KR100528639B1 - Hypodermic Graft - Google Patents

Abstract

The present invention is directed to subcutaneous polymer grafts that are not abused, inflamed, and do not degrade in vivo, for controlled release of hydromorphone for a prolonged period of time, almost near zero order. The invention also includes methods of alleviating pain caused by cancer using grafts and methods of treating opioid drug addiction.

Description

Subcutaneous graft

Field of invention

The present invention provides long-term pain relief or opioid drug addiction treatment by making illegal use of potent opioids difficult and ensuring prolonged and sustained release of the formulation, and potentially fatal consequences of irregular release of drugs from the device. A unique device for use in chronic subcutaneous grafts of potent opioids in a form that helps to prevent them.

Background of the Invention

Nearly 70% of patients with cancer experience pain due to the tumor they have or their treatment. As expected, in developed and developing countries at increasing rates, cancer and cancer-related pain are becoming a major social and medical concern. The global use of opioid analgesics for the basic treatment of most cancer-related pain varies greatly from country to country. In 1991, 86% of morphine was used in 20 developed countries worldwide, while the remaining 14% of morphine was used in the rest of the world's population [Joranson, DE, Journal of Pain and Symptom Management]. , 8 (6): 353-360, 1993].

Lack of opiates to alleviate the pain caused by most cancers in the world's population is the result of many factors, including the use of drugs and bypasses to addiction. Furthermore, many patients with cancer-related pain require long-term sustained administration of opioid analgesics, which sometimes requires the ingestion of multiple pills or tablets several times a day. However, following this medication administration plan is not easy. In addition, enteral drug administration is rarely allowed or forbidden in many patients who require constant drug administration. However, continuous parenteral administration of opioid analgesics is expensive and cumbersome, and depends on the utility of those skilled in refrigeration, catheter, pump and use thereof.

Drug addiction is an important social problem throughout the world. In the United States alone, there are hundreds of thousands of drug addicts enrolled in any clinic for any given day. Most of them apply to "metadon maintenance" as a basic part of the therapy for them. Most behavior and compliance problems usually complicate the treatment.

The cost of "metadon maintenance" therapy costs hundreds of dollars per patient per month. Much of this cost is related to frequent clinical visits and monitoring of urine tests, and drug prices associated with methadone preparations, which can reliably indicate that the medication regimen is being followed well.

Administration systems and devices for controlled release of a drug, ie controlled release and sustained or prolonged release, are well known in the art. Many methods have been published in the literature, including physiological modification of absorption or secretion, modification of solvents, chemical modification of drugs, absorption of drugs onto insoluble carriers, the use of suspensions and implanted pellets. Other methods include mixing the drug with a carrier, such as waxes, oils, fats and soluble polymers, which are slowly disintegrated by the environment causing the release of the drug. Such interest has been directed to storage containers, ie devices in which the drug is enclosed in a polymer container with or without solvent or carrier so that the drug can be passed from the reservoir.

Another type of drug administration device is a monolithic device in which the drug is dispersed in the polymer from which the drug is released by the breakdown of the polymer and / or by the passage of the drug through the polymer. Ethylene-vinyl acetate (EVA) copolymers are well known representative nonporous polymers [ Rhine , WD, et al, Journal of Pharmaceutical Sciences , 69: 265-270, 1980; Sefton, MV, et al, Journal of Pharmaceutical Sciences , 73: 1859-1861, 1984; Cohen, J., et al, J. Pharm. Sci. , 73: 1034-7, 1973]. The release kinetics of the drug from the polymer dosage system is a function of the molecular weight, lipid solubility, and charge of the formulation as well as the properties of the polymer, the percent drug load, and the properties of any matrix coating. The importance of these factors in connection with specific pharmacology, toxicology, and therapeutic targets requires that the design of the polymer graft for the particular formulation must be carefully constructed.

Ku et al . Have published a porous approach to obtain zero order emission [Ku et al, J. Pharm. Sci. , 74 , p.926 (1985).

Ongoing parenteral administration of opioid antagonists and agonists has become an area of considerable interest. Because, firstly, continuous parenteral administration may provide a new approach to the treatment of opioid drug abuse, and secondly, the under treatment of pain is widely recognized around the world.

A. Anesthetic Antagonists: Naltrexone

Over the past two decades, various approaches have been attempted to use polymers containing anesthetic antagonists in an effort to prevent drug abuse. The release properties of these antagonists are less important than the release properties of pure agonists, as evidenced by the primary kinetics well known in the literature.

1, glycerin graft

2. Cholesterol-glyceryltriacetate is demonstrated by primary kinetics in rats.

3. Glutamic Acid and Leucine-Biodegradable

4. Polylactic / Glycolic Acid (PLGA) Beads

B. Narcotic agonists / antagonists: buprenorphine

Primary dynamic release using agents that are not suitable for the treatment of chronic pain

1. Cholesterol-glyceryltriacetate is demonstrated by primary kinetics in rats.

C. Anesthetic Agonist: Morphine

Morphine is an excellent agent for the treatment of pain but is 7 times less potent than hydromorphone, making it much less suitable for long-term subcutaneous grafts. Many of these grafts have been proven to be life-threatening primary epidemiological releases for patients transplanted with grafts containing lethal amounts of opioids.

1. Polymer silicone elastomer

2. Silicones containing sodium alginate (swells in contact with water to release the drug)

3. Pellets

4. Polyanhydride Formulations

D. EVA Graft

EVA (ethylene vinyl acetate) polymers contain many types of drugs: hormones (ie prednisolone, insulin), anti-tumor agents (ie 5FU, adriamycin), proteins (ie albumin, immunoglobulins), neurotransmitters (ie Dopamine), and antibiotics. The ejection of the agents is not critical compared to the ejection of potent opioids.

1. Prednisolone [Miyazaki, S., et al, Chem. Pharm. Bull (Tokyo), 29: 2714-7, 1981]

2. 5FU [Wyszynski, RE, et al, J. Ocul. Pharmacol. , 5: 141-6, 1989]

3. Adriamycin [Lin, SY, et al, Biomat Art Cells Art Org. , 17: 189-203, 1981]

4. Insulin [Brown, L., et al, Diabetes , 35: 692-7, 1986; Brown, L., et al, Diabetes , 35: 684-91, 1986]-EVA coated with one side of the polymer and perforated EVA shows a nearly constant release rate.

5. Nerve growth factor [Hofman, D., et al, Bxp Neurol , 110: 39-44, 1990]

6. Immunoglobulins [Radomsky, ML, et al, Biomaterials , 11: 619-24, 1990]

7. Albumin [Niemi, S, M., et al, Lab Anim. Sci. , 35: 609-12, 1985]

8. Dopamine / levodopa [During, MJ, et al, Ann. Neurol. , 25: 351-356, 1989; Sabel, B, A., et al, Ann. Neurol. , 28: 714-717, 1990]

Testing mechanisms for making EVA polymers and their biocompatible and non-inflammatory properties have been described in Brown, LR, et al, J. Pharm. Sci. , 72: 1181-5, 1983; Langer, R., et al, J. Biomed. Mater. Res. , 15: 267-77, 1981; And Niemi, S, M., et al, Lab. Anim. Sci. , 35: 609-12, 1985]. All of these documents describe the non-inflammatory properties of the polymer and the techniques for making the polymer.

Critical factors involved in changing the release properties of drugs from EVA polymers have also been published [Brook, IM, et al, Br. Den. J. , 157: 11-15, 1984].

U. S. Patent No. 5,153, 002 discloses a cylinder having five sides coated with an impermeable layer and a cylinder coated with all but one flat side. Hemispheres with an impermeable coating, except for the exposed cavity in the central plane, provide zero order dynamics for albumin release [Hsieh, DS, et al, J. Pharm. Sci. , 72: 17-22, 1982. EVA, with an impermeable coating made of a polymer with a hole in the center of one side, provides zero order dynamics for insulin release. Particle size, drug loading, and matrix coating of the drug all have a significant impact on the release kinetics [Rhine, WD, et al, J. Pharm. Sci. , 69: 265-70, 1980].

Grothman et al. Published a delivery system in which the hydromorphone was embedded in a release control matrix made of poly- [ethylene-vinyl acetate] [Grossman et al, Proceedings ASCO , Vol. 19, p 337 (1991)].

Purpose of the Invention

It is an object of the present invention to provide an implantable and biocompatible polymer that delivers a continuous, subcutaneous delivery of a stable concentration of opioid analgesic periodically over a period of two weeks to six months or longer.

Another object of the present invention is to provide a means for administering hydromorphone, a form of pain relief that makes it difficult to use illegally.

Summary of the Invention

The present invention relates to a subcutaneous delivery system consisting of i) a polymer matrix material, ii) a therapeutic agent embedded in the matrix, and iii) a coating surrounding the matrix, the delivery system delivering a hydromorphone at a substantially constant rate. It is characterized in that applied to.

The present invention also provides a process for i) embedding a therapeutic agent into a polyethylene vinyl acetate matrix, ii) molding the matrix into a cylinder, iii) coating the matrix with poly (methyl methacrylate), and iv) the matrix. And a method of providing a delivery system comprising the step of making a cylindrical opening along the axis of the cylindrical matrix such that an inner wall is created, wherein the inner wall of the matrix is free of coating.

The present invention also relates to a mammal suffering from pain, which consists of subcutaneously administering at least one device to a painful mammal, in which two or three devices are administered, in which case they are combined together or administered separately. A method of alleviating pain in an extended period of time, the invention also includes a method of treating opioid drug intoxication of a mammal, consisting of subcutaneously administering at least one device to a mammal showing symptoms of opioid drug intoxication. .

Brief description of the drawings

1 is a perspective view of a delivery device according to the invention.

2 is a cross-sectional view of the delivery device along line 2-2 of FIG. 1. The thickness of the coating is exaggerated for illustrative purposes.

3 is a perspective view of a hemisphere embodiment of the invention.

4 is a perspective view of a cube embodiment of the present invention.

5 is a perspective view of a multiple device (tandem) embodiment of the present invention.

FIG. 6 shows the effect of poly (methyl methacrylate) with and without a central uncoated full thickness opening when hydromorphone is released from the device in vitro.

Figure 7 shows the effect of the change in height of a cylindrical device having a constant pore and device diameter when hydromorphone is released from a device coated with poly (methyl methacrylate) in vitro.

FIG. 8 demonstrates the release of hydromorphone from the delivery device of the present invention showing nearly zero order dynamics for up to 4 weeks in vitro. The initial release "burst", which complicates many controlled delivery devices, is omitted.

9 shows that changes in the amount of hydromorphone released per hour in vitro and the duration of hydromorphone delivery are readily accomplished through simple manipulation of the delivery device.

FIG. 10 shows that two delivery devices implanted subcutaneously in each of the five rabbits maintained stable and sustained plasma hydromorphone concentration for up to four weeks. The plasma concentrations were within the therapeutic range of humans.

Figure 11 shows the expected hydromorphone release from multiple implanted delivery devices and the plasma hydromorphone concentration observed over time in rabbits. Increasing the number of subcutaneous implant delivery devices resulted in a consistent and predictable increase in hydromorphone concentration in rabbit plasma. Systemic toxicity due to six grafts (approximately 900 μg / hour hydromorphone) was limited to temporarily increased sedation and reduced oral absorption.

Figure 12 shows that subcutaneously implanted osmotic pumps, which deliver approximately the same amount of hydromorphone per hour as the two delivery devices of the present invention, have produced comparable rabbit plasma hydromorphone concentrations.

FIG. 13 shows intravenous bolus doses equivalent to 50% (600 μg) and 100% (1200 μg) of the cumulative amount of hydromorphone released by the two delivery devices over 4 hours (typical human drug administration interval). A peak of rabbit plasma concentration is generated within one minute, followed by a rapid drop to background over several hours. Peak plasma hydromorphone concentrations were quite acceptable and were at least four times higher than the fixed state concentrations obtained with the device of the present invention.

Detailed description of the invention

The present invention is directed to an implantable device (2) that is biocompatible, does not cause inflammation, and does not biodegrade, which allows controlled release of potent opioids by subcutaneous grafts. Drugs, such as hydromorphone, are inserted into a release control matrix 14, such as polyethylene-vinyl acetate, wherein the polymer is a biocompatible, hydromorphone impermeable polymer 12, such as poly (methyl methacrylate). Coated. The graft typically has a cylindrical appearance, with the diameters of the top 4 and bottom 6 of the cylinder gradually exceeding the height of the outer wall 8 of the cylinder. The graft 2 is perforated to create an opening 10 in the top 4 and bottom 6 of the device 2 and create an uncoated inner cylinder wall 16. This structure allows for fixed hydromorphone release.

The device of the present invention minimizes the chance of drug abuse, improves the method of use and improves the need and value of expensive support equipment and personnel for patients with cancer-related pain that requires continuous opiate administration. Eliminates the need for external catheter and pump, which is expensive and sometimes inefficient. The device of the present invention delivers a stable amount of hydromorphone in vitro and in vivo for an extended period of time. Plasma hydromorphone levels made by the present invention show no significant toxicity. The fixed level achieved reduces toxicity and improves efficiency. Plasma hydromorphone levels made by the device of the present invention and the variability of such levels are almost similar to those obtained by an osmotic pump.

Coating 12 of the EVA polymer containing the drug effectively eliminates the initial "ejection" of drug release seen in many other delivery devices. Unlike intravenous bolus administration, the plasma hydromorphone levels obtained after implanting the device of the present invention remain stable and within the therapeutic range for the entire drug dosing interval.

The amount of hydromorphone released per hour, as well as the number of implanted devices, as well as the thickness (ie wall height 8) and diameter (i.e. diameter of top 4 and bottom 6) of these devices vary The duration of hydromorphone release, and the magnitude of plasma hydromorphone levels obtained, also vary accordingly.

The present invention solves the problem of "early ejection" for hydromorphone, eliminates repeated infusions of hydromorphone, provides longer duration management for stable and / or chronic cancer pain, and opioid drug addiction It provides a means for treating and prevents abuse of anesthetics, namely drug abuse. This is because the technique of making the device of the present invention makes it extremely difficult to extract hydromorphone from the device of the present invention.

Opioid

Hydromorphone (including hydromorphone hydrochloride) is a water-soluble, potent (six to seven times more potent than morphine) approved for subcutaneous use and is typically administered to patients with cancer-related pain [Vallner] et al, J. Clin. Pharmacol. , 21: 152-6, 1981, Bruera et al, J. Natl. Cancer Inst. , 80: 1152-4, 1988, Reidenberg et al, Clin. Pharmacol. Ther. 44: 376-82, 1988, Moulin et al, Can. Med. Assoc. J. , 146: 891-7, 1992, Moulin et al, Lancet , 337: 465-8, 1991]. Restrictions on the size of the subcutaneous delivery device favor the use of the opioid. Hydromorphone has good water solubility, so that the release pattern from the hydrophobic EVA polymer is advantageous.

matrix

Ethylene vinyl acetate (EVA) copolymers are polymers that are biocompatible, do not cause inflammation, and do not degrade in vivo. Polymers that do not degrade in vivo are used in the present invention to enable positioning. Furthermore, if the situation requires the physician to remove the graft 12 from the patient because of any adverse circumstances, the graft can be removed in a free state. As biodegradable grafts soften, they lose their structural density over time, making them difficult to remove in the event of an emergency or otherwise impossible to remove. Drug loaded matrices are advantageously prepared by solvent casting techniques. The polymer is first dissolved in an organic solvent, preferably a low boiling solvent such as methylene chloride or chloroform, which facilitates ultimate solvent removal by evaporation. The concentration range of the polymer solution is advantageously from 5 to 15% by weight. Too dilute concentrations lead to foam formation during casting, and too concentrated concentrations make it difficult for drug particles to disperse in solution.

The drug to be inserted into the EVA matrix is either dissolved or dispersed in the polymer solution at the high load drug level. The drug may be released by permeation through the polymer phase, or may be released by diffusion through the holes and channels if the drug has low solubility in the polymer. As the drug particles close to the matrix surface dissolve and release, the drug particles leave the holes and channels through which the drug particles inserted are released. Preferably the drug particles are classified as their size determines the size of the holes and channels. However, this process is not absolutely necessary unless the drug particles aggregate to form large clumps, for example hundreds of microns in size. Reasonably reproducible release kinetics (ie, nearly constant delivery) are also obtained with micronized, typically commercially available drug particles.

The polymer solution containing the drug can then be cast into a mold of the desired shape and size. After the solvent evaporates slowly (to prevent foam formation) the drug particles or drug molecules are inserted into the polymer matrix. Casting is normally done at low temperatures to prevent the settling of the drug particles while the solvent is evaporating. Typically the polymer solution containing the drug is poured into a mold which has been cooled to a temperature below the melting point of the solvent. The solution then cools rapidly, allowing the drug particles to be uniformly dispersed in the final matrix.

Other materials suitable for use as the matrix are silicone rubbers, hydrogels such as crosslinked poly (vinyl alcohol) and poly (hydroxy ethylmethacrylate).

coating

Coating the EVA polymer matrix eliminates the potentially lethal "spray effect" typically found in release control devices. The uncoated polymer delivers the hydromorphone spouted or spiked within the first 2 days of drug administration, and then drops to a minimum on the following days (see Figure 6). This is the most central problem in using subcutaneous grafts for drug delivery, and the present invention solves this problem for hydromorphone. In order to eliminate the ejection effect and obtain more stable or constant release kinetics without manipulation of non-uniform drug dispersion in the matrix, the EVA polymer 14 containing the drug is coated except for the small opening 10 in the center. The coating 12 should then be impermeable to the drug and should be tissue biocompatible to cause only minimal fibrous tissue encapsulation of the graft 2. Advantageously, poly (methyl methacrylate), a bone binder, is used with hydromorphone. Coating 12 should be thick enough for the intended life of the graft and is typically about 100 microns.

The coating of the matrix is advantageously made by dip-coating techniques. For example, a coating is applied by placing a disk on a needle of a selected diameter and immersing it in a polymer solution. The repetition of dip-coating and drying causes the needles to be removed after several coatings have been applied to expose the uncoated cylindrical holes. Alternatively, the opening along the axis of the matrix is created after the matrix coating. The drug is released only through this opening. In this form, almost constant drug release is obtained without gradient of drug concentration in the EVA polymer.

The coating material does not penetrate the hydromorphone and does not degrade in vivo (and negligible cutting of the polymer backbone or loss of mass within a period of two months), even if the solvent is not good for the chosen matrix. Soluble in solvent. Otherwise, the matrix must be partially dissolved during the dip-coating or the particles must be inserted into the coating. The solubility parameter of poly (methyl methacrylate) is 9-9.5 [cal / cm ³ ] ^0.5 . Other polymers that are impermeable to hydromorphone and have such solubility parameters are also suitable coatings for EVA-hydromorphone polymers.

Drug load

The proportion of hydromorphone to the EVA polymer is 10-90 hydromorphone weight%, preferably 30-70 hydromorphone weight%. The drug / EVA mixture is homogeneous. Higher levels of hydromorphone concentration are typically used when opening 10 is very small (see description below).

Graft geometry

The graft is preferably cylindrical (see FIGS. 1 and 2). Other geometries may be used where the distance between the uncoated wall and the coated wall (opposite the uncoated wall) remains constant or substantially (± 20%) constant throughout the graft. For example, hemispheres (figure 3) in which the uncoated walls are hemispherical in shape, or cubes (figure 4) with square openings extending the overall height (thickness) of the cube can be used. These geometries provide a nearly constant release rate throughout the life of the graft.

The diameter of the cylindrical graft is 5 to 100 mm, preferably 10 to 25 mm, and the height (thickness) is preferably 1 to 2 mm.

A single circular or substantially circular opening 10 extending along the axis of the cylindrical device and having a diameter of 50 microns to 3 mm, preferably 0.5 to 1.5 mm, is not coated therein through which the drug is released. To create a non-cylindrical region 16. The area of the opening for the device in a cylinder, cube, hemisphere or other shape is less than 10%, preferably less than 1% of the surface area of the top of the device.

The multi-unit device of the present invention is formed by placing cylindrical (or other shaped) grafts in parallel. That is, the axes of the individual devices are perpendicular to the axes of the multi unit device (see FIG. 5). In the case of a parallel arrangement, the contact area (ie the area where the units are joined) between the individual members (eg individual cylinders or cubes) may or may not be coated.

In another embodiment, the multi unit device is formed when the axes of the individual devices (eg cylinder or cube) are the same as the axis of the multi unit device. In order to combine the individual devices in this way and to enable drug release, the individual devices are separately separated, spaced and connected by spacer means. In one embodiment, the spacer is one or more members operated parallel to the multiple unit axis; Each of these spacers is attached to the outer wall of each individual device. Alternatively, the porous members may be alternately arranged (and combine the devices) between the individual devices, in another embodiment, a small spacer that contacts and couples the bottom of an individual device to the top of an adjacent device. These are used to form a multi unit device. Spacers are advantageously produced using a coating material such as poly (methyl methacrylate). In other embodiments, a wire coated with a coating material may be used as the spacer.

Administration of the graft

The device 12 of the present invention is implanted subcutaneously, preferably in the upper arm or abdominal region using known procedures. The dosage rate chosen is a safe and effective rate for the particular patient. Too slow a dosing rate does not lead to pain relief and too fast a rate causes sedimentation and resulting respiratory sedation. For example, in the treatment of pain caused by cancer, the use of a visible analog scale for pain measurement and titration of hydromorphone to the individual pain level of the patient selects the appropriate dose rate disc for the patient.

To treat pain due to cancer, grafts are typically designed to produce 0.1 to 25 mg, preferably 0.1 to 10 mg (eg .25 mg / hour, 1 mg / hour, and 4 mg / hour) per hour. . One to three grafts are implanted in the patient. The dose (mg / hour) is preferably adjusted by the height or opening diameter of the cylinder disc. In other words, as the height or opening diameter increases, the release rate increases (the larger uncoated surface area 16 remains exposed to the external environment) (see FIG. 7). Delivery of multiple grafts, individually or in parallel as described above, increases the rate of administration. Furthermore, increasing drug loading also increases the rate of administration.

To treat opioid dependence, grafts are typically designed to produce 0.1 to 0.5 mg of hydromorphone subcutaneously per hour. For a method of maintaining methadone, see literature [Strain et al, Ann. Intern. Med., 119 , 23-27 (1993), Gersteim and Lewin, N. Engl. J. Med., 323 , 844-848 (1990)].

The device can regulate hydromorphone release to the desired blood level for a period of two weeks to six months or longer. The life of the graft is preferably controlled by its diameter (the larger the diameter, the longer the life). Drug load, aperture size and height can also affect the life of the graft. Grafts that last for four weeks are good for the treatment of pain caused by cancer because oncologists usually evaluate their patients with chronic pain at least once a month. The degree of pain may be aggravated due to the progressive tumor requiring higher doses. Moreover, resistance to hydromorphone may also be present, such as when extended months of treatment may require higher doses to control the same degree of pain.

The device of the present invention delivers hydromorphone almost consistently. "Almost constant" is defined as a change of ± 5 times (500%), preferably ± 2 times (200%), more preferably ± 1 times (100%) of the desired delivery rate (in vitro or in vivo). do. Changes of five or more times cause an "eruption effect" which can damage the receptor or even cause death.

In one embodiment of the invention the release of the drug from the graft may add additional delivery of the opiate (oral, rectal route) when the patient experiences increased pain.

Treatment of pain

The device of the present invention can be used in any case where oral opiates are indicated. Oral opiates are indicated in 85% of patients suffering from cancer pain. The present invention is particularly advantageous when oral administration is not appropriate or available or when it is toxic due to intermittent administration. The graft of the invention is applied to the treatment of pain due to cancer in humans or other animals. Grafts also apply to the treatment of other forms of chronic pain, such as chronic severe pain due to degenerative musculoskeletal or nervous system diseases.

Treatment of Opioid Dependence

Grafts of the invention are useful for the treatment of opioid drug (such as heroin) poisoning. Hydromorphone, which is given at low doses over an extended period of time, is effective in treating drug addiction. The graft of the present invention can be used in any situation where a methadone maintenance program can be used. The graft may last for an extended period of time without the dependency of the patient on which the low rate of administration of the drug should follow the oral administration schedule. Further use of the graft provides the drug in a form that actually eliminates the possibility of illegal use of the drug.

The following examples are illustrative and do not limit the composition or method of the present invention. Other suitable modifications and applications of the various conditions and parameters normally encountered in clinical therapies apparent to those skilled in the art are within the spirit and scope of the present invention.

Example

Example 1

Polymer formulation

The low temperature solvent casting technique was used to formulate the hydromorphone graft used in this example. EVA (molecular weight about 250,000) (Elvax-40W. Dupont) containing 40% by weight of vinyl acetate was washed in water and then dissolved in methylene chloride (CH ₂ Cl ₂ ) to make a 10% solution. The polymer was extracted with distilled water for 3 days in a Soxhlet extractor and then purified by extraction with acetone for 4 days to remove impurities and antioxidants. The matrix with the hydromorphone incorporated was prepared by solvent casting. A 10% (w / v) solution of EVA was made by dissolving 2 gm of pure EVA in 20 ml of methylene chloride.

Unclassified hydromorphone hydrochloride powder (Knoll Pharmaceuticals) was added to 10% EVA at room temperature to form a 50% by weight solution which was then magnetically stirred for approximately 10 minutes. Hydromorphone powder was mechanically classified in a predetermined particle size range and suspended in EVA solution. All visible clumps remaining in this solution were destroyed by glass stir bars.

The homogeneous suspension was quickly poured into a 14 cm diameter recrystallized dish which was previously rapidly cooled to -78 ° C on ice. Cover the dish to minimize condensation. After solidification (this process takes place within 15 minutes), the samples were dried in two 48 hour steps: first at −20 ° C. and then at room temperature under vacuum.

The hydromorphone polymer disks were cut from the dried circular slab using a No. 7 cork perforator to produce approximately 15 polymers of about 0.27 cm in thickness and 1.05 cm in diameter. A double and triple thickness (0.55-0.65 cm and 0.83 cm thick) of polymer was placed in the mold for experiments designed to demonstrate a change in the amount of hydromorphone released per hour of the mixture of EVA-hydromorphone mixtures. Made by doubling and doubling amounts. The polymer, 2.13 cm in diameter, was also cut from the dried EVA-hydromorphone slab using a No. 15 cork perforator to demonstrate the change during the drug release period.

Example 2

Polymer coating

An 18 gauge hollow steel needle was passed through the entire thickness of each EVA-hydromorphone polymer near the center of the polymer's circular face prior to coating. Each polymer was then "immersion-coated" for 10 seconds in a 10% poly (methyl methacrylate) (molecular weight: about 996,000) (Aldrich) solution in acetone. The poly (methyl methacrylate) coating enabled air drying for 24 hours at room temperature, at which time the needle was removed and the polymer was converted to pass the needle back in the opposite direction through the polymer's central hole. This process was then repeated two more times to produce an impermeable coating of triple thickness poly (methyl methacrylate) that completely wrapped each polymer. However, an 18 gauge cylinder (diameter of about 1.25 mm) passes through the center of each polymer, almost similar to the button hole of the button. The coating thickness was about 100-200 μm. The solubility parameter of the coating material is 9 to 9.5 [cal / cm ³ ] ^0.5 .

Example 3

In vitro release assay

Hydromorphone release from the coated EVA-hydromorphone polymer was in vitro by placing each polymer in a glass scintillation vial containing 10 ml of pH 7.4, 0.1 M sodium phosphate buffer, warmed to 37 ° C. Measured. All vials were placed in a 37 ° C. water bath. Buffer in each vial was collected at appropriate intervals and stored in a centrifuge tube at about 4 ° C., and 10 ml fresh phosphate buffer at 37 ° C. was added to each vial. Samples were periodically assayed in volume in a matched cuvette at 254 nm on a UV spectrophotometer, with the graduation set to zero for a blank 0.1 M, pH 7.4 phosphate buffer. Hydromorphone standards were included in each assay and, if necessary, the samples were diluted in buffer so that the absorbance of the samples could be measured on the linear portion of the standard curve.

The coated EVA-hydromorphone polymer released hydromorphone at a constant average rate of 164 μg per hour 4 days after in vitro release, which continued for more than 4 weeks. These polymers were coated with an impermeable layer of poly (methyl methacrylate) except for the full thickness of the center to eliminate the initial “eruption” that complicates many other delivery control devices. Changes in the amount of hydromorphone delivered per hour and the duration of drug delivery were readily accomplished by varying the thickness and diameter of the coated EVA-hydromorphone polymer.

In vivo experiment

Example 4A

Polymer release

Under general anesthesia, two coated EVA-hydromorphone polymers were placed in the subcutaneous sac of each of the five mature rabbits. The rabbits were housed one by one so that they could eat food and water freely. Blood samples were taken from each animal at appropriate intervals prior to transplantation and for up to 6 weeks after transplantation. Blood samples were centrifuged to separate plasma and stored in a -20 ° C freezer. Plasma samples were assayed using commercially available radioimmunoassay opiate screens and hydromorphone standards. In an attempt to demonstrate the relationship between the amount of hydromorphone implanted and the resulting plasma drug levels, additionally, two rabbits were each implanted with three sets of two polymers, one after the other, at appropriate weekly intervals. It was. The implanted coated polymer was first left in place so that the rabbit had two polymers that simultaneously delivered hydromorphone, followed by four and then six. Blood was taken and the plasma assayed as described above.

Two devices placed subcutaneously in rabbits produced stable and sustained plasma hydromorphone levels of 23-37 ng / ml for a period up to 4 weeks (see FIG. 10). Increasing the number of subcutaneous grafts in individual rabbits resulted in a sustained and predictable increase in rabbit plasma hydromorphone concentrations (see FIG. 11). No noticeable toxicity was observed in these animal experiments, although there was a temporary slight sedimentation after implantation of only two devices and an increase in sedimentation with a decrease in oral absorption after implantation of a larger number of devices. This also appeared to be temporary.

Example 4B

Osmotic pump discharge

To demonstrate rabbit plasma hydromorphone levels measured after device implantation, an Alzette Osmotic Pump was prepared that delivered approximately the same amount of hydromorphone as the two devices of the present invention per hour. Under general anesthesia, an Aljet osmotic pump (average pumping rate: 2.08 μl / hour, average fill volume: 2073 μl) was implanted into each subcutaneous of four rabbits and blood samples were collected as described above. Plasma was also prepared and analyzed as described above.

Aljet osmotic pumps designed to deliver 297 μl / hour hydromorphone produced average rabbit plasma hydromorphone levels of 28-51 ng / ml over a period of 2 weeks (see FIG. 12).

Example 4C

Hydromorphone Intravenous Response

600 μg and 1200 μg of one bolus (an amount equal to 0.5 to 1 times the cumulative amount delivered subcutaneously by a polymer or pump for 4 hours, typical of human dosing intervals) to intravenously in 2 rabbits Samples were collected at 0, 1, 2, 5, 10, 20, 30, 45, 60, 90, 120, 150, 180, 210, and 240 minutes respectively.

The 600 μg and 1200 μg macrocycles produced peak rabbit plasma hydromorphone levels of almost 200 and 250 ng / ml or more at 1 minute, which quickly dropped to background after 4 hours (see FIG. 13).

It will be apparent to those skilled in the art that numerous modifications and supplements may be made to the apparatus, and related systems disclosed herein, without departing from the invention.

Claims (18)

i) a matrix comprising poly (ethylene-vinyl acetate), ii) hydromorphone homogeneously inserted into the matrix, iii) consists of poly (methyl methacrylate) coating the matrix, and has a geometry in the form having an outer wall and an uncoated inner wall applied and coated to deliver the hydromorphone at a substantially constant rate. To avoid subcutaneous delivery system. The method of claim 1, wherein the delivery system has a geometry in the form such that the distance between the uncoated wall and the coated wall opposite the uncoated wall is maintained substantially constant throughout the delivery system. Delivery system. The delivery system of claim 1, wherein the delivery system is cylindrical and has a cylindrical opening along the axis of the delivery system so that an inner wall is formed in the delivery system. The delivery system of claim 1, wherein the coating has a thickness of 0.1 to 1 mm. A delivery system according to claim 1, wherein the matrix contains 50% by weight hydromorphone and 50% by weight poly (ethylene-vinyl acetate). 6. The delivery system of claim 5, wherein the hydromorphone is homogeneously distributed in the matrix. 4. A delivery system according to claim 3, wherein the height is 1-20 mm and the diameter is 5-100 mm. 4. A delivery system according to claim 3, wherein the cylindrical opening has a diameter of 0.05 to 3 mm. i) implanting the therapeutic agent into a polyethylene vinyl acetate matrix, ii) molding the matrix into a cylinder, iii) coating the matrix with poly (methyl methacrylate), and iv) creating a cylindrical opening along the axis of the cylindrical matrix such that an inner wall is created in the matrix Method for producing a delivery system consisting of. i) a polymeric matrix material that is biocompatible, does not cause inflammation and does not degrade in vivo, Ii) a therapeutic agent inserted into said matrix, and Iii) a subcutaneous delivery system, consisting of a coating surrounding the matrix, which is cylindrical and has a cylindrical opening along its axis such that an inner wall is formed therein. The delivery system of claim 10, wherein the polymer matrix material is polyethylene-vinyl acetate. The delivery system of claim 10, wherein the therapeutic agent is hydromorphone. The delivery system of claim 10, wherein the coating is poly (methyl methacrylate). The delivery system of claim 10, wherein the coating has a thickness of 0.1 to 1 mm. 11. A delivery system according to claim 10, wherein said matrix contains 50 weight percent hydromorphone and 50 weight percent poly (ethylene-vinyl acetate). The delivery system of claim 15, wherein the hydromorphone is homogeneously distributed in the matrix. The delivery system of claim 10, wherein the height is 1-20 mm and the diameter is 5-100 mm. A multi-unit delivery system comprising at least two delivery devices of claim 1 wherein the delivery devices are arranged in parallel.