|Numéro de publication||WO1988009664 A1|
|Type de publication||Demande|
|Numéro de demande||PCT/US1988/001965|
|Date de publication||15 déc. 1988|
|Date de dépôt||9 juin 1988|
|Date de priorité||10 juin 1987|
|Numéro de publication||PCT/1988/1965, PCT/US/1988/001965, PCT/US/1988/01965, PCT/US/88/001965, PCT/US/88/01965, PCT/US1988/001965, PCT/US1988/01965, PCT/US1988001965, PCT/US198801965, PCT/US88/001965, PCT/US88/01965, PCT/US88001965, PCT/US8801965, WO 1988/009664 A1, WO 1988009664 A1, WO 1988009664A1, WO 8809664 A1, WO 8809664A1, WO-A1-1988009664, WO-A1-8809664, WO1988/009664A1, WO1988009664 A1, WO1988009664A1, WO8809664 A1, WO8809664A1|
|Inventeurs||Cato T. Laurencin, Robert S. Langer, Harry R. Allcock, Thomas X. Neenan|
|Déposant||Massachusetts Institute Of Technology|
|Exporter la citation||BiBTeX, EndNote, RefMan|
|Citations de brevets (3), Citations hors brevets (2), Référencé par (12), Classifications (9), Événements juridiques (2)|
|Liens externes: Patentscope, Espacenet|
POLYPHOSPHAZENE MATRIX EROSION
AND DIFFUSION RELEASE SYSTEMS
Background of the Invention
The invention relates to polyphosphazene sustained and controlled release systems.
Polyphosphazenes are polymers with backbones consisting of nitrogen and phosphorous separated by alternating single and double bonds. Each phosphorous atom generally is covalently bonded to two side chains ("R"). The repeat unit in polyphosphazenes has the general structure (1):
Grolleman et al., J. Controlled Release 3:143
(1986), and deVisser et al. , Proceedings of the 10th Internat, Sy . on Controlled Release of Bioactive Mate . 43 (1983), describe bioerodible drug delivery systems consisting of a polyphosphazene polymer covalently bonded to a therapeutic agent, i.e., the drug is part of the class of systems called "pendant side chain" systems in which the drug is covalently attached to the polymer backbone. Summary of the Invention
In general, one aspect of the invention features an inorganic polymeric matrix system (as distinguished from pendant side chain systems) for delivering a biologically active substance to an aqueous environment. The system includes a polyphosphazene polymer matrix body which physically entraps the biologically active substance to be released. Physically entrapped, as used herein, means that, until the body is introduced into the aqueous environment, the substance is physically retained within, but not covalently bonded to, the polyphosphazene polymer. The system components are designed and selected so that, when the system is exposed to an aqueous environment, the active substance is released to the environment at a sustained and controlled rate over a prolonged period. By "sustained release", we mean release over a period substantially longer than the period of biological activity achieved by administration in a single dose. By "controlled release", we mean release at rates that are predictable over time.
In preferred embodiments, the biologically active substance is a therapeutic agent, and the polymeric body provides controlled, sustained in vivo release of the therapeutic agent to a physiological fluid of a living organism (e.g. a mammal).
In one embodiment, the polymer is a bioerodible polyaminophosphazene that has side chains (e.g., imidizole groups or amino acid esters) that are capable of hydrolyzing when exposed to a physiological environment. The term bioerodible, as used herein, means a polymer that dissolves or degrades within a period that is acceptable in the desired application , (usually in vivo therapy), e.g. less than about five years and most preferably less than about one year, once exposed to an aqueous environment, e.g., a physiological solution of pH6-8 having a temperature of between about '25°C and 45°C. In another embodiment, the active molecule is released from the polymer substantially by diffusion when the system is exposed to an aqueous environment. Release by diffusion means release resulting from mechanisms other than erosion. A polymer is considered to release "substantially by diffusion" if its average release rate is no more than twice the rate achieved with a comparable non-eroding polymer. 5 A second aspect of the invention features reinforcing vivo tissue by applying a bioerodible polyphosphazene to the tissue. The polymer is selected to erode as its structural support is no longer needed. A third aspect of the invention features 10 treating a living organism to provide controlled sustained release of ammonia and phosphate at a desired location by implanting a bioerodible inorganic polymer body comprising a polyphosphazene at the location. The polyphosphazene release system is IS particularly advantageous because it has an inorganic backbone that is biocompatible overtime and (in the bioerodible embodiments) that degrades to harmless small-molecule products: ammonia, phosphate and water. The system can be made bioerodible to avoid surgical 20. removal of the polymer after use, and the bioerosion products are relatively benign in low concentrations. The system can accomodate a large variety of drugs including small drugs and macromolecules.
Other features and advantages of the invention 25 will be apparent from the following description of preferred embodiments thereof and from the claims.
Description of the Preferred Embodiment I . Drawings
Figs, la and b are graphs depicting polymer 30.. degradation over time.
Figs. 2-6 are graphs depicting release of various molecules over tissue. II. Structure
The preferred delivery system includes a bioerodible polyaminophosphazene polymer having side chains that hydrolyze in a physiological environment. 5 The hydrolysis results in the chemical breakdown and eventual erosion of the polymer. Mixed throughout and entrapped by the the polymer is a therapeutic agent that is released at a controlled and sustained rate when the system is placed in a physiological environment.
10 The preferred polyphosphazenes are those in which at least a portion (generally greater than 10% of the side chains (the R groups in formula 1) are capable of hydrolyzing in a physiological environment. Hydrolysis of the side chain results in hydrolysis of
15 the polymer backbone, and in erosion of the polymer. Examples of hydrolyzing side chains are unsubstituted and substituted imidizoles and a ino acid esters in which the group is bonded to the phosphorous atom through an amino linkage (polyphosphazene polymers in
20. which both R groups are attached in this manner are known as polyaminophosphazenes) . For polyimidizolephosphazenes, some of the "R" groups on the polyphosphazene backbone are imidizole rings, attached to phosphorous in the backbone through a ring nitrogen
25 atom. Other "R" groups can be organic residues that do not participate in hydrolysis, such as methyl phenoxy groups or other groups shown in Allcock et a.\ . (1977) Macromolecule 10:824-830.
The R groups that are not capable of
3Q hydrolyzing can be any alkyl, aralkyl, or aryl group having 20 carbon atoms or less (more preferably 12 carbon atoms or less); or a heteroalkyl, heteroaralkyl, or heteroaryl group having 20 or less carbons and heteroatoms (more preferably 12 or less carbon or heteroato s) . The groups can be bonded to the phosphorous atom through e.g., an oxygen, sulfur, nitrogen, or carbon atom. 5 The preferred polyphosphazenes are made by reacting poly(dichlorophosphazene) with the appropriate side chain nucleophiles, which displace the chlorines. Desired proportions of hydrolyzible to nonhydrolyzible side chains in the polymer can be achieved by adjusting 10. the quantity of the corresponding nucleophiles that are reacted with the poly(dichlorophosphazene) .
The preferred polyphosphazenes have a molecular weight of over 100,000. If the molecular weight is below 100,000, the polymer may lose some of its film 15 forming capability.
The term therapeutic agent, as used herein, means any agent used to treat or prevent any disease or disorder of the body. Both low molecular weight (less than about 1000) agents and higher molecular weight 2o (greater than about 1000) agents (macromolecules) can be used in the delivery system. Representative agents include hormones (and hormone fragments and analogues), e.g., testosterone, progesterone, luteinizing hormone-releasing hormone (LHRH); diuretics, e.g., 25. chlorothiazide; anti-inflammatories; pain killers, e.,g., morphine; antibiotics, e.g., tetracycline; antipsychotic drugs, anticancer drugs, e.g., methotrexate, actinomycin D, vinblastine, and cytosine arabinoside; vaccines; and antiarthritic drugs, e.g., ibuprofen and flurbiprofen. 0 The delivery systems can be made in virtually any shape or size, depending upon the physiological environment of use. For example, the system can be shaped and sized for buccal, oral, vaginal, intrauterine, ocular, and anal insertion; for skin patches, e.g., to fit behind the ear; or for parenteral insertion or injection, e.g., throguh a syringe (in which case the delivery systems would be in the form of powder in which each particle is small enough to fit through a syringe tip) . The bioerodible characteristic of the polymer is particularly important where the mode of administration of the delivery system is parenteral insertion or injection, as the fact that the polymer eventually dissipates makes it unnecessary to go into the body parenterally to remove the system once it is depleted of the agent.
The preferred delivery systems can contain up to 50% by weight (more preferably up to 30% by weight) of therapeutic agent. If too low a proportion of polymer is present, the mechanical properties of the delivery system may be adversly affected.
The therapeutic agent is physically entrapped by the polymer, preferably by casting a polymer/agent mixture.
When the delivery system is exposed to an aqueous physiological environment, a sustained and controlled release of the therapeutic agent occurs. Sustained release means that the agent is released continuously from the system over an appropriate prolonged period of time. As discussed below, the period of time over which the agent is released can be adjusted for a particular system by varying the size of the system and by varying the type side chains on the polyphosphazene. Controlled release means that the agent is released from the system within a desired dosage range for most of the sustained period. Towards the end of the sustained period, the amount of agent released may begin to decrease due to a depletion of the supply of agent. At the beginning of the sustained period (2-5 days), it is common to see a initial burst of agent released that is somewhat higher than the long-term release rate.
The agent can be released from the delivery system by one or both of two general mechanisms. (1) The agent can be released as the polyphosphazene erodes; and (2) the agent can be released by diffusion of the • agent and aqueous fluid through the polymer and into the environment of use.
The mechanism by which the agent is released from the system can be selected by adjusting the proportion of hydrolyzable to non-hydrolyzible side chains on the polyphosphazene. The greater the number of hydrolyzable side chains, the higher the proportion of agent that will be released through the erosion of the polymer. Vice versa, the lower the number of hydrolyzable side chains, the higher the proportion of agent that will be released by diffusion. Where the matrix is implanted in a location accessible only by surgery, it is desirable to use an erodible matrix. III. Methods
The synthesis and characterization of two polyphosphazenes is described first. A. Reagents:
Most experimental manipulations were performed under an atmosphere of dry nitrogen (Burdett) . Tetrahydrofuran (THF) (MCB Omnisolve) was distilled under nitrogen from sodium benzophenone ketyl . All other solvents used were reagent grade or better. p-Methylphenol (Aldrich) was sublimed before use. Imidazole (Aldrich) was recrystallized from absolute alcohol. Sodium spheres (Aldrich) were used as received.
H N R spectra were recorded on a Bruker 5 WP-200 spectrometer operating at 200MHz in the Fourier transform mode. All data are for samples in CgDg. p NMR spectra were recorded on a Varian CFT-20 spectrometer operating at 32 MHz in the Fourier transform mode. All spectra were recorded for samples
10 in THF. Polymer molecular weights were determined by gel permeation chromatography with the use of a Waters Associates ALC-201 instrument, with two PL Gel Columns (Polymer Laboratories) using THF as the eluting solvent. Calibration of the columns was accomplished by
15 means of polystyrene standards obtained from Waters Associates. Infrared spectra were recorded as thin films on NaCl plates using a Perkin-Ξlmer 1420 IR Spectrophotometer. Elemental analyses were performed by Galbraith Laboratories, Knoxville, Tennessee. Samples
20. were dried for at least 72 hours over phosphorus pentoxide in a vacuum desiccator before analyses.
C. Synthesis of 1.1:0.9 p-methylphenoxyl: imidazole polyphosphazene
Hexachlorocyclotriphosphazene (Ethyl 25 Corporation) was purified by two recrystallizations from hexane and by two sublimations at 50°C (6.7 Pa: 0.05 torr) . Poly(dichlorophosphazene) was prepared by the thermal polymerization of (NPCl-)- at 250°C. An average of 50%-60% conversion to the linear polymer was 30. obtained.
The sodium salt of p-methoxypheno1 was prepared as follows. A 500 ml, 3 neck round bottomed flask containing a magnetic stir bar was equipped with a gas inlet, a water cooled condenser and an addition funnel. The flask was flame dried and allowed to cool while being flushed with a stream of nitrogen. The flask was flame dried and allowed to cool while being flushed with 5 a stream of dry nitrogen. The flask was charged with 300 ml freshly distilled THF follwed by the addition of NaH (4.12g, 60% NaH in mineral oil). The flask was cooled by means of an ice bath and to the slurry was added dropwise through the addition funnel a solution of
10 p-methylphenol (13.2g, 0.122 mol.) in THF (75 ml). When addition was complete the ice bath was removed and the solution allowed to warm to room temperature. The solution was heated to 40°C by means of a heating mantle and heating was continued for 10 hours. A clear
15 colorless to pale yellow solution was obtained.
A solution was prepared of [NPC1-] (lOg 0.086 mol in THF (900 ml)) in a 3000 ml 3 neck flask equipped with an overhead mechanical stirrer, a water cooled condenser (fitted with a gas inlet) and a fritted
20. addition funnel. Dissolution of the polymer took approximately 10 hours, care being taken to rigorously exclude water and oxygen during this time. The sodium salt prepared above was transferred to the addition funnel by means of a transfer tube, and was then added
25. dropwise to the polymer solution. The addition was at such a rate that precipitation or gelling of the polymer did not occur. A heavy white precipitate of NaCl slowly formed. Upon completion of sodium salt addition, the solution was heated to reflux for 24 hours.
30. The solution of partially substituted polymer was cooled to room temperature and a solution of imidazole (15g, 0.22 moles) dissolved in THF (100 ml) was added dropwise. The solution was heated to reflux and heating was continued for a further 48 hours. Upon cooling to room. temperature, the solution was filtered to remove NaCl and the filter cake washed thoroughly with dry THF. The combined THF fractions were
5 concentrated using a rotary evaporator to 400 ml and the now viscous solution was added to a vigorously stirred solution of heptane (previously dried over MgSO.) .
The crude polymer precipitated and was recovered by filtration as a white fibrous material. The polymer was 0 redissolved in the minimum amount of dry THF and the precipitation procedure was repeated three times.
Soxhlet extraction using hot heptane followed by drying over
This polymer was prepared using the same methods and materials as with the copolymler above, with the exception that 8 grams (.069 moles) of [NPC12]
2Q in 700 ml of THF was used.
Ξ. Imidazole Substituted Polyphosphazene Matrices
2.0 grams of polymer were dissolved in THF to make a 20% solution. The solution was cast in a flat
25 bottomed glass mold (Pyrex) that had been pre-cooled.to -20°C, and allowed to dry at -20°C for 24 hours. The mold was allowed to dry at 0°C for 24 hours more, then circular disks 7.0 mm in diameter and .5 mm in thickness were formed using a cork borer. The disks were air
30. dried until no detectable changes in weight were noted.
The weight of these disks averaged 30.+1 mg.
F. 20% Imidazole Substituted Polyphosphazene Matrices Circular disks were prepared as above. The weight of these disks averaged 30.+.5 mg. G. Polymer Characteristics Table 1 gives characterization data for the 5 polymers synthesized. The polymers were rubbery and translucent and possessed glass transition temperatures of 301 K (45% imidazole substituted polymer) and 307 K (20% imidazole polymer) . No melting point temperature was detected, implying that the polymers were
10. essentially completely amorphous. The exact ratio of the two side chain substituents, imidazole and p-methylphenol, were determined by NMR from a comparison of peak intensities at 7.35 pp and 1.94 ppm and confirmed by elemental analysis. 5 The polymers used readily dissolved in THF.
20% solutions of polymer in THF were found to be optimal in achieving liquids viscous enough to prevent settling of drug or protein during the casting process. In that same regard the casting solutions and molds were kept Q cooled to below the polymers' glass transition temperatures. Use of low temperature casting procedures are quite important in achieving reproducible release kinetics from polymeric devices. The resulting polymer disks were firm but flexible and could be easily bored 5 to desired dimensions.
H. p-Nitroaniline/Polyphosphazene Matrices: 0.2% and 1% solutions of p-nitroaniline (Matheson, Coleman and Bell) were prepared in THF. 2.0 grams of 20% imidazole substituted polyphosphazene was 0 dissolved in appropriate volumes of each of these solutions to create 1% and 5% p-nitroaniline/ polyphosphazene solutions. The solutions were cast on flat bottomed glass molds (Pyrex) that had been pre-cooled to -20°C, and allowed to dry at -20°C for 24 hours. The molds were allowed to dry at 0dC for 24 hours more, then circular disks of 7.0 mm in diameter,
.5 mm thick were formed using a cork borer. The disks
5 were air dried until no detectable changes in weight were noted. These disks average 25+1 mg in weight.
I. Progesterone/Polyphosphazene Matrices:
H-progesterone (New England Nuclear) was mixed with unlabelled progesterone (Sigma) to produce Q radioactive progesterone with a specific activity of 25
7 microcuries/mg (5.5x10 dpm/mg) . 1% and 5% solutions of progesterone were prepared in THF. 2.0 grams of 20% imidazole substituted polyphosphazene was dissolved in appropriate volumes of each of these solutions to create 5 5% and 10% tritiated progesterone/polyphosphazene solutions. The solutions were cast and dried as above. Circular disks of 7.0 mm in diameter and .4 mm in thickness were formed using a cork borer. These disks averaged 20+1 mg in weight. 0 J- Bovine Serum Albumin/Polyphosphazene
14 C-bovine serum albumin (BSA, New England
Nuclear) was mixed with unlabelled BSA (Sigma) to produce radioactive BSA with a specific activity of .01 microcuries/mg (2.2x10 dpm/mg). 2 grams of 20% imidazole substituted polyphosphazene was dissolved in THF to make a 20% solution. BSA was then added to form a 2.5% BSA/polyphosphazene mixture. The solution was cast and dried as above. Circular disks of 7.0 mm in diameter and .2 mm in thickness were formed using a cork borer. These disks averaged 10+1 mg in weight. K. Degradation Studies: Degradation studies of 20% imidazole substituted polyphosphazene were carried out in .1M sodium phosphate buffer solutions at pH 7.4. Polymeric slabs were placed in 20 ml scintillation vials (Kimble) with 10 ml of buffer. Percent degradation was determined by freeze drying samples at specific time intervals and measuring weight loss. Since the rate of degradation of the 20% imidazole substituted polyphosphazene was low, and extinction coefficient for the first 10% of polymer degradation was formulated and percent degradation with time was determined spectrophotometrically, and confirmed by freeze drying samples periodically in a parallel study. The degradation of 45% imidazole substituted polphosphazene was performed in deionized water at pH 5.5. All degradation studies were performed in quadruplicate.
Fig. l shows erosion profiles for both 20% and 45% imidazole containing polyphosphazenes. Degradation of 20% imidazole substituted polyphosphazene was quite slow, with 4% of polymer degrading in 600 hours (Fig. la) . This low rate of degradation would be expected since degradation is imidazole dependent. In contrast to the slow rate of degradation of the 20% imidazole substituted polyphosphazene, 30% of the 45% imidazole substituted polyphosphazene degraded in approximately 300 hours (Fig. lb), with a marked decrease in degradation rate after that point. With kinetics continuing at the decreased rate the polymer would be expected to have a degradative lifetime of 3 years. Polyphosphazenes synthesized containing 80% imidazole and 20% methoxyphenoxy degraded on the order of hours in room humidity. Such variation in degradative characteristics provides the ability to formulate release systems based primarily on diffusion, erosion, or a mixture of erosion and diffusion.
L. Release Studies 20% imidazole substituted polyphosphazene matrices with drug or protein were placed in 20 ml scintillation vials with 10 ml .1M sodium phosphate buffer at pH 7.4. buffer was changed frequently using a
20 ml syringe fitted with a 1.5 inch 18 gauge needle (Becton-Dickinson) . Care was taken during the studies to insure that the concentration of drug or protein released was never greater than 10% of their respective solubilities in phosphate buffer. These studies were performed in triplicate. In addition to in vitro work, in vivo studies
3 were performed with H-progesterone/polyphosphazene matrices. Polymeric devices were implanted subcutaneously in 200-225 gm female Sprague-Dawley rats
(Charles River Breeding Laboratories). After shaving an animal's hair, and prepping with betadine and alcohol, a 2 cm incision was made on the dorsum of the rat at the midline. Sterile round—edged scissors were used to form a subcutaneous space 6 to 7 cm laterally from the incision site. The polymeric disk was placed into the space using sterile forceps, and the incision site was closed using sterile would clips (Autoclip Kit; Clay Adams) .
At different time points, rats were sacrificed by C02 asphyxiation, and the polymer disk was removed. The disk was dissolved in THF, and progesterone present was determined as stated below.
To determine the rate of p-nitroaniline release, the collected buffer samϋles were read spectrophotometrically at a wavelength of 380 nm, the absorption maximum for p-nitroaniline. At this wavelength, neither the polymer nor its degradation products have been found to absorb. (The extinction 5 coefficient for p-nitroaniline dissolved in the buffer used was 97.1 ml/mg-cm. ) Absorbance measurments were made using a Perkin Elmer 553 U.V./Vis. Spectrophoto¬ meter.
3 To determine the rate of H-progesterone and 10 14C-bovme serum albumin release collected samples were dissolved in Quasol II (New England Nuclear) and counted on a Packard Tri-Carb 4530 Liquid Scintillation
Counter. Dpms were determined through an external standards method.
15 * M. Release Characteristics: p-Nitroaniline was chosen as a model molecule for release since its absorbance maximum was outside the range of any polymer degradation products. Figure 2 shows release kinetics for 1% p-nitroaniline loaded 20%
20. imidazole polyphosphazene devices. Release took place over 250 hours with the amount of dye released over time being quite reproducible. When plotted as a function of square root time (Fig. 3), release of 1% and 5% loaded p-nitroanilme appeared to follow t 1/2 diffusional
25 release kinetics as theorized by Higuchi, 5_2 J. Pharm. Sci. 1145 (1963). At the loadings studied, release rates were not found to be very dependent upon loading. Using progesterone, a study of in vitro and in vivo release was performed both to illustrate the 0 possibility of this systems use for release of bioactive molecules and to compare release kinetics. Fig. 4 shows release of progesterone from 5% and 10% loaded 20% imidazole polyphosphazene matrices.' Release took place over approximately 1000 hours in vitro. Release of 10% loaded progesterone/polyphosphazene devices n vivo (Fig. 5) demonstrates a lag period of approximately 80 hours followed by a period of almost constant release for 900 hours more.
Polypeptide release was demonstrated using 2.5% loaded BSA. Release from these matrices consisted of a burst of almost 25% percent followed by release over 1000 hours^ in which a total of 55% of protein was released (Fig. 6). In an attempt to remove the burst, 2.5% loaded BSA matrices were dipped in 20% solutions of 20% imidazole polyphosphazene in THF for 3 seconds. Referring to Fig. 6, the polymer coating step eliminates the burst effect, with 5% release occurring during the first 4 hours. At 1000 hours 45% of the protein is released.
Other Embodiments Other embodiments are within the following claims. For example, polyphosphazenes that are not biodegradable can be used in the delivery system; in such systems, the therapeutic agent is released via diffusion exclusively. Examples of nonbiodegradable polyphosphazenes are described by Allcock et al., J. Inorg. Chem. ^1:515 (1982). The system can be used to release biologically active substances to aqueous fluids other than physiological fluids in animals. For example, pesticides and poisons can be released slowly to an infested site such as an agriculture site.
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|Classification internationale||A61K9/00, A61K9/20, A61K47/34|
|Classification coopérative||A61K9/0024, A61K47/34, A61K9/2031|
|Classification européenne||A61K9/00M5D, A61K47/34, A61K9/20H6D|
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