JPH11508224A - Multiple drug delivery system - Google Patents

Abstract

(57) SUMMARY A bioerodible implant for parenteral release of at least two bioactive drugs is disclosed. The implant comprises a non-polymeric core comprising a core drug. The core is covered by a polymer coating on a specific surface. This coating has the drug incorporated in the matrix. This coating limits the effective core surface area for core erosion to produce a constant zero order release kinetics over time. Also disclosed are methods and devices for use in forming bioerodible implants.

Description

DETAILED DESCRIPTION OF THE INVENTION                       Multiple drug delivery system   The present invention generally relates to drug delivery systems, and Bioerodible (bioerod) that can deliver multiple drugs when implanted under the skin ible) articles.                                 Background of the Invention   The clinical significance of certain biologically active substances has been elucidated, and various techniques for their synthesis have been elucidated. Since the development of these materials, many of these substances have had suitable ways of delivering controlled amounts. It proved useful only when provided.   For example, substances such as peptides can be broken down in the digestive tract when taken orally Must be administered parenterally. In some clinical situations, the biological Therapies involving active substances involve long-term injections of many drugs at regular intervals. It often needs to be done. Many compounds have low doses when given continuously It was also observed to be clinically effective compared to high dose intermittent dosing. This effect Has been found in a wide variety of compounds. In addition, optimal efficacy for many drugs The range is narrow, beyond which the compound becomes toxic.   New indications of known compounds that have affected and approved the use of new drugs Considering such factors that affect Certain drug delivery systems have been pursued. For example, need a capillary Cumbersome and complex systems (eg, US Pat. No. 3,946,734 No. 4,449,981 (Drake). ke) and Brocklehurst, and 4,7 20,384 (see Di Lucio et al.), Or osmotic pressure Pumps (e.g., U.S. Pat. No. 4,203,441 (Theewow) es)), No. 4,203,442 (Mihcaels, And No. 4,180,073 (see Michaels) Have been attempted to deliver several drugs sequentially.   Delivery systems based on biodegradable macromolecules Efforts have been made to use it as a subcutaneous implant for controlled release Came. Current erodible polymer-based systems typically include: Compounded with drug by one of the following methods: (1) Drug in polymer matrix Matrices where substances are distributed evenly and drugs are released as macromolecules degrade in body fluids Aggressive systems (single-piece systems); and (2) a polymer matrix Drug release occurs as a result of diffusion of the drug through it, and the surface of the device is sustained A diffusion / erosion system in which release of the drug occurs as it erodes.   Non-polymer based devices have also been used as subcutaneous implants for drug delivery. Have been used. Initially, a pellet made by compressing a mixture of drug and excipient is tried Was done. However, such pellets easily absorb body fluids and disintegrate in a short time, Therefore, it exhibited undesirable and unpredictable dynamics.   Zero-order kinetics, ie, time lapse Aiming at a drug delivery system in which the release rate does not essentially change even if you pass Effort was made. These efforts include one to limit the area from which the drug is released. Various shapes that could coat more than one surface were included. Actually embedded Achieving Sustained Zero-Order Kinetics In Vivo With Drugs Is Little Successful Was.   There are other problems that need to be solved for implants. Of water solubility Some bioactive substances, such as high macromolecules, are used in humans and animals as subcutaneous implants. When used as, it exhibits volatile dissolution kinetics. This is because the release rate of the drug And the primary kinetics, ie, the flow of the drug, is proportional to the amount present in the delivery system It is unacceptable to show dynamic behavior. In addition, some macromolecules are erodible or Is known to expand and be trapped in diffusive systems. Some peptides are If present in body fluids at a sufficient concentration, they will aggregate and therefore release from the delivery system. Obstruction has also been observed   One factor affecting drug implant efficacy is the patient's normal inflammatory immune response. Yes, this reaction is more likely for monocytes, macrophages, and foam cells (lipophagocytes). And other components of the cellular immune system, collagen, and lines derived from vascular cells There is a tendency for the covering of the implant to be covered by a coating of the fibrous tissue. Film formation is important for drug release Is the limiting factor. In some cases, this is the largest factor that determines release kinetics. You.   When the zero order kinetics dominates over time and fibrous tissue is fully formed Will develop implants to control the release and absorption of drugs in fibrous coatings. Would be useful.                               Summary of the Invention   The present invention relates to a bioerodible implant that administers a drug at a constant rate over time. Provide a filling agent. This time-invariant release rate (zero-order kinetic release) includes the drug The core limits the area where the core can be eroded, and even if the erosion progresses, This is achieved by keeping the erodable area essentially constant. Biological invasion Maintaining a constant, edible area consists of a drug-containing core and a bioerodable polymer With a coating of adhesive or other chemical or physical Bond in both ways, and the coating covers only selected areas of the core. This is achieved by: Adhesion fuses the core to the immediate adjacent polymeric coating It is preferable to achieve this. Fusion heats core and adjacent coating Can be caused by   The coating is resistant to bioerosion so that the surface area of the erodable core remains constant. Those with lower resistance than the core can be selected. By doing so, Zero-order release rates are possible until the pit is completely eroded. Erodible core surface The resistance to erosion is higher than the core so that the product increases after a preselected time. Larger coatings can also be selected. This allows for zero-order emission at first, followed by Burst and time-varying releases are possible. In either case, the drug The coating and core should be removed so that the implant does not need to be removed when things are lost. Be bioerodible.   The present invention relates to a bioerodible implant that can administer multiple drugs when implanted in an animal. Also provide. In one aspect of the invention, the implant provides for the release of two drugs. The first drug is released from the core and the second drug surrounds the selected surface of the core Released from the polymer coating. Preferably, the coating is adhered to the core. Coating The material serves as a drug release source and a constant, erodible surface area of the core. It serves both as a means of limiting the product. In this way, the present invention Simultaneous release of second drug from coating with zero order release kinetics of at least one core drug Provides emission.   The implant of the present invention is made from various core materials and a range of thicknesses and types of coatings. Can be built. Therefore, the rate and amount of drug release from the core and the coating vary widely Flexible. For example, a coating covering a cylindrical core may require that the first part of the coating be completely Eroded, other parts can be altered to leave the core covered You. When the first part is eroded, the surface area of the erodible core temporarily increases, Therefore, the drug release rate is temporarily increased.   In certain preferred embodiments of the invention, the drug-containing core is "partially fused." "Core" or "total fusion" core. Such cores are non-diffusible and erosion-based. And zero-order release kinetics when coated on selected surfaces Especially suitable for doing.   In a partially fused core, the core contains the core drug and a non-polymeric carrier. With core drugs Treat a mixture of non-polymeric carriers so that only the carrier melts and the drug does not melt . The carrier is then re-formed to form a matrix that captures the unmelted drug. Let it crystallize. This partially fused core is preferably used during the manufacturing process of the partially fused core. To adhere to the coating. Partial fusion cores are particularly suitable for peptide delivery and are According to a preferred embodiment, the core drug is an HIV proteinase inhibitor.   In an overall fusion core, the core contains the drug and the carrier is only optional. No. To form this core, substantially all of the drug (and, if present, Is melted and recrystallized to form a matrix of drug (and carrier). This fully fused core is also preferably coated and adhered during the manufacturing process of the fully fused core. Let it.   Compare the polymer film for the preferred method of manufacturing the preferred embedding agent according to the present invention. This involves molding into a hollow coating of approximately constant thickness. Next, the boundary between the core and the coating Insert the core material into the coating recess under conditions that allow the core to adhere to the coating on the surface. It is. In one preferred method, the cylindrical chamber is centered on this chamber. Insert the polymeric material into the annular space between the cylindrical pins that are placed in position To form a coating. Next, conditions are set so that the polymer can form a coating. You. Pull out the pin while leaving the hollow coating inside the chamber, and place it in the cylindrical chamber. The core material can be added to the recess of the coating within.   In the case of a fused core, it can be melted after the core material is inserted into the coating. The coating is As it is (preferably the coating becomes sticky), the core material is Molded coating and core material under conditions of partial or complete melting Process the filled chamber. Next, to cause recrystallization of the core material Treating the coating and core under conditions sufficient to ensure that the inner surface of the coating is in contact Chemical interaction between the core material and the coating polymer at the interface between the core and the coating A molten core (by application or physical mixing) is produced.   The core melts (partially or completely melted) before being inserted into the cavity of the molded coating ) You can also. Conditions to cause partial or complete melting in core material give. Next, the molten material is dispensed into the recesses of the formed coating and allowed to cool. In this way, the core material recrystallizes and adheres to the polymer coating at the interface between the core and the coating. Will be.   Other methods are also provided, including co-extrusion of the coating and the core.                             Detailed description of the drawings   FIG. 1 shows the coating selected when the coating is eroded prior to complete erosion of the core. 2 shows the release kinetics of a core drug from the implant of the present invention.   FIG. 2 shows an exploded view of an apparatus for making the implant of the present invention.   FIG. 3 is a sectional view of the apparatus of FIG. 2 for producing the coating according to the invention in the operating mode. Show.                             Detailed description of the invention   The invention, in one aspect, provides for sustained zero order release of at least one drug. Drug implants. The term "zero order release" means that the drug release rate remains Is independent of the concentration of the drug used. This is constant over time Appears as a constant sustained release. Zero-order release means that the area subject to bioerosion of the drug is This is achieved by coating only those surfaces selected to be constant.   The importance of a relatively constant erodible surface area is important for most erodible implants. In emulsifiers, the fact that the surface area of the implant changes constantly over time Is done. This fact results in non-zero order release kinetics that exhibit unpredictable fluctuations.   For a cylinder (height (L)> diameter (D)), the total surface area is the side area and bottom area [Total surface area = 2 (πr^Two) + ΠDL]. Constant if the diameter is constant Time and total release rate control the overall length of the device and the number of eroded surfaces Can be controlled by Gluing the side of the cylindrical core to the coating Eroded surface area is cylindrical bottom (less than 50% of the total cylindrical surface area) Is limited to Importantly, the release kinetics from such coated A constant surface, not controlled by a constantly decreasing surface area Product 2 (πr^Two). Not only does the drug release rate significantly decrease And the release kinetics change to zero order. In addition, the first characteristic of uncoated core The period burst is also significantly reduced.   Thus, the present invention, in one aspect, has a core containing a first drug, The core is for an implant that has at least one surface adhered to the polymer coating. You. Preferably, the molded core is pellet or cylindrical. The core is A) containing at least one type of drug uniformly distributed on the body and core surface, The drug is called the “core drug”. The coating is secondarily evenly distributed within the polymer matrix Can be contained. The term "glue" or "glue" At the interface between the core and the coating, the components of the core and the coating are On-bonding or physical bonding (eg, by mixing at the interface between the core and the coating) Finger and that the coating is elastically bonded to the core). You.   Chemical and / or physical and / or core / coating interface at the core / coating interface The other bond inhibits erosion at this interface. If the core and coating are not bonded , Fluids such as bodily fluids peel off the coating from the core, causing erosion at the interface between the core and the coating. Tends to cause. This is due in part to the liquid being absorbed by the coating itself. You. In any case, the enhanced erosion at the interface between the core and the coating occurs between the coating and the core. Create voids and increase erodible surface area. In the present invention, the core is This problem was overcome by adhering the coating to the coating.   The delivery system of the present invention comprises:     1. Thickness of polymer coating     2. Polymer types     3. Core drug concentration     4. Choosing a core drug carrier     5. Core length     6. Core diameter, and     7. Core type By adjusting various factors, including, suitable for various drugs and clinical indications It can be modified to   For example, the coating can be more resistant to bioerosion than the core . In this case, substantially all of the core is eroded prior to erosion of the coating. This is constant The core surface area of the core contacts the erosion medium, and the zero order dynamics To be achieved from to the end. Alternatively, the coating is Resistance can be lower than that of the core. In this case, the coating will erode the core Before erosion, resulting in an increase in the surface area of the erodable core and therefore Release rate increases. This emission pattern is shown in FIG.   Referring to FIG. 1, the initial release of the core drug is time-invariant (ie, zero order). 1, which is shown between time 0 and time 1 in FIG. Once the coating is eroded If so, the erodable surface area will increase significantly. The effect is shown by time 1 in FIG. This leads to an increase in the dose as seen in 2. Here is the release of the drug in the coating over time Is not listed. Typically this involves an initial burst and a steady decrease Will be recognized.A. core   The core drug can be bound or otherwise incorporated into the core matrix in various ways. To distribute. The core can be formed using standard tablet manufacturing methods. Only Preferably, the core is partially or wholly fused. Such a fusion core It has release kinetics determined by surface erosion rather than diffusion. Diffusion based A is characterized by a kinetics of release that changes over time, Cores with a determined release kinetics are preferred. Partial fusion core and total fusion core Are described in co-pending application Ser. No. 07 / 163,328, entitled "Partial Fusion Peptide Lett "(filed March 2, 1988) and Application No. 07 / 475,200, "Shoe Flow Fusion Medical Implant" (filed February 5, 1990) And the disclosures of these applications are incorporated herein by reference. Briefly, For partially fused cores, heating the homogeneous mixture of carrier and drug Substantially all of the body melts, substantially all of the drug does not melt, and a partial melt forms. As achieved, a non-polymeric carrier having a lower melting point than the core drug is selected. Next, upon cooling the partial melt, the carrier recrystallized, entrapping the core drug Form a cured core matrix. Drugs (and And, optionally, the non-polymeric carrier) is melted and recrystallized to provide the drug (and its presence, if any). Body) to form an overall fusion matrix.   Non-polymeric carriers useful for the production of fully and partially fused cores are lipophilic. You. These are also bioerodible and, therefore, may be the case for many prior art devices. As such, they do not need to be surgically removed when the drugs are depleted. Like Alternatively, the non-polymeric carrier is metabolized and excreted with erosion of the core. Most preferred Alternatively, the non-polymeric carrier is one that occurs naturally in the human body.   The non-polymeric carrier according to the present invention is compared to a coated or sleeved macromolecular polymer carrier. And has a relatively low molecular weight. For example, acetic acid, one of the preferred non-polymeric carriers, The molecular weight of resterol is about 428 daltons, but is typical of coatings and is preferred. The molecular weight of the polymer carrier depends on the degree of polymerization.^Three-10⁶On the order of Dalton is there. The non-polymeric carrier according to the invention is also confined in the matrix of the recrystallized carrier. Typically smaller than the core drug used. Preferably, the non-polymeric carrier is also highly bonded. It is crystalline. The above properties contribute to the favorable erosion properties of the formed core.   The non-polymeric carrier may be cholesterol or, without limitation, cholesterol acetate Cholesterol such as cholesterol chloride and cholesterol palmitate Derivative. Other preferred non-polymeric carriers include sterols other than cholesterol. Steroids, steroid derivatives and analogs, and cholesterol and choles Other bioerosion with lipophilicity, crystallinity, size and melting point similar to terol derivatives Compounds. Other carriers that can be used instead include, for example, core Melted with the drug, recrystallized, and when implanted in the body, Mono-, di- or triglycerides with similar erosion and release kinetics (or Certain fatty acids or neutral fats, such as combinations of two or more such lipid molecules). You. The carrier is solid at body temperature (above about 40 ° C) and carries the core drug of choice. Its bioactivity without decomposing in a short time when in a suspension of molten carrier at the melting point of the body It must have a melting point that does not lose its properties.   The core drug is a naturally occurring or synthetically derived, low molecular weight bioactive Can be a substance. For example, aldosterone, androstan, androstene, a Drostendione, androsterone, cholecalciferol, corstan, Cholic acid, corticosterone, cortisol, cortisol acetate, cortisone, Cortisone acetate, deoxycorticosterone, digitoxygenin, ergocalci Ferrol, ergosterol, estradiol, 17-α, estradiol Le-17β, estriol, estrone, estrone, hydrocortisone, la Nosterol, lithocholic acid, mestranol, β-methasone, prednisone, Pregnane, Pregnenolone, Progesterone, Spironolactone, Testosterone Steroids such as ron, triamcinolone and derivatives thereof are included. Ma Also included are types of peptides known as neuropeptides and regulatory peptides. Specific examples include, but are not limited to, growth hormone-releasing hormone, gonadotropin Releasing Hormone, Its Agonist and Antagonist Analogue, and Somatostatin And its analogs, gonadotropins, such as luteinizing hormone and follicle-stimulating hormone Peptide-T, thyrocalcitonin, parathyroid hormone, glucagon, vasopressi Oxytocin, alpha and beta melanocyte stimulating hormone, e.g. Knee stimulators (CFS1 and 2), erythropoietin and lymphokines (inter Erythrocytes, leukocytes and immune cells, including leukins I and II). Stimulating peptide molecules, angiotensin I and II, bradykinin, kallidin, Renal cortical stimulating hormone, thyroid stimulating hormone, insulin, glucagon, and There are many analogs and congeners of the peptide. Peptide Where the term is a small protein, especially a molecule having less than about 100 amino acids It should be understood that it is intended to include   Almost all core drugs, which are peptides, have about 8 to 60 amino acids and about 1,00 Has a molecular weight of 0-7,500 daltons (but one unusually small peptide The core drug, peptide-T, has only three amino acids and is a preferred carrier, Has about the same molecular weight as sterols).   Other drugs include drugs such as scopolamine and nitroglycerin, And antiviral and antimicrobial agents, ribonucleic acids and nucleotides. According to the invention Thus, virtually any bioactive low molecular weight substance can be used.   Part of the core surface binds to the polymer coating and is therefore limited for core drug erosion Surface is available. Thus, a very low release rate can be obtained and the core Ideal candidates for drugs are drugs that are effective at small doses, i.e., A certain compound. In one embodiment, the core drug is 19-nor-testosterone induced. The conductor Norgestmet (Roussel Ph) armaceutical Inc. , Somerville, NJ) You. This progestin is micro-gated to 500 kg cows to eliminate estrus. It can be administered in a ram volume. The most potent compounds useful in the present invention are It is lipopoietin. This hormone is produced with very high specific activity. It has been used to treat anemia associated with renal failure and multiple myeloma. Ludw erythropoietin therapy for anemia associated with multiple myeloma (Erythr. opoietin Treatment of Anemia Associate ted with Multiple Myeloma) "New Engla nd J.J. Med. , 322: 1693, June 14, 1990. One particularly preferred embodiment of the present invention comprises a non-polymeric carrier and a bioactive core drug. A partially fused core comprising an HIV-1 proteinase inhibitor. HIV-1 Rotainase inhibitors cause acquired immunodeficiency syndrome (AIDS) in humans Immunodeficiency, which is an infectious agent Of Ils (HIV-1)polDi- and tri-peptide derivatives of gene products You. "Peptide-based, such as Roberts," which is hereby incorporated by reference. Rational Design of HIV Proteinase Inhibitors (Rational Design) no of Peptide-Based HIV Proteinase In hibitors) "Science, 248: 358 (1990). When. Powdered HIV proteinase inhibitors are lower than HIV proteinase inhibitors Mix with a non-polymeric carrier having a melting point, e.g., cholesterol acetate. Can be. Cholesterol acetate melts, proteinase inhibitor does not melt As such, the mixture can be heated. Next, allow the partial melt to cool, The resterol is recrystallized to form a core. In this way, HIV protection The inase is bound within the composite framework of the recrystallized carrier.   The HIV proteinase inhibitor / cholesterol acetate core provides a lipophilic and It is gradually eroded in vitro due to its poor crystallinity. HIV proteiner Because of its relatively large molecular size compared to cholesterol acetate, Leakage of HIV proteinase inhibitors from cholesterol acetate crystalline matrix Is unlikely, if not impossible. Therefore, HIV protection Release of the inase inhibitor is erosion, not diffusion.   In another preferred embodiment of the partially fused core, the core drug is a nucleotide derivative, Azidothymidine (zidovudine, formerly AZT, Burroughs-Welc) ome, Inc. ) And, for example, dideoxycytidine (ddC-Hoffman) n, LaRoche, Inc. ) And dideoxyadenosine (ddA-Bris) tol-Meyers Co. ) May be inhibitors of viral reverse transcription.   Another aspect of the invention is a total fusion comprising an active steroid drug and cholesterol. The core. In the overall fusion core, the core drug (drug and optionally a carrier) is melted and reconstituted. Crystallizes to form a crystalline matrix of the drug. To make such a core In a preferred embodiment, a thin layer or "skin" of the mixture of starting materials is electrically conductive. To a thin layer of Preferably, the surface to which the skin is applied is, for example, polytetrafur. Apply a non-stick material such as ethylene (Teflon). Melting of starting materials If a heat source well above the point is supplied to the conductive material, the mixture of starting materials will not exceed 10 seconds. Reaches a transparent molten state, beading like mercury, about 45 ° to the horizontal Good flow characteristics were exhibited when tilted at an angle. When tilted in this way, The molten material is induced to leave the heat source region as soon as the molten state is reached. this is, A characteristic problem of other methods of making fused pellets is that they are produced by overexposure to heat. Eliminates the risk of shear decomposition. In addition, since the method is performed in air, air No trapping occurs (see U.S. Pat. No. 4,748,024; Indications are incorporated herein by reference).B. Coating   The coating or coating around the core serves as a reservoir for the second drug and for the core available for erosion. It is designed to function as a surface area limiter. The coating is non-toxic, erodible Is a biopolymer compatible with the production method disclosed herein.   The drug is uniformly distributed in the polymer matrix and the polymer coating itself is eroded Can be combined with the drug as a single piece matrix erosion system released according to Particularly preferred are polymeric substances that can be used. Polymers suitable for coating are polymers Consequences of drug diffusion through matrix and release of drug due to coating erosion and A macromolecule that binds the drug as a diffusion / erosion system that results in drug release.   Materials suitable for use as coatings are well known and include polylactic acid, polyglycolic acid, Copolymer of polylactic acid and polyglycolic acid, polyanhydride and polycaprolact Including tons. Poly (lactide / glycolide) biodegradable suitable for use in the present invention Macromolecules from Kitchen11 and WiseMethods in Enzymol ogy , 112 (1985).   If poly (lactide / glycolide) is selected as the polymer coating material, Adapting the solubility / deformability parameters of the capsule to drug activity and drug mechanism of action is important.   It is preferred that erosion of the coating occurs only after all of the core has been eroded In particular, polycaprolactone is particularly preferred as a coating material.   Drugs suitable for inclusion in the polymer coating may be any of the core drugs described above. Is also good. Particularly preferred drugs used in polymer coatings enhance core drug efficacy Is a drug that can cooperate with a core drug to For example, core drugs The preferred combination of the drug with the coating drug is trembelone acetate and estradiol benzoate, respectively. It is a diol. Both drugs, when administered together, increase feeding efficiency in cows. It is known to enhance.   Other examples include macromolecules released from the bottom of the core (eg, peptides and proteins). Has the ability to deliver from the coating a drug that can protect the tissue response to There are implants to be used. For example, coating can be a process that causes the loss of cartilage mucopolysaccharides. Inhibit or reduce, for example, polysulfated glycosaminoglycans, Anti-inflammatory factors, antipeptidases and / or potent protease inhibitors (eg, , Adequan-Luitpold Pharmaceuticals, In c. , 11987, Shirley, NY).   In another embodiment, a biocompatible dye is included in the coating, for example, acetate acetate. Protecting light-labile core drug compounds like Lemberon from photolysis it can. This dye protects the bioactive substance from light during handling and storage, and Does not require special conditions for packaging.   Another preferred embodiment is a peptide-based HIV as a core drug. -1 proteinase inhibitor as a coating drug such as interferon, colony A combination comprising a stimulator or an immune modulator such as an interleukin. You. Such combinations are useful as therapeutics against human immunodeficiency virus (HIV) Can be used. Core drug proteinase inhibitors include, for example,gagas well asgag -Pol Inhibits proteolysis of important HIV-1 polyproteins, such as gene products Immunomodulators such as the coated drug interleukin, for example, activate T-cells. Activates the immune system by sexualization. For example, E. R. Unanue and P.M. M. A llen, "The Basis of the Immunomodulatory Role of Macrophages and Other Accessory Cells (The B assist for the Immunoregulatory Role of   Macrophages and other Accession Cel ls) "Science: 236 551-557 (1987).   In yet another embodiment of AIDS treatment, the method for combating a virus For example, nucleotide analogues such as azidothymidine (AZT) are used in the core. To address the anemia and myelosuppression associated with azidothymidine administration Erythropoietin can be used in the coating. M. Fisch et al. Recombinant human erythropoietin (Rec) for AIDS patients treated with dovudine ombinant Human Erythropoietin for pa talents with AIDS Treated with ZidoVU d ine) ",New England J.L. Med., 322: 1488-14. 93 (1990). Furthermore, the implants of the present invention can be used in primary and secondary Long term combination therapy can be provided if infection occurs. This In addition to antiviral drugs, antibiotics such as doxycycline The quality can be administered simultaneously to address Mycoplasma infections. Low Multiple drug release at successive doses resulted in HIV-1 against AZT Can be used to prolong the resistance of the drug. Low levels to avoid liver effects Of drugs further reduce toxicity. In addition, co-administration methods allow for optimal drug combinations Enables easy screening with great synergy.   The coated implants of the present invention thus demonstrate the development of drug resistance by HIV-1. Manufacture a drug that meets the general purpose of using a combination therapy to aid prevention This offers the potential for use in AIDS therapy. In addition, As such, most drug implants will eventually have the implant coated in the fibrous tissue. Controlled by the immune response. Such immunoreactivity in AIDS patients At best, it is doubtful. Therefore, other types of dosing systems in AIDS patients A slower, more incomplete tissue immune response and the resulting more elastic It is expected that (eratic) release kinetics will be seen. Therefore, the polymer coating of the present invention CAP controls core drug release until time for tissue recruitment in HIV-infected patients I do. The polymer coating bursts at this time and the system is set up to turn into a fibrous tissue system. Can be measured. Enables both self-controlled and tissue-controlled release components The implants of the present invention offer great utility in this particular clinical setting.   The coated implants of the present invention can also be used to perform multiple drug administration for use in drug addiction therapy. It is effective. For example, buprenorphine, other thebaine or oripavine A conductor or partially molten core containing an anesthetic agonist or antagonist It can be manufactured with a coating containing a second bioactive compound useful for treating floor poisoning. Wear.   The coated implants of the present invention are also effective in administering a single drug at various dosage levels. sell. For example, coated implants may be the first of a particular compound, such as interferon. High doses (eg, "induction" doses) are coated from both the coating and the bottom of the core It may be a pellet capable of dosing until it has run out. Then the same compound Low maintenance dose is continued from the bottom of the core at zero order, and the drug-free coating is Remains in place.   The drawings illustrate a preferred method and apparatus for forming the polymer coating of the present invention.   An assembly for forming the implant of the present invention is shown in FIGS. This case The assembly includes a central holding block 10, a bottom block 12 and a top block 14. No. Blocks 10, 12, 14 are arranged in a face-to-face relationship with each other. As such, it has a substantially flat opposing surface. Blocks 10, 12, 14 Also align the blocks precisely with each other and secure them together in a face-to-face relationship Includes a structure that allows In particular, the central holding block 10 is A plurality of guide pins 16 projecting from the upper surface 17 and the lower surface 18 of the lock. You. These guide pins are preferably provided in channels passing through the holding block 10. It fits and is permanently fixed. Top surface of bottom block 12 and top block 1 4, the respective blocks 10, 12, 14 face each other. To ensure that they are accurately positioned and oriented when maintained in a fixed relationship. A lock pin 10 is positioned to receive the guide pin in an engaging manner and is sized and sized. Slot 20 is provided. Each block also faces the block Threaded holes 22 that are axially straightened relative to each other Is provided. Pass the threaded screws 24 through the straightening holes 22 to secure each block. They can be fixed to each other.   The retaining block 10 extends through the retaining block 10 from the upper surface 17 to the lower surface 18. It has at least one cylindrical hole 26 therethrough. Hole 26 is preferably a smooth surface Non-stick material such as polytetrafluoroethylene (PTFE) Covered inside. The bottom block 12 extends only partially through the bottom block Has one or more cup-shaped recesses 28 cut into the upper surface of the bottom block. I do. The recess 28 is a face-to-face relationship between the holding block 10 and the bottom block 12. When arranging and arranging, it is sized to engage with the cylindrical hole 26. , Is arranged. Preferably, recess 28 is also lined with PTFE. Hole 26 and recess Together with the filler 28, a void in the shape of a test tube is formed.   The top block 14 is a pin 3 extending perpendicular to the lower surface of the top block 14. Has zero. Preferably, this pin is covered with PTFE and each block 1 When 0, 12, and 14 are arranged in a face-to-face relationship (FIG. 3), a similar shape In the test tube-shaped space, an annular space 32 is formed between the pin 30 and the space. It is sized and shaped to fit into. This annular space 32 receives the coating material. It is intended to essentially form a mold for forming the coating of the present invention.   In a preferred embodiment, the Teflon-lined holes 26, recesses 28 and pins 30 are provided. Except for the lining, the entire assembly is made of stainless steel. Various blocks Is disc-shaped and has a diameter of about 25 millimeters. Central holding block Is a cylindrical hole having a thickness of about 9 millimeters and an inner diameter of about 2.2 millimeters Is defined. The cup-shaped recess 28 in the bottom block 12 is above the bottom block 12 Having an inner diameter of about 3.2 millimeters and a depth of about 1.5 millimeters on the outer surface . The pins are about 10 mm long and have an outer diameter of about 2.2 mm Define an elongated rod. Therefore, each block faces each other The annular space 32 that is formed when placed in , Define a central lumen of about 2.2 millimeters.   To form a coated implant according to the invention, first hold the bottom block 12 and The block 10 is placed in a face-to-face relationship to form a test tube shaped void. You. Next, the powdery coated polymer (which is mixed with the drug) is distributed in the test tube-shaped space. . Next, the powder coating polymer is allowed to flow until it becomes flowable (that is, in a glass transition state). Heat the entire assembly. Next, the top block 14 is moved to the holding block 10. Assemble into a relationship. To do this, move it upwards from the holding block 10. Align the extending guide pins 16 with corresponding slots 20 on the lower surface of the top block 12. The straightening guides the pin 30 into the open end of the test tube shaped cavity. When the top block 12 is gently pressed down, the coating material is Into the annular space 32 formed between the gaps.   Preferably, the above process is performed in an oven. This oven is a block Aluminum blowers with individual heating chambers sized to receive the assembly It can be a lock. In this way, heat is applied to set the temperature to the glass transition temperature of the polymer. Nearby Up to the end. This temperature is controlled by persons of ordinary skill in the art. It is easily measured and in many situations this temperature is on the order of about 100 ° C. This temperature At some point, the polymer begins to become sticky and begin to flow. Pin 30 and test The top block 14 is held in the center holding block for close engagement with the tube-shaped cavity. In a face-to-face relationship with the fluid 10, the flowable polymer is compressed into a thin-walled tube. You. If the center holding block and top block were placed in a face-to-face relationship, Remove the top block assembly from the oven and allow it to cool. Then pin 3 0 and the test formed by the holding block 10 and the bottom block 12 A thin sleeve or coating of macromolecule (optionally containing drug) is left in the tubular cavity.   The above method avoids the use of solvents and liquid polymers. However, solvents and liquid polymers Can also be used in accordance with the present invention, and should be of ordinary skill in the art. Will be understood by In particular, a liquid suspension of the coated polymer (and optionally the drug) The liquid is introduced into the test tube-shaped space formed by the holding block and the bottom block. You can enter. Next, place the top block facing the holding block By doing so, the pins 30 are introduced into the test tube-shaped space. Also in this case Due to the close engagement between the pin and the tube-shaped cavity, the liquid polymer Squeezed into 32. The polymeric material is cured in the annular space to form a coating.   Once the coating has been formed, the core material is then introduced into the polymer coating void. core The material can be introduced into the polymer coating cavity in various ways. Core introduced The material can be in powder form, which powder can be a powdered core drug or It comprises a powdered core drug in combination with a carrier. When introducing core material as powder The melting of the core material occurs in the polymer coating void. Or, in the molten state, A material can also be introduced.   To melt the core material in the polymer coating gap, Charge and heat. The amount of heating is a function of the number and type of components of the core material. For example, if a partially fused core is desired, the non-polymeric carrier is completely melted, Apply enough heat to leave the core drug unmelted. The heating of the core material is Achieved by placing the entire brie in an oven. Add assembly Heat is used for two purposes: to provide enough heat to melt the core components, and A sufficient heat was applied to bond the perimeter of the You. The partial melt is then allowed to cool in the coating. Preferably, the molten material recrystallizes Sometimes pressure is applied to the surface of the molten material. This is more uniform as the crystal progresses Surface and a better bond between the core material and the coating at the core-coating interface. Promotes cohesion.   Next, the coating-core is removed from the stainless steel holding block. This is Asen Cooling the brie in dry ice can help. this Cooling removes the coating from the surface of the void formed by the holding block and the bottom block. Make it easier to retrieve. Coating-core released from assembly is test tube shaped Define a cylindrical cylinder, one end of which is exposed and the other end is curved and Is protected. Coating-Cut both ends of the core and protected by a polymer coating Coating-cores having non-uniform edges may be formed.   The core material can also be melted before being introduced into the formed coating. Melting core When the heat supplied by the material introduces the molten material into the formed coating, Sufficient to create a bond at the core / coating interface, but not at the core / coating interface. Introduce molten material into the heated coating to promote better bonding at the surface More preferably,   It is recognized that other methods of forming the core bonded to the coating can also be used according to the present invention. It will be understood by those of ordinary skill in the art. For example, the part The molten core material is co-extruded with the coating material to form the coated implant of the present invention. be able to. In this case, the partially molten core material is extruded as a solid cylinder and coated. The material can be extruded as a hollow cylinder surrounding the core material.   In the embodiments described above, the core material is formed into a core shape within the coating. But, The erodible core is formed first, and then the formed core is applied to, for example, a biocompatible adhesive. Therefore, or heat from the coating material is localized only at the interface between the core and the coating. Melted coating material is applied on the surface of the formed core so that it can be melted and recrystallized Can also be coupled to the coating.   Both the core material and the cladding should be used to promote bonding at the core-cladding interface. It should also be understood that they can contain the same or complementary substances. example For example, to promote the binding and penetration of crystalline non-polymeric structures into the coating, The overlying polymer can include some of the non-polymeric carrier of the core material.   Those skilled in the art will routinely experiment with the specific products described herein. Many equivalents of articles and methods could be recognized and identified. like this Equivalents are considered to fall within the scope of the invention and are encompassed by the following claims. It is intended to be

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Claims (1)

[Claims] 1. Outside containing at least one drug and only partially covered by a polymer coating A bioerodible core having a surface, wherein the core is associated with the coating, and sustained release of the drug. An implant that can be dispensed. 2. The implant of claim 1, wherein the core is fused to the coating. 3. 3. The implant of claim 2, wherein the core is fused. 4. 4. The embedding agent according to claim 3, wherein the core has a cylindrical shape. 5. 2. The implant of claim 1, wherein the core is fused. 6. The core comprises a non-polymeric carrier, and the at least one drug is a crystal of the carrier. 6. The implant of claim 5, wherein the implant is bound in a porous matrix. 7. 7. The implant of claim 6, wherein said at least one drug is a peptide. 8. The core has a cylindrical shape with a side surface and two bottom surfaces, and the side surface is coated with a polymer. Therefore, at least one of the bottom surfaces is not covered by the polymer coating The implant according to claim 1, characterized in that: 9. Coating is polylactic acid, polyglycolic acid, copolymer of polylactic acid, polyglycol Selected from the group consisting of acid copolymers, polycaprolactone and polyanhydrides An implant according to any of the preceding claims, comprising a substance. 10. An implant according to any of the preceding claims, wherein the coating comprises a coating drug. 11. Polylactic acid, polyglycolic acid, copolymer of polylactic acid, polyglycol Selected from the group consisting of copolymers of phosphoric acid, polycaprolactone and polyanhydrides 11. The implant of claim 10, comprising a substance. 12. The implant of claim 1, wherein the coating comprises a biocompatible dye. 13. Configure and arrange the cladding and core so that the erosion of the cladding lasts longer than the erosion of the core. The implant according to claim 1, which is placed. 14． Excipients in which the coating and the core can promote the bond between the coating and the core The implant according to claim 1, comprising: 15. Form a core containing the drug, Forming a coating, Bonding the coating and core only on certain surfaces, leaving the other surface of the core exposed , A method for forming a sustained release implant, comprising the steps of: 16. Heating at least one of the coating and the core to fuse the coating to the core; 16. The method of claim 15, wherein the coating is bonded to the core. 17． 17. The method of claim 16, wherein the core is formed by melting and recrystallizing the core material. Law. 18. Form the coating before forming the core, in which the core material is melted and recrystallized 18. The method of claim 17, wherein the method is performed. 19. Furthermore, a cylindrical core having two bottom surfaces and side surfaces is formed, and the coating is formed on the side surfaces. And leave at least one bottom surface of the cylindrical core uncovered by the coating material. And thereby leave at least one bottom surface of the core exposed for erosion. The method according to claim 15, characterized in that: 20. Placing a polymeric thin-walled coating along the inner surface of the chamber, Distributing the non-polymeric core material during coating, Heating the non-polymeric material to a temperature sufficient to melt the non-polymeric material, Allowing the molten material to cool to form a recrystallized non-polymeric core bonded to the coating; A method for producing a sustained-release implant, comprising the steps of: 21. A first drug capable of inhibiting replication of the HIV-1 virus, A non-polymeric cylindrical core that binds to the polymer coating only on curved surfaces; A coating that contains a second drug capable of modulating the immune response of the patient. A sustained release device for treating an HIV infection in a patient. 22. The first drug is an HIV proteinase inhibitor or a therapeutically effective analog thereof. Wherein the second drug is selected from the group consisting of interferon and interleukin 22. The device of claim 21. 23. The first drug is azidothymidine, dideoxycytidine and dideoxyadenosine Wherein the second drug is human erythropoietin or a therapeutically effective agent thereof. 22. The device of claim 21, which is a sexual analog.