HK1177679B - Degradable removable implant for the sustained release of an active compound - Google Patents

Description

Degradable removable implant for the sustained release of active compounds

Technical Field

The present invention relates to implantable depot polymeric devices that are easily introduced into the subcutaneous space, easily removed when needed, and easily degraded after the drug delivery function is complete. One or more drugs may be incorporated. The device introduces a certain degree of flexibility in that the drug loading and the polymer properties selected for the matrix can be individually tailored to the drug to meet the specific needs of the patient.

Background

Implantable drug delivery devices are known in the art. The device is surgically implanted in a human or veterinary patient and the drug is released in an effective manner. The implantable drug delivery system is particularly useful in delivering drugs at sustained rates over an extended period of time. Examples of such drug delivery implants include: norplant^®、Lupron Depot^®And Gliadel Wafer^®。

In implantable drug delivery systems known in the art, the active ingredient is embedded in a matrix material in the form of a cylinder having dimensions small enough to be implanted subcutaneously via a hollow needle. A disadvantage associated with the delivery system is that there is a time lag between implantation and delivery of the drug, as the body fluid must be allowed to penetrate the implant and begin to break down the polymer matrix. This also typically results in irregular drug release characteristics.

Furthermore, such systems have not been designed to deliver two or more drugs simultaneously. The utility of implantable drug delivery systems is greatly enhanced if it is made possible. When the treatment comprises two or more active substances that may act together in a broader, synergistic or better way, the disease state is generally more effectively controlled. An example of this would be when treating or preventing infections, where two different classes of antibiotics are released from a single depot system. The activity of each antibiotic targets a different bacterial strain, in this way providing a broader spectrum of antibacterial therapy. Another example of utility is the delivery of analgesic drugs. The sustained release of the analgesic drug can leave the patient in an indolent state for a prolonged period of time, which provides a significant improvement in the plasma peak to trough concentrations inherent in oral therapeutic drugs. However, sustained release of multiple analgesic drugs with their respective mechanisms of action can significantly improve pain management.

More compelling examples of multi-drug depots can be found in the treatment of infectious diseases such as HIV (human immunodeficiency virus) and HBV (hepatitis b virus). Standard therapy for HIV requires a "cocktail" of at least three drugs. Sustained release therapy of HIV can significantly contribute to treatment compliance (reduced pill burden) and reduce the risk of developing tolerance to therapeutic actives. The value of such a therapy would be further enhanced if the implantable sustained release formulation contained all the components of the cocktail drug, rather than only one sustained release drug, and the other drug, were still used as an oral treatment. Other infectious diseases that benefit from this type of therapy are malaria, influenza, TB, hepatitis c. Multiple drug depots may also be used in high risk groups in pre-exposure environments, e.g., pre-exposure prophylaxis of HIV infection.

Decoupling the formulation of the two active substances into their respective processes can greatly improve stability, increase the respective drug loading, and introduce compositional flexibility in that one drug can be formulated to release faster or slower, or to increase or decrease the dosage of one drug, depending on the patient's condition.

The ability to remove the implanted sustained release device is important because many drugs used in sustained release applications are potent and can cause serious and even life-threatening reactions. Even if the particles or pellets are compressed into a unit as described in US 2001/0026804, there is no guarantee that the device can be removed because once the device is exposed to physiological media, the pellets or particles will immediately separate from each other and thus cannot be completely removed.

US2004/0082937 describes implantable devices for the controlled release of hormones. The device comprises a substrate having a plurality of reservoirs, each reservoir containing an electrically controllable release system. US2006/0269475 describes a polymeric multilayer structure having a predetermined micro-machined into a specific form, the structure comprising a predetermined reservoir and channels containing a drug. The polymeric multilayer structure is biodegradable, but it has a lifetime that is longer than the duration of the treatment delivered. The geometry of the polymer structure controls the delivery of the therapy, persisting during the delivery of the therapy. The device is fabricated in layers that fuse together at high temperatures, which can cause severe distortion of the reservoir shape, resulting in significant changes in the overall drug loading or drug release rate in the device. In addition, the device has a limited volume of drug loaded in the void or channel.

Brief Description of Drawings

FIG. 1 shows a schematic view of a

Polydioxanone extruded and laser machined tubes. The pore size was 50 microns and the number of rows of pores was 40, with 60 pores per row. 2400 wells in total. The total length of the tube was 30mm, and the total length of the holed tube was 20 mm. The inner diameter of the tube was 3 mm.

FIG. 2

Cross-section of electrospun polydioxanone tubes. The wall thickness was 500 microns. The inner diameter is 2 mm.

FIG. 3

Electrospinning the surface of polydioxanone tube. The fibers are randomly oriented and the pore size formed by the network of fibers is between 1 and 20 microns.

FIG. 4

Optical micrographs of microparticles containing 70% (w/w) TMC278 and 30% (w/w) PLGA 50/501A. The magnification is 100 x.

FIG. 5

Optical micrographs of microparticles containing 70% (w/w) TMC114 and 30% (w/w) PLGA 50/502A. Magnification was 500 x.

Description of the invention

The present invention relates to a degradable, removable, pharmaceutical implant for the sustained release of one or more drugs in a subject, wherein the pharmaceutical implant consists of a tube comprising an outer wall made of a degradable polymer completely surrounding a cavity, wherein the outer wall has a plurality of openings, wherein the cavity contains one or more sets of microparticles, which microparticles contain one active agent or a combination of two or more active agents, wherein the size of the microparticles is selected such that the majority of the microparticles cannot pass through the openings.

The tube is composed of a degradable polymer. The microparticles contain one active ingredient or a combination of two or more active ingredients that are designed to release the active ingredient upon contact with bodily fluids. The degradable polymer from which the tube is made is selected such that it does not substantially degrade until substantially finishing the release of the one or more active ingredients from the microparticle. The choice of the type of particles and their relative amounts is predicated on the particular needs of the patient subject.

The term degradable or biodegradable as used herein means degradable, i.e. degradable by a subject, in particular an animal, more in particular a human, carrying an implant according to the invention. The degradation process in the subject may be, for example, an enzymatic process or a hydrolytic process.

In one embodiment, the tube contains two or more groups of microparticles, each group containing a different active ingredient. This makes possible a multi-depot system in which combinations of drugs need to be administered. In a particular embodiment, the multi-depot system contains at least two, in particular three, anti-HIV agents, and the implant is for use in anti-HIV therapy based on administration of a combination of anti-HIV agents.

Thus, one embodiment of the present invention relates to a degradable, removable, pharmaceutical implant for the sustained release of a drug in a subject, wherein the pharmaceutical implant is comprised of a tube comprising an outer wall made of a degradable polymer completely surrounding a cavity, wherein the outer wall has a plurality of openings, wherein the cavity contains one or more sets of microparticles, said microparticles containing the drug, wherein the size of the microparticles is selected such that the majority of the microparticles cannot pass through the openings. In particular, the cavity contains a set of microparticles that contain a drug.

One embodiment of the present invention relates to a degradable, removable, pharmaceutical implant for the sustained release of two drugs in a subject, wherein the pharmaceutical implant consists of a tube comprising an outer wall made of a degradable polymer completely surrounding a cavity, wherein the outer wall has a plurality of openings, wherein the cavity contains two groups of microparticles, each group of microparticles containing a different drug, wherein the size of the microparticles is selected such that the majority of the microparticles cannot pass through the openings.

One embodiment of the present invention relates to a degradable, removable drug implant for the sustained release of two or more drugs in a subject, wherein the drug implant consists of a tube comprising an outer wall made of a degradable polymer completely surrounding a cavity, wherein the outer wall has a plurality of openings, wherein the cavity contains one or more sets of microparticles containing the drugs, wherein a set of microparticles contains all the drugs, a combination of two or more drugs but not all the drugs, or one drug, wherein the size of the microparticles is selected such that the majority of the microparticles cannot pass through the openings. In one embodiment, when one set of microparticles contains all of the drug, then preferably only one set of microparticles is present in the implant. In one embodiment, each set of microparticles contains a different drug.

The tube wall contains openings that allow the physiological fluid to permeate the lumen, thereby allowing the physiological fluid to extract one or more drugs from the microparticles and facilitating diffusion of the drug-loaded physiological fluid from within the tube to outside the tube. The openings are formed to allow penetration of physiological fluids but are too small to allow the particles to escape from the interior of the tube. Some particles may leave the implant, but the opening size and particle size are designed so that most particles are locked within the implant cavity. Most of the microparticles are locked within the implant cavity, i.e. at least 85% (w/w) of the microparticles are locked within the implant cavity; preferably at least 90% (w/w); more preferably at least 95% (w/w); even more preferably at least 98% (w/w) or 99% (w/w) of the microparticles are locked within the implant cavity. In one embodiment, the size of the particles is selected such that the particles cannot pass through the openings.

When more than one set of microparticles is present, each set of microparticles can be designed to degrade at a range of rates by varying the polymer characteristics used to produce each microparticle in the set. This ensures that the drug is delivered over a range of durations. The polymer constituting the cylindrical tube degrades at a slower rate than the microparticles. This ensures that the implant can be removed along with its contents in the event of an adverse event.

Thus, the implantable, removable, degradable implants of the present invention act as a depot system that can deliver one or more active ingredients over a sustained period of time. The implants of the invention are porous tubes containing one or more groups of microparticles, each group of microparticles containing one or more active agents. The type of active to be delivered, and the rate at which it is delivered, can be selected to suit the needs of the patient.

The microparticle-loaded tube is composed of a biocompatible, biodegradable polymer. The material of the tube composition needs to be carefully selected so that the tube degrades after the microparticles degrade. This allows the drug delivery system to be removed in the event of an adverse event. Biodegradable polymers tend to break down into small fragments when exposed to moist body tissue. The fragments are then absorbed by the body or excreted by the body. More particularly, the biodegradable fragments do not elicit a long-lasting chronic exogenous bodily response, as they are absorbed by or excreted by the body, so that the body does not retain long-lasting traces or residual fragments. Biodegradable polymers may also be referred to as bioabsorbable polymers, and the two terms may be used interchangeably in the context of the present invention.

Suitable biocompatible, biodegradable polymers include: aliphatic polyesters, poly (amino acids), copoly (ether esters), polyalkylene oxalates, polyamides, poly (imino carbonates), poly (ortho esters), polyoxaesters, polyesteramides, amine group containing polyoxaesters, poly (anhydrides), polyphosphazenes and mixtures thereof. For purposes of the present invention, aliphatic polyesters include, but are not limited to, homopolymers and copolymers of lactide (including d-lactic acid, l-lactic acid and meso-lactic acid and d-lactide, l-lactide and meso-lactide), glycolide (including glycolic acid), -caprolactone, p-dioxanone (1, 4-dioxane-one) and trimethylene carbonate. In one embodiment, the biocompatible, biodegradable polymer is a copolymer of lactide (including d-lactic acid, l-lactic acid and meso-lactic acid and d-lactide, l-lactide and meso-lactide), glycolide (including glycolic acid). In another embodiment, the biocompatible, biodegradable polymer is a homopolymer of polydioxanone.

In one embodiment, the tube is made by electrospinning. Electrospinning utilizes electricity to convert polymer solutions into fibers. The spun fibers are very fine, randomly oriented in all directions. The fibers may be spun around a mandrel such that the fibers are continuously added until a tube is formed. The diameter of the mandrel determines the inner diameter of the tube and, for practical reasons, should be able to contain sufficient particles and be easily implanted through a trocar, the diameter of the mandrel should preferably be between 1 and 5 mm.

The thickness of the fiber can be controlled by the concentration of the polymer used in the solution undergoing electrospinning. However, for practical fibers, a minimum polymer concentration is required, beyond which practical fibers can no longer be spun. Although the range may vary with the intrinsic viscosity of the polymer, a typical range is 1% to 30% (w/v).

As mentioned above, the tube is designed so that in the event of an adverse event, the tube and its contents can be completely removed. Removal is accomplished by accessing the implant area, palpating the tube, making a small opening in the skin adjacent the tube, and pulling the tube out of the incision. This requires the tube to have mechanical properties that remain intact during the process. The intrinsic viscosity of the polymer used to make the tube is the most critical factor affecting the mechanical properties. The intrinsic viscosity range for achieving adequate mechanical properties is preferably from 1.5 to 2.5 dl/g.

The porosity of the electrospinning tube (the opening of the electrospinning tube) is largely controlled by the tube wall thickness and the diameter of the spun fiber. Thicker walls are made by more fiber build-up on the mandrel resulting in greater thickness. The overall porosity of the tube decreases due to the random orientation of the fibers in the network formed with the addition of more fibers. Porosity is necessary because it provides a means for the surrounding physiological fluid to permeate into the tube to facilitate diffusion of the one or more active agents from within the microparticles. Porosity is a measure of the void space in a material, defined as the fraction or percentage of the total volume that is occupied by minute open spaces. In equation form, porosity refers to the void volume divided by the total volume, expressed as a fraction between 0 and 1 or as a percentage between 0 and 100%. Porosity should have a limit because the particles must be packed inside the tube. Alternatively, the porosity may not be so small that physiological fluids cannot penetrate into the interior of the tube. The ideal porosity should be between 60-90%, which can be achieved when manufacturing tubes with wall thickness between 50-500 microns. For example, pores of between 1 and 20 microns can be obtained with this method. Furthermore, the wall thickness should not be so thick as to affect the flexibility of the tube.

Alternatively, the tube may be manufactured by an extrusion process accompanied by laser drilling (opening) in a predetermined pattern of predetermined dimensions. As mentioned above, the polymers used to make the tubes are biodegradable. Preferred biodegradable polymers are those that are soft and therefore flexible. Examples of polymers in this preferred group are poly (caprolactone) and polydioxanone. The intrinsic viscosity of the polymer is most important in this regard. The intrinsic viscosity should be such as to provide the polymer with a viscosity that is easily extruded and easily laser etched into a predetermined pattern. In polymer chemistry, intrinsic viscosity is related to molar mass by the Mark-Houwink equation. A practical method for determining intrinsic viscosity is with a Ubbelohde viscometer. Intrinsic viscosity and intrinsic viscosity are closely related. Intrinsic viscosity is defined as the intrinsic viscosity at the limit of infinite dilution. In the intrinsic viscosity versus solution concentration graph, the y-intercept (c =0) is equal to the intrinsic viscosity. As in the case of tubes manufactured by electrospinning, the tube must have sufficient mechanical properties to be able to be pulled out of the small incision in the event of an adverse event. The intrinsic viscosity of the polymer directly affects the mechanical properties of the tube. To meet all these requirements, the intrinsic viscosity of the polymer should preferably be between 0.5 and 5 dl/g.

To obtain a tube-like shape, the polymer is extruded from an extruder equipped with a suitably designed casting mold. To maintain a constant inner diameter, a gas stream may be blown into the center of the tubing. Alternatively, the tubing may be extruded along a mandrel of a particular size. The internal diameter may be between 1 and 5mm, as in the case of an electrospinning tube. The minimum wall thickness is preferably at least 25 microns; below this value the wall does not have sufficient mechanical integrity and the tube will be very difficult to handle. The maximum wall thickness should preferably not exceed 500 microns; above this value the tube space will be limited, since the overall diameter of the tube is limited by the comfortable fit (fit) in the subcutaneous space. Furthermore, at large wall thicknesses, the flexibility of the tube may become further reduced, affecting patient comfort, while an increase in the diffusion path may reduce the rate of diffusion of the active ingredient from the interior of the tube. Preferably the wall thickness is in the range 50-500 microns. The outer diameter of the tube should preferably not exceed 5 mm; beyond this range the implant would be too large to cause discomfort of subcutaneous fit.

Holes (openings) are etched through the tube wall using a low energy laser etching process. The precursor tube is mounted on a laser processing unit and subjected to energy from a laser beam to form an implantable device having a desired geometry or pattern imparted thereon. Low energy is important to prevent heating of the polymer, which may cause reduced reproducibility of pore shape and diameter, and even degradation of the polymer. The holes or pores in the tube outer surface have a minimum diameter of 10 microns, which is the smallest diameter pore that the laser can etch in a repeatable manner. The upper limit of the diameter may be determined by the particle size. To prevent most of the particles from escaping through the pores, it is necessary that the diameter of the pores at the inner surface of the tube is not an order of magnitude or the same as the diameter of the smallest diameter particles in the particle distribution used to formulate the filling of the tube. (the laser etching process may result in the holes having a larger diameter on the tube outer surface than on the tube inner surface).

The pattern of apertures is imparted to the device by using a mask. A mask having a desired geometry or pattern is placed on the substrate and a laser beam imparts the desired pattern onto the substrate. The laser processing unit includes a coordinated multi-action unit that moves the laser beam in one direction and the substrate in another direction during the etching process. The laser beam passes through the mask and etches away the bioabsorbable material, thereby imparting a geometry or design to the device corresponding to the mask. Inert gases may be used in the laser cutting environment that reduce or eliminate moisture and oxygen related effects during laser cutting of materials. Preferably the laser beam is directed through a lens before reaching the precursor material. The lens intensifies the laser beam to more accurately impart the desired pattern or geometry to the substrate. A laser beam homogenizer may also be used to produce more uniform laser beam energy and maintain consistency of the laser beam energy as it impacts the substrate. The laser beam energy can be controlled to reduce the laser cutting time.

Pores may also be formed by including a water-miscible semi-solid, surfactant, polymer, or water-soluble solid in the wall polymer. Pores are formed when water-miscible or water-soluble substances are allowed to drain out after contact with an aqueous medium. The leaching treatment may be performed prior to implantation to form pores, or alternatively may occur immediately after implantation when the physiological medium contacts the surface of the vessel. Suitable water-miscible or soluble substances include phospholipids, fatty acids, tweens (Tween) and PEG.

Drug-loaded microparticles are prepared to fill the interior of the tube. Drug-loaded microparticles mean particles comprising a drug physically embedded in a polymer and having a particle size of less than 1000 microns. The microparticles may be microspheres, microcapsules or microparticles. Microspheres means substantially spherical microparticles in which the drug is uniformly dissolved in or encapsulated by the polymer. Microcapsules means substantially spherical particles in which the drug is coated with a polymer. Microparticles means irregular spherical microparticles in which the active ingredient is uniformly dissolved or encapsulated in a polymer.

The particle size distribution of the microparticles is preferably between about 1 and 1000 microns, more preferably between about 10 and about 500 microns, and even more preferably between about 25 and about 250 microns.

The particle size or particle size distribution can be measured or determined by techniques well known to the skilled person, for example by laser diffraction or microscopy. As noted above, the particle size is preferably related to the size of the opening of the tube such that the two cooperate to confine the particles within the tube.

To minimize the size distribution range of the microparticles, the microparticles may be sieved prior to incorporation into the implants of the present invention. The particle screening may be performed by using, for example, a typical mesh screen well known to the skilled person.

The drug-loaded microparticles may be prepared by any of a number of known methods. One preferred method is a rotating disc process, such as the process set forth in US 7261529, which is preferred because it produces high drug load microparticles. In order to accommodate as much drug as possible in the smallest space, minimizing the final size of the implant, it is strongly recommended to reach a loading of at least 10% (w/w). Preferably 60-80% (w/w) drug load. To prepare the microparticles, the polymer is typically in solution in a suitable solvent. Suitable solvents include acetone, ethyl acetate, chloroform and dichloromethane. The drug substance is usually in solution or suspension in a suitable solvent.

Another method of preparing drug-loaded microparticles is the emulsion method. To prepare microparticles by the emulsion process, the active agent is added to a solution of the organic polymer in solid or liquid form. Rapid agitation or sonication uniformly distributes the active agent throughout the polymer solution. The organic solution is then poured into an aqueous solution containing a surfactant, forming polymer droplets in the aqueous phase, and the organic solvent is evaporated by continuous stirring. The mixture was then transferred to a vat of water and mixing continued to extract the remaining solvent, hardening the droplets into microparticles. The drug-loaded microparticles can then be collected by filtration.

The term drug is meant to include all substances that affect some biological response. The term drug encompasses drugs useful for any mammal, including but not limited to humans. The term drug includes, but is not limited to, the following classes of drugs: therapeutic, prophylactic and diagnostic agents. Examples of drugs that can be incorporated into the polymer matrix are: narcotic analgesics, gold salts, corticosteroids, hormones, anti-malarial drugs, indole derivatives, drugs for treating arthritis, antibiotics, sulfur drugs, antitumor drugs, addiction control drugs, weight control drugs, thyroid regulation drugs, analgesics, anti-hypertensive drugs, anti-inflammatory drugs, antitussives, anti-epileptic drugs (anti-epileptics), anti-depressive drugs, anti-arrhythmic agents, vasodilators, blood pressure lowering diuretics, anti-diabetic agents, anti-blood clotting agents, anti-tubercular agents, drugs for treating psychosis, drugs for treating alzheimer's disease, drugs for treating central nervous system diseases or syndromes, anti-HIV drugs, anti-TB agents, drugs for treating hepatitis. The above table is not meant to be comprehensive, but merely representative of the various drugs that may be incorporated into the microparticles.

The terms drug, active agent, active ingredient, compound, active compound are used interchangeably herein.

Preferred classes of drugs are drugs for use in the treatment or prophylaxis of HIV, in particular in the treatment of HIV. These include Protease Inhibitors (PI), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs and ntrtis). Other classes are entry inhibitors including fusion inhibitors and integrase inhibitors. For HIV treatment, a combination of so-called high activity anti-reverse transcription therapy (HAART) is preferred. These typically comprise a backbone of two nucleoside reverse transcriptase inhibitors in combination with NNRTI or with PI. PI is usually combined with a so-called "adjuvant", such as ritonavir (ritonavir).

One embodiment relates to an implant comprising a set of microparticles comprising NNRTI rilpivirine (also referred to as "TMC 278") or a pharmaceutically acceptable salt thereof, e.g., the hydrochloride salt. Rilpivirine (= free base) is preferred. One embodiment relates to an implant in which one set of microparticles contains an NRTI and another set of microparticles contains an NNRTI.

One embodiment relates to an implant in which one set of microparticles contains NNRTI and another set of microparticles contains PI.

Another preferred class of drugs are those used in the treatment of hepatitis c. These include ribavirin (ribavirin), interferon, HCV (hepatitis c virus) protease inhibitors, HCV polymerase inhibitors. Combinations are also preferred herein.

One embodiment relates to an implant wherein the microparticles contain at least one drug selected from an HIV inhibitor or an HCV inhibitor.

The polymer used to make the microparticles is a biocompatible, biodegradable polymer. Suitable biocompatible, biodegradable polymers include: aliphatic polyesters, poly (amino acids), copoly (ether esters), polyalkylene oxalates, polyamides, poly (imino carbonates), poly (ortho esters), polyoxaesters, polyesteramides, amine group containing polyoxaesters, poly (anhydrides), polyphosphazenes and mixtures thereof. For the purposes of the present invention, aliphatic polyesters include, but are not limited to, homopolymers and copolymers of lactide (including d-lactic acid, l-lactic acid and meso-lactic acid and d-lactide, l-lactide and meso-lactide), glycolide (including glycolic acid), -caprolactone, p-dioxanone (1, 4-dioxane-one) and trimethylene carbonate (1, 3-dioxane-one). In one embodiment, the biocompatible, biodegradable polymer is a copolymer of lactide (including d-lactic acid, l-lactic acid and meso-lactic acid and d-lactide, l-lactide and meso-lactide), glycolide (including glycolic acid). In another embodiment, the biocompatible, biodegradable polymer is a copolymer of lactide and glycolide containing between 85% and 50% lactide mole percent.

In one embodiment of the invention, the microparticles contain a surfactant in addition to the polymer and the one or more drugs. Surfactants are used to improve the wettability of hydrophobic components and they are generally amphiphilic molecules containing a hydrophilic group and a lipophilic group. The ratio of these groups is measured by the hydrophilic-lipophilic balance (HLB) number. It is a value between 0 and 60, defining the affinity of the surfactant for water or oil. For nonionic surfactants, the HLB number is calculated from the molecular weight of the hydrophilic and hydrophobic portions of the molecule, and these surfactants have values between 0 and 20. The HLB value associated with ionic surfactants is not calculated, but is given based on their relative or comparative surface activity behavior.

Surfactants with HLB numbers >10 have affinity for water (hydrophilic); surfactants with HLB numbers <10 have an affinity for oils (lipophilic).

The surfactant includes a nonionic surfactant and an ionic surfactant. Ionic surfactants include cationic, anionic, zwitterionic surfactants such as fatty acid salts, e.g., sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, dioctyl sodium sulfosuccinate, sodium myristate, sodium palmitate, sodium stearate, sodium ricinoleate, and the like; bile salts such as sodium cholate, sodium taurocholate, sodium glycocholate, and the like; for example, phospholipids such as egg lecithin/soybean lecithin, hydroxylated lecithin, lysolecithin, lecithin, phosphatidylethanolamine, cardiolipin, phosphatidylserine, and the like; for example, phosphoric acid esters such as the esterification product of diethanolammonium polyoxyethylene10 oleyl ether phosphate, fatty alcohol or fatty alcohol ethoxylate with phosphoric acid or anhydride; for example carboxylates such as succinylated monoglyceride, sodium stearyl fumarate, monostearylpropanediol succinate, monoacylated/diacetylated tartaric acid esters of mono-and diglycerides, citric acid esters of mono-and diglycerides, glyceryl-lacto esters of fatty acids, lactic acid esters of fatty acids, calcium stearoyl-2-lactylate/sodium stearoyl-2-lactylate, calcium stearoyl lactylate/sodium stearoyl lactylate, alginates, propylene glycol alginate, ether carboxylates, and the like; such as sulfates and sulfonates such as ethoxylated alkyl sulfates, alkyl benzene sulfates, alpha olefin sulfonates, acyl isethionates, acyl taurates, alkyl glyceryl ether sulfonates, disodium octyl succinate, disodium undecylenoyl-MEA-sulfosuccinate, and the like; for example, cationic surfactants such as cetyltrimethylammonium bromide, decyltrimethylammonium bromide, cetyltrimethylammonium bromide, dodecylammonium chloride, alkylbenzyldimethylammonium salts, di-isobutylphenoxyethoxydimethylbenzylammonium salts, alkylpyridinium salts, betaines (dodecylbetaines), ethoxylated amines (polyoxyethylene-15-cocoamines), and the like.

Preferred surfactants in the present invention are nonionic surfactants

Suitable nonionic surfactants useful in the present invention include:

a) polyethylene glycol fatty acid monoesters including laurate, oleate, stearate, ricinoleate with PEG 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 32, 40, 45, 50, 55, 100, 200, 300, 400, 600 and the like, such as PEG-6 laurate or PEG-6 stearate, PEG-7 oleate or PEG-7 laurate, PEG-8 laurate or PEG-8 oleate or PEG-8 stearate, PEG-9 oleate or PEG-9 stearate, PEG-10 laurate or PEG-10 oleate or PEG-10 stearate, PEG-12 laurate or PEG-12 oleate or PEG-12 stearate or PEG-12 ricinoleate, PEG-15 stearate or PEG-15 oleate, PEG-6, PEG-8 stearate, PEG-9 oleate or PEG-9 stearate, PEG-10 laurate or PEG-10 oleate or PEG-10 stearate, PEG-12 laurate or PEG-12 oleate, PEG-12 stearate or PEG-12 ricinoleate, PEG-20 laurate or PEG-20 oleate or PEG-20 stearate, PEG-25 stearate, PEG-32 laurate or PEG-32 oleate or PEG-32 stearate, PEG-30 stearate, PEG-40 laurate or PEG-40 oleate or PEG-40 stearate, PEG-45 stearate, PEG-50 stearate, PEG-55 stearate, PEG-100 oleate or PEG-100 stearate, PEG-200 oleate, PEG-400 oleate, PEG-600 oleate; (surfactants belonging to this class are known, for example, as Cithrol, Algon, Kessco, Lauridac, Mapeg, Cremophor, Emulgante, Nikkol, Myrj, Crodet, Albunol, Lactomul);

b) polyethylene glycol fatty acid diesters including laurates, stearates, palmitates, oleates and the like with PEG-8, 10, 12, 20, 32, 400 and the like, for example PEG-8 dilaurate or PEG-8 distearate, PEG-10 dipalmitate, PEG-12 dilaurate or PEG-12 distearate or PEG-12 dioleate, PEG-20 dilaurate or PEG-20 distearate or PEG-20 dioleate, PEG-32 dilaurate or PEG-32 distearate or PEG-32 dioleate, PEG-400 dioleate or PEG-400 distearate; (surfactants belonging to this class are known as, for example, Mapeg, Polyalso, Kessco, Cithrol);

c) mixtures of polyethylene glycol fatty acid monoesters and diesters, such as PEG 4-150 monolaurate and dilaurate, PEG 4-150 monooleate and dioleate, PEG 4-150 monostearate and distearate, and the like; (surfactants belonging to this class are known as Kessco, for example);

d) polyethylene glycol fatty acid glyceride such as PEG-20 lauric acid glyceride or PEG-20 stearic acid glyceride or PEG-20 oleic acid glyceride, PEG-30 lauric acid glyceride or PEG-30 oleic acid glyceride, PEG-15 lauric acid glyceride, PEG-40 lauric acid glyceride, etc.; (surfactants belonging to this class are known, for example, as Tagat, Glycerox L, Capmul);

e) alcohol oil transesterification products, including alcohols or polyols (e.g., glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, pentaerythritol, and the like) with natural and/or hydrogenated oils or oil-soluble vitamins (e.g., castor oil, hydrogenated castor oil, vitamin a, vitamin D, vitamin E, vitamin K; edible vegetable oils, for example corn oil, olive oil, peanut oil, palm kernel oil, almond oil) such as PEG-20 castor oil or PEG-20 hydrogenated castor oil or PEG-20 corn glyceride or PEG-20 almond glyceride, PEG-23 castor oil, PEG-25 hydrogenated castor oil or PEG-25 trioleate, PEG-35 castor oil, PEG-30 castor oil or PEG-30 hydrogenated castor oil, PEG-38 castor oil, PEG-40 castor oil or PEG-40 hydrogenated castor oil or PEG-40 palm kernel oil, PEG-45 hydrogenated castor oil, PEG-50 castor oil or PEG-50 hydrogenated castor oil, PEG-56 castor oil, PEG-60 castor oil or PEG-60 hydrogenated castor oil or PEG-60 corn glyceride or PEG-60 almond glyceride, PEG-20 hydrogenated castor oil, PEG-30 hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-80 hydrogenated castor oil, PEG-100 castor oil or PEG-100 hydrogenated castor oil, PEG-200 castor oil, PEG-8 caprylic/capric glycerides, PEG-6 caprylic/capric glycerides, lauroyl macrogol-32 glycerides, stearoyl macrogol glycerides, PEG-1000 tocopheryl succinate (TPGS); (surfactants belonging to this class are known, for example, as Emalex, Cremophor, Emulgante, Eumulgin, Nikkol, Thornley, Simulsol, Cerex, Crovol, Labrasol, Softigen, Gelucire, vitamin E TPGS);

f) polyglycerolated fatty acids, including polyglycerol esters of fatty acids, such as polyglycerol-10 laurate or polyglycerol-10 oleate or polyglycerol-10 stearate, polyglycerol-10 monooleate and polyglycerol-10 dioleate, polyglycerol polyricinoleate, etc. (surfactants belonging to this class are for example known as Nikkol Decaglyn, Caprol or Polymuls);

g) sterol derivatives including polyethylene glycol derivatives of sterols such as PEG-24 cholesterol ether, PEG-30 cholestanol, PEG-25 phytosterol, PEG-30 soyasterol, etc.; (surfactants belonging to this class are known, for example, as Solulan or Nikkol BPSH);

h) polyethylene glycol fatty acid sorbitan ester, such as PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate or PEG-20 sorbitan tristearate or PEG-20 sorbitan monooleate or PEG-20 sorbitan trioleate or PEG-20 sorbitan monoisostearate or PEG-20 sorbitan monopalmitate or PEG-20 sorbitan monostearate, PEG-4 sorbitan monolaurate, PEG-5 sorbitan monooleate, PEG-6 sorbitan monooleate or PEG-6 sorbitan monolaurate or PEG-6 sorbitan monostearate, PEG-8 sorbitan monostearate, PEG-30 sorbitan tetraoleate, PEG-40 sorbitan oleate or PEG-40 sorbitan tetraoleate, PEG-60 sorbitan tetraoleate, sorbitan monoglyceryl laurate, sorbitan monoglyceryl monostearate, sorbitan monooleate, sorbitan tetraoleate, sorbitan, PEG-80 sorbitan monolaurate, PEG sorbitol hexaoleate (Atlas G-1086), and the like; (surfactants belonging to this class are known, for example, as Liposorb, Tween, Dacol MSS, Nikkol, Emalex, Atlas);

i) polyethylene glycol alkyl ethers such as polyethylene glycol-10 oleyl ether or polyethylene glycol-10 cetyl ether or polyethylene glycol-10 stearyl ether, PEG-20 oleyl ether or PEG-20 cetyl ether or PEG-20 stearyl ether, PEG-9 lauryl ether, PEG-23 lauryl ether (laureth-23), PEG-100 stearyl ether and the like; (surfactants belonging to this class are known, for example, as Volpo, Brij);

j) sugar esters such as sucrose distearate/monostearate, sucrose monostearate or sucrose monopalmitate or sucrose monolaurate and the like; (surfactants belonging to this class are known, for example, as Sucro esters, Crodesta, sucrose monolaurate);

k) polyethylene glycol alkylphenols such as PEG-10-100 nonylphenol (Triton X series), PEG-15-100 octylphenol ether (Triton N series), and the like;

l) polyoxyethylene and polyoxypropylene block copolymers (poloxamers), such as poloxamer 108, poloxamer 188, poloxamer 237, poloxamer 288, and the like; (surfactants belonging to this class are known, for example, as Synperonic PE, Pluronic, Emkalyx, Lutrol ™ cells, supranic, Monolan, Pluracare, Plurodac).

More preferred surfactants are nonionic surfactants having an HLB value of 20 or less. A suitable surfactant is F108 (BASF).

To facilitate loading of the microparticles into the tube, different sets of microparticles may be adhered together using hydrogel as a binder prior to loading the microparticles into the tube. The binder may be carefully selected so as not only to bind but also to act as a means of wicking moisture into the interior of the tube, which facilitates drug diffusion, especially when the microparticles are composed of hydrophobic drugs. In addition, the binder may be selected to actually enhance the solubility of poorly water soluble compounds formulated into the microparticles. This can be achieved, for example, by providing a low pH environment for these compounds which are more soluble at low pH. Alternatively, the binder may be a polymer that self-emulsifies in an aqueous system that provides a surfactant environment for poorly water soluble drugs incorporated into the microparticles. Some examples of binders include albumin, casein, waxes, starches, cross-linked starches, monosaccharides, glucose, polysucrose, polyvinyl alcohol, gelatin, modified cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl-ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, sodium alginate, hyaluronic acid derivatives, polyvinylpyrrolidone, polymaleic anhydride esters, polyorthoesters, polyethylene diamine, ethylene glycol, polyethylene glycol, methoxypolyethylene glycol, ethoxypolyethylene glycol, polyethylene oxide, poly-1, 3-bis (p-carboxyphenoxy) propane-co-sebacic anhydride, N-diethylaminoacetic acid, block copolymers of polyethylene oxide and polypropylene oxide, polyacrylic acid and polyacrylic acid derivatives, and mixtures thereof, Guar gum, carob gum, chitin, self-emulsifying polymers or agents. An effective amount of binder is one that has sufficient viscosity to bind the particles together but has a lower solids content to minimize the amount of interior space it requires.

In one embodiment of the invention, the hydrogel itself contains one or more drugs in addition to the one or more drugs present in the microparticles. This facilitates achieving high initial plasma concentrations of the one or more drugs.

The microparticles or microparticle/hydrogel mixtures can be introduced into the tube by manual techniques or by automated techniques. The manual technique involved transferring the mixture into a tube with a spatula. Automated techniques include the use of filling machines commonly used in the pharmaceutical industry.

To close the tube to completely enclose the cavity, the tube ends may be heat sealed. This can be done, for example, by cryosurgical burning with Bovie. Before heating, a small piece of tubular material is first inserted into the section of the end of the tube to be sealed, and then the local end zone is heated to melt the material; the seal may be formed by squeezing the tip by hand. One end of the tube was first sealed and then the tube was filled with the indicated contents. The open end can thereafter be sealed in the same manner. There are many other possible ways to seal the ends. For example, a conventional heat sealer can be used, wherein the end section of the tube to be sealed is placed between two edges of the heat sealer. Sealing is accomplished by simultaneous application of heat and pressure. The ends may also be glued by using a suitable adhesive; a small amount of adhesive may be placed inside the end region of the tube and pressure is then applied to compress the end. A predetermined hold time is typically required to form a secure seal.

The implant may have any shape including, but not limited to, a disc, a sphere, or a cylinder, but preferably the implant is cylindrical. The cylinder may be 1-5mm in diameter and 0.5-5cm in length, more preferably 1-4mm in diameter and 1-5cm in length. It is particularly useful in antiviral therapy, such as anti-HIV therapy and anti-hepatitis therapy.

Examples

Example 1

An adhesive solution was prepared with poly (acrylic acid) (PAA) (Aldrich) with a molecular weight of 1.25 million kilodaltons. Solutions of 3 concentrations of hydrogel were prepared by dissolving poly (acrylic acid) with deionized water. The concentrations were 5% (w/w), 0.5% (w/w) and 0.25% (w/w). Although a mixture of microparticles containing all three hydrogels was obtained, the most manageable mixture was 0.5% (w/w) in terms of not being so viscous that the microparticles were difficult to disperse in the hydrogel and in terms of the hydrogel not being too fluid to be easily loaded into the tube. The pH of each hydrogel was measured using pH paper, with 5% of the hydrogels having a pH between 2 and 3 and the other two hydrogels having a pH of 3.

The particle/hydrogel mixture can be prepared so that it is one part hydrogel and two parts microparticles in such a way as to minimize the space in the tube required for the gel and maximize the internal space of the microparticles. Microparticles consisting of 70(w/w) TMC278 and 30% (w/w) poly (lactic-co-glycolic acid) (PLGA) (DLG 50501A Surmodics Pharmaceuticals, Birmingham, AL) were prepared using a spinning disk method. Generally, to prepare particles using a rotating disk process, a disk of a particular size is selected and mounted to a motor having an adjustable rotation rate to control the disk speed. The polymer is dissolved in a suitable solvent, such as acetone, and the drug is added to the polymer solution and stirred. The resulting mixture was fed onto a disk at a specific rate. As the disk rotates, the centripetal force forms droplets or particles to the edge of the disk. The pellets are directed to a drying cone with a predetermined temperature gradient. The solvent is removed from the granules during this drying step, causing the granules to harden or solidify, and the granules are collected.

In this embodiment of the present invention,a4% (w/v) PLGA solution was prepared in acetone. The speed of the disc (Southwest research institute, San Antonio, TX) was 9250rpm, the disc size was 7.62cm, the feed rate was 45 g/min, and the cone exit region temperature was between 45-48 ℃. TMC278 is added to the PLGA solution, stirred for about 15-20 minutes and then fed to the pan. Particle size distribution was measured using a Malvern Mastersizer (Malvern Instruments, Ltd, Worcestershire, UK). As a result: d₁₀Is 29 μm, d₅₀Is 48 μm, d₉₀Is 69 microns.

The tubes were prepared by electrospinning 120mg/ml polydioxanone in hexafluoroisopropanol. The tube has an inner diameter of 3mm and a wall thickness of 50 μm. The length of the tube used was about 2.54 cm. Scanning electron microscopy (JEOL JSM 5900LV, Tokyo, Japan) analysis of the tubes showed that the size of the openings (pores) in the network formed by the randomly oriented fibers was between 1-20 microns. First, one end of the tube is heat sealed. Heat sealing was accomplished by cryosurgical burns with Bovie. Before heating, a small piece of tubular material is first inserted into the section of the end of the tube to be sealed, and then the local end zone is heated to melt the material; the seal may be formed by squeezing the tip by hand. After one end was sealed, the tube was weighed together with a small piece of tubing material that would be added to the other end of the tube when the other end was heat sealed (empty tube mass was recorded) and then filled with the microparticle/hydrogel mixture using a spatula. The other end of the tube was heat sealed (with the added pieces) following the same procedure as described above. The sealed tube was weighed. The weight difference between the filled and unfilled tubes is equal to the weight of the contents. The contents of each tube are detailed as summarized in table 1.

Table 1: electrospinning tube containing microparticle/PAA mixture

Sample ID	Gel concentration (w/w)	Gel pH	Tube content mass (mg) (microparticle/hydrogel mixture)	Mass (mg) of TMC278 in tube
					3895-42-1	5%	2-3	45.12	16
3895-42-2	0.5	3	59.83	21
					3895-42-3	0.25	3	36.1	17

The sample was placed in the method 1 sampling system using a Hanson resolution Tester (Hanson Research corp., Chatsworth, CA) with 500ml elution containers. The medium was 500ml of distilled water and samples were taken on days 1,3, 7, 10 and 14. The release data are summarized in table 2. The experiment was carried out at 37 ℃.

Table 2: elution of TMC278 from Poly (acrylic acid) gel from electrospinning tubes

Time (sky)	Eluted 3895-42-1 microgram/% of total load%	Eluted 3895-42-2 micrograms/% of total load%	Eluted 3895-42-3 micrograms/% of total load%
				1	434 / 2.7	444 / 2.1	429 / 2.5
3	445 / 2.8	398 / 1.9	408 / 2.4
				7	443 / 2.8	388 / 1.8	400 / 2.3
10	443 / 2.8	402 / 1.9	381 / 2.2
				14	448 / 2.8	399 / 1.9	406 / 2.4

The solubility of TMC278 increased significantly when pH = 2. Solubility experiments demonstrated that the solubility in water at pH =2 was 950 times higher than at pH = 7. The rate of elution of TMC278 from the polymer matrix may be increased by using an acidic adhesive gel that is effective in lowering the pH. Increasing the concentration of acidic polymer in the gel can even further decrease the pH (table 1). As shown in Table 2, dispersing TMC278 particles in a 5% (w/w) poly (acrylic acid) gel with a pH of 2-3 results in a greater amount of TMC278 being eluted from the particles than TMC278 particles dispersed in a hydrogel at a low concentration of pH 3.

Example 2

A3% (w/v) carboxymethyl cellulose (CMC; Hercules, 7H3SFPH) gel was prepared in PBS. The viscosity of the gel when prepared in water is 3000-6000 cps. However, when prepared in a salt solution, the viscosity of the polymer is reduced 2/3 due to its sensitivity to ionic strength, and therefore it is easily mixed with the microparticles. Microparticles consisting of 70% (w/w) TMC278 and 30% (w/w) poly (lactic-co-glycolic acid) (PLGA) (DLG 50501A, Surmodics Pharmaceuticals, Birmingham, AL) were prepared using a spinning disk method. Briefly, a 4% (w/v) polymer solution was prepared in acetone. The speed and size of the discs were 9250rpm and 7.62cm, respectively. The feed rate was 45 g/min and the cone exit temperature was between 45-48 ℃. TMC278 is added to the PLGA solution, stirred for about 15-20 minutes, and then fed to the discs. The particle size distribution was measured using a MalvernMastersizer (Malvern Instruments, Worcestshire, UK). The results show that d₁₀Is 29 μm, d₅₀Is 48 μm, d₉₀Is 69 microns. A2 mg sample of microparticles was mixed with 2ml of a 3% CMC gel, the total loading of TMC278 in this mixture being 2.25% (w/w).

The tube was prepared with a polylactide-co-glycolic acid copolymer with lactide/glycolide molar ratio 85/15. Tubes were extruded using a small scale commercial extrusion line consisting of a 1 "single screw extruder (Davis Standard), a water cooling tank, a tractor and a cutter. The diameter and roundness of the tube were also monitored with an in-line laser diameter measurement system. In the extrusion process, raw material in the form of resin is fed from a top mounted hopper into the barrel of the extruder, where a rotating screw pushes the resin forward into the barrel, which is heated to the desired melting temperature. The appropriate temperature profile was set and maintained in the three heating zones of the extruder. This causes the plastic resin to gradually melt as it passes through the barrel (reducing the risk of excessive heating which can lead to polymer degradation).

At the front end of the barrel, the molten plastic leaves the screw, passing through a screen to remove contaminants from the melt, which also helps to establish a more stable back pressure. The molten plastic enters the mold after passing through the screen plate. The casting mold is a tubular structure having a mandrel in the center that creates an annular structure for creating the tubular profile. A small amount of air was injected into the interior of the polymer tube through the end of the mandrel (the air flow rate was controlled by an air flow controller). The extrudate in the form of a tube is drawn off by a downstream rubber roller and passed through a cold water tank where the tube cools to harden. Downstream of the tractor is a cutter where the extruded final sized tube is cut to a predetermined length and collected. An on-line laser diameter measurement system is installed after the cooling bath and before the tractor for continuous on-line measurement and monitoring of extruded tube dimensions.

The extruded tube was pierced with a 10 micron hole using a laser. The polymer tube was perforated with a pattern of 20 rows by 20 columns of holes. The inner diameter of the tube was 1.5mm and the outer diameter was 1.6 mm. A2.54 cm sample was cut from the tube and one end was heat sealed (following the same procedure described in example 1). A 33.67mg sample of the microparticle/CMC gel mixture was transferred into the tube by using a spatula and the other end of the tube was heat sealed as described above.

The sample was placed in the method 1 sampling system using a 500ml container using a Hanson resolution Tester (Chatsworth, Calif.). The medium was 500ml of distilled water. Samples were taken on days 1,3, 7, 10 and 14. The release data are summarized in table 3. The experiment was carried out at 37 ℃.

Table 3: release of TMC278 from particulates in porous tubes

Sky	Cumulative amount (micrograms) of TMC278 released	Cumulative release of TMC 278; (percentage of total loading)
			1	58	7.6
3	59	7.8
			7	112	14.7
10	125	16.4
			14	138	18.2

Example 3

A0.5% (w/w) poly (acrylic acid) (Aldrich) gel was prepared in water and 400mg of the gel was mixed with 960mg of TMC278 particles. The microparticles consisted of 70% (w/w) TMC278 and 30% (w/w) poly (lactic-co-glycolic acid) (DLG 50501A, Surmodics Pharmaceuticals, Birmingham, AL) as in example 1 and2. Measuring the particle size distribution of the microparticles as described above; d₁₀Is 29 μm, d₅₀=48 μm, d₉₀Is 68 microns. The mixture was charged into a polydioxanone tube, which was prepared according to the procedure described in example 2. The tube is perforated using the laser techniques described above. The tube was 30mm long and 5mm from each edge was unperforated. The perforations in the middle 30mm long section were arranged in 40 rows of 2400 holes each. Each pore had a diameter of 50 microns. The mass of the tube before filling was 102.01 mg. The mass of the tube after filling was 190.64mg (the calculated TMC278 content in the tube was 43.4 mg).

Two further samples were prepared in this manner, with the mass of the microparticle/gel mixture in the tube being 53.7mg and 46.3mg respectively. HPLC analysis confirmed the content of TMC278 in the respective tubes to be 39.2 and 32.1 mg.

Example 4

An electrospun polydioxanone tube was prepared with a 120mg/ml polymer solution in hexafluoroisopropanol. The wall thickness of the tube was 500 microns. By a particle size distribution of d₁₀= 29、d₅₀=48 and d₉₀Particles of = 68 μm to prepare a microparticle mixture. The composition of the microparticles was 70% (w/w) TMC278 and 30% (w/w) PLGA 50/50 (0.1 dl/g). 1200mg of the microparticle sample was mixed with 500mg of a 0.5% poly (acrylic acid) hydrogel. The mass of the tube 2cm long was 82.8mg before filling and 203.0mg after filling.

Example 5

An electrospinning tube made from 150mg/ml polydioxanone solution as prepared in example 1 was filled with the microparticle mixture described in example 4. The wall thickness of the tube was 200 microns. The 2cm tube had a mass of 29.0mg before filling and 129.3mg after filling.

Example 6

An electrospinning tube made from 60mg/ml polydioxanone solution as prepared in example 1 was filled with the microparticle mixture described in example 4. The wall thickness of the tube was 500 microns. The 2cm tube had a mass of 55.4mg before filling and 151.9mg after filling.

Example 7

Two different sets of TMC 278-containing microparticles were prepared. A set of microparticles was prepared from a 4% (w/v) solution of poly (lactic-co-glycolic acid) (DLG 50501A, Surmodics Pharmaceuticals, Birmingham, AL) in acetone. The microparticles were prepared using the rotating disk method described in example 1. The disc speed was 7500rpm and the disc size was 7.62 cm. The feed rate was 45 g/min and the cone exit temperature was 45-48 ℃. The majority of the microparticles formed were between 50-75 microns with a TMC278 loading of 70% (w/w) in the granules. A second set of microparticles was prepared from a 4% (w/v) poly (lactic-co-glycolic acid) (DLG 50501A, containing 2.5% (w/w) lactide-glycolide oligomer (5050 DLG1CA, Surmodics pharmaceuticals, Birmingham, AL) in acetone solution.TMC 278 loading in the second set of microparticles was also 70% w/w. these were also prepared using the rotating disk method the disk speed was 9250rpm, the feed speed was 50-55 g/min, the cone exit temperature was 45 ℃. 519mg of a 0.5% poly (acrylic acid) aqueous gel sample was mixed with 606mg of TMC microparticles prepared from DLG 50502A polymer and 599mg of TMC particles prepared from DLG 50501A with added DLG1 CA. the microparticle mixture was filled with a perforated polydioxanone tube as described in example 3. the empty tube mass was 85.01mg and the mass of the tube filled with the microparticle mixture was 211 mg.

Example 8

Two different groups of microparticles were prepared, one containing TMC278, a potent non-nucleoside reverse transcriptase inhibitor for HIV treatment. The second group contains TMC114, a protease inhibitor for HIV therapy, also known as darunavir (darunavir). TMC278 particles were prepared using the rotating disc method described above. For these particles, 4% (w/v) poly (lactic-co-glycolic acid) (5050 DLG 1A, Surming Pharmaceutics, Birmingham, AL) acetone solution with 7.5% (w/v) oligomer poly (lactic-co-glycolic acid) (5050 DLG1CA, Surming Pharmaceutics, Birmingham, AL) added was prepared. The loading of TMC278 relative to polymer was 70% (w/w). The particle size is between 20 and 75 microns.

A second set of microparticles was prepared by dissolving TMC114 in a 4% (w/v) poly (lactic-co-glycolic acid) (5050 DLG 1A, Surmodics Pharmaceutics, Birmingham, AL) acetone solution. The drug-polymer solution was applied to a 7.62cm disk at 9500rpm at a feed rate of 45 g/min. The disk chamber exit temperature (cone exit temperature) was 42-45 ℃ and the TMC114 loading in the particles was 70% (w/w). A microparticle mixture was prepared by preparing a 0.5% (w/w) poly (acrylic acid) aqueous gel and mixing 507 mg of this gel with 502 mg of TMC78 microparticles and 507 mg of TMC114 microparticles. The microparticle mixture was charged into an extruded and perforated polydioxanone tube (see example 3). The perforation pattern and the perforation size are as described in example 3. As before, one end of the tube is first heat sealed, filled with the mixture, and then the other end is heat sealed. 5 different samples were prepared and the elution rates of the two drugs were measured (Table 4). Due to the extreme insolubility of TMC278 in water, the medium used to measure the elution rate was 90% (v/v) methanol and 10% (v/v) water.

Table 4: TMC114 and TMC278 from isolation of particle build-up release in polydioxanone extruded and perforated tubes

Sample numbering	Quality of microparticle/gel mixture (mg)	Day 1 TMC114(mg)	Day 3 TMC114(mg)	Day 7 TMC114(mg)	Day 1 TMC278(mg)	Day 3 TMC278(mg)	Day 7 TMC278(mg)
								3998-8-1	62.93	3.0	16	22	7.1	13.1	21.4
3998-8-2	80.71	3.5	20	33	8.5	15.7	35.5
								3998-8-3	72.88	4.0	19	19	8.4	16.5	19.5
3998-8-4	74.96	4.0	22	28	9.8	16.8	25.4
								3998-8-58-5	66.77	3.8	22	22	9.3	14.8	19.7

Example 9

In vivo testing of electrospun tubes containing two groups of microparticles

From 100 mg/ml polydioxanone (IV)_HFIP= 1.99 dl/g) was electrospun into a tube. A 4mm mandrel was used to provide a constant inner diameter of 4 mm. The spindle rotation speed was 400 rpm, the charging voltage was between 20/-10kV and the pump flow rate was 10 ml/h. The resulting wall thickness was 500 microns. The fibers had a diameter of 1-2 microns and the average pore size formed by the network of fibers was 20 microns as determined by scanning electron microscopy.

Microparticles were prepared by the rotating disk method with polymer/acetone solutions at concentrations between 3-4% (w/w). Two sets of microparticles were prepared. One set of target compositions was 70% (w/w) TMC278 and 30% (w/w) PLGA 50/50 (Lakeshore biomaterials IV)_HFIP= 0.79 dl/g). Another set of microparticles had a target composition of 70% (w/w) Compound 1 (= Compound 14 of WO 01/25240) and 30% (w/w) PLGA 50/50 (Lakeshore)Biomaterials IV_HFIP=0.18 dl/g). This compound 1 has the following structure, which will be referred to hereinafter as compound 1:

the disc speed was between 7300 and 7500rpm, and the cone inlet and outlet temperatures were 56-57 deg.C and 33.5 deg.C, respectively. The loading of TMC278 and Compound 1 in the respective microparticles was measured by HPLC, with TMC278 and Compound 1 concentrations of 65% (w/w) and 35% (w/w), respectively. The difference between the target concentration and the actual concentration of compound 1 indicates that there is a greater difficulty in encapsulating compound 1.

The particle size range was determined by placing a randomly selected sample on the stage of an optical microscope and measuring the different sizes of the particles in the randomly selected sample with a ruler. The resulting TMC278 particles ranged in size from 10-100 microns, with compound 1 particles ranging in size from 20-100 microns.

Mixing of the two types of microparticles was accomplished by transferring the two sets of microparticles into a 50ml glass round bottom flask and mixing with an overhead mixer equipped with a glass stir bar and a teflon paddle. The microparticles were dry blended at 100rpm for 30 minutes (previously determined as sufficient mixing time to obtain a uniform, reproducible mixture of the two microparticles).

Approximately 133mg of the microparticle mixture was introduced into the electrostatically prepared tube with a spatula.

The prepared tubes were implanted into the dorsal subcutaneous space of 4 male Sprague-Dawley rats weighing 250-350 g. The dose of TMC278 was 139mg/kg and the dose of Compound 1 was 64 mg/kg. The tail vein was sampled at a predetermined time point. Blood samples were immediately centrifuged to extract plasma, which was analyzed for compound 1 and TMC278 using LC/MS. The lower limit of the quantitation of TMC278 and Compound 1 was 0.4 ng/ml and 2 ng/ml, respectively. The plasma concentration values at each time point for each drug tested are shown in table 5.

Table 5: plasma concentrations of TMC278 and Compound 1

Medicine	Animal numbering	3 hours ng/ml	1 day ng/ml	3 ng/ml for day	7 days ng/ml	14 days ng/ml	28 days ng/ml	35 ng/ml day
									TMC278	1	0.505	<0.4	<0.4	0.421	<0.4	<0.4	<0.4
TMC278	2	0.562	0.441	0.518	0.645	<0.4	<0.4	0.527
									TMC278	3	0.462	<0.4	<0.4	<0.4	<0.4	<0.4	0.769
TMC278	4	0.576	0.575	0.549	<0.4	0.424	0.475	0.400
									Compound I	1	3.93	6.39	10.0	9.95	7.17	6.07	5.75
Compound I	2	2.37	12.6	15.1	13.6	12.7	8.86	12.0
									Compound I	3	4.08	9.95	14.2	13.2	16.6	12.4	20.0
Compound I	4	4.46	10.5	15.9	13.0	9.89	10.5	11.6

Example 10

In vivo test for laser drilling melting extruded tube containing two groups of particles

Microspheres prepared with a single-screw extruder fitted with a tube mold, polydioxanone (IV)_HFIP= 1.99 dl/g) a tube having an inner diameter of 4.5mm was extruded. Tube size monitoring with on-line laser diameter measurement system and tractor hold. And performing laser hole drilling on the tube after extruding the tube. In preparation for the laser drilling, mask patterns were prepared with holes 260 microns apart from each other. The inside and outside diameters of the holes were measured by scanning electron microscopy. The results show an average outer diameter of 100 microns and an average inner diameter of 30 microns. Microparticles were prepared as described in example 9. Approximately 133mg of the microparticle mixture was introduced into the tube.

The prepared tubes were implanted into the dorsal subcutaneous space of 4 male Sprague-Dawley rats weighing 250-350 g. The dose of TMC278 was 139mg/kg and the dose of Compound 1 was 64 mg/kg. The tail vein was sampled at a predetermined time point. Blood samples were immediately centrifuged to extract plasma, which was analyzed for compound 1 and TMC278 using LC/MS. The lower limit of the quantitation of TMC278 and Compound 1 was 0.4 ng/ml and 2 ng/ml, respectively. The plasma concentration values at each time point for each drug tested are shown in table 6.

Table 6: plasma concentrations of TMC278 and Compound 1

Analyte	Animal numbering	3 hours ng/ml	1 day ng/ml	3 ng/ml for day	7 days ng/ml	14 days ng/ml	28 days ng/ml	35 ng/ml day
									TMC278	1	0.551	<0.4	<0.4	<0.4	<0.4	<0.4	<0.4
TMC278	2	1.42	0.432	<0.4	0.4	<0.4	0.451	0.403
									TMC278	3	2.51	1.22	1.14	0.695	0.425	1.36	2.11
TMC278	4	1.61	<0.4	<0.4	<0.4	0.456	0.773	0.881
									Compound I	1	2.88	<2	<2	<2	<2	<2	<2
Compound I	2	16.4	4.20	3.35	3.44	2.70	4.32	3.56
									Compound I	3	27.0	9.25	6.06	3.13	2.26	13.0	13.0
Compound I	4	16.5	3.71	<2	<2	3.66	4.30	2.57

Example 11

In vivo testing of laser-drilled melt extruded tubes containing two sets of particles formulated with F108

Laser-drilled melt extruded tubes were prepared as described above in example 10. Microparticles were prepared from a 3% (w/w) polymer/acetone solution by the rotating disk method. Two sets of microparticles were prepared. One group had a target composition of 70% (w/w) TMC278, 20% (w/w) PLGA 50/50 (Lakeshore Biomaterials IV)_HFIP= 0.79 dl/g) and 10% (w/w) F108 (BASF). Another group of microparticles has a target composition of 70% (w/w) Compound 1, 20% (w/w) PLGA 50/50 (Lakeshore biomaterials IV)_HFIP=0.18 dl/g) and 10% (w/w) F108. F108 was added to the polymer solution.

The disc speed and conical inlet and outlet temperature conditions were the same as those used in examples 9 and 10. The loading of TMC278 and Compound 1 in the microparticles was measured by HPLC and the resulting concentrations were 61% (w/w) and 50% (w/w), respectively.

The range of particle sizes was determined by randomly picking a sample of particles and placing it on the stage of an optical microscope and measuring with a ruler the different sizes of particles in the randomly picked sample. The particle sizes of TMC278 and compound 1 ranged from 10-100 microns and 20-100 microns, respectively. Microparticles were mixed as described in example 9. Approximately 133mg of the microparticle mixture was introduced into the tube with a spatula to transfer the contents.

The prepared tubes were implanted into the dorsal subcutaneous space of 4 male Sprague-Dawley rats weighing 250-350 g. The doses of TMC278 and Compound 1 were 109mg/kg and 78mg/kg, respectively. The tail vein was sampled at a predetermined time point. Blood samples were immediately centrifuged to extract plasma, which was analyzed for compound 1 and TMC278 using LC/MS. The lower limit of the quantitation of TMC278 and Compound 1 was 0.4 ng/ml and 2 ng/ml, respectively. The results of plasma concentrations at each time point for each drug tested are shown in table 7.

Table 7: plasma concentrations of TMC278 and Compound 1

。

Claims (15)

1. A degradable, removable, pharmaceutical subcutaneous implant for the sustained release of one or more drugs in a subject, wherein the pharmaceutical subcutaneous implant is comprised of a tube comprising an outer wall made of a degradable polymer completely surrounding a lumen, wherein the outer wall has a plurality of openings, wherein the lumen contains one or more sets of microparticles containing one active agent or a combination of two or more active agents, wherein at least one active agent is selected from HIV inhibitors or HCV inhibitors, wherein the microparticles are made of a biocompatible, biodegradable polymer, wherein the size of the microparticles is selected such that a majority of the microparticles cannot pass through the openings, wherein the rate of degradation of the polymer comprising the tube is slower than the rate of degradation of the microparticles.

2. The implant of claim 1, wherein the cavity contains two or more sets of microparticles.

3. The implant of claim 1, wherein the microparticles are embedded in a hydrogel.

4. The implant of claim 1, wherein the degradable polymer of the tube is selected from the group consisting of: aliphatic polyesters, polyamino acids, copolyether esters, polyalkylene oxalates, polyamides, polyiminocarbonates, polyorthoesters, polyoxaesters, polyesteramides, polyanhydrides, polyphosphazenes and mixtures thereof.

5. The implant of claim 4 wherein said polyoxaester is an amine group containing polyoxaester.

6. The implant of claim 4, wherein the degradable polymer is selected from copolymers of lactide and glycolide.

7. The implant of claim 4, wherein the degradable polymer is a homopolymer of polydioxanone.

8. The implant of claim 1, wherein said microparticles are made from a biocompatible, biodegradable polymer selected from the group consisting of: aliphatic polyesters, polyamino acids, copolyether esters, polyalkylene oxalates, polyamides, polyiminocarbonates, polyorthoesters, polyoxaesters, polyesteramides, polyanhydrides, polyphosphazenes and mixtures thereof.

9. The implant of claim 8 wherein said polyoxaester is an amine group containing polyoxaester.

10. The implant of claim 8, wherein the polymer used to make the microparticles is a biocompatible, biodegradable polymer selected from the group consisting of homopolymers and copolymers of lactide, glycolide, -caprolactone, p-dioxanone, and trimethylene carbonate.

11. The implant of claim 8, wherein the polymer used to make the microparticles is a biocompatible, biodegradable polymer selected from copolymers of lactide and glycolide.

12. The implant of claim 8, wherein the polymer used to make the microparticles is a biocompatible, biodegradable polymer selected from a copolymer of lactide and glycolide containing from 85% to 50% mole percent lactide.

13. The implant of claim 2 wherein one set of microparticles contains a nucleoside reverse transcriptase inhibitor and the other set of microparticles contains a non-nucleoside reverse transcriptase inhibitor.

14. The implant of claim 2 wherein one set of microparticles contains a non-nucleoside reverse transcriptase inhibitor and the other set of microparticles contains a protease inhibitor.

15. An implant according to any preceding claim, comprising rilpivirine.