Carriers for drug delivery, methods of making such carriers and for associating them to drugs, the resulting carrier and drug combination and methods for drug delivery, particularly controlled or sustained release delivery, using such carrier and drug combinations.

The invention includes carriers for drug delivery, methods of making such carriers and for associating them to drugs, the resulting carrier and drug combination and methods for drug delivery, particularly controlled or sustained release delivery, using such carrier and drug combinations.

In one aspect of the invention hydrogels of modified alginates or other polysaccharide gels are provided as carriers with drugs associated to them by biodegradeable covalent bonds, ionic bonds and/or by diffusion control within the gel. A variety of release profiles of the drugs or prodrugs thereof can be obtained with release rates ranging, for example, from a few days to several months, particularly from three weeks to four months. In a preferred embodiment, alginates are treated to reduce their molecular weight so that they are of a size which is biodegradeable and biocompatible, crosslinked covalently and/or ionically through the action of divalent cations and reacted with a drug or prodrug so that they are degradeably bonded to the alginate. The extent of lowering of the molecular weight and of covalent or ionic crosslinking can be adjusted to provide mechanical properties and degradation rates which are suitable for the particular application. Applications include, but are not limited to, delivery of chemotherapy drugs, growth factors for localized vascularization, steroids for contraception or hormone replacement therapy and localized delivery of drugs following angioplasty to prevent smooth muscle cell proliferation.

In another aspect of the invention, preferably water-soluble polymers are modified so that they can reversibly bind multiple molecules of drug per molecule of polymer. These polymer-drug conjugates can be administered as prodrugs to give a sustained release of the active drug over time. Advantages thereof include a decrease in toxicity effects of the free drug, economizing of the amount of drug needed due to an increase in circulation time and facilitating solubilization of hydrophobic drugs. The particular polymer and molecular weight thereof can be selected to suit the particular application, of which chemotherapy applications are of particular interest.

Hydrogels have been extensively investigated as drug delivery carriers in biomedical applications. They are relatively inexpensive and well suited to deliver drugs in a minimally invasive manner. For example, hydrogels have been widely investigated as delivery vehicles for the localized, sustained release of antineoplastic agents (Jeong et al., Biodegradable block copolymers as injectable drug delivery systems. Nature 1997, 388, 860 861; and Patil et al., Macroporous poly(sucrose acrylate) hydrogel for controlled release of macromolecules. Biomaterials 1996, 17, 2343 2350). Many synthetic and naturally derived materials have been reported to form hydrogels (Hubbell, J. A., Hydrogel systems for barriers and local drug delivery in the control of wound healing. J. Control. Rel. 1996, 39, 305 313; Inoue et al., A hydrophobically-modified bioadhesive polyelectrolyte hydrogel for drug delivery. J. Control. Rel. 1997, 49, 167 176; Zhao et al., Novel degradeable poly(ethylene glycol) hydrogels for controlled release of protein. J. Pharm. Sc. 1998, 87, 1450 1458; and Andreopolos et al., Photoscissable hydrogel synthesis via rapid photopolymerization of novel PEG-based polymers in the absence of photoinitiators. J. Am. Chem. Soc. 1996, 118, 6235 6240), and one widely used hydrogel is formed from the ionic cross-linking of sodium alginate, a linear polysaccharide isolated from seaweed. Alginate is comprised of (1,4)-linked .beta.-D-mannuronic and .alpha.-L-guluronic acid residues arranged in blocks of polymannuronate, polyguluronate, and alternating units of both sugars. Divalent cations, such as calcium, ionically cross-link the carboxylate groups on adjacent alginate strands to form hydrogels. The polyguluronate block of alginate is known to be responsible for this gelling feature (Sutherland, I. W. Alginates. In Biomaterials: novel materials from biological sources, Byron D., Ed.; Stockton Press: New York, 1991, pp 309 331). The favorable properties of alginate, including non-immunogenicity, hydrophilicity, and relatively low cost have prompted attempts to use this material as wound dressing, dental impression, and immnobilization scaffolds for cultured and transplanted cells (Gombotz et al., Protein release from alginate matrices. Adv. Drug Deliv. Rev. 1998, 31, 267 285; Shapiro et al., Novel alginate sponges for cell culture and transplantation. Biomaterials 1997, 18, 583 590). Alginate is considered to be a biocompatible polymer (Klock et al., Biocompatibility of mannuronic acid-rich alginates. Biomaterials 1997, 18, 707 713.), although contaminating factors may induce significant inflammation if the polymer is not suitably purified (Skjak-Braek et al., Alginate as immobilization material. II: determination of polyphenol contaminants by fluorescence spectroscopy, and evaluation of methods for their removal. Biotech. Bioeng. 1989, 33, 90 94). Alginate hydrogels have been previously proposed for a number of drug delivery applications (Kikuchi et al., Pulsed dextran release from calcium-alginate gel beads. J. Control. Rel. 1997, 47, 21 29; Morgan et al., Alginates as drug carriers: covalent attachment of alginates to therapeutic agents containing primary amine groups. Int. J. Pharm. 1995, 122, 121 128; Murata et al., Additive effect of chondroitin sulfate and chitosan on drug release from calcium-induced alginate gel beads. J. Control. Rel. 1996, 38, 101 108). One disadvantage of alginate hydrogels is that they are not chemically broken down in mammals, e.g., because of the lack of alginase. They instead dissolve in an uncontrollable and unpredictable manner following the dissolution of calcium into the surrounding medium. Furthermore, the molecular weight of intact alginate is typically above the renal clearance threshold of the kidney thus preventing it from being excreted from the body (Al-Shamkhani et al., Radioiodination of alginate via covalently-bound tyrosinamide allows for monitoring of its fate in vivo. J. Bioact. Compat. Polym. 1995, 10, 4 13). Further, some of the limitations of hydrogels include the poor release profile of small molecules as well as low molecular weight polymers. The release of such compounds is typically diffusion controlled which results in an initial burst of the drug in a short time period. Limitations on the control of drug release makes hydrogels unsuitable for many types of drug delivery applications where different release profiles are desirable.

A related application, PCT/US97/16890, international filing date Sep. 17, 1997, describes modified alginates covalently coupled to molecules useful for cellular interaction. While the current invention is directed to different drug delivery applications and provides a detailed description of a particular manner of coupling of the drug, several aspects of the related application are applicable in achieving the current invention or are useful in combination with the current invention. The disclosure of PCT/US97/116890 is, therefore, incorporated by reference herein, as a whole.

Also in connection with PCT/US97/16890, it is another aspect of this invention that the PAG (poly(aldehyde guluronate)) materials and coupling chemistry described herein may be used for the cellular interaction uses described in the related application. For example, the PAG material herein could be used as the modified alginate and means for covalently coupling the molecules could be used for bonding the molecules for cellular interaction where those molecules have a functional group useful for such coupling or can be modified to provide such.

In one method for obtaining materials suitable for the invention, a natural or synthetically produced alginate or other polysaccharide is oxidized to convert at least a portion of the guluronate units to aldehyde guluronate units.

Natural source alginates, for example from seaweed or bacteria, are useful and can be selected to provide side chains with appropriate M (mannuronate) and G (guluronate) units for the ultimate use of the polymer. It is also preferred to use an alginate material of high guluronate content since the guluronate units, as opposed to the mannuronate units, provide sites for ionic crosslinking through divalent cations to gel the polymer. Isolation of alginate chains from natural sources for use as the side chains herein can be conducted by conventional methods. See Biomaterials: Novel Materials from Biological Sources, ed. Byrum, Alginates chapter (ed. Sutherland), p. 309 331 (1991). Alternatively, synthetically prepared alginates having a selected M and G unit proportion and distribution prepared by synthetic routes, such as those analogous to methods known in the art, can be used. Further, either natural or synthetic source alginates may be modified to provide M and G units with a modified structure. The M and/or G units may also be modified, for example, with polyalkylene oxide units of varied molecular weight such as shown for modification of polysaccharides in Spaltro (U.S. Pat. No. 5,490,978) with other alcohols such as glycols. Such modification generally will make the polymer more soluble, which generally will result in a less viscous material. Such modifying groups can also enhance the stability of the polymer. Further, modification to provide alkali resistance, for example, as shown by U.S. Pat. No. 2,536,893, can be conducted.

The oxidation of the alginate material is preferably conducted with a periodate oxidation agent, particularly sodium periodate, to provide the alginate with aldehyde groups, preferably poly(aldehyde guluronate) (PAG). The degree of oxidation is controllable by the mole equivalent of oxidation agent, e.g., periodate, to guluronate unit. For example, using sodium periodate in an equivalent % of from 2% to 100%, preferably 5% to 50%, a resulting degree of oxidation, i.e., % if guluronate units converted to aldehyde guluronate units, from about 2% to 70%, preferably 5% to 50%, can be obtained. The aldehyde groups provide functional sites for crosslinking and for bonding to a drug or prodrug. Further, oxidation of the alginate materials facilitates their degradation in vivo, even if they are not lowered in molecular weight. Thus, high molecular weight alginates, e.g., of up to 300,000 daltons, may be degradeable in vivo, when sufficiently oxidized, i.e., preferably at least 5% of the guluronate units are oxidized to aldehyde guluronate units.

Before, during or after the oxidation, the alginate material may be treated to provide a material of lower molecular weight, particularly at or below the renal threshold for clearance by humans. Preferably, the alginate or polysaccharide is reduced to a molecular weight of 1000 to 80,000 daltons, more preferably 1000 to 60,000 daltons. The reduction in molecular weight can be effected by hydrolysis under acidic conditions or by oxidation, to provide the desired molecular weight. The hydrolysis is preferably conducted in accordance with a modified procedure of Haug et al. (Acta. Chem. Scand., 20, p. 183 190 (1966), and Acta. Chem. Scand., 21, p. 691 704 (1967)), which results in a sodium poly(guluronate) of lower molecular weight which is essentially absent of mannuronic acid units. The oxidation to lower molecular weight is preferably conducted with a periodate oxidation agent, particularly sodium periodate; see PCT/US97/16890. Oxidizing commercially available high molecular weight alginates according to the invention, the average molecular weights and the aldehyde contents of the resulting materials can be readily controlled based on the oxidation conditions employed. Thereby, materials which can be eliminated from the body after degradation of the crosslinking therein can be provided. If the molecular weight lowering step is conducted by oxidation, the molecular weight lowering and oxidation step discussed above can be conducted as one step.

The oxidized and optionally molecular weight lowered alginate, for example a PAG material, is then crosslinked by a covalent crosslinking agent and optionally also by divalent cations. The covalent crosslinking agent provides two or more functional groups per molecule which are capable of degradeable covalent bonding to the aldehyde groups of the oxidized alginate. Preferred crosslinking agents are compounds with two or more hydrazide groups, particularly dihydrazides, more particularly adipic acid dihydrazide (AAD). The hydrazide group reacts with the aldehyde to provide a hydrazone bond which is hydrolyzable in vivo. The extent of crosslinking can be controlled by the concentration of crosslinking agent and the concentration of the oxidized alginate in aqueous solution; the higher concentration of either corresponding to a higher extent of crosslinking. Useful concentrations therefor are, for example, from 50 to 300 mM of crosslinking agent and from 5 to 10 wt % of oxidized alginate, e.g., PAG. The extent of crosslinking alters the mechanical properties of the gel and can be controlled as desired for the particular application; see PCT/US97/16890. In general, a higher degree of crosslinking results in a stiffer gel having a lower degradation rate.

Without oxidation, optionally molecular weight lowering and crosslinking, alginate hydrogels have limited mechanical properties and their degradation cannot be readily controlled. They dissolve in an uncontrollable manner upon loss of divalent cations and release high and low molecular weight alginates. The high molecular weight non-oxidized degradation products are not readily broken down in mammals and are slow to clear from the body.

The reaction from guluronate alginate units (1) to aldehyde guluronate (PAG) units (2) and then crosslinking by adipic dihydrazide (AAD) to crosslinked PAG (3) is exemplified in Equation 3 in Example 1.

Either during or after covalent crosslinking, ionic crosslinking of the oxidized alginate through divalent cations, particularly calcium, can also be conducted. Such crosslinking is effected with oxidized alginates, e.g., PAG, in a similar manner to alginates or other modified alginates; see PCT/US97/16890. Such crosslinking will also alter the mechanical properties and can be used if desired depending on the particular application.

Also, either before or during covalent crosslinking and/or ionic crosslinking of the oxidized alginate, the drug or prodrug is bonded to the hydrogel. Drugs which have a functional group capable of providing a degradeable covalent bond directly to the aldehyde groups of the oxidized alginate can be coupled to the hydrogel thereby. Further, drugs which have a functional group capable of providing a degradeable covalent bond to a linking compound which linking compound has a further functional group capable of providing a degradeable covalent bond to the aldehyde groups of the oxidized alginate can be coupled to the hydrogel. See, e.g., Heindel et al., Bioconjugate Chemistry, vol. 1, p. 77 82 (1990). In this case, hydrolysis of the bond between the drug and linking compound will release the active drug, while, hydrolysis of the bond between the linking compound and the oxidized alginate will provide a prodrug which will not be active until the bond between the drug and linking compound is hydrolyzed. Providing a prodrug in this manner may be advantageous in certain controlled release applications. Also, drugs which can form ionic bonds with the oxidized alginate hydrogel can be coupled thereby.

Thus, for example, drugs with a hydrazide group can be degradeably covalently bonded directly to the oxidized alginate, particularly PAG. However, because few drugs have hydrazide groups, the more applicable means of providing a degradeable covalent bonding of the drug is to react a drug having an aldehyde or ketone functional group with a compound having one or more hydrazide groups, particularly dihydrazides such as adipic acid dihydrazide (AAD), to provide a structure wherein there is degradeable covalent hydrazone bond between PAG and AAD and between AAD and the drug. See, e.g., Example 1 herein. As described above, hydrolysis of the bond between the drug and AAD will release the active drug, while, hydrolysis of the bond between AAD and the PAG will provide a prodrug which will not be active until the bond between the drug and AAD is hydrolyzed.

Drugs which have a positively charged ionic group may exhibit ionic bonding to the hydrogel through affinity with negatively charged carboxylate groups on guluronate units remaining in the oxidized alginate. Particularly, drugs with positively charged amine or ammonium groups may be carried by the hydrogel through ionic bonding.

Drugs which do not have the functional groups suitable for degradeable covalent bonding or ionic bonding will still exhibit some extent of controlled release from the hydrogels of this invention due to the need for the drug to diffuse from the hydrogel. But such diffusion controlled release does not provide as much control as the bond degradation effects described above.

This invention further contemplates any combination of the above bonding and other controlled release effects to fulfill the needs of a particular application. As described above, many variables are adjustable to tailor the mechanical properties of the carrier to the particular ultimate utility. Further, the different means of carrier-drug combination can be used, for example, to provide release of the same or different drugs by different mechanisms (e.g., covalent bond degradation, ionic bond degradation and diffusion control) from the same gel carrier or different gel carriers used in combination.

As described above, a second part of this invention involves modifying polymers, such as poly(vinyl alcohol) (PVA) and polyacrylamides, so that they can reversibly bind multiple molecules of drug per molecule of polymer. Any polymer which is biocompatible, water-soluble, preferably of less than 80,000 dalton molecular weight and can be bonded by a degradeable covalent bond to a drug, can be used. The conjugate of drug and polymer can be injected as a prodrug which will give a sustained release of active drug over time, i.e., as the degradeable bond hydrolyzes. This method can be used as a means to decrease the toxicity of the free drug, economize on the amount of drug given by increasing circulation time, and help to solubilize hydrophobic drugs. For example, because the active form of the drugs are released over time, the concentration of the active form of the drug at any given time can be minimized to levels where it is not substantially detrimental to certain organs. Further, conjugation with the polymer can be used to prevent a large portion of the drug from being eliminated through the kidneys before it has been able to act on the desired area. Additionally, these polymers can be used as cross-linkers for the oxidized alginate and poly(aldehyde guluronate) materials discussed above to form hydrogels. These polymers could be used to incorporate drugs and cross-link oxidized alginate and poly(aldehyde guluronate) simultaneously. The advantage over bifunctional cross-linkers is that a higher concentration of drugs could be incorporated into the same volume of gel.

Molecular weight of the backbone may be adjusted to achieve different average circulation times. For example, the molecular weight preferably ranges from 500 to 80,000. There are several different classes of drugs and types of applications which are well suited to this invention.

The linking of the polymer to the drug can be carried out through any of a number of chemistries which will provide a degradeable covalent bond between the polymer and the drug or a prodrug which is degradeably covalently bonded to release the active drug. For example, polymers which contain pendant carboxylic acid groups or can be modified to contain such groups can be transformed to hydrazides, e.g., by reaction with t-butyl carbazate followed by acid hydrolysis. The pendant hydrazide groups can then be reacted with drugs having an aldehyde or ketone functional group to provide a degradeable hydrazone bond. Similarly, excess hydrazine and a carbodiimide, e.g., EDC or DCC, can be used to provide a hydrazide functional group for linking. See PCT/US97/16890 further regarding the carbodiimide chemistry. Carbodiimidazole is another activator that can be utilized to couple amines, carbazides and hydrazides to carboxylic acid groups. The length of the pendant group in these polymers can also be controlled by using adipic dihydrazides (as well as other dihydrazides) to couple with the activated carboxylic acids in a manner similar to that described above for the hydrogels.

All drugs containing aldehyde and/or ketone groups could potentially be coupled to these modified polymers through the pendant hydrazide groups. The drugs may be coupled via the formation of a hydrazone bond between the drug and the carrier. The polymeric drug carrier is water soluble and could be administered by injecting aqueous solutions of the carrier intravenously. The drug is then released by the slow hydrolysis of the hydrazone bond. The linkage of the drug Taxol to poly(vinyl alcohol) modified with succinic anhydride, for example, is shown in the following equation -- see Original Patent.

The linkages between the hydrazide groups and PVA is through ester bonds which are known to be degradeable. After degradation of the ester bonds in the polymeric carrier (see equation below), PVA is expected to be cleared from the body due to its low molecular weight-- see Original Patent.

Water soluble polymeric drug carriers have been extensively investigated to deliver anti-neoplastic agents for several reasons. Some drugs, such as paclitaxel, have low solubility in aqueous solutions. By incorporating these drugs in a water soluble polymer, the solubility of the drug in aqueous solutions can be enhanced. Other advantages of such an application include increasing the half life of drugs in the blood stream when administered intravenously. For example, by utilizing a polymeric drug carrier of high molecular weight, the rate of clearance of the carrier is expected to be much slower than the clearance of small drug molecules. Polymeric drug carriers can also be designed to release drugs in a sustained manner, which in turn eliminates the need for frequent intravenous administration of these drugs. This may also decrease the cytotoxicity of these agents. Even though the circulation half life of the carrier is high in the blood stream, the circulation half life of the free drug remains low, and it is at a much lower concentration than the prodrug at any given time.

Although not intending to be limiting upon the potential applications of the invention, some specific applications for the hydrogels and/or water-soluble polymers, which also further illustrate the invention, are provided below.

Cancer is the second leading cause of death in the United States today and thus draws a good fraction of the resources of the health care industry. A large portion of cancer research is focused on finding new ways to deliver existing anticancer drugs in more efficient treatments. Today many cancers are treated with chemotherapy, where the patient receives large doses of anticancer drugs intravenously. Unfortunately, these anticancer drugs are highly toxic and cause wide spread systemic damage to the patient in addition to killing the tumor. A variety of materials had been utilized to incorporate drugs and deliver them in a controlled manner over a wide range of time frames. These materials include synthetic and natural polymers formulated as nanoparticles, microspheres, biodegradable polymeric disks, liposomes, inclusion complexes, and hydrogels (Ulbrich et al., "Synthesis of novel hydrolytically degradable hydrogels for controlled drug release" J. Control. Rel. 1995, 34, 155 165; and Draye et al., "In vitro release characteristics of bioactive molecules from dextran dialdehyde cross-linked gelatin hydrogel films" Biomaterials 1998, 19, 99 107). According to the invention, cross-linked oxidized alginate hydrogels can be used as an injectable drug delivery carrier for drugs. Drugs such as daunomycin and doxorubicin can be incorporated into the hydrogel via covalent attachment. Mitoxantrone and cisplatin, for example, were incorporated via the ionic complexation of these drugs onto the alginate backbone. Methotrexate, for example, can be physically entrapped into the hydrogel. Thus, the hydrogels can provide controlled release on the basis of the degradeable covalent linking effect, degradeable ionic bonding effect and diffusional effect from the gel, as well as by the degradation of crosslinking and ionic gelling of the gel itself. For example: Methotrexate was quantitatively released from the hydrogels within 5 days at all conditions by diffusing out from the gel; and a wide range of release profiles was observed with mitoxantrone and doxorubicin infused hydrogels depending on the concentration of covalent and ionic cross-linkers. The duration of the release of these to drugs could be controlled from as little as 2 days to greater than 3 months, for example.

Also because of the side effects of chemotherapy drugs, including nausea, weight loss, hair loss, severe immune suppression, myelosuppression (e.g., bone marrow depression), nephrotoxicity, gastrointestinal disturbances and cardiotoxicity, it would be desirable to provide localized delivery whenever possible to minimize these effects. For example, this may be the case in the following instances: 1) the tumor(s) are confined to a relatively small area (e.g. the peritoneal cavity), 2) the tumor is inoperable (e.g. some brain cancers), or 3) following removal of a tumor which does not appear to have metastasized to kill any cells that might not have been removed (e.g. following lumpectomy of breast cancers). Several types of currently approved chemotherapy drugs would work well using the delivery systems of the invention in such a manner. For example, anthracyclines such as daunomycin, doxorubicin, epirubicin and idarubicin contain a ketone functional group which can be reacted with the above-described modified hydrogels to form a controlled release drug-carrier combination with a degradeable hydrazone bond. Others drugs which contain amine groups, such as mitoxantrone, interact ionically with the hydrogel and also can provide a gradual release over time. Other chemotherapy drugs which may be suitable to the inventive carrier systems include: bleomycins and mitomycins which have amine groups, plicamycin which has ketone groups, and platinum complexes which have amine groups. Other drugs which may be developed or are in clinical trials and which have similar structural features may be useful with the described carriers.

Paclitaxel (TAXOL) and docetaxel (TAXOTERE) also contain ketones and can be covalently linked to the modified hydrogels. These and other water insoluble drugs may be suitable for diffusion controlled release as well.

Other types of cancer, where the tumor has metastasized or where the cancer is widespread, such as in leukemia, require systemic chemotherapy or other treatment to eliminate cancer cells throughout the body. In these cases, prodrugs may be advantageous over delivery of free drug to reduce toxicity to the heart, blood vessels, immune system, etc., as well as to lengthen circulation time of the drug. For example, it has been shown that systemic delivery of TAXOL may be more effective against Kaposi's sarcoma when given over a 96 hour period intravenously instead of over 3 hours (J. Clin Oncol, 1998, 16(3):1112 1121). In addition, solubilizing highly hydrophobic drugs such as TAXOL by binding to a suitable water-soluble polymer backbone will decrease side effects seen with current carriers. According to the manufacturer of TAXOL (Mead Johnson Oncology Products, a Bristol-Myers Squibb Co. Princeton, N.J.), the carrier for TAXOL is a 50/50 mixture of castor oil and ethanol which can cause anaphylaxis and severe hypersensitivity reactions in some patients which may be fatal. The previously mentioned anthracycline and other drugs which form covalent linkages to the modified alginates may also be used to form prodrugs.

TAXOL and TAXOTERE coupling to the hydrogel may also be used to prevent re-occlusion of arteries following angioplasty. Previous studies have demonstrated that TAXOL will inhibit smooth muscle cell proliferation and prevent neointima formation in rabbits following balloon angioplasty (Circulation, 1997, 96(2):636 645).

Other applications for this invention include localized or systemic delivery of growth factors. Particularly, vascular endothelial growth factor (VEGF) may be used for localized vascularization. Sustained slow release of growth factors will allow a greater or similar effect to be achieved with a much smaller amount of drug.

The hydrogel system is ideally suited to many types of steroid delivery as well. Gels are inexpensive, injectable and can be engineered to release the drug over a period of a few weeks to several months, for example. Progestin-only contraceptives are particularly well suited to this application. The progestin could be either covalently bound, such as progesterone, medroxy-progesterone acetate, norethynodrel, and hydroxyprogesterone caproate, or subject to diffusion release since the hydrophobic nature of these drugs (as well as others such as norgestrel, norethindrone, norgestimate, desogestrel and 19-nortestosterone which may not be chemically bound) would result in a slow release from the gel. The gels could be pre-formed and implanted or injected directly, making them versatile and easy to administer. An injectable sustained release system would be an improvement over the commercially available NORPLANT which requires implantation. In addition, they could easily be injected closer to the sight of action rather than in the arm, as with NORPLANT, reducing the amount of drug required. The gels are not easily removed; however, those designed for a limited period of delivery, such as a few weeks, could be used on a trial basis. This system would also provide a significant improvement over commercially available injectable progestin-only contraceptives such as DEPO-PROVERA (150 mg of medroxy progesterone acetate given by intramuscular injection every 3 months; Pharmacological Basis of Therapeutics, 9th Edition, Hardman and Limbird, Editors-in-Chief, McGraw Hill, 1996, p. 1432) because a sustained low level of the drug would be in the system at all times rather than in periodic very high concentrations. This would be a more efficient use of drug and should decrease side effects associated with this form of contraception. Other steroid applications include hormone replacement therapy using diffusion controlled release of estrogen and/or progesterone related compounds and release of cortisone or other suitable drugs to inflamed joints in rheumatoid arthritis.

Claim 1 of 13 Claims

1. A water-soluble polymer/drug compound which comprises a water-soluble polymer bonded to a drug or prodrug by an in vivo degradeable covalent bond, wherein the bond is provided by a linking compound having two or more hydrazide groups which react with the polymer and drug to form separate hydrazone bonds to each of the polymer and the drug, and wherein the water-soluble polymer is a poly(vinyl alcohol), an alginate modified to convert at least a portion of its guluronate units to aldehyde guluronate units, a polyamine dendrimer, a poly(ethylene glycol) dendrimer, a poly(allyl amine), a poly(vinyl amine), a polyacrylamide or a polyalkyl(meth)acrylate, wherein the linking compound is adipic acid dihydrazide" after "polyalkyl(meth)acrylate.

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