Gel composition and methods

专利摘要:
Methods and compositions are described for systemic or topical administration of an agonist to a subject to be treated, such as compositions having a burst index of 8 or less for systemic application, and total agonist administration within the first 24 hours after transplantation for topical application. It includes a system that releases less than 10% of the amount. The composition contains a biocompatible polymer, a biocompatible solvent having a low water miscibility, which forms a viscous gel with the polymer to limit water absorption by the implant, and an agonist.
公开号:KR20000069564A
申请号:KR1019997005514
申请日:1997-12-18
公开日:2000-11-25
发明作者:디오더오 티 쉔
申请人:스톤 스티븐 에프.；알자 코포레이션；
IPC主号:

专利说明:

Gel Compositions and Methods {GEL COMPOSITION AND METHODS}
[2] Biodegradable polymers have been used for many years in the medical field. Illustrative devices comprised of biodegradable polymers include sutures, surgical clips, staples, implants, and sustained release drug delivery systems. Most of these biodegradable polymers have been based on glycolide, lactide, caprolactone, and copolymers thereof.
[3] Biodegradable polymers can be thermoplastics, meaning that they can be formed into various shapes such as fibers, clips, staples, pins, films, etc., when heated. Alternatively, they may be thermosetting materials formed by crosslinking reactions in which high molecular weight materials are produced that do not melt at high temperatures or do not form a flowable liquid.
[4] Although thermoplastic and thermoset biodegradable polymers are quite useful in the biomedical field, they have some important vulnerabilities for use in the body of various animals, including humans, animals, birds, fish and reptiles. Since these polymers are usually solids, all of them inevitably form polymerizable structures initially outside of the body and then insert the solid structures into the body. For example, sutures, clips and staples are all made from thermoplastic biodegradable polymers prior to use. When inserted into the body, they retain their original shape. While this feature is essential in some cases, it is undesirable if the material is molded or flowed to fill voids or cavities that may most need the material.
[5] In addition, drug delivery systems using thermoplastic or thermoset biodegradable polymers often have to be formed or formed outside of the body. In this case, the agent is incorporated into the polymer and then the mixture is shaped into a specific form such as a cylinder, disc, or fiber for implantation. For such solid implants, the drug delivery system must be inserted into the body through the incision. Such incisions sometimes become larger than intended by doctors so that patients are often reluctant to accept the implant or drug delivery system. Nevertheless, biodegradable and non-biodegradable implantable drug delivery systems have been successfully used extensively.
[6] One reservoir with a rate controlling membrane and in particular a zero release agent designed for oral implants is described in US Pat. No. 5,085,866. The instrument is made from a core sprayed with a solution having a polymer and a solvent consisting of a low boiling first solvent and a slowly boiling high boiling second solvent.
[7] Other osmotic delivery systems include U.S. Patents 3,797,492, 3,987,790, 4,008,719, 4,865,845, 5,057,318, 5,059,423, 5,112,614, 5,137,727, 5,151,093, 5,234,692, 5,234,693, 5,279,608 and 5,336,057. Pulsatile vehicles are also known that deliver agonists in a pulsating manner as disclosed in US Pat. Nos. 5,209,746, 5,308,348 and 5,456,679.
[8] One way to avoid the incision necessary to implant the drug delivery system is to inject the drug delivery system as small particles, microspheres, or microcapsules. For example, US Pat. No. 5,019,400 describes the preparation of microspheres whose release is controlled by a very low temperature casting method. These substances may or may not include agents that can be released into the body. Although these materials can be injected into the body using syringes, they do not always meet the need for biodegradable implants. Because they are essentially particulate, they do not form a continuous film or solid implant with the structural integrity required for certain prostheses. When inserted into certain body cavities such as the oral cavity, periodontal pockets, eyes or vagina with significant fluid flow, the small particles, microspheres or microcapsules are poorly maintained due to their small size and discontinuous nature. Moreover, the particles become swarmed and difficult to predict their behavior. In addition, microspheres or microcapsules that are prepared from the polymer and contain agents for release into the body are often difficult to produce on a large scale, and their storage and infusion properties provide problems. In addition, another major vulnerability of microcapsules or small particle systems is the lack of reversibility without extensive surgical intervention. In other words, when difficult ejaculation occurs after they are injected, it is more difficult to remove them from the body than with solid implants. Yet another vulnerability to particulate or microencapsulation is that it is difficult to encapsulate protein and DNA-based pharmaceuticals without degradation caused by the denaturing solvent and temperature extremes used during processing.
[9] The art has developed a variety of drug delivery systems to address the above challenges. For example, US Pat. No. 4,938,763 and its splitting application No. 5,278,201 to biodegradable polymers for use in providing solid biodegradable implants in in situ forming and injectable for animals. It is about. In one embodiment, a thermoplastic system is used in which a non-reactive polymer is dissolved in an aqueous, biocompatible solvent to form a medicament that is placed into an animal (the solvent dissipates within the animal to form a solid implant). Alternatively, a thermosetting system is used in which an effective amount of liquid acrylic ester terminal biodegradable prepolymer and a curing agent are formed and the liquid mixture is placed in an animal (in which the prepolymer cures to form a solid implant). The systems are said to provide an injectable solid biodegradable delivery system by adding an effective amount of a biologically active agent to the liquid prior to injection into the animal.
[10] U. S. Patent 5,599, 552 describes thermoplastic and thermosetting polymer compositions that result in a polymer solution that can quickly absorb water from surrounding tissue using a miscible, dispersible solvent, such as N-methyl-2-pyrrolidone. Doing. The polarity of the solvent is described as effective to provide at least about 10% or more water solubility. The polymer matrix system is described as forming a porous core surrounded by porous skin.
[11] U. S. Patent No. 5,242, 910 describes a sustained release composition containing a medicament for treating periodontal disease. This composition contains a copolymer of lactide and glycolide, triacetin (as a solvent / plasticizer), and agents that alleviate the pain of oral disease. The composition can take the form of a gel and can be inserted into the periodontal cavity using a syringe using a needle or catheter. As a further optional component, the composition may include surfactants, flavoring agents, viscosity modifiers, complexing agents, antioxidants, other polymers, gums, waxes / oils, and colorants. One exemplary viscosity modifier described in one of the examples is polyethylene glycol 400.
[12] U. S. Patent No. 5,620, 700 describes a polymer-pharmaceutical matrix comprising a plasticizer in an amount of up to about 30% by weight for topical application of the medicament to the periodontal cavity. Among the plasticizers listed are especially triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, diethyl phthalate, diethyl tartrate, ethyl lactate, triacetin and diacetin. The polymer matrix is heated until administration so that it is non-flowable so that the polymer matrix can be dispensed into the periodontal cavity where it solidifies. While the patent discusses possible systemic applications by transport through the eye's eye bag or intravaginal transport, it does not address the problem of bursts of drugs or how to control the bursts.
[13] U.S. Patent No. 3,923,939 describes a method for reducing the initial burst of active agent from a carrier by removing the active agent prior to implantation, through the layer of at least 5% of the total body thickness extending from the outer surface of the carrier and from the outer surface of the carrier. .
[14] U. S. Patent No. 5,556, 905 describes a degradable thermoplastic composition modified by a plasticizer consisting of a partial ester of several citric acids.
[15] The polymer compositions for injectable implants of the prior art facilitated the rapid solidification of the polymer at the site of implantation using solvents / plasticizers that are very or relatively soluble in aqueous body fluids to promote diffusion of the medicament from the implant. However, it has now been observed that a serious problem associated with polymerizable implants of the prior art using water soluble polymer solvents is the rapid migration of water into the polymer composition when the implant is placed in the body and exposed to aqueous body fluids. This property often provides uncontrolled release of the agonist, which is manifested by early and rapid release of the agonist from the polymer composition, which corresponds to the “burst” of the agonist released from the implant. Bursts, if not all, often cause substantial portions of the agonist to be released within a very short time, such as hours or 1-2 days. These results may be due to sustained delivery, i.e. delivery of the agonist over a week or month, or when the therapeutic window is narrow and the release of the agonist in excess may have adverse consequences for the subject to be treated, or It is especially unacceptable when it is essential to conceive the daily profile of naturally occurring agonists such as hormones in the body.
[16] Attempts to control bursts and to control and stabilize delivery of agonists in the prior art have coated particles of agonists to prolong release of agonists over time by delaying release to the aqueous environment. Alternatively, various stabilization or release modulators, for example US Pat. No. 5,656,297; 5,654,010; 5,654,010; The metal salts described in US Pat. Nos. 4,985,404 and 4,853,218 and the like have been used. Despite some success, the methods have not been entirely satisfactory for many agonists that can be effectively transported by the implant because in many cases a complex of metal ions and agonists is formed due to regulatory and stabilizing effects. If no such complex is formed, the stabilization / regulation results may not be suitable to prevent “burst” of the agonist where the agonist is undesirable when the agonist is introduced to the site of implantation.
[17] Additionally, in the case of typically low viscosity solvent based depot compositions composed of polymers dissolved in a solvent, another problem that sometimes arises is after injection as the solvent diffuses out of the reservoir and water moves into the reservoir. The composition slowly solidifies. Because these compositions are relatively invisible so that they can be injected, the drug can be rapidly released in high percentages as the system is formed by diffusion of the solvent, especially when the agonist is soluble in the solvent and the solvent rapidly diffuses into the body fluids. Rapid solvent release contributes to the "burst" effect with storage hardening due to water absorption. Because of this, conventional solvent-based compositions typically have a drug burst in which 30-75% of the drug contained therein is released within the first day of the initial infusion.
[18] Rapid water absorption into polymer implants and solvent diffusion into body fluids represented by conventional devices often result in implants having pore structures that are heterogeneous in size and shape. Typically, the surface pores take a pore-like pore structure that extends about 1/3 mm or more from the surface of the implant into the implant, and these finger-like pores open at the surface of the implant with respect to the environment in use. Internal pores tend to become smaller and less accessible to fluids present in the environment of use. Thus, when such devices are implanted, finger-like pores allow the aqueous body fluids to be absorbed very quickly into the implant, resulting in a significant amount of agonist dissolving immediately and quickly and unaffected diffusion into the environment of use. Create the burst effect discussed above.
[19] Moreover, the rapid absorption of water can result in immature polymer precipitates that can produce cured implants or implants with cured surfaces. A large portion of the interior of the polymer containing the internal pores and agonists may be excluded from contact with body fluids and the release of agonists may be reduced to a significant extent over an insignificant time (“lag time”). . This delay is undesirable in that it is intended to provide controlled sustained release of the agonist to the subject to be treated. What is then observed is a burst of agonist released for a short time immediately after transplantation, a delay time at which the agonist is released at all or little, and consequently until the supplied agonist is consumed (assuming the agonist remains after the burst) The third is a continuous conveyance.
[20] <Summary of invention>
[21] The present invention provides methods and implantable systems for the propagation and topical delivery of agonists to a subject to be treated. This method and system provide for the subjects to be treated a tropic drug and limit the initial burst of agonist from the implantation system. In addition, the present invention provides a method of making an implantation system with limited initial burst of agonist.
[22] In one aspect, the present invention provides a system containing an agonist dispersed or dissolved substantially throughout the viscous gel, wherein the system contains up to 20% by weight of the agonist present in the viscous gel within the first 24 hours after implantation into the treatment subject. And topical or systemic administration of the agonist to the subject being treated. Preferably, up to 10% by weight of the agonist will be released within the first 24 hours after implantation.
[23] In another aspect, the invention provides a systemic administration of an agonist to a treated subject, comprising implanting a system containing an agonist dispersed or dissolved substantially throughout the viscous gel, the burst index of the system being 8 or less. It includes how to do it.
[24] In yet another aspect, the invention provides a biocompatible polymer, a biocompatible solvent that has a water solubility of less than 7% and forms a viscous gel with the polymer, and an agonist (the loading of the agonist inside the polymer gel is agonist in water Systemic administration of the agonist to the subject in a controlled manner approaching zero release by implanting a gel composition).
[25] In yet another aspect, the invention provides a polymer, an amount of solvent to form a viscous gel with the polymer, which solvent comprises a single solvent or a solvent mixture with one or more solvents having a water miscibility of less than 7% by weight. The amount of solvent comprises at least 40% by weight of the gel vehicle), and an implantable biodegradable composition for systemic delivery of the agonist to the therapeutic subject, containing the agonist dissolved or dispersed in the gel.
[26] In a further aspect, the present invention provides an effective plasticizing amount of solvent for forming a viscous gel with a polymer, the solvent containing a solvent mixture with at least one solvent in a mixture having a water miscibility of less than 7% by weight. ) And an implantable biodegradable composition for sustained delivery of the agonist to a therapeutic subject, containing the agonist dissolved or dispersed in the gel. Preferably, the water miscibility of the solvent mixture is 20% by weight or less, more preferably 10% by weight or less.
[27] In yet another aspect, the present invention provides a polymer, an effective plasticization amount of solvent for forming a viscous gel with the polymer, wherein the solvent has a water miscibility of 7 weights selected from a single solvent or a lower alkyl and aralkyl ester system of benzoic acid. Implantable biodegradable compositions for the delivery of agonists to a therapeutic subject, containing a mixture with one or more solvents that are less than%) and dissolved or dispersed in a gel.
[28] In another aspect, the invention
[29] A) biocompatible polymers;
[30] B) A biocompatible solvent selected from the group consisting of compounds having the following structural formulas having a water miscibility of less than 7% by weight and capable of dissolving the polymer to form a viscous gel:
[31] And
[32] Wherein R ₁ is lower alkyl, aryl or aralkyl, R ₂ is aralkyl or lower alkyl, and R ₁ and R ₂ may be the same or different, provided that R ₁ and R ₂ are each lower Provided that the total number of carbon atoms represented by R ₁ and R ₂ when alkyl is 4 or more.);
[33] C) agonists; And optionally one or more
[34] D) emulsifiers;
[35] E) pore formers;
[36] F) solubility modifiers of agonists; And
[37] G) Osmosis
[38] Provided is an implantable gel composition for systemic administration of an agonist to a subject to be treated.
[39] In another aspect, the invention
[40] A) biocompatible polymers;
[41] B) A biocompatible solvent selected from the group consisting of compounds having the following structural formulas having a water miscibility of less than 7% by weight and capable of dissolving the polymer to form a viscous gel:
[42]
[43] (Wherein, R ₁ and R ₂ are as defined above.)
[44] It provides an implantable gel composition containing.
[45] In another aspect, the present invention limits water absorption by forming a gel composition from a polymer and a solvent that forms a viscous gel with the polymer (the water miscibility of the solvent is less than 7% by weight). Provide a way to. Preferably, the water miscibility of the solvent is 6% by weight or less, more preferably 5% by weight or less.
[46] In another aspect, the invention
[47] A) mixing a biocompatible polymer with a solvent having a water miscibility of 7% or less selected from the lower alkyl and aralkyl esters of benzoic acid to form a viscous gel;
[48] B) dispersing or dissolving the agonist optionally in combination with the solubility modifier of the agonist in the emulsifier to form an emulsifier containing the agonist; And
[49] C) mixing the viscous gel with an agonist containing emulsifier (the agonist containing emulsifier forms a droplet phase dispersed in the viscous gel); And in some cases
[50] D) mixing the viscous gel with one or more pore formers and osmotic agents
[51] It provides a method for producing an injectable storage gel composition comprising a.
[52] In another aspect, the invention
[53] A) mixing a biocompatible polymer with a solvent having a water miscibility of 7% or less selected from the lower alkyl and aralkyl esters of benzoic acid to form a viscous gel;
[54] B) dispersing or dissolving the agonist optionally in combination with the solubility modifier of the agonist in a viscous gel; And
[55] C) optionally mixing the agonist-containing gel with at least one of an emulsifier, pore former, agonist solubility modifier and osmotic agent
[56] It provides a method for producing an implantable gel composition comprising a.
[57] In yet another aspect, the invention
[58] A) biocompatible polymers;
[59] B) biocompatible solvents having a water miscibility of less than 7% by weight;
[60] C) an agonist selected from the group consisting of cDNA, DNA, peptides, proteins and fragments and derivatives thereof; And optionally one or more
[61] D) emulsifiers;
[62] E) pore formers;
[63] F) solubility modifiers of agonists; And
[64] G) Osmosis
[65] And a gel composition having a burst index of less than 8.
[66] In yet another aspect, the invention
[67] A) biocompatible polymers;
[68] B) a solvent having a water miscibility of no greater than 7% by weight to dissolve the polymer to form a viscous gel;
[69] C) agonists; And optionally one or more
[70] D) emulsifiers;
[71] E) pore formers;
[72] F) solubility modifiers of agonists optionally combined with agonists; And
[73] G) Osmosis
[74] And an agonist optionally combined with a solubility modifier comprises a kit for administering the agonist to the treated subject that remains separated from the solvent at least until the time of administering the agonist to the treated subject.
[75] In yet another aspect, the present invention provides a poly (lactide-co-glycolide) copolymer, an effective plasticizing amount of solvent for forming a viscous gel with the polymer; And implantable compositions for systemic delivery of an agonist containing an agonist selected from the group consisting of cDNA, DNA, peptides, proteins and fragments and derivatives thereof, wherein the burst index of the composition is 8 or less.
[76] In another aspect, the invention provides a poly (lactide-co-glycolide) copolymer, an effective plasticization amount of solvent selected from the lower alkyl and aralkyl ester systems of benzoic acid to form viscous gels with the copolymer, and efficacy Implantable compositions for sustained delivery of an agonist containing the agent.
[77] In a further aspect, the present invention includes an implantable composition containing a viscous gel and agonists dispersed or dissolved therein, wherein the viscous gel maintains a glass transition temperature of less than 37 ° C. for at least 24 hours after implantation.
[78] In yet another aspect, the invention provides a system comprising an agonist substantially dissolved or dispersed throughout a viscous gel formed from a biocompatible polymer, a solvent having a water solubility of 7% or less, and a solubility modifier of the agonist (the system of which Burst index is less than or equal to 8).
[79] In a further aspect, the present invention relates to an implantable system containing an agonist substantially dissolved or dispersed throughout a viscous gel formed from a biocompatible polymer, a solvent having a water solubility of 7% or less, and a solubility modifier of the agonist, the burst index of which is 8 or less).
[1] The present invention relates to a gel composition which can be implanted at a desired location and the release of a beeficial agent can be controlled. The invention also relates to a method of controlling the release of an agonist from a composition.
[80] The above and other objects, features and advantages of the present invention will be more readily understood by interpreting the following detailed description taken in conjunction with the accompanying drawings.
[81] 1 is a diagram illustrating the dispensing force (in psig) required for dispensing emulsified and non-emulsified viscous gel composition through 20 gauge needles at 2 cc / min.
[82] FIG. 2 is a diagram illustrating the in vitro release profile of lysozyme from three different compositions in days.
[83] FIG. 3 is a diagram illustrating the viscosity profile of an emulsion at different shear rates of an emulsifier-free viscous gel of an aqueous mixture of ethanol only with water.
[84] 4A and 4B are views illustrating the water absorption of several polymer-solvent mixtures, some of which form part of the present invention, wherein the amount of water absorbed in the implant as the water miscibility of the solvent decreases. Prove that this decreases.
[85] 5A and 5B are diagrams of the in vivo release rate profile of unstabilized and zinc-stabilized human growth hormone obtained from PLGA and gels formed from solvent triacetin and benzyl benzoate, respectively.
[86] The present invention relates to a method of systemically or topically administering an agonist to a subject by implanting a isisable system formed as a viscous gel formed of a biocompatible polymer and a biocompatible solvent into the subject, wherein the agonist is substantially dissolved throughout the gel. Or dispersed. By properly selecting the solvent, the movement of water from the aqueous environment surrounding the implantation system is limited, and the agonist is released to the treated subject over a long period of time, after which the controlled burst and sustained release of the agonist is controlled for delivery of the agonist. To provide.
[87] The inventors have found that proper burst control and sustained delivery of agonists are achieved when a solvent having a water solubility of less than 7% by weight is present in the system regardless of whether or not a solubility control crab is present in the system. Typically, transplant systems useful in the present invention will release up to 20%, preferably up to 15%, more preferably up to 10% of the total amount of agonist to be delivered from the transplant system to the treatment subject within the first 24 hours after transplantation. will be. The viscous gel formed is preferably biocorrosive so that the implantation system does not have to be surgically removed after the agonist is depleted from the implant.
[88] Water absorption and bursts are those solvents that are substantially water immiscible, i.e., 7 weights in water, to control the rate of water migration into the polymer implant and ultimately to control the bursting of the agonist and the sustained delivery of the agonist. It can be adjusted using a polymer-solvent composition that is dissolved at less than%. In general, the compositions of the present invention, even if the medicament is cured, can become gel and will be formed to have a substantially homogeneous pore structure throughout the implant during implantation and during drug delivery. Moreover, the polymer gel implant will cure slowly when placed in an aqueous environment, while the cured implant can maintain a rubbery (non-hard) composition with a glass transition temperature of less than 37 ° C.
[89] Since the composition is often very viscous prior to implantation, if the composition is to be implanted by injection, the viscosity may optionally be modified by an emulsifier to obtain a gel composition in which the viscosity is low enough to allow the gel composition to pass through the needle. Can be. In addition, along with representative pharmaceutical excipients and other additives that do not change the beneficial aspects of the present invention, solubility modifiers of pore formers and agonists can be added to the implantation system to provide a desired release profile from the implantation system. The addition of solubility modifiers to the implantation system allows the use of solvents with a solubility of at least 7% in the implantation system, which minimizes burst and sustained transport under specific circumstances. However, it is presently preferred for the implantation system to use one or more solvents with water solubility of less than 7% by weight, whether these solvents are present alone or as part of a solvent mixture. We also obtain an implantation system that exhibits limited water absorption and minimal burst and sustained transport properties when a solvent mixture comprising a solvent having a water solubility of 7% or less and optionally one or more miscible solvents having a higher solubility is used.
[90] Justice
[91] The term “agonist”, alone or in combination with other pharmaceutical excipients or inactive ingredients, refers to a medicament that produces the desired beneficial and often pharmacological effect when administered to a human or animal.
[92] The term “AUC” refers to the area under the curve obtained from the in vivo analysis at the treatment subject by plotting the plasma concentration of the agonist at the treatment subject over time, measured from the implantation time of the composition, against time “t” after implantation. Means. Time t will correspond to the delivery time of the agonist to the treated subject.
[93] The term “burst index” refers to a particular composition intended for systemic delivery of an agonist, comprising: (i) the calculated AUC divided by 24 for the first 24 hours after implantation of the composition into the subject of treatment; The ratio obtained by dividing the calculated AUC over time divided by the total delivery time (hours).
[94] The phrase “dissolved or dispersed” is intended to include all means of establishing the presence of an agonist in the gel composition, including dissolved, dispersed, suspended, and the like.
[95] The term “systemic” means that in the delivery or administration of an agonist to a therapeutic subject, the agonist can be detected at a biologically meaningful level in the plasma of the therapeutic subject.
[96] The term "local" means that in the delivery or administration of an agonist to a treatment subject, the agonist cannot be transported to a local site of the treatment subject and detected at a biologically meaningful level in the plasma of the treatment subject.
[97] The term "gel vehicle" means a composition formed by a mixture of a polymer and a solvent in the absence of an agonist.
[98] The term “prolonged period” means the time at which release of the agonist occurs from the implant of the invention and will generally be about 1 week or more, preferably about 30 days or more.
[99] The term “initial burst” refers to a particular composition of the present invention, wherein (i) the amount of agonist released from the composition within a given initial time after implantation, in units of weight, (ii) the agonist being delivered from the implanted composition The ratio obtained by dividing by the total amount of. It is believed that the initial burst may depend on the shape and surface area of the implant. Thus, the percentages and burst indices associated with the initial bursts described herein are intended to be applied to the compositions tested in shapes obtained by dispensing the compositions from standard syringes.
[100] The term "solubility modifier" refers to a reagent that, with respect to the agonist, can change the solubility of the agonist with reference to the polymer solvent or water from the solubility of the agonist in the absence of the modifier. Modulators can enhance or delay the solubility of agonists in solvents or water. However, for highly water soluble agonists, solubility modifiers will generally be reagents that can delay the solubility of the agonist in water. The effect of the solubility modifier of the agonist may result from the interaction of the solubility modifier with the agonist itself, such as by formation of a solvent, or a complex. For this purpose, all interactions or formation that can occur when a solubility modifier is "bound" with an agonist are intended. Solubility modifiers may be mixed with the agonist prior to combination with the viscous gel or, if appropriate, added to the viscous gel prior to the addition of the agonist.
[101] With respect to the administration of the compositions of the present invention the term "treatment subject" means animal or human.
[102] The term "immiscibility" as used herein, as used herein, means that at least on the molecular level all solvents are soluble in water (i.e., miscible with water) to some very limited degree. It can be dissolved or miscible with water. For the purpose of this technique, the water solubility value of the solvent is considered to be measured at 20 ° C. Since it is generally recognized that the reported solubility values cannot always be taken under the same conditions, the solubility (wt%) limits cited herein that are miscible or soluble with water as part or upper limit of the range cannot be absolute. For example, if the upper limit for solvent water solubility is quoted herein as "7% by weight" and there are no further restrictions on the solvent, the solvent "triacetin" with a reported water solubility of 7.17 g for 100 ml of water. Is considered to fall within the 7% limit. As used herein, a water solubility limit of less than 7% by weight does not include solvents having a water solubility equal to or greater than solvent triacetin or triacetin.
[103] The polymers, solvents and other reagents of the present invention should be biocompatible, that is to say they should not cause irritation or necrosis in the environment of use. The environment of use is a fluid environment, and can include a human or animal body or intramuscular site or subcutaneous site.
[104] Polymers that may be useful in the present invention may be biodegradable, polylactide based, polyglycolide based, polycaprolactone based, polyanhydride, polyamine based, polyurethane based, polyesteramide based, polyorthoester based, polydi Oxanone type, polyacetal type, polyketal type, polycarbonate type, polyorthocarbonate type, polyphosphazene type, succinate type, poly (malic acid), poly (amino acid), polyvinylpyrrolidone, polyethylene Glycols, polyhydroxycelluloses, chitin, chitosan, and copolymers, terpolymers, and mixtures thereof, but are not limited thereto.
[105] Currently preferred polymers are based on lactic acid and glycolic acid, which may be based entirely on lactic acid, i.e., may contain small amounts of other comonomers which do not substantially affect the beneficial results that can be achieved according to the present invention. Lactic acid-based polymers that may be copolymers. As used herein, the term "lactic acid" includes isomer L-lactic acid, D-lactic acid, DL-lactic acid and lactide while the term "glycolic acid" includes glycolide. Most preferred are poly (lactide-co-glycolide) copolymers collectively called PLGA. The polymer may have a monomer ratio of lactic acid / glycolic acid from about 100: 0 to about 15:85, preferably from about 60:40 to about 75:25, and particularly useful copolymers may have a monomer ratio of lactic acid / glycolic acid. About 50:50.
[106] The number average molecular weight of the lactic acid-based polymer, as measured by gas phase chromatography, is about 1,000 to about 120,000, preferably about 5,000 to about 30,000. As indicated in the aforementioned US Pat. No. 5,242,910, the polymer may be prepared as taught in US Pat. No. 4,443,340. Alternatively, the lactic acid-based polymer can be prepared directly from lactic acid or a mixture of lactic acid and glycolic acid (with or without additional comonomers) according to the technique disclosed in US Pat. No. 5,310,865. The contents of all these patents are incorporated by reference. Suitable lactic acid-based polymers are commercially available. For example, molecular weights of 5,000, 10,000, 30,000 and 100,000, preferably about 8,000 to 13,000, most preferably about 10,000 and have a wide variety of end groups for changing the sensitivity to hydrolysis and subsequent breakage of the polymer chain. 50:50 lactic acid: glycolic acid copolymers are available from Boehringer Ingelheim (Petersburg, VA).
[107] The biocompatible polymer is present in the gel polymer in an amount of about 5 to about 80 weight percent, preferably about 30 to about 70 weight percent, and often 40 to 60 weight percent of the viscous gel, wherein the viscous gel is composed of biocompatible polymers and solvents. In the sum of the quantities. This solvent will be added to the polymer in the amounts described below to provide an implantable or injectable viscous gel.
[108] The solvent must be biocompatible, form a viscous gel with the polymer, and limit water absorption into the implant. The solvent may be a single solvent or a mixture of solvents expressing the above-described properties. Unless specifically indicated otherwise, the term “solvent” means a single solvent or solvent mixture. Suitable solvents will substantially limit the absorption of water by the implant and can be characterized as water immiscible (ie, water solubility less than 7 wt%). Preferably, the solvent can be dissolved in water up to 5% by weight, more preferably in water up to 3% by weight, even more preferably in water up to 1% by weight. Most preferably, the water solubility is 0.5% by weight or less.
[109] Water miscibility can be determined experimentally as follows: Water (1-5 g) is placed in a transparent container weighed at controlled temperature, about 20 ° C. and weighed and the candidate solvent added dropwise. Stir this solution to observe phase separation. When the saturation point, determined by observing phase separation, is reached, the solution is left overnight and tested again the next day. If the solution is still saturated as measured and observed by phase separation, then the percentage of solvent added (w / w) is then observed. Alternately add more solvent and repeat the process. Solubility or miscibility is measured by dividing the total weight of the added solvent by the final weight of the solvent / water mixture. For example, when a solvent mixture of 20% triacetin and 80% benzyl benzoate is used, they are premixed before adding to water.
[110] Solvents useful in the present invention are generally water soluble at less than 7% by weight as described above. Solvents having such solubility parameters include lower alkyl and aralkyl esters of aryl acids (e.g. benzoic acid, phthalic acid, salicylic acid), lower alkyl esters of citric acid, such as triethyl citrate and tributyl citrate, And aryl, aralkyl and lower alkyl ketone systems. Among preferred solvents, (i) a compound having the following structural formula
[111] And
[112] Wherein R ₁ is aryl or aralkyl, R ₂ is lower alkyl or aralkyl, and R ₁ and R ₂ are the same or different, as appropriate, provided that each of R ₁ and R ₂ is lower alkyl Where the total total carbon number of R ₁ and R ₂ is 4 or more.)
[113] And (ii) lower alkyl and aralkyl esters of phthalic acid, isophthalic acid and terephthalic acid, and (iii) lower alkyl and aralkyl esters of citric acid. For this purpose, lower alkyl refers to straight or branched chain hydrocarbons having 1 to 6 carbon atoms, optionally substituted with non-interfering substituents, and aralkyl is (lower alkyl) phenyl such as benzyl, phenethyl, 1- Phenylpropyl, 2-phenylpropyl, and the like, wherein the alkyl moiety has 1-6 carbon atoms, and aryl means phenyl optionally substituted by non-interfering substituents. Most of the solvents useful in the present invention are either commercially available (Aldrich Chemical, Sigma Chemical) or use acid halides and optionally esterification catalysts, as described in US Pat. No. 5,556,905, which is incorporated herein by reference. Can be prepared by conventional esterification of separate arylalkanoic acids and in the case of ketones by oxidation of their respective secondary alcohol precursors.
[114] Benzoic acid derivatives recognized in the industry in which solvents with the required solubility can be selected include 1,4-cyclohexane dimethanol dibenzoate, diethylene glycol dibenzoate, dipropylene glycol dibenzoate, polypropylene glycol dibenzoate, Propylene Glycol Dibenzoate, Diethylene Glycol Benzoate, and Dipropylene Glycol Dibenzoate Blend, Polyethylene Glycol (200) Dibenzoate, Isodecyl Benzoate, Neopentyl Glycol Dibenzoate, Glyceryl Tribenzoate, Pentaeryte Lititol tetrabenzoate, cumylphenyl benzoate, trimethyl pentanediol dibenzoate.
[115] Phthalic acid derivatives recognized in the industry in which solvents with the required solubility can be selected include alkyl benzyl phthalate, bis-cumyl-phenyl isophthalate, dibutoxyethyl phthalate, dimethyl phthalate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, diiso Butyl phthalate, butyl octyl phthalate, diisoheptyl phthalate, butyl octyl phthalate, diisonoyl phthalate, nonyl undecyl phthalate, dioctyl phthalate, di-iso octyl phthalate, dicapryl phthalate, mixed alcohol phthalate, di- (2-ethyl Hexyl) phthalate, linear heptyl, nonyl, phthalate, linear heptyl, nonyl, undecyl phthalate, linear nonyl phthalate, linear nonyl undecyl phthalate, linear dinoyl, didecyl phthalate (diisodecyl phthalate), diundecyl phthalate, di Tridecyl Phthalate, Undecyldode And a phthalate, decyl and tridecyl phthalate, dioctyl and blend (50/50), butyl benzyl phthalate didecyl phthalate, and dicyclohexyl phthalate.
[116] Preferred solvents include the lower alkyl and aralkyl esters of aryl acids described above. Representative acids are benzoic acid and phthalic acid, such as phthalic acid, isophthalic acid, and terephthalic acid. Most preferred solvents are derivatives of benzoic acid, methyl benzoate, ethyl benzoate, n-propyl benzoate, isopropyl benzoate, butyl benzoate, isobutyl benzoate, sec-butyl benzoate, tert-butyl benzoate, iso Most particularly preferred is benzyl benzoate, including but not limited to amyl benzoate and benzyl benzoate. Preferred solvent mixtures are those wherein benzyl benzoate is the first solvent and mixtures formed with benzyl benzoate and triacetin, tributyl citrate, triethyl citrate or N-methyl-2-pyrrolidone. Preferred mixtures are those in which benzyl benzoate is present in an amount of at least 50% by weight of the total amount of solvent present, more preferably in an amount of at least 60% by weight and most preferably in an amount of at least 80% by weight. Particularly preferred mixtures are benzyl benzoate / triacetin and benzyl benzoate / N-methyl-2-pyrrolidone mixtures in an 80/20 weight ratio.
[117] Surprisingly, the aforementioned solvents having a water miscibility of less than 7% by weight may be mixed with one or more additional miscible solvents ("component solvents"). Component solvents that are compatible and miscible with the base solvent may have high miscibility with water, and the resulting mixture may still be significantly limited in water absorption into the implant. Such mixtures may be referred to as "component solvent mixtures". Useful component solvent mixtures may exhibit greater solubility in water than the first solvent itself, typically from 0.1% to 50% by weight, preferably up to 30% by weight, most preferably up to 10% by weight, the implant of the present invention There is no detrimental effect on the restriction of water absorption expressed by water. Especially preferred are component solvent mixtures having a water solubility of about 0.1% to about 7% by weight.
[118] Useful component solvents for the component solvent mixtures are solvents miscible with the first solvent or solvent mixture, triacetin, tributyline, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, tri Ethylglyceride, 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 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, decylmethylsulfoxide, oleic acid, and 1-dodecylazacyclo-heptan-2- , And mixtures thereof but is not limited thereto.
[119] In one particularly preferred embodiment, the first solvent is selected from lower alkyl and aralkyl esters of benzoic acid, the polymer is a lactic acid based polymer, most preferably a number average molecular weight of about 8,000 to about 13,000, preferably about 10,000 Is PLGA. Currently, the most preferred solvents are the lower alkyl esters of benzyl benzoate and benzoic acid. The benzoic acid ester system can be used alone or in admixture with other miscible solvents such as triacetin and the like described herein. Implants are prepared as viscous gels where the agonist is substantially dissolved or dispersed throughout the viscous gel, and such compositions are useful for both systemic and topical administration of agonists, whether or not initial bursts are an important consideration. In addition, the use of esters of benzoic acid increases the control of water transport, which in turn increases the stability of the agonist. The low water uptake after implantation, i.e. the limited number of transfers into the gel composition, limits the delivery of agonists by diffusion and allows the biocorrosion properties of the polymer to be adjusted to improve control of the agonist's transport profile. Preferred compositions allow the agonist to be loaded into the polymer at a concentration greater than necessary to saturate the agonist in water to promote zero order release of the agonist. In addition, the preferred compositions can provide a viscous gel with a glass transition temperature of less than 37 ° C. such that the gel remains non-hard for a period of at least 24 hours after injection.
[120] The solvent or solvent mixture may dissolve the polymer to form a viscous gel that can retain particles of agonists that are isolated from the environment of use and dissolved or dispersed prior to release. The composition of the present invention provides an implant with a low burst index. Water absorption is controlled using solvents or component solvent mixtures that dissolve or plasticize the polymer or substantially limit water absorption into the implant.
[121] The importance of water absorption restriction can be recognized with reference to FIGS. 4A-4B illustrating bulk water absorption for various compositions as a function of time, and Table 1, illustrating representative formulations for which burst indices were measured.
[122] In the absence of an agonist the water uptake for various polymer vehicles, ie 50% polymer-50% solvent composition, was measured. As shown in FIG. 4A, the water absorption by the gel vehicle formed using more water miscible solvent N-methyl-2-pyrrolidone (NMP) is about 4 or more than that of any other solvent-polymer combination. The factor is high. The water absorbency for the combination of vehicle having a solvent ratio of 80% by weight benzyl benzoate and 20% by weight NMP is less than one third of that of NMP alone. Compared to other solvents alone or in admixture with benzyl benzoate, implants with benzyl benzoate absorb the least water. Additionally, it can be seen that the 80/20 mixture of benzyl benzoate and triacetin absorbs less than 10% water by weight and exhibits less water absorption than triacetin alone. 4B provides a control of several single solvents, again demonstrating the benefits of the benzoic acid ester system, in particular of benzyl benzoate. A comparative comparison of the water uptake and burst index for the various solvents reproduced in Table 1 above shows the correlation between the low water uptake value and the low burst index. The gel compositions of the present invention, as tested in the water transfer assay described herein, contain no more than 25% of the bulk weight of the composition in water in the first 7 days, 30% in the first 14 days, and 40% in the first 21 days. Can absorb.
[123]
[124] In addition to controlling the water uptake associated with the initial burst by the choice of solvent, reagents that control the water solubility of the agonist may also be used with the preferred solvent to control the burst of the agonist from the implant. The burst index and percentage of agonist released within the first 24 hours after transplantation may be reduced by 1/3 to 2/3 or more by the use of solubility modifiers associated with the agonist. Such modulators may typically be coatings that form a complex or otherwise bind or stabilize the agonist (eg, metal ions, other stabilizers, waxes, lipids, oils, nonpolar emulsions, and the like). These solubility modifiers allow the use of higher water soluble solvents or mixtures thereof, with a burst index of 8 or less for systemic applications, or 20% or less of agonists administered within the first 24 hours after transplantation for topical applications. Release can be achieved. Preferably the release will be at most 15%, more preferably at most 10%.
[125] Limited water absorption by the compositions of the present invention can often provide an opportunity to prepare the composition in the absence of solubility modifiers when such regulators are essential in other compositions. For example, referring to Table 1, a suitable burst index is obtained for compositions of human growth hormone without PLGA, benzyl benzoate and Zn ions. Similar results can be obtained for other agonists such as interferon, including interferon alpha 2a, interferon alpha-2b and consensus interferon.
[126] If the selection of solvents and polymers results in compositions that severely limit water absorption by themselves, it may be desirable to add osmotic agents or other reagents and hydroattractants that promote water absorption to the extent desired. Such reagents may be, for example, sugars, etc., and are well known in the art for finger-like pores on the surface of implants formed using the methods of the prior art. Typically, the compositions of the present invention take the form of a homogeneous sponge gel, with the pores inside the implant being substantially the same as the pores on the surface of the implant. The compositions of the present invention maintain gel-like robustness over longer periods of time than prior art instruments and allow agonists to be transported over long periods of time. This is possible because the glass transition temperature (Tg) of the implant of the invention is generally less than the body temperature of the subject to be treated, such as 37 ° C. in humans. Because of the incompatibility of solvents and water useful in the present invention, water absorption by the implant is limited, and the pores formed do not open at the surface of the implant, much of the pores extending from the surface of the implant to larger pores or into the implant. There is a tendency to enclose closed cell structures. Moreover, surface pores only modulate the burst effect by limiting the chance that water from body fluids will get into the implant immediately after implantation. If the composition is intended to be implanted by injection, the composition is often very viscous prior to implantation so that the viscosity may sometimes be low with viscosity reducing miscible solvents, emulsifiers, or gel compositions passing through the needle. It can be heated and deformed to obtain a gel composition having a viscosity or shear resistance.
[127] Limits on the amount of agonist released in the first 24 hours that are desirable or necessary may include the total duration of the delivery period, the therapeutic window of the agonist, the potential adverse consequences of overdose, the cost of the agonist and the type of effect desired, For example, it will depend on circumstances such as systemic or local form. Preferably, up to 20% of the agonist will be released within the first 24 hours after transplantation, with the percentage based on the total amount of agonist to be delivered over the delivery period. Typically, if the delivery period is relatively short, such as less than 7-14 days, or if the agonist has a wide therapeutic window with little potential for side effects, or if the agonist acts locally, the release of the release within the first 24 hours High percentages can be tolerated.
[128] Depending on the specific solvent or solvent mixture selected, the polymer and the agonist, and optionally the solubility modifier of the agonist, the compositions of the invention for systemic delivery purposes have a burst index of 8 or less, preferably 6 or less, more preferred. It is possible to provide a gel composition which is preferably 4 or less, most preferably 2 or less. Water miscibility, optionally in combination with other solvents, to provide an implant for the purpose of systemic delivery of an agonist having a burst index of 10 or less, preferably 7 or less, more preferably 5 or less and most preferably 3 or less. Particularly advantageous are compositions of PLGA with a solvent of less than 7% by weight. The use of the solvent mixtures discussed herein may be particularly advantageous as a means to provide sufficient plasticization of the polymer to form a viscous gel and at the same time satisfy the desired burst index and the purpose of the percentage release of the composition of the present invention.
[129] Compositions intended for topical delivery of agonists are formed in the same manner as compositions intended for systemic use. However, since local delivery of an agonist to a treated subject cannot provide a detectable plasma concentration of the agonist, such a system is based on the percentage of agonist released within a given initial time rather than a burst index as defined herein. Should be characterized by Most typically, this time will be the first 24 hours after transplantation, wherein the percentage is the amount of agonist (unit: weight) that is intended to deliver the amount of agonist released in this period (unit: weight) within the delivery period. It will be equal to the division and multiply by 100. For all applications the initial burst of the composition of the invention will be 20% or less, preferably 15% or less, most preferably 10% or less. Implant systems with an initial burst of 5% or less are particularly preferred.
[130] In many cases, it may be desirable to reduce the initial burst of agonist during topical administration to prevent side effects. For example, an implant of the invention containing a chemotherapeutic agent is suitable for injecting directly into a tumor. However, many chemotherapeutic agents can exhibit side effects of toxicity when administered systemically. As a result, topical administration into the tumor may be the method of treatment of choice. However, this is essential to avoid the administration of bursty chemotherapeutic agents if the chemotherapeutic agent can enter the vascular or lymphatic system, which may have side effects. Thus, in such a situation, the implantable system of the present invention having the limited burst described herein is advantageous.
[131] The solvent or solvent mixture is typically present in an amount of from about 95% to about 20% by weight of the viscous gel, ie the combined amount of polymer and solvent, preferably in an amount from about 70% to about 30% by weight, often It is present in an amount of 60-40% by weight. The viscous gel formed by mixing the polymer and solvent is typically about 1,000 to about 200,000 poise, preferably about 1000, as measured at 1.0 sec ⁻¹ shear rate and 25 ° C. using a Haake ammeter about 1-2 days after completion of mixing. Viscosity of 5,000 to about 50,000 poise. Although a shorter and longer time may be selected by those skilled in the art depending on the specific properties of the composition to be prepared, the mixing of the solvent and the polymer may be conventional, such as a Ross dual planetary mixer for about 10 minutes to about 1 hour. It can be achieved using low shear equipment. Because it is often desirable to administer implants as injectable compositions, countervailing considerations when forming implants that are viscous gels are that the viscosity of the polymer / solvent / agonist composition is sufficiently low that they are small diameter, such as 18 It can penetrate -20 gauge needles. If desired, viscosity adjustment of the gel for injection can be accomplished using an emulsifier as described herein. Nevertheless, the composition should have adequate dimensional stability so that it can be kept topically and removed if necessary. Specific gels or gel-like compositions of the present invention satisfy this requirement.
[132] If the polymer composition is administered as an injectable gel, the polymer solubility will need to be balanced with the gel viscosity obtained in order to give a suitable force and potential burst effect for dispensing the viscous gel from the needle. Highly viscous gels allow agonists to be transported without exhibiting a significant burst effect, but can make it difficult to dispense the gel through the needle. In such cases, emulsifiers may optionally be added to the composition. In addition, since the viscosity can generally decrease as the temperature of the composition increases, it may be advantageous in some applications to reduce the viscosity of the gel by heating in order to provide a more easily injectable composition.
[133] For example, as shown in FIG. 1, a gel made from 40 wt% 50:50 lactic acid: glycolic acid polymer and 60 wt% triacetin dispenses the gel at 2 cc / min through a standard 20 gauge needle While about 40 psig was needed to make, a gel made from the same amount of polymer and 60% by weight of N-methyl-2-pyrrolidone only needed about 8 psig. Figure 1 also shows that when an emulsifier (33% by weight of 10% ethanol solution in this case) is added to the viscous gel according to the invention, the required partitioning force is only about 2 psig. The shear thinning properties of the storage gel compositions of the present invention allow them to be easily injected into animals, including humans, using standard gauge needles without excessive distribution pressure.
[134] When the emulsifier is mixed with a viscous gel formed from a polymer and a solvent using a conventional static or mechanical mixing device, such as an orifice mixer, the emulsifier is typically composed of ultra-sized dispersed droplets having an average diameter of less than about 100 microns. Forms a phase. The continuous phase is formed of a polymer and a solvent. The agonist particles may be dissolved or dispersed in a continuous phase or a droplet phase. In the resulting thixotropic composition, droplets of emulsifier extend in the shear direction and substantially reduce the viscosity of the viscous gel formed from the polymer and solvent. For example, if the viscosity of the viscous gel measured at 25 ° C., 1.0 sec ⁻¹ is from about 5,000 to about 50,000 poises, it is 100 when emulsified with a 10% ethanol / water solution at 25 ° C. as measured by a Haake ammeter. Viscosity reductions below poise can be obtained.
[135] When emulsifiers are used, emulsifiers are typically from about 5 to about 80% by weight, preferably from about 20 to about, based on the amount of implantable storage gel composition (ie, the combined amount of polymer, solvent, emulsifier and agonist) It is present in an amount ranging from 60% by weight, often 30 to 50% by weight. Emulsifiers include, for example, solvents that are not sufficiently miscible with the polymer solvent or solvent mixture. Illustrative emulsifiers are water, alcohols, polyols, esters, carboxylic acids, ketones, aldehydes and mixtures thereof. Preferred emulsifiers are alcoholic, propylene glycol, ethylene glycol, glycerol, water and solutions and mixtures thereof. Especially preferred are water, ethanol, and isopropyl alcohol and solutions and mixtures thereof. The type of emulsifier affects the size of the dispersed droplets. For example, ethanol will provide droplets with an average diameter that can be about 10 times or more close to those obtained using isotonic saline solutions containing 0.9 wt.% Sodium chloride at 21 ° C.
[136] FIG. 3 shows water and a 2: 1 weight ratio (gel: emulsifier) using a viscous gel formed from 50% by weight of triacetin and 50% by weight of 50:50 lactic acid: glycolic acid compared to the viscosity of a viscous gel without emulsifier The viscosity at different shear rates is shown using an aqueous mixture containing 10% by volume of ethanol.
[137] It is understood that emulsifiers are not comprised solely of diluents that lower the viscosity by simply reducing the concentration of the composition components. Conventional diluents can be used to reduce viscosity, but can also cause the previously described burst effect when the diluted composition is injected. In contrast, the injectable storage compositions of the present invention can be formulated to avoid burst effects by selecting solvents and emulsifiers so that, once injected at a particular site, the emulsifier has little impact on the release of the original system.
[138] Since the implantation system of the present invention is preferably formed as a viscous gel, the means of administration of the implant is not limited to infusion, although the mode of delivery may often be desirable. When the implant is administered as a leave-behind product, it may be formed to fit into the cavities present after the surgery or applied as a flowable gel by brushing or palletizing the gel on residual tissue or bone. Can be. This application allows the agonist to be loaded into the gel above the concentrations typically provided in injectable compositions.
[139] Agonists include any physiologically or pharmaceutically active agent or pharmaceutically acceptable carrier, and antioxidants, stabilizers, penetration enhancers, etc., which do not substantially adversely affect the beneficial results achievable by the present invention. It may be a material in any combination with additional components of. An agonist may be any agent known to be delivered to the human or animal body that is more soluble in water than a polymer soluble solvent. These drugs include drugs, medicines, vitamins, nutrients and the like. Among the types of medicaments that meet the above description include low molecular weight compounds, proteins, peptides, genetic material, nutrients, vitamins, food supplements, sex sterilants, fertility inhibitors and fertility promoters.
[140] Agents that can be carried by the present invention include peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscle, cardiovascular system, smooth muscle, blood circulation, synoptic site, neuroactive organ junctions, endocrine system and hormone system, Drugs that act on the immune system, reproductive system, skeletal system, otacoid system, digestive system and embryo design, histamine system and central nervous system. Suitable agents include, for example, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polyproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotics, anti-inflammatory corticosteroids, eye drops and synthetic derivatives of these species. You can choose from.
[141] Examples of medicaments that may be carried by the compositions of the present invention include prochlorpergin edylate, ferrous sulfate, aminocaproic acid, mecamylamine hydrochloride, procaineamide hydrochloride, amphetamine sulfate, methamphetamine hydrochloride, benzamphetamine hydrochloride, Isoprotegenol sulphate, penmetrazine hydrochloride, betanechol chloride, methacholine chloride, pyrocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropide iodide, tridihexel chloride, phenformin hydrochloride, methyl Phendate hydrochloride, theophylline collinate, separexin hydrochloride, diphenidol, meclizin hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperazine maleate, anicindon, diphenadione erythritol tetranitrate Latex, digosine, isofluoroate, acetazoleamide, metazolamide, bendroflumethiazide, chloroproma Id, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrecetate, acetyl sulfisoxazole, erythromycin, hydrocortisone, hydrocortisosterone acetate, cortisone acetate, dexamethasone and derivatives thereof (E.g. betamethasone, triamcinolone, methyltestosterone, 17-S-estradiol, ethynyl estradiol, ethynyl estradiol 3-methyl ether, prednisolone, 17α-hydroxyprogesterone acetate, 19-nor-progesterone, norgest Noel, noethine drone, noethysterone, noethieredone, progesterone, norgesterone, norerinodrel, aspirin, indomethacin, naprosen, phenopropene, sulindac, indopropene, nitro Glycerin, Isosorbide Dinitrate, Propranolol, Timolol, Athenol, Alprenol, Cimetidine, Chloro Dine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, ceparexin, erythromycin, haloperidol, jomepilac, ferros lactate, Vincarmine, diazepam, phenoxybenzamine, diltiazem, milnon, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenofene, fluprofen, tolmetin, alclofenac, mefena Mic, flufenamic, definial, nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine, lidofrazine, thiafamil, galopamil, amylodipine, myoflavin, ricinol frill, Enalapril, enalaprirat, captopril, ramipril, famotidine, nizatidine, sucralate, ethyntidine, tetratolol, minoxidil, chlordiazepoxide, diazepam, amitrifthilin, and already Including but not limited to pramin It is not. Bone morphogenic proteins, insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, renin, prolactin, corticotropin, thyroid hormone, vesicle stimulating hormone, chorionic gonadotropin, gonadotropin releasing hormone Bovine somatotropin, bovine somatotropin, oxytocin, vasopressin, GRF, somatostatin, ripressin, pancrezimin, luteinizing hormone, LHRH, LHRH agonists and antagonists, leuprolide, interferon (e.g. interferon Alpha-2a, interferon alpha-2b and consensus interferon), interleukins, human growth hormones and derivatives thereof (e.g. methion-human growth hormone and des-phenylalanine human growth hormone, bovine growth hormone and pig growth hormone) Growth hormones, fertility inhibitors such as prostaglandins, fertility promoters, growth factors such as insulinogenic growth factors, Proteins and peptides, including but not limited to coagulation factors, human pancreatic hormone releasing factors, analogs and derivatives of these compounds, and pharmaceutically acceptable salts of these compounds, or analogs or derivatives thereof.
[142] The present invention also relates to the application of a chemotherapeutic agent for topical application of the medicament to avoid or minimize systemic side effects. Gels of the invention containing a chemotherapeutic agent may be injected directly into tumor tissue for sustained delivery of the chemotherapeutic agent over time. In some cases, especially after excision of the tumor, the gel can be implanted directly into the resulting cavity or applied as a coating to the remaining tissue. If gels are implanted after surgery, higher viscosity gels can be used because they do not need to pass through small diameter needles. Representative chemotherapeutic agents that can be delivered in accordance with the practice of the present invention include, for example, carboplatin, cisplatin, paclitasel, BCNU, vincristine, camptothecin, etophside, cytokines, ribozymes, interferons, Oligonucleotides, and oligonucleotide sequences that inhibit metastasis or transcription of tumor genes, and functional derivatives of commonly known chemotherapeutic agents such as those described above and in US Pat. No. 5,651,986. The present application has particular utility in the continuous delivery of water soluble chemotherapeutic agents such as, for example, cisplatin and water soluble derivatives of carboplatin and paclitacell. Features of the present invention that minimize the burst effect are particularly advantageous for the characterization of water soluble agonists of all kinds, but especially compounds that are clinically useful and effective but may have adverse side effects.
[143] To the extent not described above, agonists described in the aforementioned U.S. Patent No. 5,242,910 may also be used. One particular advantage of the present invention is the enzymatic lazozyme and materials such as proteins such as those exemplified by cDNA and DNA inserted into viral and nonviral vectors, which are difficult to microencapsulate or process into microspheres, It can be incorporated into the compositions of the present invention without the degree of degradation caused by exposure to high temperature and modified solvents often present in other processing techniques.
[144] Agonists are preferably incorporated into viscous gels prepared from polymers and solvents in the form of particles having an average particle size of typically about 0.1 to about 100 microns, preferably about 1 to about 25 microns, often 2 to 10 microns. For example, particles having an average particle size of about 5 microns are sprayed with an aqueous mixture containing 50% sucrose and 50% chicken lysozyme (dry weight basis) and a mixture of 10-20% hGH and 15-30 mM zinc acetate. Prepared by drying or freeze drying. These particles were used in the specific examples illustrated in the figures. Conventional freeze-drying procedures may also be used to form particles of agonist that change size using suitable freezing and drying cycles.
[145] In order to form suspensions or dispersions of agonist particles in viscous gels formed from polymers and solvents, Ross dual satellite mixers can be used in any conventional low shear device such as ambient conditions. In this way, the agonist can be efficiently distributed substantially without degrading the agonist.
[146] The agonist is typically in an amount of about 1 to about 50 weight percent of the combined amount of polymer, solvent and agonist, preferably in an amount of about 5 to about 30 weight percent, often in an amount of 10 to 20 weight percent Dissolved or dispersed in the air. Depending on the amount of agonist present in the composition, different release profiles and burst indices can be obtained. More specifically, for provided polymers and solvents, the amount of the components and the amount of agonist can be adjusted to obtain a release profile that is more dependent on the degradation of the composition than the diffusion of the agonist from the composition or vice versa. In this respect, degradation reflected release profiles of polymers are generally obtained in which the release rate increases with time when the agonist loading rate is low. At higher loading speeds, a release profile is usually caused by the diffusion of the agonist whose release rate decreases with time. At intermediate loading speeds, if desired, a combined release profile is obtained to achieve a substantially constant release rate. In order to minimize bursts, it is preferred to load the agonists in order of up to 30% by weight of the total gel composition, i.e. the polymer, solvent and agonist, more preferably 20% by weight or less.
[147] The release rate and loading of the agonist will be adjusted to provide therapeutically effective delivery of the agonist over the desired sustained delivery period. Preferably, the agonist will be present in the polymer gel at a concentration above the saturation concentration of the agonist in water to provide a pharmaceutical reservoir into which the agonist is dispensed. While the release rate of the agonist depends on the particular environment, such as the agonist to be administered, the release is in the order of about 0.1 to about 100 μg / day, preferably about 1 to about 10 μg / day, for about 7 to about 90 days. Speed can be achieved. Larger quantities can be delivered if the transport takes place over a short time. In general, the release rate can be greater if a larger burst can be tolerated. When the gel composition is implanted by surgery, or when the gel composition is used as a "rib behind" reservoir when surgery to treat a disease or another condition is performed at the same time, Can provide a unit dose. In addition, the dose of agonist can be controlled by adjusting the volume of the implanted gel or the volume of the injectable gel injected. As can be seen in FIG. 2 for lysozyme, the burst effect can be avoided if the system is more viscous and can be delivered in the order of 1% by weight of the agonist in the composition during the first day.
[148] 5A and 5B illustrate exemplary release profiles of human growth hormone (“hGH”) obtained in mice from preferred compositions of the invention. The benefit of benzyl benzoate is evident in the comparison. hGH-benzyl benzoate implants show almost zero order sustained release of hGH with low burst and release time both when hGH is not stabilized (FIG. 5A) and when hGH is stabilized with zinc ions (FIG. 5B).
[149] Other ingredients may be present in the gel composition to the extent that they can provide or wish useful properties to the composition, which are polyethylene glycols, hydroscopic agents, stabilizers, pore formers, and others. If the composition comprises a peptide or protein that is soluble or labile in an aqueous environment, it may be highly desirable to include a solubility modifier in the composition, which may be, for example, a stabilizer. Various modifiers are described in US Pat. Nos. 5,654,010 and 5,656,297, which are incorporated herein by reference. For example, in the case of hGH it is preferred to include salts of divalent metals, preferably zinc. Examples of such modifiers and stabilizers, which can form or combine with agonists to provide a stabilizing or controlled release effect, are magnesium carbonate, zinc carbonate, calcium carbonate, magnesium acetate, magnesium sulfate, zinc acetate, zinc sulfate, Zinc chloride, magnesium chloride, magnesium oxide, magnesium hydroxide, other antacids, and the like, which are present in the composition, preferably include divalent metals. The amount of such reagents used will, if any, depend on the nature of the complex formed or the nature of the binding between the agonist and the reagents. The molar ratio of solubility modifier or stabilizer to agonist may be used from about 100: 1 to 1: 1, preferably from 10: 1 to 1: 1.
[150] Pore formers include biocompatible materials that, upon contact with body fluids, dissolve, disperse, or decompose to form pores or channels in the polymer matrix. Typically, sugars (eg sucrose, dextrose), water soluble salts (eg sodium chloride, sodium phosphate, calcium chloride, and sodium carbonate), water soluble solvents (eg N-methyl-2-pyrrolidone and polyethylene Water-soluble organic and inorganic materials, such as glycols) and water-soluble polymers (eg, carboxymethylcellulose, hydroxypropylcellulose, etc.), etc., can typically be used as pore formers. Such materials may be present in varying amounts of about 0.1 to about 100% by weight of the polymer, but will typically be less than 50%, more typically less than 10-20%.
[151] The compositions of the present invention without agonists are useful for wound healing, bone correction and other structural support purposes.
[152] In order to further understand various aspects of the present invention, the results disclosed in the foregoing drawings were obtained according to the following examples.
[153] Example 1
[154] Lysozyme particles were spray dried by lysozyme (dry weight basis) of 50% sucrose and 50% chicken.
[155] Various gel materials were prepared by heating 60% by weight of triacetin with 40% by weight of a 50:50 lactic acid: glycolic acid copolymer overnight at 37 ° C. The viscous gel was left to cool to room temperature. Lysozyme particles were added to the viscous gel in a ratio of 20:80 lysozyme particles: gel (weight ratio). The combination was mixed for 5 minutes. Immediately before use, 10% ethanol, 90% isotonic saline solution was added as emulsifier. The emulsifier made up one third of the total injectable storage gel composition. The prepared composition was suitable for infusion.
[156] FIG. 2 shows the in vitro release rate obtained from the composition described with respect to FIG. 1. Gels made from 40% by weight 50:50 lactic acid: glycolic acid polymer and 60% by weight triacetin were thick and therefore difficult to inject but had little burst (less than 2% of the agonist was delivered in the first 8 days). Gels prepared from 40% by weight 50:50 lactic acid: glycolic acid polymer and 60% by weight of n-methyl-2-pyrrolidone are thin and injectable but have a high burst (more than 70% of the agonist is delivered in the first 8 days) ). Gels made from 27% by weight of 50:50 lactic acid: glycolic acid polymer, 40% by weight triacetin and 10% ethanol, 33% by weight 90% isotonic saline solution are thin and injectable but have little burst (10% of agonist) Less than are delivered in the first 8 days). In each case, lysozyme is an agonist and constitutes 20% by weight of the formulation of the agonist, polymer and solvent.
[157] Example 2 Preparation of hGH Particles
[158] Human growth hormone (hGH) particles (containing zinc acetate optionally) were prepared as follows:
[159] HGH solution in water (5 mg / ml) (BresaGen Corporation, Adelaide, Australia) was concentrated to 10 mg / ml using a concentration / dialysis selector diafiltering apparatus. The diafiltered hGH solution was then washed with 5 volumes of Tris or phosphate buffer solution (pH 7.6). HGH particles were then formed by spray drying or freeze drying using conventional techniques. hGH (5 mg / mL) containing phosphate buffer solution (5-50 mM) and various concentrations of zinc acetate (0-30 mM) were spray dried with a Yamato Mini Spraydryer set in the following parameters.
[160] Spray dryer parameters Set Atomizing air 2 psi Inlet temperature 120 ℃ Inhaler dial 7.5 Solution pump 2-4 Main air valve 40-45 psi
[161] HGH particles between 2 and 100 microns in size were obtained. The lyophilized particles were hGH containing (5 mg / ml) Tris buffer solution (5 or 50 mM: pH 7.6) and zinc acetate at various concentrations using a Durastop μP freeze dryer according to the following freezing and drying cycles. 0-30 mM).
[162] Refrigeration cycle Thirty minutes at 2.5 C / min to -30 ° C and held for 30 minutes Hold for 60 minutes after sprinting from -30 ° C to -50 ° C at 2.5 C / min Drying cycle 960 minutes after ramping to 10 ° C at 0.5 C / min 480 minutes at 20 ° C at 0.5 C / min 300 min at 0.5 C / min and hold for 300 min 300 min at 0.5 C / min and hold for 300 min 5000 min at 0.5 C / min and held for 5 min
[163] HGH particles between 2 and 100 microns in size were obtained.
[164] hGH zinc complex solution manufacturer
[165] Zinc acetate solution was prepared using Tris buffer and phosphate buffer. Preferred molar volumes of Trisma hydrochloride and Trisma base were prepared separately (5 or 50 mM). The pH of the Trisma base solution was measured and the pH of the Trisma base solution was adjusted to a final pH of 7.6 by addition of the corresponding Trisma hydrochloride solution. Desired molar volume of zinc acetate was added to the buffer solution. Sodium phosphate monobasic and sodium phosphate dibasic in the desired molar volume were prepared separately (5 or 50 mM). Sodium azide (0.2% w / w) was added to each phosphate solution. In order to measure the pH of the dibasic solution and to adjust the pH of the dibasic solution, the corresponding monobasic solution was added to bring the final pH to 7.6. Desired molar volume of zinc acetate was added to the buffer solution. Zinc acetate containing tris or phosphate buffer was added to the diafiltered hGH solution to obtain the desired final zinc acetate molar volume (between 5 and 30 mM). Final hGH concentration was 5 mg / ml.
[166] Gel vehicle manufacturing
[167] The glass container was weighed on a Mettler PJ3000 top loader balance. Poly (D, L-lactide-co-glycolide) 50:50 RESOMER® RG502 (PLGA-502) was weighed in a glass container. The glass container containing PLGA-502 was weighed and the corresponding solvent was added. The amounts expressed as percentages for the various polymer / solvent combinations are set forth in Table 2 below. The polymer / solvent mixture was manually stirred with a stainless steel square end spatula to obtain a sticky amber paste-like material containing white polymer particles. The vessel containing the polymer / solvent mixture was sealed and placed in a temperature controlled incubator balanced at 39 ° C. When the polymer / solvent mixture appeared to be a clear amber homogeneous gel, they were removed from the incubator. Incubation time intervals range from 1 to 4 days depending on solvent and polymer type and solvent and polymer ratios. Additional storage gel vehicles are prepared from the following polymers: poly (D, L-lactide-co-glycolide) 50:50 RESOMER® L104, PLGA-L104, code number. 33007, poly (D, L-lactide-co-glycolide) 50:50 RESOMER® RG206, PLGA-206, code number. 8815, poly (D, L-lactide-co-glycolide) 50:50 RESOMER® RG502, PLGA-502, code 0000366, poly (D, L-lactide-co-glycolide) 50:50 RESOMER® RG502H, PLGA-502H, code number. 260187, poly (D, L-lactide-co-glycolide) 50:50 RESOMER® RG503, PLGA-503, code number. 0080765, poly (D, L-lactide-co-glycolide) 50:50 RESOMER® RG506, PLGA-506, code number. 95051, poly (D, L-lactide-co-glycolide) 50:50 RESOMER® RG755, PLGA-755, code number. 95037 (Boehringer Ingelheim Chemicals, Inc., Petersburg, VA), and the following solvents or mixtures: glyceryl triacetate (Eastman Chemical Co., Kingsport, TN), benzyl benzoate ("BB"), ethyl benzoate (" EB "), methyl benzoate (" MB "), triacetin (" TA ") and triethyl citrate (" TC ") (Aldrich Chemical Co., St Louis, MO). When solvent combinations such as 20% triacetin and 80% benzyl benzoate were used, the solvent mixture was added directly to the pre-weighed dry polymer. Representative polymer molecular weights were in the range 14,000-39,700 (M _w ) [6,400-12,200 (M _n )]. Representative gel vehicles are described in Table 2 below.
[168] Gel vehicle Solvent / polymer menstruum polymer Solvent Polymer amount Gel weight ratio 50/50 BB PLGA-502 5 g 5 g 10 g 1.0 50/50 TA / BB mixture PLGA-502 5 g 5 g 10 g 1.0 60/40 TA / BB mixture PLGA-502 6 g 4 g 10 g 1.5 70/30 TA / BB mixture PLGA-502 7 g 3 g 10 g 2.3 80/20 TA / BB mixture PLGA-502 8 g 2 g 10 g 4.0 50/50 EB PLGA-502 5 g 5 g 10 g 1.0 50/50 TA / EB mixture PLGA-502 5 g 5 g 10 g 1.0 50/50 BB PLGA-502 25 g 25 g 50 g 1.0 55/45 BB PLGA-502 27.5 g 22.5 g 50 g 1.2 50/50 BB PLGA-502 50 g 50 g 100 g 1.0 50/50 TA / BB mixture PLGA-502 50 g 50 g 100 g 1.0 50/50 BB PLGA-502H 5 g 5 g 10 g 1.0 50/50 BB PLGA-503 50 g 50 g 100 g 1.0
[169] Pharmaceutical loading
[170] Spray dried or lyophilized hGH particles (10-20% w / w) with or without zinc acetate, prepared as described above, are added to a specific transparent amber storage gel vehicle and manually dried until the dry powder is fully wetted. Blended by. The milky pale yellow particle / gel mixture is then conventionally mixed and thoroughly blended using a Capramo mechanical stirrer with square-ended metal specella. The resulting formulations are illustrated in Tables 3 and 4 below. "L" represents lyophilized hGH particles and "SD" represents spray dried hGH particles. The final homogeneous gel formulation was transferred to 3, 10 or 30 cc disposable syringes for storage or dispensing.
[171] In vivo hGH Formulation polymer menstruum Pharmaceutical particles Trisma Buffer (mM) density PLGA density Kinds density Way Zinc concentration (mM) A 45% 502 45% TA 10% L 0 50 B 45% 502 45% TA 10% L 7.5 50 C 45% 502 45% TA 10% L 15 50 D 45% 502 45% BB 10% L 0 50 E 45% 502 45% BB 10% L 7.5 50 F 45% 502 45% BB 10% L 15 50 G 45% 502 45% NMP 10% L 0 50 H 45% 502 45% NMP 10% L 15 50 I 45% 502 45% TA 10% SD 0 50 J 45% 502 45% TA 10% SD 7.5 50 K 45% 502 45% BB 10% SD 0 50 L 45% 502 45% BB 10% SD 7.5 50
[172] In vivo hGH (Zinc concentration in all cases is 15 mM) Formulation polymer menstruum Pharmaceutical particles Trisma Buffer (mM) density PLGA density Kinds density Way F 45% 502 45% BB 10% L 50 N 45% 502 45% 80% BB / 20% TA 10% L 5 P 45% 502H 45% TA 10% L 5 Q 45% 502H 45% BB 10% L 5 R 45% 502 45% EB 10% L 5 S 45% 502 45% TC 10% L 5 T 40% 502 40% BB 20% L 5 W 45% 502-2 45% BB 10% L 5 X 45% 502 45% TA 10% L 5
[173] Example 3 Lysozyme In Vitro Study
[174] In vitro studies of lysozyme (Sigma Chemicals Co., St Louis, MO) obtained from egg whites to test different vehicle formulations of highly water soluble solvent NMP and less soluble solvent triacetin and benzyl benzoate useful in the present invention Was used. Storage gel formulations were dispensed into 3 cc disposable syringes and weighed on a Delrin ^™ cup platform or 250 μmesh 1 inch ² polypropylene screen. The cup or screen containing the storage gel formulation was then immersed in a plastic vial containing 10 ml of receptor buffer. A snap lid was placed on the plastic vial to inhibit evaporation. The vial containing the stored gel formulation was immersed in a Haake stirred bath set at 37 ° C. At each time point, the Delrin ^™ cup platform or polypropylene screen platform containing the storage gel formulation with tweezers was transferred to a new plastic vial containing 10 ml of receptor buffer. Receptor samples were transferred to HPLC vials with a disposable delivery pipette. Receptor buffer was phosphate buffered saline, PBS, adjusted to pH 7 containing sodium azide (0.2%). In most cases the receptor buffer contained tween-80 (0.1%). Collection intervals were typically 2, 4, 8 hours, 1, 2, 3, 4, 7, 10 days and 2, 3, 4, 5, 6, 7, 8 weeks. All receptor samples were analyzed for lysozyme concentrations using a gradient elution reverse phase high performance liquid chromatography (RP-HPLC) assay using a frozen autosampler (4 ° C.). The results showed that the compositions of the present invention using benzyl benzoate and benzyl benzoate solvent mixtures had substantially less lysozyme bursts than those represented by the gel compositions formed with NMP.
[175] Example 4-In Vitro Moisture Study
[176] As described in Example 3 for in vivo drug release using the Delrin ^TM cup platform, except the entire cup platform containing the storage gel vehicle was removed, blotted dry and placed in dry plastic vials at specific time intervals. The same procedure was used. The receptor solution was sterile water and the remaining samples were exchanged at each time interval. Initial and final stored gel vehicle weights were recorded to observe weight changes. Water content was determined in a storage gel vehicle using a Karl Fischer Apparatus, Mitsubishi Moisture Meter CA-06 equipped with Vaporizer VA-06. Results for the selected gels are illustrated in FIGS. 4A-4B. These results demonstrate that the gel compositions of the present invention absorb substantially less water than gel compositions formed using only NMP.
[177] Example 5-hGH In Vivo Studies
[178] In vivo studies in mice were conducted with the following open protocol for measuring serum concentrations of hGH for systemic administration of hGH through the implantation system of the present invention. Spray dried (SD) or lyophilized (L) stored gel hGH formulations were loaded into a customized 0.5 cc disposable syringe. A disposable 16 gauge needle was attached to the syringe and heated to 37 ° C. with a circulator tank. Storage gel hGH formulations were injected into rats and blood was collected at specific time intervals. All serum samples were stored at 4 ° C. and analyzed. Samples were analyzed for unchanged hGH content using radioimmunoassay (RIA). Representative results for triacetin and benzyl benzoate are illustrated in FIGS. 5A and 5B, demonstrating that the burst is controlled by the compositions of the present invention.
[179] Example 6
[180] The implantation system of the present invention was prepared according to Example 2 using the same amount of interferon alfa-2a and -2b, consensus interferon, methionine human growth hormone, des-phenylalanine human growth hormone, carboplatin and insulinic growth factor. Prepared. The amount of viscous gel containing the agent administered to the rat according to Example 5 is adjusted in consideration of the relative biological activity of the individual agents. The transplant system is implanted in mice to provide systemic concentrations of the active agent.
[181] Example 7
[182] Carboplatin-containing transplant systems were prepared according to Example 6 and injected directly into solid tumors of tumor bearing mice. Implantation systems are suitable for topical delivery of carboplatin to tumors.
[183] Example 8
[184] 100 mg transplant containing 0.5, 1.5 and 3 mg of interferon alfa-2b, stabilized with 0.5, 1 and 2 mg of sucrose, respectively, and 50 mg benzyl benzoate and 45-49 mg of PLGA 502 where the remainder is applicable Possible stocks (number average molecular weight about 10,000) were prepared according to Example 2 (without zinc). The implant exhibits a limited burst and is suitable for transplantation. The transplant system is implanted in mice to provide systemic concentrations of interferon alpha-2b.
[185] According to various aspects of the present invention, one or more meaningful advantages can be obtained. More specifically, implantable or injectable viscous gels are obtained that contain agonists for systemic and topical administration that exert a low or minimal burst effect when implanted. Moreover, a gel composition can be obtained which can be implanted surgically in an animal using simple processing steps or injected into a place in the animal without surgery using low dispensing power through a standard needle. Once in place, the composition will substantially avoid the burst effect to provide the desired agonist release profile. In addition, if sufficient general agonists have been administered, they do not need to be removed because they are completely biodegradable. As yet another advantage, the present invention avoids the use of microencapsulation techniques or microencapsulation techniques (particulates and microcapsules can be difficult to remove from the environment of use) that can degrade certain agonists, such as peptides and hexane based agents. Will. Since viscous gels are formed without requiring water, extreme temperatures, or other solvents, suspended particles of agonists remain dry and in their original shape, which contributes to their stability. In addition, because agglomerates are formed, injectable storage gel compositions can be recovered from the environment of use if desired.
[186] The exemplary embodiments described above are intended to be illustrative in all respects rather than to limit the invention. Accordingly, the present invention may be modified in many respects in terms of detailed implementation that may be derived from the technical details contained herein by those skilled in the art. All such modifications and variations are considered to be within the scope and spirit of the invention as defined by the following claims.

权利要求:
Claims (63)
[1" claim-type="Currently amended] A method of systemic administration of an agonist to a treated subject, comprising implanting a system having an agonist substantially dissolved or dispersed throughout the viscous gel and having a burst index of 8 or less.
[2" claim-type="Currently amended] The method of claim 1 wherein the viscous gel contains a biocompatible polymer and a solvent.
[3" claim-type="Currently amended] The method of claim 2 wherein the viscous gel optionally comprises one or more of an emulsifier, a pore former, a solubility modifier of an agonist and an osmotic agent.
[4" claim-type="Currently amended] The method of claim 2 wherein the solvent contains a solvent having a water miscibility of less than 7 wt%.
[5" claim-type="Currently amended] 5. The process of claim 4 wherein the solvent is selected from the group of lower alkyl and aralkyl esters of aryl acids; Aryl, aralkyl and lower alkyl ketones; And lower alkyl esters of citric acid.
[6" claim-type="Currently amended] 3. The polymer according to claim 2, wherein the polymer is polylactide, polyglycolide, polycaprolactone, polyanhydride, polyamine, polyurethane, polyesteramide, polyorthoester, polydioxanone, polyacetal Type, polyketal type, polycarbonate type, polyorthocarbonate type, polyphosphazene type, succinate type, poly (malic acid), poly (amino acid), polyvinylpyrrolidone, polyethylene glycol, polyhydroxy Cellulose, chitin, chitosan, and copolymers, terpolymers and mixtures thereof.
[7" claim-type="Currently amended] 6. The process of claim 5 wherein the polymer is a lactic acid based polymer and the solvent is selected from lower alkyl and aralkyl esters of benzoic acid.
[8" claim-type="Currently amended] Implanting a system containing agonist substantially dissolved or dispersed throughout the viscous gel, the system comprising releasing up to 20% by weight of the agonist that must be transported over the delivery period within 24 hours after implantation Topical method of administration of agonists
[9" claim-type="Currently amended] The method of claim 8, wherein the viscous gel contains a biocompatible polymer and a solvent.
[10" claim-type="Currently amended] 10. The method of claim 9, wherein the viscous gel optionally comprises one or more emulsifiers, pore formers, solubility modifiers of agonists, and at least one osmotic agent.
[11" claim-type="Currently amended] The method of claim 10 wherein the solvent contains a solvent having a water miscibility of less than 7% by weight.
[12" claim-type="Currently amended] 12. The process of claim 11 wherein the solvent is selected from the group of lower alkyl and aralkyl esters of aryl acids; Aryl, aralkyl and lower alkyl ketones; And lower alkyl esters of citric acid.
[13" claim-type="Currently amended] 10. The method of claim 9, wherein the polymer is polylactide, polyglycolide, polycaprolactone, polyanhydride, polyamine, polyurethane, polyesteramide, polyorthoester, polydioxanone, polyacetal Type, polyketal type, polycarbonate type, polyorthocarbonate type, polyphosphazene type, succinate type, poly (malic acid), poly (amino acid), polyvinylpyrrolidone, polyethylene glycol, polyhydroxy Cellulose, chitin, chitosan, and copolymers, terpolymers and mixtures thereof.
[14" claim-type="Currently amended] 13. The process according to claim 12, wherein the polymer is a lactic acid-based polymer and the solvent is selected from lower alkyl and aralkyl ester systems of benzoic acid.
[15" claim-type="Currently amended] Close to zero release by implanting a gel composition comprising a biocompatible polymer, a biocompatible solvent having a water solubility of less than 7% and an agonist (the load of the agonist inside the polymer is more than necessary to saturate the agonist in water) A method of administering an agonist to a treated subject in a controlled manner.
[16" claim-type="Currently amended] Implanting a system containing an agonist substantially dissolved or dispersed throughout the viscous gel formed with a biocompatible polymer and a solvent having a water solubility of 7% or less, and a solubility modifier of the agonist, the burst index being 8 or less A method of administering an agonist for.
[17" claim-type="Currently amended] The method of claim 16, wherein the polymer is a lactic acid-based polymer.
[18" claim-type="Currently amended] A polymer, an amount of solvent to form a viscous gel with the polymer, the solvent comprising a single solvent or a mixture of solvents with one or more solvents having a water miscibility of less than 7% by weight, the total amount of solvent being at least 40% by weight of the gel vehicle And an agonist dissolved or dispersed in a gel and having a burst index of 8 or less, an implantable composition for systemic delivery of an agonist to a treatment subject.
[19" claim-type="Currently amended] An effective plasticization amount of solvent to form a viscous gel with the polymer, the solvent comprising a solvent mixture with at least one solvent in a mixture having a water miscibility of less than 7% by weight, and dissolved or dispersed in the gel An implantable biodegradable composition for sustained delivery of an agonist to a therapeutic subject, containing the agonist.
[20" claim-type="Currently amended] The composition of claim 19, wherein the water miscibility of the solvent mixture is 10 wt% or less.
[21" claim-type="Currently amended] An effective plasticizing amount of solvent for forming a viscous gel with the polymer, the solvent being a single solvent or a solvent with one or more solvents having a water miscibility of less than 7% by weight selected from the lower alkyl and aralkyl ester systems of benzoic acid And agonists dissolved or dispersed in the gel. 10. An implantable biodegradable composition for the delivery of an agonist to a therapeutic subject.
[22" claim-type="Currently amended] A) biocompatible polymers;
D) emulsifiers;
E) pore formers;
F) solubility modifiers of agonists; And
G) Osmosis
An implantable gel composition for the delivery of agonists to a subject to be treated.
[23" claim-type="Currently amended] omission
[24" claim-type="Currently amended] The composition of claim 23, wherein R ₁ is phenyl.
[25" claim-type="Currently amended] The composition of claim 24, wherein R ₂ is benzyl.
[26" claim-type="Currently amended] A) mixing a biocompatible polymer with a solvent having a water miscibility of 7% or less selected from the lower alkyl and aralkyl esters of benzoic acid to form a viscous gel;
B) dispersing or dissolving the agonist optionally combined with the solubility modifier in the emulsifier to form an emulsifier containing the agonist; And
C) mixing the viscous gel with an agonist containing emulsifier (the agonist containing emulsifier forms a droplet phase dispersed in the viscous gel); And in some cases
D) mixing the viscous gel with at least one pore former and osmotic agent to provide an injectable gel composition
Method of producing an injectable storage gel composition comprising a.
[27" claim-type="Currently amended] A) biocompatible polymers;
B) biocompatible solvents having a water miscibility of less than 7%;
C) an agonist selected from cDNA, DNA, peptides, proteins and fragments and derivatives thereof; And optionally one or more
D) emulsifiers;
E) pore formers;
F) solubility modifiers of agonists; And
G) Osmosis
A gel composition for systemic administration, containing a burst index of less than 8.
[28" claim-type="Currently amended] A) biocompatible polymers;
B) a solvent having a water miscibility of no greater than 7% by weight to dissolve the polymer to form a viscous gel;
C) an agonist, and optionally one or more
D) emulsifiers;
E) pore formers;
F) solubility modifiers of agonists that optionally bind agonists; And
G) Osmosis
Wherein the agonist optionally combined with a solubility modifier is maintained separate from the solvent until at least the time of administration of the agonist to the subject.
[29" claim-type="Currently amended] Agonists containing a poly (lactide-co-glycolide) copolymer having a burst index of 8 or less, an effective plasticizing amount of solvent for forming a viscous gel with the polymer; And an implantable composition for systemic delivery of an agonist containing an agonist selected from cDNA, DNA, peptides, proteins and fragments and derivatives thereof.
[30" claim-type="Currently amended] Poly (lactide-co-glycolide) copolymers; An implantable composition for sustained delivery of an agonist containing an effective plasticizing amount of a solvent containing a lower alkyl or aralkyl ester of benzoic acid to form a viscous gel with this polymer, and an agonist.
[31" claim-type="Currently amended] 31. The composition of claim 30, wherein the solvent has a water miscibility of less than 7% by weight.
[32" claim-type="Currently amended] 31. The composition of claim 30, wherein the solvent is benzyl benzoate.
[33" claim-type="Currently amended] 31. The composition of claim 30 containing a solubility modifier of agonist.
[34" claim-type="Currently amended] 31. The composition of claim 30 containing a pore former.
[35" claim-type="Currently amended] The composition of claim 30 containing an emulsifier.
[36" claim-type="Currently amended] 31. The composition of claim 30 containing an osmotic agent.
[37" claim-type="Currently amended] 34. The composition of claim 33, wherein the solubility modifier is selected from salts of divalent metals.
[38" claim-type="Currently amended] 35. The composition of claim 34, wherein the pore former is water soluble.
[39" claim-type="Currently amended] 35. The composition of claim 34, wherein the pore former is selected from the group consisting of water soluble sugars, salts, solvents, and polymers.
[40" claim-type="Currently amended] 36. The composition of claim 35, wherein an emulsifier can form a droplet phase dispersed in said viscous gel.
[41" claim-type="Currently amended] 36. The composition of claim 35 wherein the emulsifier is selected from the group consisting of alcoholic, propylene glycol, ethylene glycol, glycerol, water and solutions and mixtures thereof.
[42" claim-type="Currently amended] 36. The composition of claim 35, wherein the emulsifier is selected from the group consisting of ethanol, isopropyl alcohol, water, solutions and mixtures thereof.
[43" claim-type="Currently amended] The composition of claim 30 wherein the monomer ratio of lactic acid to glycolic acid of the copolymer is from 100: 0 to about 15:85.
[44" claim-type="Currently amended] 31. The composition of claim 30, wherein the copolymer has a number average molecular weight of 1,000 to 120,000.
[45" claim-type="Currently amended] 31. The composition of claim 30, wherein the solvent contains a component solvent that is miscible with the solvent.
[46" claim-type="Currently amended] 46. The composition of claim 45, wherein the component solvent is triacetin, diacetin, tributyline, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, 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, oxidation Ethylene, propylene oxide, N-methyl-2-pyrrolidone, 2-pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, Decylmethylsulfoxide, oleic acid, and 1-dodecylazacyclo-heptan-2-one and mixtures thereof Composition.
[47" claim-type="Currently amended] 46. The composition of claim 45, wherein the component solvent is selected from the group consisting of triacetin and N-methyl-2-pyrrolidone and mixtures thereof.
[48" claim-type="Currently amended] 46. The composition of claim 45, wherein the component solvent is triacetin.
[49" claim-type="Currently amended] The method of claim 2 wherein the agonist is present in an amount from 1 to 50% by weight of the combined amount of polymer, solvent and agonist.
[50" claim-type="Currently amended] The agonist is a cDNA, DNA, protein, peptide and derivatives or fragments thereof or a chemotherapeutic agent.
[51" claim-type="Currently amended] 51. The method of claim 50, wherein the agonist is human growth hormone, methionine-human growth hormone, des-phenylalanine human growth hormone, interferon alpha-2a, interferon alpha-2b, or consensus interferon.
[52" claim-type="Currently amended] The method of claim 8, wherein the agonist is cDNA, DNA, protein, peptide and derivatives or fragments thereof, or chemotherapeutic agent.
[53" claim-type="Currently amended] The method of claim 1, wherein the agonist is released from the system over a long period of time.
[54" claim-type="Currently amended] The method of claim 8, wherein the agonist is released from the system over a long period of time.
[55" claim-type="Currently amended] The method of claim 1, wherein the system is non-rigid after implantation.
[56" claim-type="Currently amended] The method of claim 55, wherein the system maintains a glass transition temperature of 37 ° C. or less for at least 24 hours after implantation.
[57" claim-type="Currently amended] The method of claim 9, wherein the system is non-rigid after implantation.
[58" claim-type="Currently amended] The method of claim 57, wherein the system maintains a glass transition temperature of 37 ° C. or less for at least 24 hours after implantation.
[59" claim-type="Currently amended] 19. The composition of claim 18, wherein the gel remains amorphous after implantation.
[60" claim-type="Currently amended] 60. The composition of claim 59, wherein the gel maintains a glass transition temperature of 37 degrees C or less for at least 24 hours after implantation.
[61" claim-type="Currently amended] An implantable gel composition containing a biocompatible polymer, a biocompatible solvent that forms a viscous gel with the polymer, and an agonist and absorbing up to 40% of its bulk weight in water within the first 21 days after implantation.
[62" claim-type="Currently amended] The composition of claim 61, wherein the composition absorbs less than 30% of its bulk weight in water within the first 14 days after implantation.
[63" claim-type="Currently amended] 63. The composition of claim 62, wherein the composition absorbs less than 25% of its bulk weight in water within the first 7 days after implantation.

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1996-12-20|Priority to US3343996P

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1996-12-20|Priority to US60/033,439

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1997-12-18|Application filed by 스톤 스티븐 에프., 알자 코포레이션

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1997-12-18|Priority to PCT/US1997/023659

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2000-11-25|Publication of KR20000069564A

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2006-08-28|Application granted

---

2006-08-28|Publication of KR100616793B1

---

2012-03-15|First worldwide family litigation filed

优先权:

---

申请号 | 申请日 | 专利标题

---

US3343996P| true| 1996-12-20|1996-12-20|

---

US60/033,439|1996-12-20|

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PCT/US1997/023659|WO1998027963A2|1996-12-20|1997-12-18|Gel composition and methods|