adhesive gel within the first 24 hours after implantation in the subject. More preferably, 30% by weight or less of the beneficial ingredient will be released within the first 24 hours after implantation, and the implanted composition will have a Burst Release Index of 12 or less, preferably 8 or less.

可选的其他组分Optional other components

在凝胶组合物中可以存在其他组分，只要有需要或者为组合物提供有用的性质，例如聚乙二醇、吸湿剂、稳定剂、成孔剂、触变剂和其他。当组合物包括在水性环境中可溶或不稳定的肽或蛋白质时，可能高度需要在组合物中包括溶解度调控剂，例如可以是稳定剂。各种调控剂描述在美国专利Nos.5,654,010和5,656,297中，其公开内容引用在此作为参考。例如在hGH的情况下，优选地包括一定量的二价金属盐，优选锌。可以与有益成分配合或缔合提供稳定化或调控释放效应的这类调控剂和稳定剂实例包括金属阳离子，优选二价的，在组合物中以下列形式存在：碳酸镁、碳酸锌、碳酸钙、乙酸镁、硫酸镁、乙酸锌、硫酸锌、氯化锌、氯化镁、氧化镁、氢氧化镁、其他抗酸剂等。所用这类成分的量将依赖于在有益成分与该成分之间生成的配合物的属性，如果有的话，或者缔合作用的属性。溶解度调控剂或稳定剂与有益成分的摩尔比通常可以采用约100∶1至1∶1，优选10∶1至1∶1。Other components may be present in the gel composition as needed or to provide useful properties to the composition, such as polyethylene glycols, hygroscopic agents, stabilizers, pore formers, thixotropic agents and others. When the composition includes peptides or proteins that are soluble or unstable in an aqueous environment, it may be highly desirable to include a solubility modifier in the composition, which may be a stabilizer, for example. Various modulators are described in US Patent Nos. 5,654,010 and 5,656,297, the disclosures of which are incorporated herein by reference. For example in the case of hGH it is preferred to include an amount of a divalent metal salt, preferably zinc. Examples of such modulators and stabilizers that can be complexed or associated with the benefit ingredient to provide a stabilizing or modified release effect include metal cations, preferably divalent, present in the composition as: 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 such ingredients used will depend on the nature of the complex, if any, or association formed between the benefit ingredient and the ingredient. The molar ratio of solubility modifying agent or stabilizer to benefit ingredient can generally be about 100:1 to 1:1, preferably 10:1 to 1:1.

成孔剂包括生物相容性材料，它们在与体液接触时溶解、分散或降解，在聚合物基质中产生孔或通道。通常，按照惯例可以使用有机和无机材料作为成孔剂，它们有水溶性糖(例如蔗糖、葡萄糖)、水溶性盐(例如氯化钠、磷酸钠、氯化钾和碳酸钠)、水溶性溶剂(例如N-甲基-2-吡咯烷酮和聚乙二醇)和水溶性聚合物(例如羧甲基纤维素、羟丙基纤维素等)。这类材料的含量可以占聚合物重量的约0.1％至约100％，但是通常将小于聚合物重量的50％，更通常小于10-20％。Pore formers include biocompatible materials that dissolve, disperse, or degrade upon contact with bodily fluids to create pores or channels in a polymer matrix. Generally, organic and inorganic materials can be conventionally used as pore-forming agents, and they include water-soluble sugars (such as sucrose, glucose), water-soluble salts (such as sodium chloride, sodium phosphate, potassium chloride, and sodium carbonate), water-soluble solvents (such as N-methyl-2-pyrrolidone and polyethylene glycol) and water-soluble polymers (such as carboxymethylcellulose, hydroxypropylcellulose, etc.). Such materials may comprise from about 0.1% to about 100% by weight of the polymer, but typically will be less than 50% by weight of the polymer, more typically less than 10-20%.

触变剂包括赋予聚合物凝胶以触变性质的成分，例如低级烷醇(例如乙醇、异丙醇)等。不言而喻，本发明的触变剂不会构成简单的稀释剂或聚合物溶剂，仅仅通过降低组合物的各组分浓度而减少粘度。常规稀释剂的使用可以减少粘度，但是在注射经过稀释的组合物时也可以导致前面提到的突释效应。相反，本发明的可注射储库组合物经过配制，通过选择触变剂可以避免突释效应，以便一旦注射进入空间，触变剂对原始系统的释放性质仅有微不足道的影响。优选地，该系统在植入受治疗者后前24小时内释放40重量％或以下的存在于粘性凝胶中的有益成分。更优选地，在植入后前24小时内将释放30重量％或以下的有益成分，所植入的组合物的突释指数为12或以下，优选8或以下。Thixotropic agents include ingredients that impart thixotropic properties to polymer gels, such as lower alkanols (eg, ethanol, isopropanol), and the like. It goes without saying that the thixotropic agents according to the invention do not constitute simple diluents or polymer solvents, but only reduce the viscosity by reducing the concentration of the individual components of the composition. The use of conventional diluents can reduce viscosity, but can also lead to the aforementioned burst release effect when injecting diluted compositions. In contrast, the injectable depot compositions of the present invention are formulated such that the burst release effect can be avoided by selecting the thixotropic agent such that once injected into the space, the thixotropic agent has only a negligible effect on the release properties of the original system. Preferably, the system releases 40% by weight or less of the beneficial ingredient present in the adhesive gel within the first 24 hours after implantation in the subject. More preferably, 30% by weight or less of the beneficial ingredient will be released within the first 24 hours after implantation, and the implanted composition will have a Burst Release Index of 12 or less, preferably 8 or less.

II.应用和给药II. Application and Administration

植入物的给药手段不限于注射，不过该递送方式可能经常是优选的。若植入物将作为遗留产物给药，它可以适应手术完成后存在的体腔，或者可以将可流动的凝胶刷涂或涂抹在残余组织或骨上。这类应用可以允许在凝胶中加载高于通常以可注射组合物存在的浓度的有益成分。The means of administration of the implant is not limited to injection, although this mode of delivery may often be preferred. If the implant is to be administered as a legacy product, it can be adapted to the body cavity that exists after surgery is complete, or the flowable gel can be brushed or spread over residual tissue or bone. Such applications may allow loading of the gel with beneficial ingredients at concentrations higher than those normally present in injectable compositions.

为了进一步理解本发明的各个方面，按照下列实施例获得前述附图所述结果。To further understand the various aspects of the present invention, the results described in the preceding figures were obtained in accordance with the following examples.

实施例Example

下面是实施本发明的具体实施方式的若干实施例。这些实施例仅供说明，不打算以任何方式限制本发明的范围。The following are several examples of specific embodiments for implementing the invention. These examples are for illustration only and are not intended to limit the scope of the invention in any way.

实施例1Example 1

储库凝胶制备物depot gel preparation

如下制备用在可注射储库组合物中的凝胶媒介物。将玻璃容器置于Mettler PJ3000顶部承载天平上。向玻璃容器称入聚(D，L-丙交酯-共-乙交酯)(PLGA)，为50∶50 DL-PLG，固有粘度为0.15(PLGA-BPI，Birmingham Polymers，Inc.，Birmingham，AL)，和50∶50

RG502(PLGA RG502)。向含有聚合物的玻璃容器称皮重，加入相应的溶剂。各种聚合物/溶剂组合的百分比如下表1所述。将聚合物/溶剂混合物在250±50rpm下搅拌(IKA电搅拌器，IKH-Werke GmbH and Co.，Stanfen，Germany)约5-10分钟，得到含有聚合物粒子的粘性糊样物质。将含有聚合物/溶剂混合物的容器密封，置于平衡至37℃的温控恒温箱中达1至4天，间歇性搅拌，这依赖于溶剂与聚合物类型和溶剂与聚合物之比。当呈现澄清琥珀色均匀溶液时从恒温箱中取出聚合物/溶剂混合物。然后，将混合物置于烘箱(65℃)中达30分钟。注意到从烘箱中取出后PLGA溶解在混合物中。Gel vehicles for use in injectable depot compositions are prepared as follows. Place the glass container on a Mettler PJ3000 top loading balance. Poly(D,L-lactide-co-glycolide) (PLGA) was weighed into a glass container as 50:50 DL-PLG with an intrinsic viscosity of 0.15 (PLGA-BPI, Birmingham Polymers, Inc., Birmingham, AL), and 50:50

RG502 (PLGA RG502). The glass container containing the polymer was tared and the corresponding solvent was added. The percentages for various polymer/solvent combinations are described in Table 1 below. The polymer/solvent mixture was stirred (IKA electric stirrer, IKH-Werke GmbH and Co., Stanfen, Germany) at 250±50 rpm for about 5-10 minutes to obtain a viscous paste-like mass containing polymer particles. The vessel containing the polymer/solvent mixture was sealed and placed in a temperature-controlled incubator equilibrated to 37°C for 1 to 4 days with intermittent agitation, depending on solvent to polymer type and solvent to polymer ratio. The polymer/solvent mixture was removed from the oven when a clear amber homogeneous solution appeared. Then, the mixture was placed in an oven (65°C) for 30 minutes. Note that PLGA dissolves in the mixture after removal from the oven.

利用下列溶剂或溶剂混合物和下列聚合物制备其他储库凝胶媒介物：苯甲酸苄基酯(BB)、苄醇(BA)、苯甲酸乙酯(EB)、BB/BA、BB/乙醇、BB/EB；聚(D，L-交酯)

L104，PLA-L104，code no.33007，聚(D，L-交酯-共-乙交酯)50∶50

RG502，code no.0000366，聚(D，L-交酯-共-乙交酯)50∶50RG502H，PLGA-502H，code no.260187，聚(D，L-交酯-共-乙交酯)50∶50RG503，PLGA-503，code no.0080765，聚(D，L-交酯-共-乙交酯)50∶50

RG755，PLGA-755，code no.95037，聚L-交酯MW 2,000(

L 206，L 207，L 209，L214)；聚D，L-交酯(R 104，R 202，

R203，R 206，

R 207，R 208)；聚L-交酯-共-D，L-交酯90∶10(LR 209)；聚D-L-交酯-共-乙交酯75∶25(RG 752，

RG 756)；聚D，L-交酯-共-乙交酯85∶15(RG 858)；聚L-交酯-共-碳酸三亚甲基酯70∶30(

LT 706)；聚二噁烷酮(

X 210)(Boehringer Ingelheim Chemicals，Inc.，Petersburg，VA)；DL-交酯/乙交酯100∶0(Polymer 100 DL High，

Polymer 100 DL Low)；DL-交酯/乙交酯85/15(

Polymer8515 DL High，Polymer 8515 DL Low)；DL-交酯/乙交酯75/25(

Polymer 7525 DL High，

Polymer 7525DL Low)；DL-交酯/乙交酯65/35(Polymer 6535 DL High，Polymer 6535 DL Low)；DL-交酯/乙交酯54/46(

Polymer 5050 DL High，Polymer 5050 DL Low)；和DL-交酯/乙交酯54/46(Polymer 5050 DL 2A(3)，Polymer 5050 DL 3A(3)，

Polymer 5050 DL4A(3))(Medisorb Technologies International L.P.，Cincinnati，OH)；和聚D，L-交酯-共-乙交酯50∶50；聚D，L-交酯-共-乙交酯65∶35；聚D，L-交酯-共-乙交酯75∶25；聚D，L-交酯-共-乙交酯85∶15；聚DL-交酯；聚L-交酯；聚乙交酯；聚ε-己内酯；聚DL-交酯-共-己内酯25∶75；和聚DL-交酯-共-己内酯75∶25(BirminghamPolymers，Inc.，Birmingham，AL)。Other depot gel vehicles were prepared using the following solvents or solvent mixtures and the following polymers: benzyl benzoate (BB), benzyl alcohol (BA), ethyl benzoate (EB), BB/BA, BB/ethanol, BB/EB; poly(D,L-lactide)

L104, PLA-L104, code no.33007, poly(D,L-lactide-co-glycolide) 50:50

RG502, code no.0000366, poly(D,L-lactide-co-glycolide) 50:50 RG502H, PLGA-502H, code no.260187, poly(D,L-lactide-co-glycolide) 50:50 RG503, PLGA-503, code no.0080765, poly(D,L-lactide-co-glycolide) 50:50

RG755, PLGA-755, code no.95037, poly L-lactide MW 2,000 (

L 206, L 207, L 209, L214); poly D, L-lactide ( R 104, R 202,

R203, R 206,

R 207, R 208); Poly L-lactide-co-D, L-lactide 90:10 ( LR 209); poly DL-lactide-co-glycolide 75:25 ( RG 752,

RG 756); poly D, L-lactide-co-glycolide 85:15 ( RG 858); Poly L-lactide-co-trimethylene carbonate 70:30 (

LT 706); polydioxanone (

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); and DL-lactide/glycolide 54/46 ( Polymer 5050 DL 2A(3), Polymer 5050 DL 3A(3),

Polymer 5050 DL4A(3)) (Medisorb Technologies International LP, Cincinnati, OH); and poly D,L-lactide-co-glycolide 50:50; poly D,L-lactide-co-glycolide 65 : 35; Poly D, L-lactide-co-glycolide 75:25; Poly D, L-lactide-co-glycolide 85:15; Poly DL-lactide; Poly L-lactide; Poly Glycolide; polyε-caprolactone; polyDL-lactide-co-caprolactone 25:75; and polyDL-lactide-co-caprolactone 75:25 (Birmingham Polymers, Inc., Birmingham, AL ).

实施例2Example 2

布比卡因碱制备物Bupivacaine base preparation

将盐酸布比卡因(Sigma-Aldrich Corporation，St.Louis，MO)溶于去离子(DI)水，浓度为40mg/ml(饱和)。向该溶液加入计算量的氢氧化钠(1N溶液)，调节最终混合物的pH至10，以沉淀出BP碱。将所沉淀的产物过滤，进一步用DI水洗涤至少三次。将所沉淀的产物在大约40℃真空中干燥24小时。Bupivacaine hydrochloride (Sigma-Aldrich Corporation, St. Louis, MO) was dissolved in deionized (DI) water at a concentration of 40 mg/ml (saturated). To this solution was added a calculated amount of sodium hydroxide (1 N solution) to adjust the pH of the final mixture to 10 to precipitate out the BP base. The precipitated product was filtered and further washed with DI water at least three times. The precipitated product was dried under vacuum at about 40°C for 24 hours.

实施例3Example 3

布比卡因粒子制备物Bupivacaine particle preparation

如下使用盐酸布比卡因(Sigma-Aldrich Corporation，St.Louis，MO)或按照实施例2制备的布比卡因碱和盐酸盐制备布比卡因药物粒子。研磨布比卡因，然后利用3”不锈钢筛过筛。典型的范围包括25μm至38μm、38μm至63μm和63μm至125μm。Bupivacaine drug particles were prepared using bupivacaine hydrochloride (Sigma-Aldrich Corporation, St. Louis, MO) or bupivacaine base and hydrochloride prepared according to Example 2 as follows. Bupivacaine was ground and then sieved using a 3" stainless steel sieve. Typical ranges included 25 μm to 38 μm, 38 μm to 63 μm, and 63 μm to 125 μm.

实施例4Example 4

hGH/Zn配合物制备物hGH/Zn complex preparation

利用浓缩/透析选择渗滤仪，将hGH水溶液(5mg/ml)(BresaGenCorporation，Adelaide，Australia)浓缩至10mg/ml。将经过渗滤的hGH溶液用5倍体积的TRIS(pH 7.6)洗涤，进一步在5mM TRIS缓冲液中浓缩至hGH的40mg/ml溶液。加入等份的27.2mM锌(来自乙酸锌)在5mM TRIS缓冲液中的溶液，得到最终的混合物，锌∶hGH的摩尔比为15∶1。使该混合物在4℃下配合大约1小时。然后将该配合物预冷却至-70℃，按照下述冷冻干燥周期利用Durastop μP冻干器冻干Aqueous hGH (5 mg/ml) (BresaGen Corporation, Adelaide, Australia) was concentrated to 10 mg/ml using a concentration/dialysis selective diafilter. The diafiltered hGH solution was washed with 5 volumes of TRIS (pH 7.6) and further concentrated to a 40 mg/ml solution of hGH in 5 mM TRIS buffer. Aliquots of 27.2 mM zinc (from zinc acetate) in 5 mM TRIS buffer were added to obtain a final mixture with a zinc:hGH molar ratio of 15:1. The mixture was allowed to complex for approximately 1 hour at 4°C. The complex was then pre-cooled to -70°C and lyophilized using a Durastop μP lyophilizer according to the following freeze-drying cycle

实施例5Example 5

hGH/Zn配合物制备物的粒子Particles of hGH/Zn complex preparation

从实施例4所制备的冻干hGH/Zn配合物制备hGH/Zn配合物的不同粒子，没有压制或者经过压制：1)利用Waring掺合机研磨经过冻干的hGH/Zn配合物，没有压制。收集120目(125μm)与400目(38μm)之间的粒子。2)将经过冻干的hGH/Zn配合物转移至13mm圆形压制冲模，在5吨压力下压制5分钟，形成颗粒。利用Waring掺合机研磨颗粒。收集120目(125μm)与400目(38μm)之间的粒子。Preparation of different particles of the hGH/Zn complex from the lyophilized hGH/Zn complex prepared in Example 4, without compression or with compression: 1) Grinding the lyophilized hGH/Zn complex with a Waring blender without compression . Particles between 120 mesh (125 μm) and 400 mesh (38 μm) were collected. 2) The freeze-dried hGH/Zn complex was transferred to a 13 mm circular pressing die, and pressed under a pressure of 5 tons for 5 minutes to form granules. The particles were milled using a Waring blender. Particles between 120 mesh (125 μm) and 400 mesh (38 μm) were collected.

实施例6Example 6

碳酸锌粒子制备物Zinc carbonate particle preparation

利用3”不锈钢筛，通过38μm过筛，保留15μm，制备碳酸锌氢氧化锌水合物(ZnCO₃ 2Zn(OH)₂ XH₂O)(Aldrich，Milwaukee，WI，USA)的粒子，大小为15-38μm。Using a 3" stainless steel sieve, sieve through 38 μm and retain 15 μm to prepare particles of zinc carbonate zinc hydroxide hydrate (ZnCO₃ 2Zn(OH)₂ XH₂ O) (Aldrich, Milwaukee, WI, USA) with a size of 15- 38 μm.

实施例7Example 7

药物加载drug loading

将如上制备的粒子加入到凝胶媒介物中，用量为10-30重量％，手工掺合，直至干粉完全湿润。然后利用附有方形-尖端金属匙的Caframo机械搅拌器借助常规混合充分掺合乳状浅黄色粒子/凝胶混合物。所得制剂如表1、2和3所述。The particles prepared as above were added to the gel vehicle in an amount of 10-30% by weight and blended by hand until the dry powder was completely wetted. The milky buff particle/gel mixture was then blended well with regular mixing using a Caframo mechanical stirrer attached to a square-tip metal spoon. The resulting formulations are described in Tables 1, 2 and 3.

表1Table 1

  制剂preparation  PLGA RG 502^a(wt％)PLGA RG^502a (wt%)  苯甲酸苄基酯(wt％)Benzyl Benzoate (wt%)  布比卡因碱(wt％)Bupivacaine base (wt%)  ZnCO₃(wt％)ZnCO₃ (wt%)  1 1  4545  4545  1010  00  2 2  43.543.5  43.543.5  1010  33

^aPLGA RG 502，MW＝16,000^a PLGA RG 502, MW=16,000

表2Table 2

  制剂preparation  LMW PLGA^a(wt％)LMW PLGA^a (wt%)  苄醇(wt％)Benzyl alcohol (wt%)  布比卡因HCl(wt％)Bupivacaine HCl(wt%)  ZnCO₃(wt％)ZnCO₃ (wt%)3367.567.522.522.51010004465.265.221.821.81010335563.063.021twenty one101066

^a具有羧基末端的低分子量(LMW，MW＝10,000)PLGA^a Low molecular weight (LMW, MW=10,000) PLGA with carboxyl terminus

实施例8Example 8

布比卡因与碳酸锌的共同加载Co-loading of Bupivacaine and Zinc Carbonate

将实施例3所制备的药物粒子与实施例6所制备的碳酸锌粒子按预定比例预混合，在如实施例7所述过程中将药物与碳酸锌的粒子混合物加入到凝胶媒介物中。所得制剂如表1和2所述。The drug particles prepared in Example 3 and the zinc carbonate particles prepared in Example 6 were pre-mixed in a predetermined ratio, and the particle mixture of drug and zinc carbonate was added to the gel vehicle in the process as described in Example 7. The resulting formulations are described in Tables 1 and 2.

实施例9Example 9

hGH/Zn配合物粒子与碳酸锌的共同加载Co-loading of hGH/Zn complex particles and zinc carbonate

将实施例5所制备的hGH/Zn配合物粒子与实施例6所制备的碳酸锌粒子按预定比例单独加入到凝胶媒介物中，在如实施例7所述过程中在凝胶媒介物中混合hGH/Zn配合物和碳酸锌的粒子。所得制剂如表3所述。The hGH/Zn complex particles prepared in Example 5 and the zinc carbonate particles prepared in Example 6 were separately added to the gel vehicle in a predetermined ratio, and in the gel vehicle in the process as described in Example 7 Particles of hGH/Zn complex and zinc carbonate were mixed. The resulting formulations are described in Table 3.

表3table 3

  制剂preparation  PLGA RG502^a(wt％)PLGA^RG502a (wt%)  苯甲酸苄基酯(wt％)Benzyl Benzoate (wt%)  hGH/Zn配合物(wt％)hGH/Zn complex (wt%)  ZnCO₃(wt％)ZnCO₃ (wt%)  66  45.045.0  45.045.0  10^b10b  00  77  45.045.0  45.045.0  10^c10c  00  8 8  43.543.5  43.543.5  10^c10c  33

^aPLGA RG 502，MW＝16,000；^a PLGA RG 502, MW=16,000;

^b没有预先压制制备hGH/Zn配合物粒子；^b Preparation of hGH/Zn complex particles without pre-compression;

^c经过预先压制制备hGH/Zn配合物粒子。^c Preparation of hGH/Zn complex particles by pre-compression.

实施例10Example 10

布比卡因体内研究Bupivacaine in vivo studies

遵循开放方案进行大鼠体内研究(每组4或5只)，以测定在布比卡因经由本发明植入系统全身给药后的布比卡因血浆水平。将储库凝胶布比卡因制剂加载到定制的0.5cc一次性注射器中。向注射器安装一次性18gauge针头，利用循环浴加热至37℃。将储库凝胶布比卡因制剂注射到大鼠中，按指定时间间隔(1小时、4小时和第1、2、5、7、9、14、21和28天)抽血，利用LC/MS分析布比卡因。In vivo studies in rats (4 or 5 per group) were performed following an open protocol to determine bupivacaine plasma levels following systemic administration of bupivacaine via the implant system of the invention. The depot gel bupivacaine formulation was loaded into a custom 0.5cc disposable syringe. A disposable 18 gauge needle was fitted to the syringe and heated to 37° C. using a circulating bath. Depot gel bupivacaine formulations were injected into rats, blood was drawn at indicated time intervals (1 hour, 4 hours and days 1, 2, 5, 7, 9, 14, 21, and 28) and analyzed using LC /MS analysis of bupivacaine.

图1阐述从各种长期系统用储库制剂(大约1个月)获得的代表性布比卡因碱大鼠体内释放曲线，包括本发明的那些。没有ZnCO₃共同加载的储库制剂(制剂1)表现两相释放曲线，也就是说在第一阶段(＜1-2周)，释放速率随着时间而降低(主要受扩散的控制)，而在后一阶段(1-2周后)，释放变得平稳或者随着时间而增加(由于聚合物降解和扩散)。有ZnCO₃共同加载的储库制剂(制剂2)不表现典型的两相释放曲线，在初始突释释放后释放曲线更加平稳(接近没有ZnCO₃的制剂1)，代之以短暂的释放持续时间。这一发现清楚地证明，向储库制剂加入ZnCO₃能够把释放速率曲线从典型的两相型变为接近零级释放速率曲线，以及调控释放持续时间。Figure 1 illustrates representative rat in vivo release profiles of bupivacaine base obtained from various long-term systemic depot formulations (approximately 1 month), including those of the present invention. The depot formulation without_ZnCO3 co-loading (formulation 1) exhibited a biphasic release profile, that is, in the first phase (<1-2 weeks), the release rate decreased with time (mainly controlled by diffusion), while In the latter phase (after 1-2 weeks), the release becomes plateau or increases over time (due to polymer degradation and diffusion). The depot formulation co-loaded with ZnCO₃ (Formulation 2) did not exhibit the typical biphasic release profile, the release profile was more even after the initial burst release (closer to Formulation 1 without ZnCO₃ ), instead a brief release duration . This finding clearly demonstrates that the addition of ZnCO₃ to the depot formulation can change the release rate profile from a typical biphasic type to a near zero-order release rate profile, as well as modulate the release duration.

惊人的是由有ZnCO₃共同加载的储库制剂(制剂2)所显示的释放速率快于没有ZnCO₃共同加载的制剂(制剂1)。通常，在碱性环境中(pH＞7.0)，预期布比卡因保持其碱形式，由于其疏水性将表现缓慢的释放。不过如制剂2所示，在弱碱的存在下，例如ZnCO₃(pKa＞7)，释放速率快于没有弱碱，与由处于亲水性状态的布比卡因所表现的相似。Surprisingly, the release rate shown by the depot formulation co-loaded with_ZnCO3 (Formulation 2) was faster than the formulation without_ZnCO3 co-loaded (Formulation 1). Generally, in an alkaline environment (pH > 7.0), bupivacaine is expected to remain in its base form and will exhibit a slow release due to its hydrophobicity. However, as shown in Formulation 2, in the presence of a weak base, such as_ZnCO3 (pKa > 7), the release rate was faster than without the weak base, similar to that exhibited by bupivacaine in the hydrophilic state.

图2阐述从各种短期系统用储库制剂(至多2周)获得的代表性盐酸布比卡因大鼠体内释放曲线，包括本发明的那些。没有ZnCO₃共同加载的储库制剂(制剂3)表现药物随时间降低的释放，表明主要为扩散控制的释放曲线。不过，有ZnCO₃共同加载的储库制剂(制剂4和5)与没有ZnCO₃共同加载的制剂(制剂3)相比表现减少了的突释释放和更加平稳的释放曲线(接近零级)，表明向储库制剂加入ZnCO₃也能改变短期储库的释放速率曲线。Figure 2 illustrates representative rat in vivo release profiles of bupivacaine hydrochloride obtained from various short-term systemic depot formulations (up to 2 weeks), including those of the present invention. The depot formulation without_ZnCO3 co-loading (Formulation 3) exhibited a decreased release of drug over time, indicating a predominantly diffusion controlled release profile. However, the depot formulations co-loaded with_ZnCO3 (Formulations 4 and 5) exhibited reduced burst release and a more flat release profile (closer to zero order) than the formulation without_ZnCO3 co-loaded (Formulation 3), It was shown that the addition of ZnCO₃ to the depot formulation can also alter the release rate profile of the short-term depot.

实施例11Example 11

hGH体内研究hGH in vivo studies

遵循开放方案进行大鼠体内研究，以测定在hGH经由本发明植入系统全身给药后的hGH血清水平。将储库凝胶hGH制剂加载到定制的0.5cc一次性注射器中。向注射器安装一次性18gauge 1”针头，利用循环浴加热至37℃。将储库凝胶hGH制剂注射到免疫抑制大鼠中，在注射后1小时、4小时、第1、2、4、7、10、14、21和28天收集血清样品。在分析前，全部血清样品贮存在4℃下。利用放射免疫测定法(RIA)分析样品的完整hGH含量。在研究结束时使大鼠安乐死，进行粗略临床观察，取回储库，进行完整性观察。An in vivo study in rats was performed following an open protocol to determine hGH serum levels following systemic administration of hGH via the implant system of the invention. The depot gel hGH formulation was loaded into a custom 0.5cc disposable syringe. Fit a disposable 18gauge 1” needle to the syringe and heat to 37°C using a circulating bath. Inject the depot gel hGH preparation into immunosuppressed rats at 1 hour, 4 hours, 1, 2, 4, 7 days after injection Serum samples were collected ondays 1, 10, 14, 21 and 28. Prior to analysis, all serum samples were stored at 4°C. Samples were analyzed for intact hGH content by radioimmunoassay (RIA). Rats were euthanized at the end of the study, Perform gross clinical observation, retrieve reservoir, conduct integrity observation.

图3阐述从各种储库组合物获得的代表性人生长激素(hGH)大鼠体内释放曲线，包括本发明的那些。有ZnCO₃共同加载的储库制剂(制剂8)与没有ZnCO₃共同加载的制剂(制剂6和7)相比趋于具有更平稳的释放速率曲线和更短的释放持续时间，如图1中的布比卡因。这进一步表明如本发明所述向储库制剂加入ZnCO₃也能改变蛋白质释放速率曲线和调控释放持续时间。Figure 3 illustrates representative human growth hormone (hGH) rat in vivo release profiles obtained from various depot compositions, including those of the present invention. The depot formulation (Formulation 8) with ZnCO₃ co-loading tended to have a smoother release rate profile and shorter release duration than the formulations without ZnCO₃ co-loading (Formulation 6 and 7), as shown in Figure 1 of bupivacaine. This further indicates that the addition of_ZnCO3 to the depot formulation as described in the present invention can also alter the protein release rate profile and modulate release duration.

实施例12Example 12

还原剂的粒子制备物Particle preparation of reducing agent

利用3”不锈钢筛通过38μm过筛，保留15μm，制备还原剂甲硫氨酸(Sigma，St.Louis，MO，USA)的粒子，大小为15-38μm。Particles of the reducing agent methionine (Sigma, St. Louis, MO, USA) were prepared with a size of 15-38 μm by sieving through a 3” stainless steel sieve through 38 μm, retaining 15 μm.

实施例13Example 13

向储库中加载hGH和甲硫氨酸以及体内测试Loading of hGH and methionine into reservoirs and in vivo testing

向凝胶媒介物加入实施例12的还原剂甲硫氨酸，用量为0.1-20重量％，手工掺合，直至干粉完全湿润。然后利用附有方形-尖端金属匙的Caframo机械搅拌器借助常规混合充分掺合乳状浅黄色粒子/凝胶混合物。向凝胶媒介物加载治疗剂，例如蛋白质，象hGH，或者小分子，例如布比卡因。甲硫氨酸与治疗剂的比例在约0.1∶99.9至约70∶30之间。进行体内测试，以生成释放速率曲线。The reducing agent methionine of Example 12 was added to the gel vehicle in an amount of 0.1-20% by weight and blended by hand until the dry powder was completely wetted. The milky buff particle/gel mixture was then blended well with regular mixing using a Caframo mechanical stirrer attached to a square-tip metal spoon. The gel vehicle is loaded with therapeutic agents, such as proteins, like hGH, or small molecules, such as bupivacaine. The ratio of methionine to therapeutic agent is between about 0.1:99.9 to about 70:30. In vivo testing was performed to generate release rate profiles.

实施例14Example 14

抗氧化剂的粒子制备物Granular preparation of antioxidants

利用3”不锈钢筛通过38μm过筛，保留15μm，制备抗氧化剂维生素E酸式琥珀酸盐(Sigma，St.Louis，MO，USA)的粒子，大小为15-38μm。The antioxidant vitamin E acid succinate (Sigma, St. Louis, MO, USA) was sieved through 38 μm using a 3” stainless steel sieve, retaining 15 μm, to prepare particles of 15-38 μm in size.

实施例15Example 15

药物加载和体内测试Drug loading and in vivo testing

向凝胶媒介物加入实施例14的抗氧化剂维生素E，用量为0.1-20重量％，手工掺合，直至干粉完全湿润。然后利用附有方形-尖端金属匙的Caframo机械搅拌器借助常规混合充分掺合乳状浅黄色粒子/凝胶混合物。当维生素E的含量很低时(在约0.1至约5重量％之间)，它溶解在凝胶媒介物中。向凝胶媒介物加载治疗剂，例如蛋白质，象hGH，或者小分子，例如布比卡因。维生素E与治疗剂的比例在约0.1∶99.9至约70∶30之间。进行体内测试，以生成释放速率曲线。The antioxidant vitamin E of Example 14 was added to the gel vehicle in an amount of 0.1-20% by weight and blended by hand until the dry powder was completely wetted. The milky buff particle/gel mixture was then blended well with regular mixing using a Caframo mechanical stirrer attached to a square-tip metal spoon. When the vitamin E content is very low (between about 0.1 to about 5% by weight), it dissolves in the gel vehicle. The gel vehicle is loaded with therapeutic agents, such as proteins, like hGH, or small molecules, such as bupivacaine. The ratio of vitamin E to therapeutic agent is between about 0.1:99.9 to about 70:30. In vivo testing was performed to generate release rate profiles.

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.

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