Biodegradable polymer composition
Abstract
A pharmaceutical system suitable for forming a biodegradable article for use in the body, comprising: a fluid composition of a biodegradable and biocompatible branched thermoplastic polymer that is at least substantially insoluble in an aqueous medium, water or a body fluid, and an organic solvent biocompatible that is at least slightly soluble in an aqueous medium, water or a body fluid.

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Projected expiry passed 16 November 2020, 5.9 years ago.
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20 claims: 3 independent, 17 dependent
- 1ES 2 240 236 T3 REIVINDICACIONES 1. Un sistema farmacéutico adecuado para formar un artículo biodegradable para usar en el cuerpo, que comprende:una composición fluida de un polímero termoplástico ramificado biodegradable y biocompatible que es al menos substancialmente insoluble en un medio acuoso, agua o un fluido corporal, y un disolvente orgánico biocompatible que es al menos ligeramente soluble en un medio acuoso, agua o un fluido corporal.
- 2Un sistema farmacéutico de acuerdo con la reivindicación 1, en el que el polímero termoplástico ramificado biodegradable y biocompatible tiene cadenas o esqueletos de polímero que contienen grupos de conexión de unidades monómeras seleccionados del grupos que consiste en éster, amida, uretano, anhídrido, carbonato, urea, esteramida, acetal, cetal, ortocarbonato y cualquier grupo funcional orgánico que pueda hidrolizarse mediante reacción enzimática o hidrolítica y cualquier combinación de los mismos.
- 3Un sistema farmacéutico de acuerdo con la reivindicación 1, en el que el polímero termoplástico ramificado biodegradable y biocompatible se forma al menos en parte a partir de un monómero que tiene al menos tres grupos funcionales.
- 4Un sistema farmacéutico de acuerdo con la reivindicación 1, en el que el disolvente orgánico biocompatible es un compuesto orgánico, alifático, arílico o arilalquílico cíclico, lineal o ramificado que es líquido a temperatura ambiente y fisiológica y contiene al menos un grupo funcional seleccionado del grupo que consiste en alcoholes, cetonas, éteres, aminas, amidas, ésteres, carbonatos, sulfóxidos, sulfonas y combinaciones de los mismos.
- 5Un sistema farmacéutico de acuerdo con la reivindicación 1, en el que el disolvente orgánico biocompatible se selecciona de un grupo que consiste en N-metil-2-pirrolidona, 2-pirrolidona, alcanoles de 2 a 6 átomos de carbono, propilenglicol, solcetal, acetona, acetato de metilo, acetato de etilo, lactato de etilo, metil-etil-cetona, dimetilformamida, dimetilsulfóxido, dimetilsulfona, tetrahidrofurano, caprolactama, decilmetilsulfóxido, ácido oleico, carbonato de propileno, triacetina, N,N-dietil-m-toluamida o 1-dodecilazacicloheptan-2-ona.
- 6Un sistema farmacéutico de acuerdo con la reivindicación 1, que comprende además uno o más agentes biológicamente activos.
- 7Un sistema farmacéutico de acuerdo con la reivindicación 6, en el que el agente biológicamente activo es una substancia usada para el tratamiento, la prevención, el diagnóstico, la curación o la mitigación de una enfermedad o dolencia, una substancia que afecta a la estructura o la función del cuerpo, o profármacos, que se convierten en biológicamente activos o más activos después de que se hayan situado en un ambiente fisiológico predeterminado.
- 8Un sistema farmacéutico de acuerdo con la reivindicación 6, en el que el agente biológicamente activo se selecciona de un grupo que consiste en agentes anabólicos, antiácidos, agentes antiasmáticos, agentes anticolesterolémicos y antilipídicos, anticoagulantes, anticonvulsivos, antidiarreicos, antieméticos, agentes antiinfecciosos incluyendo agentes antibacterianos y antimicrobianos, agentes antiinflamatorios, agentes antimaniacos, agentes antimetabolíticos, antinauseantes, agentes antineoplásticos, agentes antiobesidad, agentes antipiréticos y analgésicos, agentes antiespasmódicos, agentes antitrombóticos, agentes antitusivos, agentes antiuricémicos, agentes antianginales, antihistamidas, supresores del apetito, materiales biológicos, dilatadores cerebrales, dilatadores coronoarios, broncodilatadores, agentes citotóxicos, descongestivos, diuréticos, agentes de diagnóstico, agentes eritropoyéticos, espectorantes, sedantes gastrointestinales, agentes hiperglucémicos, hipnóticos, agentes hipoglucémicos, agentes inmunomoduladores, resinas de intercambio iónico, laxantes, suplementos minerales, agentes mucolíticos, fármacos neuromusculares, vasodilatadores periféricos, psicotrópicos, sedantes, estimulantes, agentes tiroideos y antitiroideos, agentes de crecimiento de tejidos, relajantes uterinos, vitaminas o materiales antigénicos.
- 9Un sistema farmacéutico de acuerdo con la reivindicación 6, en el que el agente biológicamente activo se selecciona de un grupo que consiste en inhibidores de andrógenos, polisacáridos, factores de crecimiento, hormonas, factores antiangiogénesis, dextrometorfano, hidrobromuro de dextrometorfano, noscapina, citrato de carbetapentano, hidrocloruro de clofedianol, maleato de clorfeniramina, tartrato de fenindamina, maleato de pirilamina, succinato de doxilamina, citrato de feniltoloxamina, hidrocloruro de fenilefrina, hidrocloruro de fenilpropanolamina, hidrocloruro de pseudoefedrina, efedrina, fosfato de codeína, sulfato de codeína, morfina, suplementos minerales, colestiramina, Nacetilprocainamida, acetaminofeno, aspirina, ibuprofeno, hidrocloruro de fenilpropanolamina, cafeína, guaifenesina, hidróxido de aluminio, hidróxido de magnesio, péptidos, polipéptidos, proteínas, aminoácidos, hormonas, interferones, citoquinas y vacunas.
- 10Un sistema farmacéutico de acuerdo con la reivindicación 1, en el que el porcentaje de sólidos del polímero termoplástico ramificado en la composición fluida está en el intervalo de aproximadamente 0,01% en peso a aproximadamente 95% en peso, preferiblemente de aproximadamente 2% en peso a aproximadamente 80% en peso, más preferiblemente de aproximadamente 5% en peso a aproximadamente 70% en peso, lo más preferiblemente de aproximadamente 30% en peso a aproximadamente 80% en peso con relación al peso total de la composición fluida.
- 11Un sistema farmacéutico de acuerdo con la reivindicación 1, que es capaz de formar una matriz microporosa durante su contacto con un medio acuoso, agua o un fluido corporal, en el que la matriz es un núcleo rodeado por una ES 2 240 236 T3 envuelta, conteniendo el núcleo poros de diámetros de aproximadamente 1 a 600 micras, y conteniendo la envuelta poros de diámetros más pequeños que los de los poros del núcleo.
- 12Un sistema farmacéutico de acuerdo con la reivindicación 11, en el que los poros de la envuelta son de un tamaño tal que la envuelta es funcionalmente no porosa en comparación con el núcleo.
- 13Un sistema farmacéutico de acuerdo con la reivindicación 1, en el que la composición fluida puede convertirse en sujeciones, microcápsulas, micropartículas, implantes o revestimientos sobre implantes.
- 14Un artículo biocompatible que se produce ex vivo o in situ poniendo en contacto un medio acuoso, agua o un fluido corporal y una composición fluida de un polímero termoplástico ramificado biodegradable y biocompatible, que es al menos substancialmente insoluble en un medio acuoso, agua o un fluido corporal, y un disolvente orgánico biocompatible que es al menos ligeramente soluble en un medio acuoso, agua o un fluido corporal.
- 15Un artículo de acuerdo con la reivindicación 14, que está en la forma de una o más sujeciones absorbibles, una o más microcápsulas, una o más micropartículas, uno o más implantes o uno o más revestimientos sobre un implante.
- 16Un artículo de acuerdo con la reivindicación 16, que está implantado en tejido vivo.
- 17Uso de un sistema farmacéutico de acuerdo con la reivindicación 6, para la fabricación de un medicamento para usar en un método para la liberación controlada de un agente biológicamente activo, que comprende situar en el cuerpo un sistema farmacéutico de acuerdo con la reivindicación 6 y permitir que el sistema farmacéutico forme un implante in situ que contiene el agente biológicamente activo.
- 18Un uso de acuerdo con la reivindicación 17, en el que el sistema farmacéutico está adaptado como un implante, una inyección, microcápsulas, sujeciones absorbibles, material para tratar lesiones óseas, o un revestimiento sobre un dispositivo de implante adecuado para la liberación de fármaco controlada y para proporcionar un efecto biológico, terapéutico o fisiológico en un organismo vivo.
- 19Una matriz de liberación sostenida que comprende un polímero termoplástico ramificado biodegradable y biocompatible que es al menos substancialmente insoluble en un medio acuoso, agua o un fluido corporal, y uno o más agentes biológicamente activos, teniendo la matriz una estructura substancialmente sólida que comprende un núcleo rodeado por una envuelta, conteniendo el núcleo poros de diámetros de aproximadamente 1 a 600 micras y conteniendo la envuelta poros de diámetros menores que los de los poros de los núcleos.
- 20Una matriz de liberación sostenida de acuerdo con la reivindicación 19, que comprende además hasta aproximadamente 40% en peso, preferiblemente 30% en peso, más preferiblemente 20% en peso, lo más preferiblemente 10% en peso, de un disolvente orgánico biocompatible que es soluble o insoluble en agua y es al menos ligeramente dispersable en un fluido corporal dentro de tejido vivo, siendo el porcentaje en peso relativo al peso total de la matriz.
Independent claims20
140 paragraphs in 9 sections, as filed
IS 2 240 236 T3
DESCRIPTION
Biodegradable polymer composition.
Background of the invention
Biodegradable polymers have been used for many years in medical applications. Medical devices made from biodegradable polymers include sutures, surgical clips, staples, implants, and drug delivery systems. Most of these biodegradable polymers have been solid thermoplastic materials based on glycolide, lactide, caprolactone and copolymers thereof. Some of these biodegradable polymers are star-shaped branched polymers, such as those described in US Patent Nos. 5,922,338 and 5,922,682, that can be used in sustained release medical devices (US Pat. Nos. 5,538,739, 5,639,480 and 5,688,530). Additional polymers used in implants are described in WO-A-9844020.
Placing medical devices such as implants and other solid items in the body often involves a surgical procedure. An incision is made, for example, and the solid implant is placed inside the body at the incision site. In other variants, such as those described in US Patent No. 4,938,763, the biodegradable polymer is introduced into the body as a flowable formulation. In these examples, a solution of the biodegradable polymer and an organic solvent is injected into the body. Upon contact with aqueous or body fluid, the polymer coagulates, forming a solid implant.
Flowable formulations often require the use of different concentrations of polymer, depending on the particular intended application. However, typical biodegradable polymers do not perform well at widely varying concentrations in fluid delivery systems.
Accordingly, there is a need for a method and composition that provides a biodegradable polymer system that operates at widely different concentrations of polymer. Specifically, there is a need for a method and composition for a pharmaceutical system that can be used to provide implants of all types and also to provide controlled delivery systems.
Summary of the invention
These and other needs are met by the present invention, which is directed to a flowable composition suitable for use in medical applications. The present invention is also directed to the use of branched biodegradable biocompatible thermoplastic polymers as solid matrices in situ and ex vivo, and as delivery systems. In situ and ex vivo implants as well as delivery systems are produced by solidification of the fluid composition through its contact with an aqueous medium, a body fluid or water. Ex vivo implants are formed outside the body and used as solid devices. These include, for example, microcapsules, microparticles, simple body implants, sutures, surgical clips, staples, and endovascular prostheses ("stents").
The fluid composition is a solution or dispersion of a biodegradable and biocompatible branched thermoplastic polymer or copolymer that is at least substantially insoluble in water and an organic solvent that is biocompatible and is at least slightly soluble in an aqueous medium, water or a body fluid. Once the fluid composition is placed within a substrate, such as the body or an aqueous medium, the polymer coagulates or solidifies as a solid matrix. The disposition of the fluid composition can be anywhere within the body, including a soft tissue such as muscle or fat, a hard tissue such as bone, or a cavity such as periodontal, oral, vaginal, rectal, nasal, etc. or a pocket such as a periodontal pocket or the cul-de-sac of the eye.
In applications where the flowable composition is used for controlled drug release, a biologically active agent is added to the composition. The biologically active agent is dissolved or dispersed in the biocompatible and biodegradable branched thermoplastic polymer composition and organic solvent to form a solution, suspension or dispersion. When this pharmaceutical composition is brought into contact with an aqueous medium, with a body fluid or with water, a solid polymer-bioactive agent matrix is formed.
Rate modifying agents can be included to control the release rate of the bioactive agent relative to the solid matrix without the additive. Preservatives, homogenizing agents, surfactants, colorants, fillers, and excipients can also be included.
Several advantages are achieved with the flowable composition of the invention compared to other systems. The fluid composition can be injected through a syringe and needle into the body while in fluid form and a solid biodegradable matrix will be formed in situ. The need to form an incision is eliminated and the implant will adopt the shape of its socket. A drug-eluting implant can be provided by adding a biologically active agent to the fluid composition system prior to injection. Once the implant is formed, it will release the bioactive agent into the body over a period of time and it will also biodegrade. The so-called explosive effect or initial release of bioactive agent can be controlled with the flowable composition because high concentrations of polymer can be used in the flowable composition. Furthermore, the same bioactive agent release profile is achieved as that provided by implants from linear polymer compositions.
IS 2 240 236 T3
The invention also relates to solid articles for medical applications, which are formed from the flowable compositions. Solid articles such as microcapsules, microparticles, monolithic implants, fasteners, medical devices, and controlled drug delivery systems are produced by ex vivo solidification of the fluid composition. The solid articles are then used within the body by, for example, suturing, pressing, inserting, injection, incision, inhalation, and the like. When used as surgical clips, sutures, and nails, solid items provide necessary support in medical applications. When used as drug delivery implants, these solid articles provide controlled release of a bioactive agent.
The invention also relates to a sustained release matrix of a biodegradable and biocompatible branched thermoplastic polymer that is at least substantially insoluble in an aqueous medium, water or a body fluid, and one or more biologically active agents, the matrix having a substantially structural structure. solid comprising a core surrounded by a shell, the core containing pores with diameters of approximately 1 to 600 microns, and the shell containing pores of smaller diameters than those of the core pores. The sustained release matrix further includes up to about 40% by weight, preferably 30% by weight, more preferably 20% by weight, most preferably 10% by weight, of a biocompatible organic solvent that is soluble or insoluble in water and is al less slightly dispersible in body fluid within living tissue, the percentage by weight being relative to the total weight of the matrix.
Detailed description of the invention
The present invention is directed to a flowable composition composed of a biodegradable and biocompatible branched thermoplastic polymer and an organic solvent. The branched thermoplastic polymer is at least substantially, preferably essentially completely soluble, in an organic solvent and is at least substantially, preferably completely, insoluble in an aqueous medium, a body fluid and water. The organic solvent is at least slightly soluble in water, preferably moderately soluble in water, and especially preferably substantially soluble in water. The fluid composition is pharmaceutically suitable for injection into the body, where it will form a solid pharmaceutically acceptable matrix, which is typically a simple body implant or drug delivery system. In one aspect of the flowable composition, a biologically active agent is included and the solid implant will release the biologically active agent at a controlled rate. The release rate can be altered to be faster or slower by including a rate modifying agent.
The present invention is also directed to biodegradable implants and methods for producing the same. These implants are solid articles that can be made from the flowable composition. Included are microcapsules, microparticles, structured articles, such as sutures, staples, medical devices, stents, and the like, as well as monolithic implants and films, filamentous membranes, and implant matrices. These implants differ in microscopic structures from known materials due to the method (ie, coagulation) by which they are made.
The microcapsules are sized on the order of 10 to 400 microns, and are preferably sized to avoid causing emboli if introduced into the bloodstream of a mammal. They are typically composed of a porous shell of the branched thermoplastic polymer and a core of another material such as a bioactive agent or a bioactive agent in a diluent or carrier.
The microparticles have approximately the same dimensions as the microcapsules. Microparticles are typically composed of a porous matrix of branched thermoplastic polymer and bioactive agent. The bioactive agent is typically contained within the polymer matrix as a homogeneous dispersion or solution or as heterogeneous domains.
Structured articles have the known conformations that are indicated by the information conveyed by their names. They may or may not contain a bioactive agent. Monolithic implants are simple body implants formed outside the body by solidifying the fluid composition in an aqueous medium. The different shapes can be obtained through the use of a molding or extrusion device designed to provide such shapes as the flowable composition comes into contact with the solidification bath. These implants can have shapes such as spherical, ellipsoidal, cylindrical, chord-like, or disc-like, as well as any other shape suitable for placement in a body site.
The films may or may not contain a bioactive agent. These can be formed by casting over the aqueous medium or by other known techniques to provide such films.
Filamentous membranes may or may not contain a bioactive agent. They may be formed by the technique described in copending US Patent Application Serial No. 09/110723, filed July 7, 1998, the disclosure of which is incorporated herein by reference.
IS 2 240 236 T3
Fluid composition
In accordance with the present invention, a flowable composition is provided in which a biocompatible and biodegradable branched thermoplastic polymer is dissolved or dispersed in a biocompatible organic solvent. Upon contact with an aqueous medium, a body fluid, or water, the fluid composition solidifies to form an implant or implantable article. Implants and implantable articles that are formed from the flowable polymer compositions of the present invention can be used for controlled drug release. In these applications, a bioactive agent is added to the flowable composition. The bioactive agent is contained within the solidified polymer matrix as the flowable composition undergoes its transformation into an implant or implantable article. When the implant is present within the body, the bioactive agent is released in a sustained manner through diffusion through the polymer matrix, by direct dissolution at implant surfaces, and by degradation and erosion of the thermoplastic polymer.
The use of the branched thermoplastic polymer in the flowable composition provides an ability to use a higher solids content for the flowable composition relative to flowable blends formed with linear thermoplastic polymers such as those described in US Patent No. 4,938. 763. Typically, a high solids content, such as 50% by weight or more, of linear thermoplastic polymer of average molecular weight of 40,000 or more in a biocompatible organic solvent results in a solution viscosity so high that the thermoplastic polymer mixture linear and organic solvent will not be easily fluid. Although these mixtures are not readily flowable, they are sufficiently flowable to be used as thick putties or gels for direct placement and manipulation at a surgically created or augmented site on the body. The use of a high solids flowable composition of the present invention, however, results in easily flowable compositions that can be injected. At the same solid contents and mean polymer molecular weights, the flowable compositions of the present invention have lower viscosities than the linear thermoplastic polymer blends disclosed in the '763 patent.
It is believed that a high solids content of the branched thermoplastic polymer in the flowable compositions of the present invention will provide substantial control of the so-called explosive effect. The explosive effect is the final release of bioactive agent from the fluid composition as it transforms into a solid implant. It is believed to occur as a result of the infusion of aqueous or body fluid into the fluid composition and the dispersion of the organic solvent from the fluid composition during this transformation phase. Typically, the explosive effect of a transforming mixture of thermoplastic polymer, organic solvent, and bioactive agent, such as that described in US Patent No. 4,938,763, releases a "peak" concentration of bioactive agent over a period of time. short period of time. This initial "spike" release is often undesirable.
Polymer
The biocompatible and biodegradable branched thermoplastic polymers used in accordance with the invention can be made from a variety of monomers that form polymer chains or monomer units linked together by connecting groups. These include polymers with polymer chains or backbones containing connecting groups such as ester, amide, urethane, anhydride, carbonate, urea, steramide, acetal, ketal, and orthocarbonate groups, as well as any other organic functional groups that can be hydrolyzed by enzymatic reaction. or hydrolytic (that is, it is biodegradable through this hydrolytic action). These polymers are usually formed by the reaction of starting monomers containing the reacting groups that will form these backbone connecting groups. For example, alcohols and carboxylic acids will form ester linking groups. Isocyanates and amines or alcohols will respectively form urea or urethane linking groups.
According to the present invention, some fraction of one of these starting monomers will be at least trifunctional, preferably multifunctional. This multifunctional character provides at least some branching of the resulting polymer chain. For example, when the chosen polymer contains ester linking groups throughout its polymer backbone, the starting monomers will usually be hydroxycarboxylic acids or they will be diols and dicarboxylic acids. The polymers of the present invention are obtained by including some fraction of a starting monomer that is at least multifunctional. Furthermore, the starting polymers of the present invention may incorporate more than one multifunctional unit per polymer molecule, and typically many multifunctional units, depending on the stoichiometry of the polymerization reaction. Preferably, the branched polymers of the present invention incorporate at least one multifunctional unit per polymer molecule. The so-called star-shaped branched polymer is formed when a multifunctional unit is incorporated into each polymer molecule.
For example, for the polymer with ester linking groups described previously, a dihydroxycarboxylic acid would be included with the first type of starting monomer or a triol and / or a dicarboxylic acid would be included with the second type of starting monomer. Similarly, a triol, quatraol, pentaol, or hexaol, such as sorbitol or glucose, can be included with the first type of starting monomer. The same logic would apply to polyamides. A triamine and / or a triacid would be included with starting monomers of a diamine and a dicarboxylic acid. An aminodicarboxylic acid, a diaminocarboxylic acid or a triamine would be included with the second type of starting monomer, amino acid. Any aliphatic, aromatic or arylalkyl starting monomer having the specified functional groups can be used in accordance with the invention to make the branched thermoplastic polymers of the
ES 2 240 236 T3 invention, provided that the polymers and their degradation products are biocompatible. The biocompatibility specifications of such starting monomers are known in the art.
In particular, the monomers used to make the biocompatible thermoplastic branched polymers of the present invention will produce polymers or copolymers that are biocompatible and biodegradable. Examples of biocompatible and biodegradable polymers suitable for use as the biocompatible branched thermoplastic polymers of the present invention include polyesters, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polydioxanones, polyyacetals, polykettals, polyiortocarbonates, polyphysesters, polyyorthocarbonates, polyorthocarbonates, polycarbonates polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, poly (alkylene oxalates), poly (alkylene succinates), poly (malic acid), poly (amino acids) and copolymers, terpolymers or combinations or mixtures of the previous materials.
The polymer composition of the invention may also include combinations of polymers of the polymers of the present invention with other biocompatible polymers, provided they do not undesirably interfere with the biodegradable characteristics of the composition. Combinations of the polymer of the invention with such other polymers can offer even greater flexibility in designing the precise release profile desired for the delivery of the chosen drug or the precise rate of biodegradability desired for structural implants, such as for orthopedic applications.
The preferred biocompatible branched thermoplastic polymers or copolymers of the present invention are those that have a lower degree of crystallization and are more hydrophobic. These polymers and copolymers are more soluble in biocompatible organic solvents than highly crystalline polymers such as polyglycolide or chitin, which have a high degree of hydrogen bonding. Preferred materials with the desired solubility parameters are branched polylactides and polycaprolactones and copolymers of these with glycolide in which there are more amorphous regions to improve solubility. Generally, the biodegradable and biocompatible branched thermoplastic polymer is substantially soluble in organic solvents so that up to 50-60% by weight solids can be formed. Preferably, the polymers used according to the invention are essentially completely soluble in the organic solvent so that mixtures of up to 85-98% by weight solids can be formed. The polymers are also at least substantially insoluble in water so that less than 0.1 g of polymer per ml of water will dissolve or disperse in water. Preferably, the polymers used in accordance with the invention are essentially completely insoluble in water so that less than 0.001 g of polymer per ml of water will dissolve or disperse in water. At this preferred level, the fluid composition with a completely water-miscible solvent will almost immediately transform to a solid polymer.
Solvents
Suitable solvents for use in the fluid composition are biocompatible and are at least slightly soluble in an aqueous medium, a body fluid, or water. The organic solvent is preferably at least moderately soluble, more preferably highly soluble, and most preferably soluble at all concentrations in an aqueous medium, a body fluid, or water. A solvent that is at least slightly soluble in an aqueous or body fluid will allow water to penetrate the polymer solution for a period of time ranging from seconds to weeks and will cause it to coagulate or solidify. Slightly soluble solvents will diffuse slowly from the flowable composition and will typically allow transformation over a period of days to weeks, for example from about 1 day to several weeks. Moderately soluble to highly soluble solvents will diffuse from the flowable composition over a period of minutes to days so that transformation will occur rapidly but with sufficient time to allow handling as a flexible implant after placement. The highly soluble solvents will diffuse from the flowable composition over a period of seconds to hours so that transformation will occur almost immediately. The organic solvent is preferably a polar aprotic or polar protic organic solvent. Preferably, the organic solvent has a molecular weight in the range of from about 30 to about 1000.
Although not to be construed as a limitation of the invention, it is believed that the transition from the fluid composition to a solid is the result of the dissipation of the organic solvent from the fluid composition into the surrounding aqueous medium or body fluid and the infusion of water from the fluid composition. the aqueous medium or surrounding body fluid to the organic solvent within the fluid composition. It is believed that during this transition, the thermoplastic polymer and organic solvent within the flowable composition are partitioned between polymer rich and poor regions. The polymer-poor region is infused with water and provides the porous nature of the resulting solid structure.
Examples of biocompatible organic solvents that can be used to form the flowable compositions of the present invention include linear, cyclic and branched aliphatic, aryl and arylalkyl organic compounds that are liquid or at least fluid at room and physiological temperature and contain functional groups such as alcohols, ketones, ethers, amides, esters, carbonates, sulfoxides, sulfones, and any other functional group that is compatible with living tissue.
Preferred biocompatible organic solvents that are at least slightly soluble in aqueous or body fluid include N-methyl-2-pyrrolidone, 2-pyrrolidone; alcohols, diols, triols and tetraols of 1 to 15 carbon atoms such as ethanol, glycerin, propylene glycol, butanol; C 3 to 15 alkyl ketones such as acetone, diethyl ketone and methyl ethyl ketone; esters of 3 to 15 carbon atoms such as methyl acetate, ethyl acetate,
ES 2 240 236 T3 ethyl lactate; C 1 to 15 amides such as dimethylformamide, dimethylacetamide, and caprolactam; ethers of 3 to 20 carbon atoms such as tetrahydrofuran or solketal; Tweens, triacetin, propylene carbonate, decylmethylsulfoxide, dimethylsulfoxide, oleic acid, and 1-dodecylazacycloheptan-2-one. Other preferred solvents are benzyl alcohol, benzyl benzoate, dipropylene glycol, tributyrin, ethyl oleate, glycerin, glycofural, isopropyl myristate, isopropyl palmitate, oleic acid, polyethylene glycol, propylene carbonate, and triethyl citrate. The most preferred solvents are N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, triacetin, and propylene carbonate, due to their solvating ability and compatibility.
The solubility of branched biodegradable thermoplastic polymers in various solvents will differ depending on their crystallinity, hydrophilicity, hydrogen bonding, and molecular weight. Lower molecular weight polymers will normally dissolve more easily in solvents than high molecular weight polymers. As a result, the concentration of a polymer dissolved in the various solvents will differ depending on the type of polymer and its molecular weight. On the other hand, higher molecular weight polymers will tend to give higher solution viscosities than low molecular weight materials.
Generally, the concentration of the polymer in the organic solvent according to the invention will vary from about 0.01 g per ml of solvent to a saturated concentration. Typically, the saturated concentration will be in the range of 80 to 95% by weight of solids or 4 to about 5 g per ml of solvent assuming the solvent weighs about 1 g per ml.
For polymers that tend to coagulate slowly, a mixture of solvents can be used to increase the rate of coagulation. In essence, one liquid component of the solvent mixture is a good solvent for the polymer and the other liquid component of the solvent mixture is a poorer solvent or a non-solvent. The two liquids are mixed in such a ratio that the polymer is still soluble but precipitates with the slightest increase in the amount of non-solvent, such as water in a physiological environment. By necessity, the solvent system must be miscible with both the polymer and water. An example of such a binary solvent system is the use of N-methylpyrrolidone and ethanol. Adding ethanol to the NMP / polymer solution increases its coagulation rate.
Bioactive Agents
The terms "drug," "drug," or "bioactive agent" (ie, biologically active agent), as used herein, include, without limitation, physiologically or pharmacologically active substances that act locally or systemically in the body. A biologically active agent is a substance used for the treatment, prevention, diagnosis, cure or mitigation of a disease or disease, a substance that affects the structure or function of the body, or prodrugs, which become biologically active. or more active after they have been placed in a predetermined physiological environment, substances biologically, physiologically or pharmacologically active acting locally or systemically in the human or animal body. Various forms of the drugs or biologically active materials can be used that are capable of being released from the solid matrix into adjacent tissues or fluids. The drugs are at least very slightly soluble in water, preferably moderately soluble in water, and are diffusible through the polymeric composition. They can be acidic, basic or amphoteric salts. They can be non-ionic molecules, polar molecules, or molecular complexes capable of hydrogen bonding. The biologically active agent can be included in the compositions in the form of, for example, an uncharged molecule, a molecular complex, a salt, an ether, an ester, an amide, a polymer-drug conjugate, or another form that provides the effective biological or physiological activity. When the bioactive agent and the flowable composition are combined, an embodiment of the pharmaceutical composition is provided.
Bioactive agents contemplated for use in the fluid composition of the present invention include anabolic agents, antacids, antiasthmatic agents, anticolesterolemic and antilipidic agents, anticoagulants, anticonvulsants, antidiarrheals, antiemetics, anti-infective agents including antibacterial and antimicrobial agents, anti-inflammatory agents, anti-inflammatory agents, anti-inflammatory agents, antimetabolitics, antinauseants, antineoplastic agents, antiobesity agents, antipyretic and analgesic agents, antispasmodic agents, antithrombotic agents, antitussive agents, anturicemic agents, antianginal agents, antihistamides, appetite suppressants, biological materials, brain dilators, coronary dilators, bronchodilators, cytotoxic agents, decongestants, diuretics, diagnostic agents , expectorants, gastrointestinal sedatives, hyperglycemic agents, hypnotics, hypoglycemic agents, immunomodulating agents, ion exchange resins, laxatives, mineral supplements, mucolytic agents, neuromuscular drugs, peripheral vasodilators, psychotropics, sedatives, stimulants, thyroid and antithyroid agents, tissue growth agents, uterine relaxants, vitamins or antigenic materials.
More particularly, preferred biologically active agents for use with the fluid composition of the present invention include androgen inhibitors, polysaccharides, growth factors, hormones, anti-angiogenesis factors, dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, chlorophedianol hydrochloride, chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, codeine phosphate, codeine sulfate, morphine, mineral supplements, cholestyramine, N-acetylprocainamide, acetaminophen, aspirin, ibuprofen, caffeine hydrochloride, aluminum hydrochloride , magnesium hydroxide, peptides, polypeptides, proteins, amino acids, hormones, interferons, cytokines
ES 2 240 236 T3 and vaccines. Representative drugs or bioactive materials that can be used in the polymer system or solid matrix of the present invention include, but are not limited to, peptide drugs, protein drugs, desensitizing materials, antigens, anti-infective agents such as antibiotics, antimicrobial agents, substances antiviral, antibacterial, antiparasitic and antifungal and combinations thereof, antiallergens, androgenic steroids, decongestants, hypnotics, steroidal anti-inflammatory agents, anticholinergics, sympathomimetics, sedatives, miotics, psychic energizers, tranquilizers, vaccines, estrogens, progestational agents, humoral agents, prostaglandins, analgesics, antispasmodics, antimalarials, antihistamines, cardioactive agents, anti-inflammatory agents, anti-inflammatory agents antihypertensive agents, t-adrenergic / blocking agents, nutritional agents and benzophenanthridine alkaloids. The agent may further be a substance capable of acting as a stimulant, sedative, hypnotic, analgesic, anticonvulsant, and the like.
The pharmaceutical composition can contain a large number of biologically active agents individually or in combination. Biologically active agents can be in a controlled release component, which is dissolved, dispersed, or entrapped in the auxiliary polymer system. The controlled release component can include microstructures, macrostructures, conjugates, complexing agents, low water solubility salts, and the like. Microstructures include nanoparticles, cyclodextrins, microcapsules, micelles, liposomes, and the like. The macrostructures include fibers, beads, and the like. Controlled release compositions are described in US Patent No. 5,702,716, the disclosure of which is incorporated herein by reference.
Examples of these biologically active agents include, but are not limited to: anti-inflammatory agents such as hydrocortisone, prednisone, fludrotisone, triamcinolone, dexamethasone, betamethasone, and the like.
Antibacterial agents such as penicillins, cephalosporins, vancomycin, bacitracin, polymycins, tetracyclines, chloramphenicol, etyromycin, streptomycin, quinolone, and the like.
Antifungal agents such as nystatin, gentamicin, miconazole, tolnaphtate, undecyclic acid and its salts, and the like.
Analgesic agents such as salicylic acid, salicylate salts and esters, acetaminophen, ibuprofen, morphine, phenylbutazone, indomethacin, sulindac, tolmetin, zomepirac, and the like.
Local anesthetics such as cocaine, benzocaine, novocaine, lidocaine, and the like.
The bioactive material can also be a substance, or a metabolic precursor thereof, that is capable of promoting the growth and survival of cells and tissues, or increasing the activity of functioning cells, such as, for example, blood cells, neurons. , muscle cells and tissues, bone marrow, bone and the like. For example, the bioactive material can be a nerve growth promoting substance, such as, for example, a ganglioside, a phosphatidylserine, a nerve growth factor, a neurotrophic factor derived from the brain. The bioactive material can also be a growth factor for soft or fibrous connective tissue, such as, for example, a fibroblast growth factor, an epidermal growth factor, an endothelial cell growth factor, a platelet-derived growth factor. , an insulin-like growth factor, a periodontal ligament cell growth factor, cementum-binding extracts, and fibronectin.
To promote bone growth, the biologically active material can be an osteoinductive or an osteoconductive substance. Suitable bone growth promoting agents include, for example, osteoinductive factor (OIF), bone morphogenetic protein (BMP) or protein derived therefrom, demineralized bone matrix, and releasing factors thereof. Furthermore, the agent may be a bone growth promoting substance such as hydroxyapatite, tricalcium phosphate, a di- or poly-phosphonic acid, an antiestrogen, a sodium fluoride preparation, a substance having a phosphate to calcium ratio similar to bone. natural, and the like. A bone growth promoting substance may be in the form, for example, of pieces of bone, bone crystals or mineral fractions of bone and / or tooth, a synthetic hydroxyapatite or other suitable form. The agent may further be capable of treating metabolic bone disorders such as abnormal calcium and phosphate metabolism, for example, by inhibiting bone resorption, promoting bone mineralization or inhibiting calcification. The active agent can also be used to promote bone cell growth and survival, such as, for example, a colony stimulating factor, and erythropoietin.
During the formation of the bone matrix from the pharmaceutical composition, the biologically active agent is incorporated into the polymer matrix. The bioactive agent will be released from the matrix into adjacent tissues or fluids through diffusion, migration, dissolution, and through mechanisms of polymer erosion and degradation. Manipulation of these mechanisms can also influence the release of the active agent to the surroundings at a controlled rate. For example, the polymer matrix can be formulated to degrade after an effective and / or substantial amount of the bioactive agent is released from the matrix. Release of an agent that has low water solubility, such as a peptide or protein, typically requires the degradation of a substantial portion of the polymer matrix to expose the agent directly to surrounding tissue fluids. Thus, the release of the biologically active agent from the matrix can be varied, for example, by the solubility of the bioactive agent in water, the distribution of the bioactive agent within the matrix, or the size, shape, porosity, solubility and the biodegradability of the polymer matrix, among other factors. Release of the biologically active agent can facilitate pore formation. The release of the biologically active agent from the
ES 2 240 236 T3 matrix is controlled in relation to its intrinsic rate by varying the polymer composition, molecular weight, and / or polymer concentration, and adding a rate modifying agent to provide a desired duration and rate of release, depending on described previously.
The pharmaceutical composition is formulated to provide a solid matrix containing the bioactive agent in an amount effective to provide a desired biological, physiological and / or therapeutic effect. The "effective amount" of a biologically active agent incorporated into the pharmaceutical composition of the invention depends on a variety of factors, such as the desired release profile, the concentration of bioactive agent required for a desired biological effect, and the period of time during which the bioactive agent needs to be released for a desired treatment. Ultimately, this amount is determined by the patient's physician, who will apply his or her experience and skill to prescribe the appropriate type and amount of bioactive agent to provide therapy for the patient. Generally, there is no critical upper limit on the amount of bioactive agent incorporated into the polymer solution. The only limitation is a physical limitation for an advantageous application, that is, the bioactive agent must not be present in a high concentration such that the viscosity of the solution or dispersion is too high for use. The lower limit of bioactive agent incorporated into the polymer system typically depends only on the activity of the bioactive agent and the desired period of time for treatment.
For those skilled in the art, any biologically active agent that can be released into an aqueous environment can be used in the disclosed pharmaceutical composition. In addition, various forms of the biologically active agents can be used. These include, without limitation, forms such as uncharged molecules, molecular complexes, salts, ethers, esters, amides, etc., that are biologically activated when injected into the body.
Bioactive agents can be combined with the flowable composition to provide a pharmaceutical composition for drug delivery. In its simplest form, the pharmaceutical composition is a dispersion or solution of the bioactive agent in a matrix of the biodegradable and biocompatible branched thermoplastic polymer.
To prepare such a pharmaceutical composition, a bioactive agent is added to the flowable composition of the present invention prior to use. The pharmaceutical composition is then administered or otherwise processed to cause its transformation in vivo or ex vivo into the desired implant, implantable article, or medical device, and the like.
In some cases, the bioactive agent will be soluble in the solvent, and a homogeneous solution of fluid composition and bioactive agent will be available for transformation processing. In other cases, the bioactive agent will not be soluble in the solvent and a suspension or dispersion of the bioactive agent will result in the flowable composition. This suspension or dispersion can also be processed into the desired implant, implantable article, and the like. In either case, the solvent will dissipate and the polymer will solidify and incorporate the bioactive agent into the solid matrix. The release of bioactive agent from these solid implants will follow the same general rules for the release of a bioactive agent from a monolithic polymer device. Bioactive agent release can be affected by implant size and conformation, bioactive agent loading within the implant, permeability factors involving the bioactive agent and the particular polymer, and polymer degradation. Depending on the bioactive agent selected for delivery, the previous parameters can be adjusted by a person skilled in the art of drug delivery to give the desired rate and duration of release.
According to the parameters and conditions of the invention, the release of the bioactive agent can be controlled. In particular, the rate and extent of release of the bioactive agent from an implant, an implantable article, a device and the like according to the invention can be controlled by varying the type and molecular weight of the polymer, the use of an agent rate modifier, use of plasticizers and percolating agents, and concentrations and types of thermoplastic polymer and bioactive agent.
Rate modifying agents, plasticizers and percolating agents can be included to manage the rate of bioactive agent release and the flexibility of the matrix. The rate modifying agent can increase or retard the release rate depending on the nature of the rate modifying agent incorporated in the solid matrix according to the invention. Known plasticizers, as well as organic compounds that are suitable for secondary pseudo-bonding in polymer systems, are acceptable as rate modifying agents and also as flexibility modifiers and percolation agents. Generally, these agents are esters of mono-, di-, and tri-carboxylic acids, diols and polyols, polyesters, nonionic surfactants, fatty acids, fatty acid esters, oils such as vegetable oils, and the like. The concentrations of such agents within the solid matrix may vary in an amount of up to 60% by weight relative to the total weight of the matrix, preferably up to 30% by weight and more preferably up to 15% by weight. Generally, these rate modifying agents, percolation agents, plasticizers, and flexibility modifiers and their application are described in US Pat. Nos. 5,702,716 and 5,447,725, the disclosures of which are incorporated herein by reference, provided that the polymers to be used are the biocompatible and biodegradable branched thermoplastic polymers of the present invention.
Moldable Implant Precursor
The fluid composition can be formed as a moldable implant precursor by contact with an aqueous medium such as water or saline, or contact with a body fluid such as blood serum, lymph and
Similar ES 2 240 236 T3, according to the techniques described in US Patent No. 5,487,897, the disclosure of which is incorporated herein by reference, with the specification that the thermoplastic polymer of the '897 patent is a biodegradable and biocompatible branched thermoplastic polymer as described herein.
Briefly, the technique disclosed by the '897 patent converts the fluid composition with or without a bioactive agent into a two-part structure comprising an outer pouch with fluid content. The technique applies a limited amount of aqueous medium and the like to an amount of the pharmaceutical system so that only the outer surface of the system becomes solid, thus forming the sac with a fluid content inside. The fluid content of the implant precursor can vary in consistency from aqueous to viscous. The outer bag can vary in consistency from gelatinous to printable, moldable, and waxy. The resulting device, or implant precursor, can then be applied to an implant site. During implantation, the solvent from the implant precursor diffuses into the surrounding tissue fluids to form an implant having a solid polymer matrix. Preferably, the implant precursor solidifies in situ to a solid matrix in about 0.5-4 hours after implantation, preferably in about 1-3 hours, preferably in about 2 hours. Thus, when placed in an implant site in the body, the implant precursor eventually coagulates to a solid microporous matrix structure.
Porous structure
The porous structure of solid matrices, for example formed-in-situ implants, implants, implantable articles, diodegradable articles and devices of the invention, is influenced by the nature of the organic solvent and the branched thermoplastic polymer, by its solubility in water, aqueous medium. or body fluid (which may differ for each medium) and by the presence of an additional pore-forming moiety. The porous structure is believed to be formed by various mechanisms and their combinations. The dissipation, waste, or diffusion of the solvent out of the solidifying fluid composition into adjacent fluids can generate pores, including porous channels, within the polymer matrix. Infusion of an aqueous medium, water or a body fluid into the fluid composition also occurs and is also partly responsible for the creation of pores. Generally, it is believed that the porous structure is formed during the transformation of the fluid composition into a solid implant, article, and the like. It is believed that, as previously explained, during this process, the organic solvent and thermoplastic polymer partition within the flowable composition into regions that are rich and poor in thermoplastic polymer. Partition is believed to occur as a result of the dynamic interaction of aqueous infusion and solvent dissipation. Infusion involves the movement of aqueous medium, water, or body fluid into the fluid composition and dissipation involves the movement of organic solvent into the medium surrounding the fluid composition. Regions of the fluid composition that are poor in thermoplastic polymer are infused with a mixture of organic solvent and water, aqueous medium, or body fluid. These regions are believed to eventually become the porous network of the solid implant, article, and the like.
Typically, the macroscopic structure of the solid matrix involves a core and a shell. Typically, the core and shell are microporous but the pores in the shell are smaller in size than the core unless a separate pore-forming agent is used as discussed previously. Preferably, the outer shell portion of the solid matrix has pores with significantly smaller diameters than these pores in the inner core portion. The pores of the core are preferably substantially uniform in shape and the shell is typically functionally non-porous compared to the porous nature of the core. The pore size of the solid implant, article or device and the like is in the range of about 4-1000 microns, preferably the pore size of the shell layer is about 1-500 microns. The porosity of such matrices is described by US Pat. No. 5,324,519, the description of which is incorporated herein by reference.
The solid microporous implant, article or device and the like will have a porosity in the range of about 5-95%, as measured by the solid percent volume of the solid. The development of the degree of porosity will be governed at least in part by the degree of solubility in water of the organic solvent and the branched thermoplastic polymer. If the water solubility of the organic solvent is high and that of the polymer is extremely low or non-existent, a substantial degree of porosity will develop, typically on the order of 30 to 95%. If the organic solvent has low water solubility and the polymer has low to no water solubility, a low degree of porosity will develop, typically on the order of 5 to 40%. The degree of porosity is believed to be in part controlled by the polymer-solvent partition when the flowable composition comes into contact with an aqueous medium and the like. Controlling the degree of porosity is beneficial for the generation of different types of biodegradable articles, implants and devices according to the invention. For example, if strength is a requirement for the article, implant or device and the like, it may be beneficial to have a low degree of porosity. Sutures and clips are such examples.
Pore Forming Additive
Additives can advantageously be used to further control the size of the pores in the solid matrix, which influences the structure of the matrix and the release rate of a bioactive agent or the rate of diffusion of body fluids. For example, if the flowable composition is too impervious to aqueous medium, water, or internally growing tissue, a pore-forming agent can be added to generate additional pores in the matrix. Any biocompatible water soluble material can be used as the pore-forming additive. These
ES 2 240 236 T3 additives may be soluble in the flowable composition or simply be dispersed within it. They are capable of dissolving, diffusing, or dispersing from the coagulating polymer matrix, thereby generating pores and porous channels. The amount of pore-forming additive (and the size of the dispersed particles of such pore-forming agent, if appropriate) within the flowable composition will directly affect the size and number of the pores in the polymer matrix.
Pore-forming additives include any pharmaceutically acceptable organic or inorganic substance that is substantially miscible in water and body fluids and dissipates from the forming and formed matrix into an aqueous medium or body fluids or water-immiscible substances that rapidly degrade to soluble substances. in water. It is further preferred that the pore-forming additive is miscible or dispersible in the organic solvent to form a uniform mixture. Suitable pore-forming agents include, for example, sugars such as sucrose and dextrose, salts such as sodium chloride and sodium carbonate, and polymers such as hydroxypropylcellulose, carboxymethylcellulose, polyethylene glycol, and polyvinylpyrrolidone. The size and extent of the pores can be varied over a wide range by changing the molecular weight and the percentage of the pore-forming additive incorporated in the flowable composition.
As indicated, during contact with body fluid, the solvent and optional pore-forming additive dissipate into surrounding tissue fluids. This causes the formation of microporous channels within the coagulating polymer matrix. Optionally, the pore-forming additive can dissipate from the matrix into the surrounding tissue fluids at a slower rate than that of the solvent, or be released from the matrix over time by biodegradation or bioerosion of the matrix. Preferably, the pore-forming additive dissipates from the implant matrix which coagulates in a short time after implantation, so that a matrix is formed with effective porosity and pore structure to fulfill the particular purpose of the implant, such as, for example, a barrier system for a tissue regeneration site, a matrix for the timed release of a drug or medicament, and the like.
The porosity of the solid polymer matrix can be varied by the concentration of water-soluble or water-miscible ingredients, such as the solvent and / or the pore-forming agent, in the polymer composition. For example, a high concentration of water soluble substances in the thermoplastic composition can produce a polymer matrix that has a high degree of porosity. The concentration of the pore-forming agent relative to the polymer in the composition can be varied to achieve different degrees of pore formation, or porosity, in the matrix. Generally, the polymer composition will include about 0.01-1 gram of pore-forming agent per gram of polymer.
The size or diameter of the pores formed in the solid implant matrix can be varied according to the size and / or distribution of the pore-forming agent within the polymer matrix. For example, pore-forming agents that are relatively insoluble in the polymer mixture can be selectively included in the polymer composition according to particle size to generate pores that have a diameter that corresponds to the size of the pore-forming agent. Pore-forming agents that are soluble in the polymer blend can be used to vary the pore size and porosity of the implant matrix by the distribution pattern and / or ratio of the pore-forming agent within the polymer blend and the polymer matrix that coagulates and solid.
When the implant is used to promote guided tissue regeneration, it is preferred that the pore diameter of the matrix is effective in preventing epithelial cell growth and enhancing connective tissue cell growth in the polymer matrix of the implant. It is further preferred that the pore size and porosity of the implant matrix facilitate the diffusion of nutrients and other growth promoting substances, such as growth factors, to cells that have grown within the matrix. Preferably, the degree of porosity of the matrix provides an implant that is capable of substantially maintaining structural integrity for the desired period of time without rupture or fracture during use.
To provide an effective implant for bone cell regrowth and tissue regeneration, it is preferred that the pore diameter of the implant is about 3-500 microns, more preferably about 3-200 microns, more preferably about 75-150 microns. It is further preferred that the matrix have a porosity of about 5-95%, preferably about 25-85%, to provide optimal internal growth of cells and tissues in the matrix and optimal structural integrity.
The diameter and distribution of the pores within the polymer matrix of the solid implant can be measured, as an example, according to scanning electron microscopy methods, by examining cross-sections of the polymer matrix. The porosity of the polymer matrix can be measured according to suitable methods known in the art, such as, for example, mercury intrusion porosimetry, specific gravity or density comparisons, calculation from scanning electron microscopy photographs, and Similar. Additionally, porosity can be calculated according to the proportion or percentage of the water soluble material included in the polymer composition. For example, a polymer composition containing about 30% polymer and about 70% solvent and / or other water soluble components will generate an implant having a polymer matrix of about 70% porosity.
IS 2 240 236 T3
In a particularly preferred embodiment, an article is used for implantation, injection, or is otherwise fully or partially placed within the body, the article comprising the biodegradable polymer composition of the invention. The biologically active substance of the composition and the polymer of the invention can form a homogeneous matrix, or the biologically active substance can be encapsulated in some way within the polymer. For example, the biologically active substance can be encapsulated first in a microsphere and then combined with the polymer in such a way that at least a portion of the microsphere structure is maintained. Alternatively, the biologically active substance may be sufficiently immiscible in the polymer of the invention so that it disperses as small droplets, rather than dissolves, in the polymer. Either form is acceptable, but it is preferred that, regardless of the homogeneity of the composition, the release rate of the biologically active substance in vivo remains controlled, at least partially as a function of the hydrolysis of the polymer ester bond during biodegradation.
In a preferred embodiment, the article of the invention is designed for implantation or injection into the body of a mammal. It is particularly important that such an article results in minimal tissue irritation when implanted or injected into vascular tissue.
As a structural medical device, the polymer compositions of the invention provide a physical form that has specific chemical, physical, and mechanical properties sufficient for the application and a composition that degrades in vivo to non-toxic waste. Typical structural medical articles include implants such as orthopedic fixation devices, ventricular shunts, degradable fabric laminates, drug carriers, bioabsorbable sutures, burn dressings, coatings to be placed over other implant devices, and the like.
In orthopedic articles, the composition of the invention may be useful for repairing injuries to bone and connective tissue. For example, a biodegradable porous material can be loaded with bone morphogenetic proteins to form a bone graft useful for even large segmental defects. In vascular graft applications, a biodegradable material in the form of woven fabric can be used to promote tissue ingrowth. The composition of the invention can be used as a temporary barrier to prevent tissue adhesion, for example after abdominal surgery.
On the other hand, in nerve regeneration articles, the presence of a biodegradable support matrix can be used to facilitate cell adhesion and proliferation. When the polymer composition is manufactured as a tube for nerve generation, for example, the tubular article can also serve as a geometric guide for axonal elongation in the direction of functional recovery.
As a drug delivery device, the polymer compositions of the invention provide a polymeric matrix capable of sequestering a biologically active substance and providing a predictable controlled delivery of the substance. The polymer matrix is then degraded to non-toxic residues.
In all cases, the solid implant formed within the injectable polymer solution will slowly biodegrade within the body and allow natural tissue to grow in and replace the implant as it disappears. Thus, when the material is injected into a soft tissue defect, it will fill in that defect and provide a scaffold for the natural collagen tissue to grow. This collagenized fabric will gradually replace the biodegradable polymer. With hard tissue such as bone, the biodegradable polymer will support the growth of new bone cells, which will also gradually replace the degrading polymer. For drug compositions, the solid implant formed from the injectable system will release the drug contained within its matrix at a controlled rate until the drug is depleted. With certain drugs, the polymer will degrade after the drug has been fully released. With other drugs, such as peptides or proteins, the drug will be fully released only after the polymer has degraded to a point where the non-diffusing drug has been exposed to body fluids.
Solid Biodegradable Items
Biodegradable medical implants, microcapsules, microparticles, medical devices and drug delivery products can be prepared by the transformation process using water or an aqueous medium or body fluid to cause solidification. These products are generally solid ex vivo matrices. If the ex vivo solid matrix is to have a particular conformation, such as a stent or medical device, it can be obtained by transforming the fluid composition into a suitable mold following the previously described castable implant precursor technique. After the precursor has been formed, it can be contacted with additional aqueous medium to complete the transformation. Alternatively, the flowable composition can be placed in a closed mold that is permeable to the aqueous medium and the mold with the composition can be contacted with an aqueous medium such as by immersing it in an aqueous bath. Preferably, the flowable composition in this case will have a moderate to high viscosity.
Microcapsules and microparticles can be formed by techniques known in the art. Briefly, the preparation of microcapsules involves the formation of a micelle emulsion of bioactive carrier agent in the fluid composition in which the carrier is a non-solvent for the biodegradable and biocompatible branched thermoplastic polymer of the invention. The micelles are filtered and then suspended in medium.
ES 2 240 236 T3 aqueous. The coating of the flowable composition on the surfaces of the micelles is then solidified to form the porous microcapsules. The microparticles are formed in a similar procedure. A mixture of flowable composition and bioactive agent is added dropwise by spraying, blasting, aerosolization or by other similar techniques to a non-solvent for the flowable composition. The size and composition of the droplets is controlled to produce the desired shape and size of the porous microparticles. Sheets, membranes and films can be produced by casting the flowable composition over a suitable non-solvent and allowing transformation to take place. Similarly, the viscosity of the flowable composition can be adjusted so that when sprayed or aerosolized, ropes are formed instead of droplets. These cords can be cast over a non-solvent for the flowable composition so that a filamentary scaffold or membrane is produced. In addition, a suture or other similar material can be formed by extruding the flowable composition into a bath of non-solvent. The extrusion hole will control the size and shape of the extrudate. Techniques for the formation of these solid matrices ex vivo are described in US Pat. No. 4,652,441; 4,917,893; 4,954,298; 5,061,492; 5,330,767; 5,476,663; 5,575,987; 5,480,656; 5,643,607; 5,631,020; 5,631,021; 5,651,990, the disclosures of which are incorporated herein by reference, provided that the polymers used are biocompatible and biodegradable branched thermoplastic polymers of the invention.
These solid ex vivo matrices can be used according to their known functions. For example, fasteners such as sutures and staples can be used according to techniques known in the art. Implants and other solid articles can be inserted into the body using techniques known in the art such as through an incision or through a trocar.
Examples
The present invention is more particularly described in the following examples which are intended for purposes of illustration only, as numerous modifications and variations will be apparent to those skilled in the art.
Example 1
Biodegradable polymer synthesis
A 360 ml Teflon container was charged with D, L-lactide (275 g), polyol (0.4-1.4% w / w) and stannous octoate (0.045% w / w). The mixture was heated at 145 ° C for 20 hours. The resulting polyester was removed from the reaction vessel and dissolved in anhydrous dichloromethane and purified by precipitation from anhydrous methanol. The polymers were dried under vacuum at room temperature to remove most of the residual solvent. The resulting hard solid masses were cooled in liquid nitrogen and cut into small pieces. The small pieces were ground in a Wiley mill to a powder coarse enough to pass through a 6mm screen. The resulting polymer was dried under vacuum at room temperature before final packaging.
Example 2
Characterization of the biodegradable polymer
Weight average molecular weights were determined from light scattering using a system incorporating a Waters 510 pump, two Polymer Labs "Mixed C" columns in series, a Shimadzu CTO-10-A column oven, a differential refractometer Waters 410 and a Minidawn® multi-angle light scattering detector (Wyatt Technologies). Data was obtained and analyzed on a PC using Astra® software (Wyatt Technologies). Data are presented in daltons. Weight average molecular weights and number average molecular weights from standard calibration were obtained using the previously described system through the Waters 410 differential refractometer using a Polymer Labs data capture unit and Caliber software.<sup>®</sup>. A calibration curve was obtained using Polymer Laboratories Easi-Cal PS-1 polystyrene standards. Data are presented in daltons. Inherent Viscosities (VI) were obtained using 0.45 to 0.55 weight / volume percent polymer solutions in a Canon-enske size 25 viscometer at 30 ° C. Data are presented in dl / g. Brookfield viscosities (BV) were obtained from 40 weight / weight percent polymer solutions in N-methylpyrrolidone using a Brookfield digital viscometer with a SC4-218 spindle at 0.3 rpm and 25 ° C. Data are presented in centipoises. The polymer characterization data is summarized in Table 1. The data indicate that branched polymers derived from at least trifunctional triols have molecular weights comparable to linear polymers, but substantially lower viscosities, particularly Brookfield viscosities.
IS 2 240 236 T3
Table I
Polymer Characterization Data Data for Linear and Branched Poly (DL-lactide) s
<td>To 07-55</td><td>Pentaerythritol</td><td>Tetrabranched</td><td>4-Hydroxyl</td><td> 16.200</td><td> 21.600</td><td> 18.100</td><td> 0,22</td><td> 069</td>
<td>A107-43</td><td>Trimethylolpropane</td><td>Tri-branched</td><td>3-Hydroxyl</td><td> 17.500</td><td> 22.400</td><td> 18.500</td><td> 0,30</td><td> 890</td>
<td>A107-41</td><td>Ethylene glycol</td><td>Linear</td><td>'S i £ t IN</td><td> 18.300</td><td> 25.800</td><td> 19.300</td><td>Γ * Ί θ '</td><td> 1410</td>
<td>A107-35</td><td>Dodecanol</td><td>Linear</td><td>1-Hydroxyl, 1-Ester</td><td>000 l</td><td> 23.100</td><td> 17.100</td><td>Κ'0</td><td> © 00 00</td>
<td>Show</td><td>Initiator</td><td>Molecular Architecture</td><td>Extreme Groups</td><td>Pm (LS)</td><td>Pm (CC)</td><td>Mn (CC)</td><td>VI, dl / g</td><td>cu or > ></td>
IS 2 240 236 T3
Example 3
Biodegradable polymer degradation studies
Biodegradable polymers were degraded in duplicate samples and analyzed at seven time points: no exposure; 3 days; 7 days; 14 days; 28 days; 42 days; 56 days and 84 days. Approximately 0.5 g of biodegradable polymer was beaten in glass bottles containing 100 ml of 0.01 M phosphate buffered saline (PBS) with a pH of 7.4 at 37 ° C in an environmental mixer. The buffer was changed at 72 hour intervals. At each time point, samples were isolated and vacuum dried. Each sample was analyzed twice for GPC (LS), GPC (CC) and VI as described in Examples 2. The two experiments were averaged to construct degradation profiles. The results of the degradation studies are summarized in Diagrams 1-3.
Diagram 1
Degradation Study 1
<img file="ES2240236T3_D0001.tif" />
- · - Linear (A107-35)
Linear (A107-41)
- «- Tri-branched (A107-43) - · —T etrabranched (A107-55)
Days
Diagram 2
Degradation Study 2
<img file="ES2240236T3_D0002.tif" />
- • —Linear i (AKJ7-3S) I
- «- Linear (AÍO7-41) -« - Tribranched I (A107-O) j - * - T etrabranched (AfO7-55) I
IS 2 240 236 T3
Diagram 3
Degradation Study 3
<img file="ES2240236T3_D0003.tif" />
- • —Linear (AWM5)
- • -Linear (A1OT-41)
- • -TiOTwnWcado (A10M3)
- • -Tetrabranched (A1O7-fig) |
Example 4
Controlled release studies
The biodegradable polymer of the present invention dissolved in N-methylpyrrolidone was filled into a 1 ml syringe. Doxycycline hyclate was loaded into another 1 ml syringe to give a drug loading of 8.5 percent doxycycline. The syringes were attached to each other and mixed for 50 cycles. The syringe was then placed on a balance and tared. The composition containing doxycycline was then added dropwise to 5 ml of phosphate buffer solution at a pH of 7.40 and a temperature of 37 ° C. The syringe was then placed back on the scale and the weight of the implant was recorded. This was repeated for each formulation four more times to give an n of five at each time point. The samples were then put in an environmental mixer at 37 ° C with a speed of 150 rpm. At various time points, the phosphate buffer solution was decanted and the polymer implant was left in the vial. Fresh 5 ml of phosphate buffer solution was added to the precipitated polymer and put back into the blender. The decanted phosphate buffer solution was then analyzed by UV visibility for doxycycline content. Based on the weight of the implant, a theoretical amount of doxycycline was calculated. Drug release was then based on this theoretical amount. The release data is represented in Diagram 4.
(Diagram goes to next page)
IS 2 240 236 T3
Diagram 4
Controlled Release Study Cumulative% Doxycycline Released
<img file="ES2240236T3_D0004.tif" />
—Linear I (A1O7-35) I —Linear 'tMOT-U] ¡- * - Tri-branched ¡(A1OT-43) I - * - T etrabranched (A1O7-55) |
Contents9
4 sheets
Sheet 1 Sheet 2 Sheet 3 Sheet 4
18 members in 10 offices
Priority claims2
| Document | Office | Kind | Date |
|---|---|---|---|
| 19990442203 | United States of America | – | |
| 44220399 | United States of America | A |
Members18
| Document | Office | Kind | |
|---|---|---|---|
| CA2394672A1 | Canada | A1 | |
| WO0135929A2 | World Intellectual Property Organization (WIPO) | A2 | |
| AU3439401A | Australia | A | |
| WO0135929A3 | World Intellectual Property Organization (WIPO) | A3 | |
| US2002090398A1 | United States of America | A1 | |
| US6461631B1 | United States of America | B1 | |
| US6528080B2 | United States of America | B2 | |
| JP2003514006A | Japan | A | |
| EP1404294A2 | European Patent Office (EPO) | A2 | |
| EP1404294B1 | European Patent Office (EPO) | B1 | |
| AT288258T | Austria | T | |
| ATE288258T1 | Austria | T1 | |
| DE60017956D1 | Germany | D1 | |
| DK1404294T3 | Denmark | T3 | |
| AU782265B2 | Australia | B2 | |
| ES2240236T3This record | Spain | T3 | |
| DE60017956T2 | Germany | T2 | |
| CA2394672C | Canada | C |
Numbers
- Publication
- 2240236
- Application
- 991743
Titles2
- Spanish
- COMPOSICION DE POLIMERO BIODEGRADABLE.
- English
- COMPOSITION OF BIODEGRADABLE POLYMER.
Classification
- CPC, 2
- A61K9/0024
- A61K47/34
- IPC, 15
- A61K9 10
- A61K9 00
- A61K9 16
- A61K9 50
- A61K45 00
- A61K47 08
- A61K47 10
- A61K47 12
- A61K47 14
- A61K47 16
- A61K47 20
- A61K47 22
- A61K47 30
- A61L17 00
- A61L27 00