The invention relates to poly(phosphoesters), compositions comprising the poly(phosphoesters), and methods of use.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to poly(phosphoesters) and methods of using 
these polymers. 
2. Description of the Background Art 
Many polymeric materials have been used as components of devices for 
diagnosis or therapy, and they have made a significant impact on the 
clinical success of implant technology. These materials have been used as, 
for example, orthopedic devices, ventricular shunts, drug-carriers, 
contact lens', heart valves, sutures, and burn dressings. These polymers 
can be non-biodegradable or biodegradable. 
In traditional drug delivery, it has long been recognized that tablets, 
capsules, and injections may not be the best mode of administration. These 
conventional routes often involve frequent and repeated doses, resulting 
in a "peak and valley" pattern of therapeutic agent concentration. Since 
each therapeutic agent has a therapeutic range above which it is toxic and 
below which it is ineffective, a fluctuating therapeutic agent 
concentration may cause alternating periods of ineffectiveness and 
toxicity. For this reason, controlled release provides a way of 
maintaining the therapeutic agent level within the desired therapeutic 
range for the duration of treatment. Using a polymeric carrier is one 
effective means to deliver the therapeutic agent locally and in a 
controlled fashion (Langer, et al., Rev. Macro. Chem. Phys., C23(1), 61, 
1983). As a result of less total drug required, systemic side effects can 
be minimized. 
Polymers have been used as carriers of the therapeutic agents to effect a 
localized and sustained release (Controlled Drug Delivery, Vol. I and II, 
Bruck, S. Dak., (ed.), CRC Press, Boca Raton, Fla., 1983; Novel Drug 
Delivery Systems, Chien, Y. W., Marcel Dekker, New York, 1982). These 
therapeutic agent delivery systems simulate infusion and offer the 
potential of enhanced therapeutic efficacy and reduced systemic toxicity. 
For a non-biodegradable matrix, the steps leading to release of the 
therapeutic agent are water diffusion into the matrix, dissolution of the 
therapeutic agent, and outdiffusion of the therapeutic agent through the 
channels of the matrix. As a consequence, the mean residence time of the 
therapeutic agent existing in the soluble state is longer for a 
non-biodegradable matrix than for a biodegradable matrix where a long 
passage through the channels is no longer required. Since many 
pharmaceuticals have short half-lives it is likely that the therapeutic 
agent is decomposed or inactivated inside the non-biodegradable matrix 
before it can be released. This issue is particularly significant for many 
bio-macromolecules and smaller polypeptides, since these molecules are 
generally unstable in buffer and have low permeability through polymers. 
In fact, in a non-biodegradable matrix, many bio-macromolecules will 
aggregate and precipitate, clogging the channels necessary for diffusion 
out of the carrier matrix. This problem is largely alleviated by using a 
biodegradable matrix which allows controlled release of the therapeutic 
agent. 
Biodegradable polymers differ from non-biodegradable polymers in that they 
are consumed or biodegraded during therapy. This usually involves 
breakdown of the polymer to its monomeric subunits, which should be 
biocompatible with the surrounding tissue. The life of a biodegradable 
polymer in vivo depends on its molecular weight and degree of 
cross-linking; the greater the molecular weight and degree of 
crosslinking, the longer the life. The most highly investigated 
biodegradable polymers are polylactic acid (PLA), polyglycolic acid (PGA), 
copolymers of PLA and PGA, polyamides, and copolymers of polyamides and 
polyesters. PLA, sometimes referred to as polylactide, undergoes 
hydrolytic de-esterification to lactic acid, a normal product of muscle 
metabolism. PGA is chemically related to PLA and is commonly used for 
absorbable surgical sutures, as is PLA/PGA copolymer. However, the use of 
PGA in sustained-release implants has been limited due to its low 
solubility in common solvents and subsequent difficulty in fabrication of 
devices. 
An advantage of a biodegradable material is the elimination of the need for 
surgical removal after it has fulfilled its mission. The appeal of such a 
material is more than simply for convenience. From a technical standpoint, 
a material which biodegrades gradually and is excreted over time can offer 
many unique advantages. 
A biodegradable therapeutic agent delivery system has several additional 
advantages: 1) the therapeutic agent release rate is amenable to control 
through variation of the matrix composition; 2) implantation can be done 
at sites difficult or impossible for retrieval; 3) delivery of unstable 
therapeutic agents is more practical. This last point is of particular 
importance in light of the advances in molecular biology and genetic 
engineering which have lead to the commercial availability of many potent 
bio-macromolecules. The short in vivo half-lives and low GI tract 
absorption of these polypeptides render them totally unsuitable for 
conventional oral or intravenous administration. Also, because these 
substances are often unstable in buffer, such polypeptides cannot be 
effectively delivered by pumping devices. 
In its simplest form, a biodegradable therapeutic agent delivery system 
consist of a dispersion of the drug solutes in a polymer matrix. The 
therapeutic agent is released as the polymeric matrix decomposes, or 
biodegrades into soluble products which are excreted from the body. 
Several classes of synthetic polymers, including polyesters (Pitt, et al., 
in Controlled Release of Bioactive Materials, R. Baker, Ed., Academic 
Press, New York, 1980); polyamides (Sidman, et al., Journal of Membrane 
Science, 7:227, 1979); polyurethanes (Maser, et al., Journal of Polymer 
Science, Polymer Symposium, 66:259, 1979); polyorthoesters (Heller, et 
al., Polymer Engineering Science, 21:727, 1981); and polyanhydrides 
(Leong, et al., Biomaterials, 7:364, 1986) have been studied for this 
purpose. 
By far most research has been done on the polyesters of PLA and PLA/PGA. 
Undoubtedly, this is a consequence of convenience and safety 
considerations. These polymers are readily available, as they have been 
used as biodegradable sutures, and they decompose into non-toxic lactic 
and glycolic acids. However, a major problem with these polymers is that 
it is often difficult to control and predict their degradation. 
Polyorthoesters and polyanhydrides have been specifically designed for 
controlled release purposes. While these polymers are promising, they also 
have significant drawbacks. For example, polyorthoesters biodegrade in a 
desirable manner only if additives are included in the matrix. By taking 
advantage of the pH dependence of the rate of orthoester cleavage, 
preferential hydrolysis at the surface is achieved by either the addition 
of basic substances to suppress degradation in bulk, or the incorporation 
of acidic catalysts to promote surface degradation. Unfortunately, these 
additives often lead to unnecessary complications in terms of release 
behavior and biocompatibility. 
The polyanhydrides, on the other hand, are unstable even in the solid 
state. In addition, the poor solubility of the hydrophobic polyanhydrides 
also render characterization and fabrication difficult. Hence there exists 
the need for new biodegradable polymers. 
The biodegradable matrix of the invention also finds broad utility as a 
transient prosthetic support in orthopedic applications. For centuries, 
physicians have attempted to repair and replace various components of the 
skeletal system. These attempts have utilized various kinds of materials 
including bone, ivory, collagen, wood, metals, alloys, ceramics, glasses, 
corals, carbons, polymers, and composites of materials as bone prostheses. 
Ideally, the bone prosthesis should be a material that is biologically 
inert, readily available, easily adaptable to the site in terms of shape 
and size, and replaceable by the host bone. Replacement of the prothesis 
by the host bone necessitates that the substitute be biodegradable. 
The different elastic moduli of the prior art prosthetic implants versus 
that of bone often causes cortical bone to atrophy. The theoretical 
advantage of gradual load transfer from the bone plate to the bone and the 
elimination of the need for surgical removal after the healing of a 
fracture would make an absorbable osteosynthesis material extremely 
useful. As a temporary support in a load-bearing area of an articular 
joint, a resorbable porous material also has the advantage of preventing 
further destruction of cartilage defects and promoting bone and 
cartilage-forming cells. Hence, a need exists for a biodegradable 
prosthesis of sufficient post-implantation strength and rigidity to 
provide structural support. 
SUMMARY OF THE INVENTION 
The present invention pertains to a biodegradable composition useful as a 
structural prosthesis and a therapeutic agent delivery vehicle and methods 
for its manufacture and use. The composition comprises a biocompatible 
poly(phosphoester) matrix, prepared in preselected dimensions and 
configurations, which predictably degrades in vivo into non-toxic 
residues. The method of using the composition as an implant and prosthesis 
comprises the step of introducing a specifically configured composition 
into an individual in vivo at a predetermined site. 
Although it is preferred that the polymers of the invention be 
biodegradable and in matrix form, these characteristics are not essential 
for the polymers. 
The composition of the invention, through its transient in vivo presence, 
provides a matrix which persists for a period of time sufficient to 
achieve a medical effect, essentially lacks host toxicity upon 
degradation, provides mechanical strength, and is readily fabricated.

DETAILED DESCRIPTION 
The present invention is directed to compositions useful as prostheses and 
as therapeutic agent delivery vehicles. These compositions comprise a 
biodegradable, biocompatible class of poly(phosphoesters). The polymers 
are biodegradable because of the hydrolyzable phosphoesters, or P(O)--O--C 
bond, in the backbone. With the phosphoester the polymers can be 
classified as polyphosphates, polyphosphonates, or polyamidophosphates, 
depending on the structure of the pendant groups. With the phosphorous 
atom existing in the trivalent state, the polymers can be either 
polyphosphites or polyphosphonites. 
Preferred are compositions comprising a biodegradable poly-phosphate or 
polyphosphonate matrix which have the general formula: 
##STR1## 
wherein R and R', are preferably organic or organometallic moieties and n 
is from about 10 to about 10.sup.5. 
The R' group can be a therapeutic agent or, alternatively, can be selected 
from the group consisting of: 
##STR2## 
wherein R.sub.1 is alkyl, halogen, nitro, hydroxyl, amino, carboxyl, 
alkoxy, or combinations thereof, R.sub.2 is oxygen or N--CH.sub.3, and a 
ranges from 2 to 6, b ranges from 10 to 100, d ranges from 2 to 16, f 
ranges from 1 to 6, and m ranges from 1 to 2. 
Other R' groups that function equivalently to these R' groups are within 
the scope of the invention. 
The R group can be a therapeutic agent or, alternatively, can be selected 
from the group consisting of: 
##STR3## 
wherein R.sub.1 is alkyl, halogen, nitro, hydroxyl, amino, carboxyl, 
alkoxy, or combinations thereof, R.sub.3 is 
##STR4## 
and p ranges from 1 to 16. 
Other R groups that function equivalently to these R groups are within the 
scope of the invention. 
It is also possible for R and R' to be the same or different therapeutic 
agent. 
Other R groups that function equivalently to these R groups are within the 
scope of the invention. 
The common synthesis and chemical structures of polyphosphates and 
polyphosphonates are shown in Eqs. 1 and 2, respectively. On hydrolysis 
the polymers decompose into monomeric phosphates and diols (Eq. 3). 
However, because of the hydrolytic instability of the phosphorous ester 
bond, there have not been any commercial applications for these polymers 
(Sandler, et al., in Polymer Synthesis, Vol. 1, Chap. 13, Academic Press, 
New York, 1974). It is this instability, however, which the present 
inventor discovered, renders these polymers attractive for achieving a 
medical effect for both transient structural prosthesis and therapeutic 
agent controlled release applications. 
##STR5## 
In comparing the hydrolytic reactivity of different carbonyl bonds, the 
phosphorous ester is comparable to, or slightly more reactive than, the 
carboxylic ester. Thus, this water labile linkage provides the basis for a 
versatile delivery system. 
A wide range of degradation rates can be obtained by adjusting the 
hydrophobicities of the backbones of the polymers and yet the 
biodegradability is assured. This can be achieved by varying the 
functional groups R or R'. The combination of a hydrophobic backbone and a 
hydrophilic linkage also leads to heterogeneous degradation as cleavage is 
encouraged, but water penetration is resisted. 
The polyphosphates and polyphosphonates of the invention show favorable 
mechanical strength because of the high molecular weights obtainable. 
Average molecular weight of up to 600,000 has been obtained by an 
interfacial polymerization (Sandler, et al., ibid). This high molecular 
weight leads to transparency, and film and fiber properties. It has also 
been observed that the P--O--C group provides a plasticizing effect, which 
lowers the glass transition temperature of the polymer and confers 
solubility in organic solvents. Both effects are desirable for fabrication 
of the composition. 
The term "therapeutic agent" as used herein for the compositions of the 
invention includes, without limitation, drugs, radioisotopes, 
immunomodulators, and lectins. Similar substances are within the skill of 
the art. The term "individual" includes human as well as non-human 
animals. 
The drugs with which can be incorporated in the compositions of the 
invention include non-proteinaceous as well as proteinaceous drugs. The 
term "non-proteinaceous drugs" encompasses compounds which are classically 
referred to as drugs such as, for example, mitomycin C, daunorubicin, 
vinblastine, AZT, and hormones. Similar substances are within the skill of 
the art. 
The proteinaceous drugs which can be incorporated in the compositions of 
the invention include immunomodulators and other biological response 
modifiers. The term "biological response modifiers" is meant to encompass 
substances which are involved in modifying the immune response in such 
manner as to enhance the particular desired therapeutic effect, for 
example, the destruction of the tumor cells. Examples of immune response 
modifiers include such compounds as lymphokines. Examples of lymphokines 
include tumor necrosis factor, the interleukins, lymphotoxin, macrophage 
activating factor, migration inhibition factor, colony stimulating factor 
and the interferons. Interferons which can be incorporated into the 
compositions of the invention include alpha-interferon, beta-interferon, 
and gamma-interferon and their subtypes. In addition, peptide or 
polysaccharide fragments derived from these proteinaceous drugs, or 
independently, can also be incorporated. Also, encompassed by the term 
"biological response modifiers" are substances generally referred to as 
vaccines wherein a foreign substance, usually a pathogenic organism or 
some fraction thereof, is used to modify the host immune response with 
respect to the pathogen to which the vaccine relates. Those of skill in 
the art will know, or can readily ascertain, other substances which can 
act as proteinaceous drugs. 
In using radioisotopes certain isotopes may be more preferable than others 
depending on such factors, for example, as tumor distribution and mass as 
well as isotope stability and emission. Depending on the type of 
malignancy present come emitters may be preferable to others. In general, 
alpha and beta particle-emitting radioisotopes are preferred in 
immunotherapy. For example, if an animal has solid tumor foci a high 
energy beta emitter capable of penetrating several millimeters of tissue, 
such as .sup.90 Y, may be preferable. On the other hand, if the malignancy 
consists of single target cells, as in the case of leukemia, a short 
range, high energy alpha emitter such as .sup.212 Bi may be preferred. 
Examples of radioisotopes which can be incorporated in the compositions of 
the invention for therapeutic purposes are .sup.125 I, .sup.131 I, .sup.90 
Y, .sup.67 Cu, .sup.212 Bi, .sup.211 At, .sup.212 Pb, .sup.47 Sc, .sup.109 
Pd and .sup.188 Re. Other radioisotopes which can be incorporated into the 
compositions of the invention are within the skill in the art. 
Lectins are proteins, usually isolated from plant material, which bind to 
specific sugar moieties. Many lectins are also able to agglutinate cells 
and stimulate lymphocytes. Other therapeutic agents which can be used 
therapeutically with the biodegradable compositions of the invention are 
known, or can be easily ascertained, by those of ordinary skill in the 
art. 
The term "therapeutically effective" as it pertains to the compositions of 
the invention means that the therapeutic agent is present at 
concentrations sufficient to achieve a particular medical effect for which 
the therapeutic agent is intended. Examples, without limitation, of 
desirable medical effects which can be attained are chemotherapy, 
antibiotic therapy, birth control, and regulation of metabolism. 
"Therapeutic-agent bearing" as it applies to the compositions of the 
invention denotes that the composition incorporates a therapeutic agent 
which is 1) not bound to the polymeric matrix, or 2) bound within the 
polymeric backbone matrix, or 3) pendantly bound to the polymeric matrix, 
or 4) bound within the polymeric backbone matrix and pendantly bound to 
the polymeric matrix. When the therapeutic agent is not bound to the 
matrix, then it is merely physically dispersed with the polymer matrix. 
When the therapeutic agent is bound within the matrix it is part of the 
poly(phosphoester) backbone (R'). When the therapeutic agent is pendantly 
attached it is chemically linked through, for example, by ionic or 
covalent bonding, to the side chain (R) of the matrix polymer. In the 
first two instances the therapeutic agent is released as the matrix 
biodegrades. The drug can also be released by diffusion through the 
polymeric matrix. In the pendant system, the drug is released as the 
polymer-drug bond is cleaved at the bodily tissue. 
A combination of more than one therapeutic agent can be incorporated into 
the compositions of the invention. Such multiple incorporation can be 
done, for example, 1) by substituting a first therapeutic agent into the 
backbone matrix (R') and a second therapeutic agent by pendant attachment 
(R), 2) by providing mixtures of different poly(phosphoesters) which have 
different agents substituted in the backbone matrix (R') or at their 
pendant positions (R), 3) by using mixtures of unbound therapeutic agents 
with the poly(phosphoester) which is then formed into the composition, 4) 
by use of a copolymer with the general structure 
##STR6## 
wherein m or n can be from about 1 to about 99% of the polymer, or 5) by 
combinations of the above. 
The concentration of therapeutic agent in the composition will vary with 
the nature of the agent and its physiological role and desired therapeutic 
effect. Thus, for example, the concentration of a hormone used in 
providing birth control as a therapeutic effect will likely be different 
from the concentration of an anti-tumor drug in which the therapeutic 
effect is to ameliorate a cell-proliferative disease. In any event, the 
desired concentration in a particular instance for a particular 
therapeutic agent is readily ascertainable by one of skill in the art. 
The therapeutic agent loading level for a composition of the invention can 
vary, for example, on whether the therapeutic agent is bound to the 
poly(phosphoester) backbone polymer matrix. For those compositions in 
which the therapeutic agent is not bound to the backbone matrix, in which 
the agent is physically disposed with the poly(phosphoester), the 
concentration of agent will typically not exceed 50 wt %. For compositions 
in which the therapeutic agent is bound within the polymeric backbone 
matrix, or pendantly bound to the polymeric matrix, the drug loading level 
is up to the stoichiometric ratio of agent per monomeric unit. 
The term "transient structural prosthesis" when used to describe the 
compositions of the invention means a prosthesis which is biodegradable 
with time and provides a structural function in the individual such as, 
for example, as a vascular graft, suture and bone plate. 
A poly(phosphoester) composition of the invention can function 
simultaneously both as a transient structural prosthesis and as a 
therapeutic agent-bearing composition. An example of this would be a 
suture bearing a therapeutic agent such as, for example, an antibiotic, 
or, alternatively, a bone plate incorporating a growth factor. 
A novel advantage of the polymers of the invention is the availability of 
functional side groups which allow the chemical linkage of therapeutic 
agents to the polymers. For example, drugs with carboxyl groups can be 
coupled to the phosphorous atom via an ester bond, which is hydrolyzable 
(Eq. 4). The rate of therapeutic agent release will then be dependent on 
the hydrolytic cleavage of the polymer therapeutic agent conjugate. This 
pendant delivery system has the advantage of attaining a high drug loading 
level. Therapeutic agents which exist in the liquid state can also be 
accommodated. 
Alternatively, therapeutic agents containing two hydroxyl groups can be 
directly incorporated into the backbone of the polymers (Eq. 5). For 
instance, steroids such as estradiol can be reacted with 
dichlorophosphates to form the polymer. Other therapeutic agents can also 
be derivatized for incorporation into the backbone. For instance, a drug 
with two amino groups can be reacted with the carboxyl group of a hydroxyl 
carboxylic acid. The hydroxyl groups can then be used to form the 
poly(phosphoester). A sustained delivery is then effected by hydrolysis of 
the polymeric prodrug. 
##STR7## 
The poly(phosphoester) of the invention can be synthesized using such 
polymerization methods as bulk polymerization, interfacial polymerization, 
solution polymerization, and ring opening polymerization (Odian, G., 
Principles of Polymerization, 2nd ed., John Wiley & Sons, New York, 1981). 
Using any of these methods, a variety of different synthetic polymers 
having a broad range of mechanical, chemical, and biodegradable properties 
are obtained; the differences in properties and characteristics are 
controlled by varying the parameters of reaction temperatures, reactant 
concentration, types of solvent, and reaction time. 
The poly(phosphoester) of the invention can range in molecular weight from 
about 2,000 to about 10.sup.6 containing from about 10 to about 10,000 
monomeric units. 
All of the compositions useful as prostheses or implants are synthetic 
poly(phosphoester) compositions which share such characteristics as 
predictable and controllable degradation rates, biocompatibility and 
biodegradability, mechanical strength, and ease of fabrication. 
The rate of biodegradation of the poly(phosphoester) compositions of the 
invention may also be controlled by varying the hydrophobicity of the 
polymer. The mechanism of predictable degradation preferably relies on 
either group R' in the poly(phosphoester) backbone being hydrophobic for 
example, an aromatic structure, or, alternatively, if the group R' is not 
hydrophobic, for example an aliphatic group, then the group R is 
preferably aromatic. 
The rates of degradation for each poly(phosphoester) composition are 
generally predictable and constant at a single pH. This permits the 
compositions to be introduced into the individual at a variety of tissue 
sites. This is especially valuable in that a wide variety of compositions 
and devices to meet different, but specific, applications may be composed 
and configured to meet specific demands, dimensions, and shapes--each of 
which offers individual, but different, predictable periods for 
degradation. 
When the composition of the invention is used for long term delivery of a 
therapeutic agent a relatively hydrophobic backbone matrix, for example, 
containing bisphenol A, is preferred. It is possible to enhance the 
degradation rate of the poly(phosphoester) or shorten the functional life 
of the device, by introducing hydrophilic or polar groups, into the 
backbone matrix. Further, the introduction of methylene groups into the 
backbone matrix will usually increase the flexibility of the backbone and 
decrease the crystallinity of the polymer. Conversely, to obtain a more 
rigid backbone matrix, for example, when used orthopedically, an aromatic 
structure, such as a diphenyl group, can be incorporated into the matrix. 
Also, the poly(phosphoester) can be crosslinked, for example, using 
1,3,5-trihydroxybenzene or (CH.sub.2 OH).sub.4 C, to enhance the modulus 
of the polymer. Similar considerations hold for the structure of the side 
chain (R). 
The entire class of poly(phosphoester) are biocompatible and biodegradable. 
In view of their intended function as a therapeutic agent-bearing implant 
or prosthesis to be introduced into a subject in vivo, it is desirable 
that these compositions be essentially non-inflammatory, and 
non-immunogenic. 
The use of the poly(phosphoester) of the invention as an implant which also 
functions as a therapeutic agent-bearing polymeric composition, for 
example, subcutaneously or in various body cavities, is particularly 
useful in cases where chronic administration of drug over periods ranging 
from days to years is required. Examples of drugs which can be used in 
this manner include insulin for diabetes, pilocarpine for glaucoma, immune 
agents for various diseases and allergies, contraceptive steroids, 
narcotic antagonists, antibiotics, anticancer, and antihypertensive drugs. 
Subcutaneous implantation is currently one of the most popular routes used 
for sustained drug delivery. This is partly due to the simplicity of the 
surgical procedures involved in implantation and removal, and the 
relatively favorable absorption site offered compared to the oral or 
percutaneous routes. Surgery could be viewed as a disadvantage, however, 
depending on the patient and the location and frequency of implantation. 
It can be avoided in some cases by injecting the implant directly into 
subcutaneous tissue, provided the implant is capable of being delivered 
through a syringe. This is the method used for many of the 
sustained-release insulin products. 
Implantation using a syringe is particularly effective when the composition 
of the invention is in the form of microspheres which can be suspended in 
a pharmaceutical buffer and introduced via the syringe to the desired 
site. 
For example, compositions in the form of microspheres incorporating 
cortisone could be injected into the region of an inflammatory joint or 
muscle. 
The use of the biodegradable polymers of the invention to act as a matrix 
for the release of a therapeutic agent from subcutaneously implanted 
compositions offers several advantages over prior art compositions. The 
most obvious is that no surgical removal of the device is necessary after 
it has fulfilled its function. Also, an additional mechanism for release 
of drug is provided by degradation. Complete delivery and, thus, maximal 
absorption occurs after the device has degraded. 
The mechanism of release of therapeutic agent from biodegradable slabs, 
cylinders, and spheres has been described by Hopfenberg (in Controlled 
Release Polymeric Formulations, pp. 26-32, Paul, D. R. and Harris, F. W., 
Eds., American Chemical Society, Washington, D.C., 1976). A simple 
expression describing additive release from these devices where release is 
controlled primarily by matrix degradation is 
EQU M.sub.t /M.sub..infin. =1-[1-k.sub.0 t/C.sub.0 a].sup.n 
where n=3 for a sphere, n=2 for a cylinder, and n=1 for a slab. The symbol 
a represents the radius of a sphere or cylinder or the half-thickness of a 
slab. M.sub.t and M.sub..infin. are the masses of drug released at time t 
and at infinity, respectively. 
Biodegradable subcutaneous implants can also be used, for example, for the 
delivery of narcotic antagonists, steroids, and anticancer agents. 
Narcotic antagonists, such as naltrexone, cyclazocine, and naloxone, are 
therapeutically useful in the postdetoxification stage of rehabilitation 
of drug-dependent patients. Steroids which can be used include 
contraceptives (for example, progesterone), anti-inflammatory agents (for 
example, dexamethasone), and anabolics (for example, estradiol). 
Anticancer agents which can be used include cyclophosphamide, doxorubicin, 
and cisplatin. 
Intravaginal implants are used for the sustained release of contraceptive 
steroid hormones due to the more favorable site of absorption offered by 
the vaginal mucosa relative to the oral route for these drugs. First-pass 
hepatic metabolism, which inactivates many steroid hormones, and 
gastrointestinal incompatibility are avoided by using the vaginal route. 
In addition, the vaginal route allows self-insertion ensuring better 
patient compliance. More stable poly(phosphoester) are preferred in this 
usage. 
The intrauterine device (IUD) is one of the more popular methods of 
contraception which can utilize the compositions of the invention. Initial 
investigations involving nonmedicated IUDs revealed that the larger the 
device, the more effective it was in preventing pregnancy. Unfortunately, 
large devices caused increased incidences of uterine cramps, bleeding, and 
expulsion. The effort to improve intrauterine contraception and avoid 
previously demonstrated side effects has led to the development of 
medicated IUDs. More stable poly(phosphoester) are preferred in this 
usage. Two classes of agents have been used in IUDs of this type: 
contraceptive metals, such as copper, and steroid hormones, such as 
progesterone. 
The compositions of the invention are also useful in the treatment of 
glaucoma. Chronic open-angle glaucoma usually requires therapy for the 
lifetime of the patient with a miotic agent such as pilocarpine, for 
control of intraocular pressure. Conventional pilocarpine therapy requires 
instillation of eyedrops four times a day. Hence, compositions of the 
invention incorporating an anti-glaucoma agent such as pilocorpine would 
require less frequent and more sustained administration. 
In addition to the embodiments described above, compositions comprising the 
poly(phosphoester) of the invention can be used for agricultural purposes. 
This can be accomplished by substituting for the therapeutic agent, 
without limitation, a pesticide, a plant growth horomone, a fungicide, a 
fertilizer, and the like, others of which are known or readily 
ascertainable to those of skill in the art. 
The above disclosure generally describes the present invention. A further 
understanding can be obtained by reference to the following specific 
examples which are provided herein for purposes of illustration only, and 
are not intended to be limiting unless otherwise specified. 
EXAMPLE 1 
General Polymer Synthesis Techniques 
Four different methods were used for the synthesis of the 
phosphorus-containing polymers: bulk polycondensation, solution 
polymerization, interfacial polycondensation, and ring-opening 
polymerization. In these syntheses, care was taken to eliminate traces of 
moisture from the system. The reaction vessels were carefully dried and 
purged with dry nitrogen before use. The nitrogen stream was passed 
through a Deoxo purifier for oxygen removal. The polymerization, except in 
the case of interfacial polycondensation, was conducted under nitrogen 
sweep. All reactants were fractionally distilled under vacuum or 
recrystallized before use. In particular, the phosphorus diacid chlorides 
were freshly distilled before each experiment. Solvents were dried over 
molecular sieves. The phase transfer catalysts of cetyltrimethylammonium 
chloride and crown ether 18 were used for the interfacial 
polycondensation. Lewis acids of ferric chloride and magnesium chloride 
were used for melt-polycondensation. For ring-opening polymerization, 
t-BuOK or (i-C.sub.4 H.sub.9).sub.3 Al were used as initiators. In 
reactions involving diols oxidizable to quinones in base the procedures 
were performed in the dark, and small amounts of sodium hydrosulfite were 
added to the interfacial polycondensation to prevent oxidation of the 
diol. 
A. Melt-Polycondensation: 
In melt, or bulk, polycondensation the phosphonic or phosphoric dichloride 
is mixed with the diol in the absence of solvent. A Lewis acid catalyst 
(FeCl.sub.3, MgCl.sub.2, etc.) is added and the mixture is heated, often 
under vacuum or nitrogen blanket, to remove the Hcl formed. These somewhat 
vigorous conditions can lead to chain acidolysis (or hydrolysis if water 
is present). Unwanted, thermally-induced side reactions such as 
adventitious crosslinking can also occur if the polymer backbone is 
susceptible to hydrogen atom abstraction or oxidation with subsequent 
macroradical recombination. On the positive side, this technique avoids 
solvents and large amounts of other additives, thus making purification 
more straightforward. It can also provide polymers of reasonable molecular 
weight. 
B. Solution-Polycondensation: 
Solution polycondensation requires that both the diol and the phosphorus 
component be soluble in a common solvent. Typically, a chlorinated organic 
solvent was used and the reaction run in the presence of a stoichiometric 
amount of an acid acceptor. The product was then isolated from the 
solution by precipitation and purified to remove the hydrochloride salt. 
Although longer reaction times may be necessary, generally much milder 
conditions are used relative to bulk-reactions. More sensitive 
functionality can thus be incorporated using this technique. 
C. Interfacial-Polycondensation: 
Interfacial polycondensation potentially yields high molecular weights for 
these polymers at high reaction rates. Since the interfacial technique is 
a non-equilibrium method, the critical dependence of high molecular weight 
on exact stoichiometric equivalence between diol and dichloridate inherent 
in bulk and solution methods is removed. The limitation of this method is 
the hydrolysis of the acid chloride in the alkaline aqueous phase. 
Phosphoro-dichloridates which have some solubility in water are generally 
subject to hydrolysis rather than polymerization. 
D. Ring Opening: 
Ring-opening polymerization of phosphorus-containing monomers was performed 
using the technique disclosed in Lapienis, et al., Journal of Polymer 
Science, Part A: Polymer Chemistry, 25:1729, 1987 and Pretula, et al., 
Macromolecules, 19:1797, 1986. This technique is particularly useful in 
producing high molecular weight polymers. 
EXAMPLE 2 
Preparation of Poly(Phosphoesters) 
A Using the melt-condensation technique, a poly(phosphoester) having the 
structure disclosed in Equation 6 was produced. Ethyl 
phosphorodichloridate was slowly added to a magnetically stirred mixture 
of an equimolar amount of ethylene glycol containing 2 mole percent of 
FeCl.sub.3 cooled to -20.degree. C. The flask was connected to a vacuum 
pump through a trap to remove HCl. When the addition was complete, the 
temperature was gradually raised to 120.degree. C. over a seven hour 
period. The mass was then cooled to room temperature, dissolved in 
methanol, and precipitated into ether. 
##STR8## 
B. Using the solution-polycondensation technique, a poly(phosphoester) with 
the structure disclosed in Equation 7 was produced. 
A solution of recrystallized bisphenol-A (10.0 g, 43.8 mmol) and dried 
pyridine (7.62 g, 2.2 equiv.) in 100 ml of dried methylene chloride was 
cooled to 5.degree. C. in a 500 ml three-necked flask equipped with a 
paddle stirrer, thermometer, and gas inlet and exit tubes. Under positive 
pressure of dry nitrogen, a solution of 7.14 g (43.8 mmol) of freshly 
distilled ethyl phosphorodichloridate in 25 ml of methylene chloride was 
added from an addition funnel over a period of 30 minutes. An increase in 
viscosity was noted during the addition. When the addition was complete, 
the temperature was allowed to rise to 25.degree. C. and stirring was 
continued under nitrogen for 18 hours. The precipitate of pyridine 
hydrochloride was removed by filtration and the filtrate was washed twice 
with 40 ml of distilled water. After drying over CaCl.sub.2, the methylene 
chloride solution was concentrated and precipitated into 500 ml of 
petroleum ether. The oily isolated was dried on a vacuum line at room 
temperature for 16 hours to give 8.42 g (60.4% yield) of the 
poly(phosphate) as a crisp white foam having M.sub.w =17,000 (by GPC 
relative to polystyrene in chloroform). 
##STR9## 
C. The poly(phosphoester) of Equation 8 was produced using the interfacial 
polycondensation technique. 
A solution of recrystallized bisphenol-A (10.0 g, 43.8 mmol) and sodium 
hydroxide (3.66 g, 1.04 equiv.) in 65 ml of distilled water was prepared; 
1.12 g (2 mole percent) of a 25% aqueous solution of 
cetyltrimethylammonium chloride (CTMAC) was then added with stirring. 
Separately a solution of phenylphosphonodichloridate (8.59 g, 43.8 mmol) 
in 60 ml of dried methylene chloride was prepared in a dropping funnel and 
kept under nitrogen. Both of these solutions were then cooled to 0.degree. 
C. The aqueous solution was transferred to the jar of a 1 L Waring 
commercial blender; low speed mixing was begun immediately. The organic 
solution was run into the agitated solution from the funnel through a hole 
in the cap over a one-minute period. The mixture was blended for four 
minutes, producing a thick, milky emulsion with a temperature of 
35.degree. C. After separating the layers in a separatory funnel, the 
lower organic layer was washed with 30 ml of water, dried over CaCl.sub.2, 
and precipitated into 750 ml of petroleum ether to give a fibrous, powdery 
solid. The solid was isolated by filtration, reprecipitated in the same 
manner, isolated again, and dried on a vacuum line at room temperature for 
16 hr to give the polyphosphonate (15.1 g, 98.4%) as a fine powder. 
##STR10## 
D. The ring-opening technique was used to produce the poly(phosphoester) 
shown in Equation 9. Using dioxaphosphorinane at a concentration of 7.0 
mol/L in methylene chloride, a polymer with a number average molecular 
weight of over 100,000 was obtained as a white, powdery material in about 
50% yield when triisobutylaluminum (0.03M) was used as the initiator at 
25.degree. C. after a 24 hour reaction (Eq. 9). The difficulty of this 
technique is the preparation of the pure cyclic monomers. In order to 
maintain a favorable thermodynamic driving force for the ring-opening 
reaction, the monomer is confined to aliphatic and non-bulky groups. The 
cyclic monomer also should not contain acidic protons. 
##STR11## 
Additional examples of some of the poly(phosphoesters) which have been 
synthesized using the above techniques and their properties are shown in 
Table 1. 
TABLE 1 
__________________________________________________________________________ 
Polymer 
R R' 
Method 
Properties 
__________________________________________________________________________ 
I OC.sub.2 H.sub.5 
1 A dark brown solid, swells in hot water 
OC.sub.2 H.sub.5 
1 C white powder; M.sub.n = 3879, M.sub.w = 35365, 
T.sub.s = 60-70.degree. C. 
OC.sub.2 H.sub.5 
1 B M.sub.n = 3920 
II OC.sub.2 H.sub.5 
2 C T.sub.m = 110-130.degree. C.; solution in chloroform 
III OC.sub.2 H.sub.5 
3 C [ ] = 0.16 dL/g, soluble in DMF 
IV OC.sub.2 H.sub.5 
4a 
A waxy solid, T.sub.m = 30-35.degree. C., soluble in pH 
7.4 
phosphate buffer, slow decomposition in 
air (spongy) 
V OC.sub.2 H.sub.5 
4b 
A solid swells up to 560% in 48 hours in 
pH 7.4 phosphate buffer, swells in MeOH 
and chloroform, T.sub.m = 140-220.degree. C. 
VI OC.sub.2 H.sub.5 
4c 
A swells in buffer, T.sub.m = 90.degree. C. 
VII OC.sub.2 H.sub.5 
4c 
A water soluble, T.sub.m = 55-65.degree. C. 
VIII C.sub.6 H.sub.5 
1 C M.sub.n = 4917, M.sub.w = 33867 
IX OC.sub.6 H.sub.5 
1 C M.sub.n = 3745, M.sub.w = 34860 
X OC.sub.6 H.sub.5 (NO.sub.2) 
1 C yellow sticky material 
__________________________________________________________________________ 
A = meltcondensation with MgCl.sub.2 as catalyst 
B = solution polymerization in refluxing methylene chloride 
C = aqueous interfacial condensation (CH.sub.2 Cl.sub.2H.sub.2 O) with 
phase transfer catalysts 
##STR12## 
##STR13## 
##STR14## 
##STR15## 
EXAMPLE 3 
Comparative Release Rates of Compounds from Pendant and Matrix Systems 
Poly(phosphoester) compositions were prepared which contained benzoic acid, 
aniline, thiophenol, or p-nitrophenol in pendant position in combination 
with an aliphatic backbone, as shown in Equation 10 below. 
##STR16## 
R=benzoic acid, aniline, thiophenol, or p-nitrophenol 
The ring-opening polymerization technique was used to prepare 
poly(2-chloro-2-oxo-1,3,2-dioxaphosphite). To prepare the cyclic monomer 
2-hydro-2-oxo-1,3,2-dioxaphosphite, a solution (100 ml) of 1,3-propanediol 
(0.165 mole) and triethylamine (TEA) (0.33 mole) in benzene was added 
dropwise to vigorously stirred anhydrous benzene (200 ml) at 0.degree. C. 
under nitrogen atmosphere. Phosphorus trichloride (0.165 mole) in 
anhydrous benzene (200 ml) was then added. After a reaction of two hours 
and the TEA HCl salt filtered off, a mixture of water (0.2 mole), TEA (0.2 
mole), and tetrahydrofuran (10 ml) were added dropwise. After two hours of 
vigorous agitation, the solvent was removed under reduced pressure. The 
residue was separated by flash chromatography using silica as the packing 
material and chloroform/toluene (50:50) as the mobile phase. The purity of 
the monomer was checked by thin layer chromatography (TLC). The TLC plates 
were developed by iodine vapor for visualization. 
The polymers were synthesized by anionic polymerization of 
2-hydro-2-oxo-1,3,2-oxaphosphorinane. The anionic polymerization was 
conducted in methylene chloride at -15.degree. C. for 48 hours under 
nitrogen atmosphere. A 1 mole % of i-Bu.sub.3 Al was used as the anionic 
initiator. The polymer was isolated by repeated precipitation into dried 
benzene. Chlorination of the polymer was achieved by passing dried 
chlorine through a solution of the polymer in methylene chloride until a 
persistent yellow color was obtained (about three hours). The excess 
chlorine was then removed by vacuum at room temperature. The polymers was 
characterized by GPC, intrinsic viscosity, FT-IR, and FT-NMR. 
After chlorination, the compounds were linked to the side chain of the 
polymer via dehydrochlorination. The chemical structures containing 
different R groups were all confirmed by FTIR and UV spectrophotometry. 
FIG. 1a shows the in vitro release of the R groups from polymer. 
The drug release rate was dependent on the stability of the linkage bond. 
For instance, benzoic acid was bound to the polymer via a phosphoric 
anhydride bond, which is extremely water labile. Consequently, a high 
release rate was seen. The model drugs are all water soluble compounds, 
which in a diffusion-controlled release system would be depleted very 
quickly. 
Shown in FIG. 1b is the comparison of the release of p-nitrophenol and 
aniline from a matrix system (in which the drug is just physically 
dispersed in the polymer and compression molded into a disc) and that 
released from the pendant system (in which the polymer-drug conjugates are 
compression molded to the same dimension). The time it took for 50% of the 
drug to be released from the polymer-drug conjugate was significantly 
longer, showing that the pendant system is indeed capable of prolonging 
the release of hydrophilic drugs through a phosphate ester or a 
phosphoroamide bond. 
EXAMPLE 4 
Comparison of Degradation Rates of Various BPA Polymers 
Various poly(phosphoesters) were prepared having a bisphenol A (BPA) 
backbone and their rates of in vitro degradation compared. 
These polymers were prepared in a manner similar to that disclosed in 
Example 1 B or C except for the substitutions to the phosphochloridate. 
The four side chains of Table 2 were commercially available from Aldrich 
Chemicals. 
In order to use side chains of other structures it is possible to start 
with the phosphorochloride of 
##STR17## 
where R is the desired structure. The monomer can be obtained either 
commercially or custom synthesized. Such synthesis can be carried out, for 
example, by reacting phosphorous oxychloride with the desired structure in 
the presence of a acid acceptor in an organic solvent, according to the 
general equation: 
##STR18## 
The polymers prepared had the structures indicated in Table 2. 
TABLE 2 
______________________________________ 
##STR19## 
R Designation 
______________________________________ 
OC.sub.2 H.sub.5 BPA-EOP 
C.sub.2 H.sub.5 BPA-EP 
##STR20## PBA-POP 
##STR21## BPA-PP 
______________________________________ 
These polymers were then placed in pH 12 phosphate buffer and their 
relative rates of degradation determined. 
The degradation experiments were conducted in 0.1M phosphate buffer (pH 
12). The polymers were compression molded into discs (1 cm.times.2 mm), 
placed in 50 ml of pH 12 buffer, and incubated at 37.degree. C. The 
release kinetics were followed by measuring the concentrations of the 
buffer solution by HPLC. The weight loss of the discs as a function of 
time was also recorded. 
The results are illustrated in FIG. 2. As expected, the hydrolysis was base 
catalyzed. In pH 7.4 buffer at 37.degree. C..sub.9 BPA-EOP lost less than 
5% of its weight in 10 days. In a 0.1M NaOH solution at 37.degree. 
C..sub.9 the polymer completely decomposed in less than one week. 
EXAMPLE 5 
Comparison of Non-Pendant Drug Release Rates from BPA Polymers 
Poly(phosphoesters) with a bisphenol A backbone and different side chains 
were prepared as described in Example 4 and compared in terms of their in 
vitro release of different drugs. 
In a first experiment compositions of BPA-PP, BPA-POP, BPA-EP, and BPA-EOP 
incorporating cortisone or lidocaine were compared. 
Drugs were incorporated into the matrix by compression molding. The polymer 
was ground and sieved into a particle size range below 90 microns. Drugs 
were sieved to the same particle size range and blended in a Vortex mixer 
with the polymer powder. The mixture was pressed into a disc (10 
mm.times.2 mm) through a mold, at a pressure of 150 Kpsi and room 
temperature for 10 min. Such a high molding pressure is useful in forming 
a compact matrix for desirable sustained release. The molds were 
specifically made with carbon and heat treated plungers to withstand the 
high pressure. The poly(phosphoester)-drug conjugates are similarly molded 
for implantation. 
A solvent evaporation technique was used to prepare the microspheres. A 
solution of 2 g of polymer and 0.4 g of drug in 20 ml of methylene 
chloride was prepared. The mixture was emulsified in 150 ml of water 
containing 0.5 wt % of poly(vinyl alcohol) in a homogenizer. The methylene 
chloride in the emulsion was evaporated over a period of one hour at room 
temperature at a reduced pressure of 40 mm Hg. The microspheres thus 
obtained were quickly washed with cold water and filtered. After drying, 
the microspheres were sieved to a narrow size fraction before use. This 
technique can be used to encapsulate, for example, such organic substances 
as sucrose and nerve growth factor. 
Release experiments were conducted in a 0.1M pH 7.4 phosphate buffer 
containing 0.02 wt % of gentamicin sulfate to inhibit bacterial growth. 
The drug-loaded matrices were placed in 10 ml of buffer in 20 ml vials and 
incubated at 37.degree. C. The release kinetics were followed by measuring 
the concentrations of the buffer solutions by scintillation counting and 
high pressure liquid chromatography (HPLC). HPLC analysis was used to 
determine the degradation rate of the matrix and to check the chemical 
purity of the drug. To approximate perfect sink conditions, the frequency 
of replacement of the buffer solutions was adjusted during the course of 
the release study to ensure that the drug concentration in buffer was 
below 20% of its saturation value. In situations where the release rates 
are rapid (100 percent release in less than 2 days) and when dealing with 
microspheres, the experiment was conducted in a flow system. The matrices 
or the microspheres were placed in a glass vial equipped with a glass 
filter and Teflon stopcock in the bottom. A counter-gravitational flow of 
0.1M pH 7.4 phosphate buffer was passed through the sample at a rate of 
0.5 ml/min. Both the buffer reservoir and the release vessel were immersed 
in a 37.degree. C. bath. The eluent was collected every hour and subjected 
to chromatographic and spectrophotometric analyses. 
The release kinetics are shown for cortisone in FIG. 3. The data indicate 
that the release rate was dependent on the chemical structure of the side 
chain (R). This is the first study which demonstrates systematically that 
the variation of the side chain of a biodegradable polymer can control the 
release rates. The EOP and EP side chains generally give faster release 
rates because they are less hydrophobic than the POP and PP structures. 
Noteworthy is the constant release of cortisone from the polymers. 
In a second experiment, the release kinetics of various non-pendant drugs 
were measured for BPA-EOP derived matrix compositions. As shown in FIG. 4, 
all four drugs were release in intact form from the polymer as determined 
by HPLC. These release profiles show that, in general, drugs of higher 
water solubility have higher release rates. 
EXAMPLE 6 
Preparation of Pendant 5-Fluorouracil Compositions 
A mixture of 5-FU (7 mmole) and 1,1,1,3,3,3-hexamethyldisilazane (30 ml) 
were heated at reflux temperature for 20 hours in the presence of a 
catalytic amount of ammonium sulphate to derivatize 5-FU. Evaporation of 
the mixture under reduced pressure resulted in the formation of 
2,4-bis-o-trimethylsilyl-5-fluorouracil. To obtain the final polymer-drug 
conjugate, the chlorinated poly(phosphoester) (5 g) in methylene chloride 
(20 ml) was reacted with the 5-FU derivative in the presence of a 
stoichiometric amount of pyridine. After stirring for 18 hours at room 
temperature, 15 ml of methanol was added. After evaporation of the 
solvent, the residue was redissolved in dimethyl formamide and repeatedly 
precipitated into acetone. Linking of iodoaminopurine (IAP) to the polymer 
can be achieved in a similar manner by taking advantage of the facile 
reaction between the primary amine of the drug and the chlorine in the 
side chain of the polymer. 
In the in vitro release studies (as in Example 5), a sustained release of 
5-FU was observed for at least 7 days and chemical integrity of the 5-FU 
was confirmed by HPLC. This release rate is far superior to similar 
studies with 5-FU pendently attached to a polyhydride carrier where nearly 
complete release occurred after only 2 days. 
The invention now being fully described, it will be apparent to one of 
ordinary skill in the art that many changes and modifications can be made 
without departing from the spirit or scope of the invention.