TWI396562B - Method for regulating release of drug, drug delivery composition, and medical device - Google Patents

Description

Drug release regulation method, drug delivery composition and medical device

The present invention relates to a drug delivery composition; particularly a drug delivery composition comprising: a polymer, one or more drugs dispersed in the polymer and a bioactive polyelectrolyte complex, wherein the bioactive polyelectrolyte complex The substance will regulate the release of the drug from the polymer. The bioactive polyelectrolyte complex comprises a polyelectrolyte and an oppositely charged component, wherein the polyelectrolyte and/or the oppositely charged component are biologically active.

The ability to control the delivery of therapeutic or prophylactic drugs to specific sites in the body has become a goal in the field of drug delivery, as there are controlled drug doses in the body that provide optimal disease treatment or prevention, so different types The mode of drug delivery has evolved to deliver drugs to specific locations in the body or outside.

For example, in a matrix drug delivery system, drug molecules will dissolve or disperse in the polymer matrix. Drug molecules are released into the environment by diffusion of the polymer matrix to the surface of the substrate. The release rate of the drug is usually determined by the polymer used in the drug delivery system. For non-biodegradable and biodegradable polymers, the release rate is usually proportional to the diffusion coefficient of the drug molecule dissolved in the polymer. For biodegradable polymers, the release rate of the drug also depends on the degradation rate of the polymer. In addition, in order to further control the release of the drug, various additives such as salts, metal cations and lipids, etc., are contained within the polymer matrix.

Although the drug delivery system will properly release the drug, when the drug delivery system continues to contact tissue or biological fluid for extended periods of time, complications associated with stability and compatibility may result. For example, in the case of contact with blood or tissue, a drug delivery system containing a synthetic polymer may cause a severe clotting reaction activation, a bodily fluid and an inflammatory response that is detrimental to the cell fluid. These adverse reactions caused by blood/tissue-substance interactions can seriously affect the safety and efficacy of implanted medical devices and may render the implanted devices ineffective.

Thus, there is a continuing need for polymer matrices that are capable of releasing a wide range of therapeutic agents and having the desired blood and/or tissue compatibility.

Briefly, various embodiments are generally directed to drug delivery compositions that modulate drug release. In one embodiment, the drug delivery composition comprises: a polymer; one or more drugs dispersed in the polymer and a bioactive polyelectrolyte complex, wherein the bioactive polyelectrolyte complex modulates from the polymerization Drug release. The bioactive polyelectrolyte complex comprises a polyelectrolyte and an oppositely charged component, wherein the polyelectrolyte and/or the oppositely charged component are biologically active.

In addition to a drug delivery composition, various embodiments of a medical device are disclosed herein. According to one embodiment, the medical device contains one or more surfaces, at least one of which contains a biocompatible drug delivery composition. The drug delivery composition comprises: a polymer; more than one drug dispersed within the polymer and a bioactive polyelectrolyte complex, wherein the bioactive polyelectrolyte complex modulates drug release from the polymer. The bioactive polyelectrolyte complex comprises a polyelectrolyte and an oppositely charged component, wherein the polyelectrolyte and/or the oppositely charged component are biologically active.

Additionally, various methods of modulating release of one or more drugs are also disclosed herein. According to one method, there is provided a drug delivery system comprising one or more drugs dispersed in a polymer matrix and a bioactive polyelectrolyte complex. Wherein the bioactive polyelectrolyte complex contains a charged bioactive component and an oppositely charged component. The drug release rate from the drug delivery system can be adjusted by adjusting the concentration of the bioactive polyelectrolyte complex. Additionally, the bioactive polyelectrolyte complex can be eluted from the drug delivery system to provide additional therapeutic or prophylactic effects.

Other features and advantages will be further clarified by the following detailed description of the various embodiments of the embodiments.

1 is a graphical representation of the release rate of a water-insoluble drug in an embodiment of a drug delivery composition containing a biologically active polyelectrolyte complex (BPEC), and a control sample in the absence of a bioactive polyelectrolyte complex. Water-soluble drug release rate, the relationship between the two; Figure 2 is a graphical representation of drug release rates in different embodiments of a drug delivery composition containing different bioactive polyelectrolyte complexes (BPEC); 3 is a graphical depiction of a water-soluble drug release rate in a drug delivery composition embodiment containing a bioactive polyelectrolyte complex (BPEC), and a water-soluble solution in a control sample containing no bioactive polyelectrolyte complex. Drug release rate, the relationship between the two; Figure 4 is a graphical representation of the release rate of a bioactive polyelectrolyte complex (BPEC) in a drug delivery composition embodiment; Figure 5 is illustrated The rate of release of water-insoluble drugs in two embodiments of a drug delivery composition containing different types of polymers is described.

The various embodiments disclosed herein are directed to drug delivery compositions for modulating the release of biological activators (also referred to herein as "drugs"). Typically the composition comprises a bioactivator and a polyelectrolyte complex dissolved or dispersed in a polymer matrix. The polyelectrolyte complex can control the drug release rate by adjusting the relative concentration of the polyelectrolyte complex and modulate the initial burst point of the bioactivator and subsequent sustained release. In addition, the polyelectrolyte complex is biologically active to provide the desired blood and/or tissue compatibility. The bioactive polyelectrolyte complex can also be released via the polymer matrix, additionally providing a prophylactic or therapeutic effect that is unaffected by the bioactivator and, in addition, altering the physical properties of the polymer matrix. For example, the presence of a polyelectrolyte complex can make the polymer more elastic and is therefore suitable for applications requiring bending and expansion.

Generally, a drug delivery composition suitable for a bioactive agent comprises at least one polymer, a bioactive polyelectrolyte complex (BPEC), and a therapeutic agent, wherein the therapeutic agent is soluble or dispersible in the polymer and polyelectrolyte complex Within the mixture. According to one embodiment, a bioactive polyelectrolyte complex suitable for regulating drug release is formed from a positively and negatively charged polyelectrolyte. A polyelectrolyte is defined as a compound with more than two charged groups. The bioactive polyelectrolyte complex contains a polyelectrolyte and an oppositely charged molecule. In these various embodiments, if a polyelectrolyte is combined with an oppositely charged molecule, a complex that can be complexed with the polymer is formed.

Examples of non-limiting polyelectrolytes for use with drug delivery systems include double-stranded and single-stranded DNA sodium salts; such as dextran sulfate, chondroitin, chondroitin sulfate, chondroitin sulfate, heparin sulfate, Glucosamine polymeric sugars such as keratan sulfate, glacial sugar, heparin, heparin, etc.; negative polysaccharide; corn syrup; polyacrylic acid; polystyrene besylate; polyamine such as poly-L-amino acid Acid; poly L-proline; polyglutamic acid; poly-L-histidine; oligopeptide; insulin; monoclonal antibody; protamine sulfate; polyhexamethylene biguanide hydrochloride; chitin; Polydimethyldiallyl ammonium chloride; poly(N-methyl-4-vinyl-pyridine salt); polymer (viologen-6,3); dimethylaminoethyl methacrylate A quaternary polymer or copolymer; other polymers or copolymers containing a charged group, but are not limited thereto.

Examples of non-limiting small molecules that are oppositely charged and can bind to a bioactive polyelectrolyte complex include: vitamin A acid; compounds containing amino or amine (eg, primary, secondary, tertiary, and tertiary amines) functional groups, Such as amitidine, penicillin, amoxicillin, tyramine, brominated anti-heparin, tris(dodecyl)ammonium, trimethyltetradecylamine chloride, n-hexane xylene methyl chloride Ammonium, tri-dodecyl ammonium chloride; other cationic, anionic and zwitterionic interfacial activators, but not limited to those described above.

As mentioned previously, the polyelectrolyte complex may also have at least one biologically active ingredient that is not associated with the drug set by the drug delivery system. Thus, the polyelectrolyte and/or complexing agent can be biologically active. For example, heparin, heparin and acesulfate heparin have been confirmed to be anticoagulant substances, and chondroitin sulfate accelerates the interaction between heparin cofactor and thrombin. In another embodiment, the use of vitamin A acid can proliferate and differentiate epithelial tissue and inhibit malignancy.

The following are examples of specific but non-limiting polyelectrolyte complexes used in drug delivery compositions: vitamin A acid (vitamin A acid) complex; poly L-amino acid; insulin and polymethacrylic acid; insulin and sugar Aldehydic acid, as well as heparin and dimethylalkylphenyl ammonium chloride.

As previously mentioned, the bioactivator release rate from the composition is controllable and can be adjusted by varying the relative concentration of the polyelectrolyte complex. The controlled release of the bioactivator as defined herein, that is, the release of the bioactivator from the polymer matrix containing the bioactive polyelectrolyte complex. Compared to a polymer matrix that does not contain a polyelectrolyte complex, the presence of a polyelectrolyte complex in the polymer matrix alters one or more drug delivery properties, such as initial drug release, sustained drug release, drug release. Total and/or release period range.

Depending on the physical properties of the bioactivating agent (eg, solubility), the bioactive polyelectrolyte complex may have different effects on drug release rates. For example, in a bioactive polyelectrolyte complex, the release rate of a water-insoluble drug may increase. Conversely, in the presence of a bioactive polyelectrolyte complex, the release rate of the water-soluble drug may be reduced. Those skilled in the art will recognize that the appropriate concentration of the bioactive polyelectrolyte complex, that is, the release of the bioactive agent from the polymer matrix and the improvement of biocompatibility, will depend on the polymer, polymerization. The physical properties and chemical properties of the electrolyte complex and the biological activator. In one embodiment, the appropriate amount of bioactive polyelectrolyte complex falls within the range of from about 0.1% to about 90% by weight. However, those skilled in the art will recognize that any range or concentration of bioactive polyelectrolyte complexes may be used in a drug delivery system.

In addition to improving biocompatibility and regulating drug release, bioactive polyelectrolyte complexes can also modify the physical properties of the polymer matrix. For example, if a bioactive polyelectrolyte complex is incorporated into a polymer matrix, the glass transition temperature of the polymer matrix is lowered (see examples). Those familiar with the art will appreciate that changes in the physical properties of the polymer matrix may be useful for implant movement, buckling, vibration or stretching during implantation and/or after implantation. In addition, the bioactive polyelectrolyte component can also modify the hydrophilicity and/or hydrophobicity of the polymer matrix, rendering the polymer more compatible or less compatible (eg, swellable, permeable, or wettable) to aqueous or organic Solvent. Furthermore, the bioactive polyelectrolyte complex can alter the diffusivity of the polymer matrix, i.e., can increase or decrease the diffusion rate of the drug through the polymer matrix.

Another component of the drug delivery composition is a polymer comprising a polymer matrix. Generally, any polymer or mixture of polymers (eg, a mixture or copolymer), whether biodegradable or non-biodegradable, physically bondable (eg, miscible, soluble, or dispersible) to the polyelectrolyte complex and drug, Both are suitable for use in the drug delivery compositions disclosed herein. Suitable biodegradable polymers include: polylactic acid, polyglycolic acid, lactic acid glycolic acid copolymer, polyanhydride, polyorthoester, polyether ester, polycaprolactone, polyester decylamine, mixtures thereof and copolymers thereof , but not limited to the above. Non-biodegradable polymers include: polyolefin, polystyrene, polyvinyl acetate, acrylic polymers, polyethers, fluoropolymers, polyesters, polyamines, polyurethanes, anthrone polymerizations. , polydiene, cellulose and derivatives, mixtures or copolymers thereof, but are not limited thereto. Other examples include crosslinkable water soluble polymers such as polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, gelatin and starch.

The following are examples of specific but non-limiting polymers used in drug delivery compositions. For example, a uniform polymer or copolymer of a poly(alkyl methacrylate) substrate can be used to form the polymer matrix. Other polymers that can be used to form the polymer matrix include polylactic acid, lactic acid glycolic acid copolymers, polyalkyl methacrylic acid, poly(ethylene vinyl acetate), and styrene diene copolymers.

Another component of the drug delivery composition is a biological activator or drug that is capable of controlled release via the composition. A biological activator as defined herein refers to an agent having therapeutic, prophylactic or diagnostic properties in vivo. Examples of suitable biological activators for treatment and/or prevention include: anti-inflammatory agents, anti-proliferative agents, agents for preventing malignant tumors, agents for inhibiting cell division, drugs for preventing migration, agents for affecting the production of extracellular matrices, and for promoting healing. And re-endothelializing agents, anticoagulant agents, anti-embolic agents, vascular cell growth promoting agents, vascular cell growth inhibitors, cholesterol lowering agents, vasodilators, anesthetics, lubricating or moisturizing agents, anti-glaucoma agents, anti-cataracts Medicament, anti-chicken agent, analgesic, anti-asthmatic, antibiotic, antidepressant, antidiabetic; antifungal, antihypertensive, anticancer, anti-anxiety, immunosuppressive, anti-migraine Anti-airlocking agent; antipsychotic agent; anti-manic agent; arthritis agent, anti-gout agent; anticoagulant, thrombolytic agent, fibrinolytic agent; platelet agent; anti-muscle agent; anti-Parkinson Agents; antihistamines; antiviral agents, antimicrobial agents, sedatives Agent, anti-blood agent, bronchodilator, steroid compound, hypoglycemic agent, hypolipidemic agent, protein, nucleic acid and vitamin; diagnostic agent, including developer such as radioisotope and radiopaque agent, but not Limited to the above.

The following are specific but non-limiting examples of drugs used in drug delivery compositions, including: ibuprofen, salicylic acid, ticlopidine anti-blood, clopidogrel antiplatelet, prasugrel anti-platelet aggregator, glycoprotein II bllla inhibition Agent, statin lowering cholesterol, heparin, hirudin, urokinase, thrombolytic enzyme, tissue plasminogen activator, nitric oxide, angiotensin transition inhibitor, dexamethasone, sirolimus, everolimus hyperplasia Inhibitor, zatarolimus, pimecrolimus, tacrolimus, biolimus, paclitaxel, estradiol, tranilast, tripidal, angiopeptin, brimonidine, timiolol, carbonic anhydrase inhibitors, analogs thereof and derivatives thereof, but are not limited thereto.

Those skilled in the art will recognize that an effective amount of bioactivator is included within the polymer matrix of the drug delivery composition. The effective amount of a biological activator is defined as the amount of therapeutic or prophylactic effect, and may be determined by the person familiar with the technique, including factors such as the patient's weight, age, physiological state, therapeutic or prophylactic or diagnostic purpose, The type of agent used, the type of polymer used, and the desired release rate (e.g., initial burst point and sustained release rate), but are not limited to the above factors. A suitable amount of bioactivator will fall between about 0.01% and 70% by weight. However, those skilled in the art will recognize that it is possible to use biological activators of any range or concentration not specifically described in the drug delivery system.

In addition to drug delivery compositions, the various embodiments disclosed herein will be directed to medical devices capable of controlling the delivery of biological activators. According to one embodiment, the drug delivery composition is contained within a medical device, possibly as a film or portion of the device, or it may be a coating of one or more surfaces of the device. Typically, at least a portion of the medical device that can be inserted or implantable will contain the drug delivery composition. In another embodiment, the drug delivery composition itself can be placed within a medical device or portion thereof.

Those skilled in the art will recognize that medical devices that can be used or provided with drug delivery compositions include contact lenses; intraocular lenses; oral and maxillofacial implants; bone cement, stents, stent grafts; Intravascular or intervascular balloon, shunt, anastomotic device; heart valve, catheter, lead, balloon, filter; vascular graft; vascular plaster; or intraluminal underlaying system, but not limited to the above.

Various methods of forming a drug delivery composition are also disclosed herein. The drug delivery composition is typically formed via a solvent evaporation process: a polymer solution containing the bioactive polyelectrolyte complex and at least one bioactivating agent is cast into a mold or applied to one or more surfaces of the device. The solvent is evaporated to leave a drug delivery composition comprising a polymer matrix, a bioactive polyelectrolyte complex and at least one bioactivating agent. Those skilled in the art will appreciate that the required amount of bioactivator, bioactive polyelectrolyte complex, and polymer can vary depending upon the desired degree of drug release and drug release interval.

According to one method, the drug delivery composition can be disposed within a medical device. The method is to dissolve the polymer in a solvent system to form a polymer solution; the bioactive polyelectrolyte complex is dissolved or dispersed in the polymer solution. Next, the bioactivating agent is dissolved or dispersed in the polymer solution. Further, when the bioactive polyelectrolyte complex is added to the polymer solution, the bio activator can be simultaneously dissolved or dispersed in the polymer solution. A polymer solution containing the bioactive polyelectrolyte complex and the bioactivator is cast into a mold. The polymer solution is then allowed to set to form a polymer matrix comprising a bioactive polyelectrolyte complex and a bioactivator dispersed.

According to another method, a suitable polymer can be dissolved in a solvent to form a polymer solution: the bioactive polyelectrolyte is dissolved or dispersed in the polymer solution. Those skilled in the art will recognize that by dissolving the polymer and the polyelectrolyte complex simultaneously in a mutual solvent, a suitable method for dissolving the polyelectrolyte complex in the polymer solution can be obtained, or polymerization can be achieved. The electrolyte complex is added to the polymer solution, and then the polyelectrolyte complex is dispersed in the polymer solution by agitation or mixing. Whether it is a dissolution or dispersion method, a solid or liquid polyelectrolyte complex may be added before, during or after the preparation of the polymer solution, and the polyelectrolyte complex may be dissolved or dispersed in the second solvent, and then The solution is added to the polymer solution. Those skilled in the art will recognize that the second solvent is suitable if it is miscible with the polymer solution.

According to one method, at least one bioactivating agent can be added to the polymer solution separately from the bioactive polyelectrolyte complex. One method is to add the biological activator directly to the polymer solution containing the bioactive polyelectrolyte complex, and the other method is to dissolve or disperse the bio activator in a solvent miscible with the polymer solution, and then The solution is mixed into the polymer solution.

Those skilled in the art will recognize that the drug contained in the drug delivery composition can be provided to a human or other animal through a graft or insert agent as a medical device. The medical device can be made from a drug delivery composition. The drug delivery composition can be considered as a film or coating on the device, wherein the device is suitable for subcutaneous, intramuscular, intraperitoneal, intradermal, intravenous, intraarterial, intraspinal or intranasal administration. For example, the drug delivery composition is infiltrated or coated onto a device such as a blood vessel of a stent, and in addition, the drug delivery composition can be administered to a patient. The drug delivery composition can be included in a cream, hydrogel, plaster, and the like.

In use, the implant or medical device disclosed herein, containing the drug delivery composition, can be delivered to the target location by any known or mature step in the art, such as by a catheter containing the drug delivery composition. The stent is delivered into the vascular system. Once implanted, the drug delivery composition is exposed to both physical stress (such as flowing blood) and chemical agents (such as various enzymes and proteins in the blood). Depending on the relative concentrations of the components of the drug delivery composition, the bioactivating agent and the bioactive polyelectrolyte complex can be released from the medical device in accordance with the desired drug elution profile as outlined in the instructions herein.

The following examples illustrate various embodiments disclosed herein. These examples are for illustrative purposes only and are not intended to be limiting.

Example 1

The bioactive polyelectrolyte complex (BPEC) used in this example is a complex formed by sulfate chondroitin and chloroalkylxylene methylammonium chloride. Paclitaxel is a water-insoluble drug that can be used as a model compound for biological activators. An appropriate amount of the non-biodegradable polybutyl methacrylate, the bioactive polyelectrolyte complex, and paclitaxel are dissolved in a solvent system of toluene and an alcohol to produce a bioactive polyelectrolyte complex having a content of 15%. The control solution was prepared with polybutyl methacrylate and paclitaxel, but it did not include the bioactive polyelectrolyte complex.

The various solutions described above were sprayed onto a stainless steel wire. The amount of solution sprayed on each wire is controlled so that each wire contains approximately the same amount as the drug delivery matrix. The coated wire is then dried until the weight remains fixed. After the drying process is completed, a film is placed on the stainless steel wire.

In order to confirm the drug release rate, each coated stainless steel wire was placed in a salt solution containing 1% polyoxyethylene hexahexyl oleate (Tween-80) at 37 ° C, and passed through a type. Three samples were tested. A portion of the culture solution was taken at different time points, the amount of drug released was analyzed, and the amount of the removed solution was replaced with a new solution. The amount of paclitaxel released into the culture solution at each time point was measured using a high pressure liquid chromatography (the separation column type was Supelco supelcosil LCF, and a mixture of cyanomethane and water was used as the mobile phase).

Figure 1 shows the cumulative amount of paclitaxel released from a drug delivery system with a bioactive polyelectrolyte complex content of 0% to 15%. As shown in Figure 1, the presence of the bioactive polyelectrolyte complex resulted in an increase in initial drug release, sustained drug release, and total drug release compared to a control sample containing no bioactive polyelectrolyte complex.

Example 2

The sample preparation and analysis techniques were identical to those mentioned in Example 1, except that heparin was substituted for sulfate chondroitin. Appropriate amount of non-biodegradable polybutyl methacrylate, bioactive polyelectrolyte complex and paclitaxel are dissolved in a solvent system of toluene and alcohol to form a bioactive polyelectrolyte complex with a content of 15% and 20% drug delivery system with a drug content maintained at 7%. The control solution was prepared with polybutyl methacrylate and paclitaxel, but it did not include the bioactive polyelectrolyte complex.

Each of the above solutions was sprayed onto a stainless steel wire. The coated wire is then dried until the weight remains fixed. After the drying process is completed, a film is placed on the stainless steel wire. The amount of solution sprayed on each wire is controlled so that each wire contains an amount equivalent to the drug delivery matrix shown below:

Figure 2 shows the release rate of the drug released from the combination containing 0%, 15% and 20%. As shown in Figure 2, the presence of the bioactive polyelectrolyte complex resulted in an increase in initial drug release, sustained drug release, and total drug release compared to a control sample containing no bioactive polyelectrolyte complex. In addition, as shown in Figure 2, the bioactive polyelectrolyte complex content (20%) increases drug release characteristics, including initial drug release, compared to a drug delivery system with a bioactive polyelectrolyte complex content of 15%. Degree, duration of drug release, and total drug release.

Example 3

The solution preparation method was the same as that mentioned in Example 2, except that the eosin dye was used as a model compound to represent a water-soluble drug. The polymer matrix solution containing the complex with the bioactive polyelectrolyte-free composite was coated on an aluminum disk using the same polymer as described in Example 2 and similar techniques.

To confirm the red dye release rate, each coated disk was placed in a salt solution containing 1% polyoxyethylene hexahexitol oleate (Tween-80) for cultivation. The amount of eosin dye released into the culture solution was measured by ultraviolet/visible spectrometer at different time points; a part of the culture solution medium was taken out at each time point to analyze the eosin dye content, and the removed amount was replaced by a new solution. Figure 3 shows the amount of eosin dye released from the polymer matrix containing and not containing BPEC.

Figure 3 illustrates the difference between a control sample and a sample containing BPEC. In the absence of a bioactive polyelectrolyte complex, all eosin dyes are immediately released from the polymer matrix, i.e., when a polymer-only drug delivery system is employed, there is no adjustment of drug release rate. In a drug delivery system containing 26% bioactive polyelectrolyte complex, the degree of initial eosin dye release, the duration of sustained eosin dye release, and the total amount of eosin release are due to the presence of bioactive polyelectrolyte complexes. There is a substantial reduction and adjustment. In addition, bioactive polyelectrolyte complexes have different effects on the release rate of water-soluble drugs and water-insoluble drugs. Comparing the release rates shown in Figures 2 and 3, it can be seen that when a bioactive polyelectrolyte complex is present in the polymer matrix, the release rate of the water-soluble drug is lowered and the release rate of the water-insoluble drug is increased.

Example 4

The sample preparation method in this example was the same as that disclosed in Example 1, except that heparin was substituted for sulfate chondroitin. To demonstrate that bioactive polyelectrolyte complexes are also released under controlled release from drug delivery systems containing drugs, polymers and bioactive polyelectrolyte complexes, each coated stainless steel wire is placed at 37 ° C with 1% The polyoxyethylene hexahexanol oleate (Tween-80) is cultured in a saline solution. A portion of the solution was withdrawn at various time points and the amount of bioactive polyelectrolyte complex released into the solution was analyzed. The amount of release of the bioactive polyelectrolyte complex can be confirmed by measuring the biological activity of heparin with the chromogen extract S2237.

Figure 4 shows the release rate of the bioactive polyelectrolyte complex. In addition, Figure 4 also illustrates that the presence of the bioactive polyelectrolyte complex not only modulates the release rate of the drug (as shown in Examples 1 to 3), but also controls the release of the bioactive polyelectrolyte complex over a period of time so that The therapeutic effect is exerted under the influence of drug release. As shown in Figure 4, about 40% of the effective bioactive polyelectrolyte complex will be released after 200 days.

Example 5

To demonstrate the compatibility of the biodegradable polymer with the drug delivery composition and the effect of the different polymers on the drug release rate, a DL water-reduced lactic acid glycolic acid copolymer or poly-L water-reduced lactic acid is used as the polymer in the combination. The sample preparation technique and the drug release rate were determined in the same manner as those mentioned in Examples 1 and 2 except that DL water-reduced lactic acid glycol copolymer or poly-L water-reduced lactic acid was used as the polymer. As shown in Fig. 5, the drug delivery composition containing the DL water-reduced lactic acid glycolic acid copolymer increases the release rate of the drug compared to the one containing the poly-L water-reducing lactic acid.

Example 6

In order to illustrate the effect of the bioactive polyelectrolyte complex on the physical properties of the polymer matrix, it is necessary to compare the glass transition temperature of polybutyl methacrylate with the glass transition temperature of polybutyl methacrylate and a composite, wherein the composite is composed of A 2:1 ratio of heparin to alkyl dimethylbenzylammonium chloride is formed. The sample was maintained at -30 ° C for 5 minutes and then heated to 75 ° C at a rate of 20 ° C / minute. The sample was then held at 75 ° C for 5 minutes and then quenched to -30 ° C. After the sample was maintained at -30 ° C for 5 minutes, it was heated to 70 ° C at a rate of 20 ° C / minute under a nitrogen atmosphere. Sample analysis was performed in accordance with DSC Thermal Image Analysis of ISO 113572-2.

Samples containing bioactive polyelectrolyte complexes showed a significant decrease in glass transition temperature compared to samples without complexes. In other words, a sample containing only polybutyl methacrylate has a glass transition temperature (indicator of polymer elasticity) of about 21 ° C, and a sample containing a mixture of polybutyl methacrylate and a bioactive polyelectrolyte complex, The glass transition temperature is about 11. A decrease in the C glass transition temperature indicates that the polymer stiffness is reduced by the presence of the bioactive polyelectrolyte complex. In addition, a single glass transition temperature would also be associated with the compatibility of bioactive polyelectrolyte complexes with polybutyl methacrylate (instead, incompatible compositions typically produce two glass transition temperatures).

The various embodiments described above are for illustrative purposes only and are not to be construed as limiting the scope of the patent application. For those skilled in the art, they can easily follow the example embodiments and applications described herein and without departing from the true spirit and scope of the claimed invention contained in the scope of the following patent application. Confirm various modifications and changes.

Claims (13)

An adjustment method for one or more drug release, comprising the steps of: providing a drug delivery system comprising one or more drugs dispersed in a polymer matrix and a bioactive polyelectrolyte complex, wherein The bioactive polyelectrolyte complex comprises a polyelectrolyte and an oppositely charged component, wherein the polyelectrolyte is a glucosamine polymerized sugar, and the oppositely charged component is a quaternary ammonium compound; by adjusting the bioactive polyelectrolyte complex The concentration, the drug release rate of the drug delivery system is adjusted; and the bioactive polyelectrolyte complex of the drug delivery system is flushed. The method for regulating release of one or more drugs according to item 1 of the patent application scope, wherein the release rate adjustment step further comprises adjusting an initial release rate of the drug or a sustained release rate of the drug. A method of regulating release of one or more drugs according to item 1 of the scope of the patent application, wherein the concentration of the drug falls within a range of from about 0.1% by weight to about 70% by weight. The method of regulating release of one or more drugs according to item 1 of the scope of the patent application, wherein the concentration of the polyelectrolyte complex falls within a range of from about 0.1% by weight to about 90% by weight. The method for regulating release of one or more drugs according to claim 1, wherein the polymer matrix comprises: polylactic acid, polyglycolic acid, lactic acid glycolic acid copolymer, polyanhydride, polyorthoester, polyether ester, Polycaprolactone, polyester decylamine, polyolefin, polystyrene, polyvinyl acetate, Acrylic polymers, polyethers, fluoropolymers, polyesters, polyamines, polyurethanes, anthrone polymers, polydienes, celluloses and their derivatives, crosslinkable water-soluble polymers, Mixture or copolymer thereof. The method for regulating release of one or more drugs according to item 1 of the scope of the patent application, wherein the bioactive polyelectrolyte complex is formed by a ratio of 2:1 heparin and alkyldimethylbenzylammonium chloride, Thereby reducing the glass transition temperature of the polymer matrix. A biocompatible drug delivery composition comprising: a polymer matrix; one or more drugs dispersed in the polymer matrix; and a bioactive polyelectrolyte complex dispersed in the polymer matrix, To regulate drug release from the polymer, wherein the bioactive polyelectrolyte complex comprises a polyelectrolyte having an opposite charge composition, wherein the polyelectrolyte is a glucosamine polymerized sugar, and the oppositely charged component is a quaternary ammonium compound And the polyelectrolyte and/or the oppositely charged composition is biologically active, wherein the polyelectrolyte complex concentration falls within a range of from about 0.1% by weight to about 90% by weight, the concentration of the drug falling From about 0.1% by weight to about 70% by weight, and the total amount of all components of the drug delivery composition does not exceed 100%. The biocompatible drug delivery composition according to claim 7, wherein the polymer matrix comprises: polylactic acid, polyglycolic acid, lactic acid glycolic acid copolymer, polyanhydride, polyorthoester, polyether ester, Polycaprolactone, polyester decylamine, polyolefin, polystyrene, polyvinyl acetate, C Alkene polymer, polyether, fluoropolymer, polyester, polyamine, polyurethane, fluorenone polymer, polydiene, cellulose and its derivatives, crosslinkable water-soluble polymer , a mixture or a copolymer thereof. The biocompatible drug delivery composition according to item 7 of the patent application is administered by subcutaneous, intramuscular, intraperitoneal, intradermal, intravenous, intraarterial, intraspinal or intranasal administration. The biocompatible drug delivery composition according to claim 7 of the patent application, which is administered through a medical device having the drug delivery composition implanted therein. The biocompatible drug delivery composition according to claim 7 of the patent application, which is administered through a medical device having a coating or film comprising the drug delivery composition. An implantable medical device comprising: one or more surfaces, wherein at least one surface is coated with a biocompatible drug delivery composition as described in claim 7 or 8. The implantable medical device according to claim 12, wherein the drug is an anti-inflammatory agent, an anti-proliferative agent, an agent for preventing malignant tumors, a drug for inhibiting cell division, a drug for preventing migration, and a device for influencing an extracellular matrix. Chemical agent, promoting healing and re-endothelializing agent, anticoagulant agent, anti-embolic agent, vascular cell growth promoting agent, cholesterol lowering agent, vascular cell growth inhibitory agent, vasodilator, anesthetic agent, lubricating or moisturizing agent, anti-drug Glaucoma agents, anti-cataract agents, anti-chicken agents, analgesics, anti-asthmatics, antibiotics, antidepressants, Antidiabetic agent; antifungal agent, antihypertensive agent, anticancer agent, anti-anxiety agent, immunosuppressive agent, anti-migraine agent, anti-airlocking agent; antipsychotic agent; anti-manic agent; arthritis agent, anti-arthritis Gout agent; anticoagulant, thrombolytic agent, fibrinolytic agent; platelet agent; anti-caries; anti-Parkinson's agent; antihistamine; antiviral, anti-microbial, sedative, anti-blood Flowing agents, bronchodilators, steroid compounds, hypoglycemic agents, hypolipidemic agents, proteins, nucleic acids and vitamins.