A formulation containing a biologically active compound having a structure with hydrogen bonding sites blended with a first polymer having a structure with complementary hydrogen bonding sites and a second polymer that degrades to form degradation products that promote the release of the active compound from the first polymer.

Description of the Invention

BACKGROUND OF THE INVENTION

The literature is replete with examples of the delayed or pulsed release of active agents using polymeric materials. However, it is possible to divide these systems into two basic categories; those that depend on an environmental stimulus to induce release of the active agent from the polymeric matrix and those that are designed to release the drug after particular intervals of time have elapsed. Examples of environmental stimuli that have been used are electrical impulses, pH or temperature changes, application of magnetic fields, or ultrasound.

Those systems that are time-controlled can further be divided into those that use a barrier technology that is placed around the active agent that is designed to degrade or dissolve after a certain time interval, and those that use the degradation of the polymer itself to induce the release of the active agent.

One approach has been to prepare a polymeric hydrogel composed of derivitized dextran and to incorporate into the hydrogel, a model protein, I.sub.gG, with an enzyme, endo-dextranase that degrades the hydrogel. It was observed that without the enzyme the release of the protein was very slow. However, when the enzyme was included in the formulation, the release rate was dependent on the concentration of the enzyme. At high concentrations, the release was fast and complete. At low concentrations, the release was delayed.

Delayed release in association with hydrolytic degradation of the polymer has also been investigated. Heller's so-called "3.sup.rd generation" poly(ortho esters) are viscous ointments at room temperature and when mixed with a model protein, lysozyme, demonstrated a delayed release profile. The length of the delay time was found to correlate with polymer molecular weight and alkyl substituent of the polymer.

Ivermectin, a water insoluble antiparasitic agent for veterinary applications, was encapsulated in PLGA (50:50) microspheres and the subsequent pulsed release of this agent, in vivo, was shown to be dependant on the degradation rate of the polymer matrix. Pulsed and delayed release of active agents from PLGA microspheres was most intensely studied by Cleland et al. The PLA or PLGA microspheres were processed using a high kinematic viscosity of polymer solution and a high ratio of polymer to aqueous solution. This produced dense microspheres, which required severe bulk erosion of the polymer to release the drug. These conditions yield microspheres that have low loading (generally 1% w/w), moderate bursts, and lag times during which significant leaching of drug occurs.

SUMMARY OF THE INVENTION

The technology described in this disclosure represents a departure from the prior art. In this system, bonding interactions between the polymer and the active compound are used to lock the active compound into the polymeric matrix. While one can envision several different types of interactions (adsorption, pi-bonding, ionic), hydrogen bonding interactions seem to be most suitable.

Therefore, according to one aspect of the present invention, a formulation containing a biologically active compound is provided having a structure with hydrogen bonding sites, blended with a first polymer having a structure with complementary hydrogen bonding sites, and a second polymer that degrades to form degradation products that promote the release of the active compound from the first polymer.

The formulation thus consists of three components, two polymers and a biologically active compound all blended together. The present invention thus provides new implantable or injectable drug release systems that release a pharmaceutically or biologically active compound in a time-controlled fashion, allowing the design of delay times prior to release, the design of pulsatile release, and the design of systems with high loadings that are resistant to "burst" (e.g., the immediate and uncontrolled release of a substantial amount of the loaded drug within a very short initial period of use).

The present invention uses the degradation products of one polymer to trigger the release of the active compound from the other polymer. In addition, the delayed release of the active compound can be achieved without the use of barrier systems that require complex and sophisticated formulation techniques. Further, the present invention relies on the formation of hydrogen-bonds between the active compound and the slow degrading, hydrophobic matrix polymer. This feature makes it possible to incorporate unexpectedly high loadings of water-soluble active compounds into the system without any burst (as defined above). Unlike the behavior that is observed when water-soluble peptides are incorporated into any of the commonly used alpha-hydroxy acid based polymers such as poly(lactic acid), poly(glycolic acid) or polydioxanone, in the system of the present invention, the formation of hydrogen-bond mediated interactions between the polymeric matrix and the active compound prevents burst, even at exceptionally high loadings.

There are many drugs that are more effective when given to the patient in a pulsatile manner as opposed to a continuous release fashion. For example, an area of great interest, currently, for this type of delivery system is single-shot immunization. Immunity is best induced by a pulsatile delivery of the antigen, hence the need for booster shots. It has been suggested that it would be more economical and effective, especially in third world countries, if a delivery system for antigens such as tetanus toxoid or gp120 (under development for an AIDS vaccine) could be implanted once into the patient and provide for the release of booster doses at preprogrammed time periods.

Therefore, the present invention also includes a method for the pulsatile delivery of a biologically active compound to a patient in need thereof by administering to the patient the formulation of the present invention.

This type of drug delivery is also important for hormonal based drug delivery. Fertility and birth control drug therapy for both animals and humans is not continuous, but rather cyclic in nature since these therapies work synergistically with the menstrual cycle and the corresponding hormonal flux. This is another direction in drug delivery in which delayed and/or pulsed release of an active compound would be applicable.

Agricultural applications which require the timed dosing of fertilizers, weed-killers, and other active agents is another area where this invention would be important.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The first polymer in the blend is a slowly degrading, relatively hydrophobic and biocompatible polymer. In order to encourage the formation of hydrogen bonding interaction with the biologically active compound, it is also necessary to choose a highly functional polymer system as the first polymer. In its broadest embodiment, the slow degrading, hydrophobic, biocompatible polymer can be any such polymer that contains hydrogen-bonding sites as part of its chemical structure. In its most preferred embodiment, this slow degrading and hydrophobic polymer is selected from the tyrosine-derived polyarylate libraries disclosed in U.S. Pat. No. 5,216,115 and WO 99/52962, the disclosures of both of which are incorporated herein by reference. Members of this library all share the same highly functional structural template but are distinguished from one another by subtle structural changes. The functional groups of the main template provide sites for interactions. These are pi stacking of its aromatic rings with an aromatic ring of a peptide, or hydrogen bonding of the .alpha.-amido carboxylate region with a corresponding group in the peptide. The small structural variations between members allow the fine-tuning of these interactions to suit particular proteins or peptides.

Also preferred are any of the polymers that can be derived from the tyrosine-derived diphenol compounds of U.S. Pat. No. 5,587,507 and the tyrosine-derived dihydroxy monomers of WO 98/36013, the disclosures of both of which are also incorporated herein by reference. In addition to the above-referenced polyarylates, examples include the polycarbonates of U.S. Pat. No. 5,099,060, the polyiminocarbonates of U.S. Pat. No. 4,980,449, the polyphosphazenes and polyphosphates of U.S. Pat. No. 5,912,225, polyurethanes, including the polyurethanes of U.S. Pat. No. 5,242,997, the random poly(alkylene oxide) block copolymers of U.S. Pat. No. 5,658,995, and a wide range of other polymers that can be derived from the above-referenced tyrosine-derived diphenol compounds, the tyrosine-derived dihydroxy compounds and similar peptides. All of the above referenced patent publications are incorporated herein by reference. Notably, corresponding polymers of the tyrosine-derived dihydroxy compounds can be made by any of the processes of any of the above-referenced patents disclosing polymers of tyrosine-derived diphenol compounds.

A particularly preferred first polymer is the poly(desaminotyrosyltyrosine hexyl ester adipate (Poly(DTH adipate)) of FIG. 1 (y=4; R=hexyl, see Original Patent). Poly(DTH adipate) having a weight-average molecular weight between about 80,000 and about 200,000 daltons is particularly preferred.

Any biologically active moiety with hydrogen-bonding sites that can be physically dispersed within the polymer blend can be used as a biologically active compound for release. Examples of hydrogen bonding sites include primary and secondary amines, hydroxyl groups, carboxylic acid and carboxylate groups, carbonyl (carboxyl) groups, and the like. While one can apply the current invention to any active compound that has hydrogen bonding sites, including natural and unnatural antibiotics, cytotoxic agents and oligonucleotides, amino acid derived drugs such as peptides and proteins seem to be most appropriate for this technology. The compositions of the present invention overcome some of the difficulties encountered in previous attempts to formulate controlled release devices that show reproducible release profiles without burst and/or lag effects. In its most preferred embodiment, the active compound is a peptide that is stable under mildly acidic conditions.

Peptide drugs suitable for formulation with the compositions of the present invention include natural and unnatural peptides, oligopeptides, cyclic peptides, library generated oligopeptides, polypeptides and proteins, as well as peptide mimetics and partly-peptides. Peptide drugs of particular interest include platelet aggregation inhibiting (PAI) peptides, which are antagonists of the cell surface glycoprotein Iib/IIIa, thus preventing platelet aggregation, and ultimately clot formation. Preferred PAI peptides include the PAI peptides disclosed by WO 90/15620, the disclosure of which is incorporated herein by reference, particularly INTEGRILIN.TM. (FIG. 2, see Original Patent), a medically useful cyclic PAI heptapeptide.

In the case of peptide drugs, interactions between the peptide and the first polymer inhibit the release of the peptide. These interactions are composed of hydrogen bonding and hydrophobic forces. It has been discovered that these interactions can be weakened under conditions of low pH, resulting in the release of the peptide. Thus, one method of achieving this is to blend in a second polymer that degrades into acidic byproducts, into the matrix, for example, poly(glycolic acid-co-lactic acid) (PGLA). The PGLA degradation products lower the pH of the matrix, causing an interruption in the interactions and the subsequent release of the peptide. Control of the timing of the release can easily be done by the choice of the initial molecular weight of this fast degrading polymer, the copolymer ratio of lactic acid and glycolic acid within the PGLA polymer, and the choice of capping of the copolymer. Since all of these factors determine the kinetics of degradation, these factors can also be used to control the release of active agents from these devices. Other useful polymers producing pH-lowering (acidic) degradation products include poly(glycolic acid), poly(lactic acid), polycaprolactone, poly(hydroxyalkanoic acids) such as polyhydroxybutyric acid) and poly(hydroxyvaleric acid), and the like.

It is impotant to note that the invention resides in the selection of a second polymer that is relatively more hydrophilic than the first polymer. Thus, when the first polymer is highly hydrophobic, a relatively less hydrophobic polymer may be used as the second polymer, even though it might otherwise ordinarily be considered hydrophobic as well. Likewise, when the second polymer is highly hydrophilic, a relatively less hydrophilic polymer may be used as the first polymer, even though it might otherwise ordinarily be considered hydrophilic as well. Thus, suitable compositions may be prepared using two polymers listed here as first polymers, or two polymers listed here as second polymers, provided that the first one hydrogen bonds with the active compound, and the second one is more hydrophilic than the first and degrades to form degradation products that promote the release of the biologically active compound from the first polymer. One of ordinary skill may even recognize combinations in which one of the first polymers functions as the second polymer and vice versa.

The compositions of the present invention are suitable for applications where localized drug delivery is desired, as well as in situations where systemic delivery is desired. Therapeutically effective dosages may be determined by either in vivo or in vitro methods. For each particular compound of the present invention, individual determinations may be made to determine the optimal dosage required. The range of therapeutically effective dosages will naturally be influenced by the route of administration, the therapeutic objectives, and the condition of the patient. For the various suitable routes of administration, the absorption efficiency must be individually determined for each drug by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of effective dosage levels, that is, the dosage levels necessary to achieve the desired result, will be within the ambit of one skilled in the art. Typically, applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved. The release rate of the drug from the formulations of this invention are also varied within the routine skill in the art to determine an advantageous profile, depending on the therapeutic conditions to be treated.

A typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferably from about 0.10 mg/kg to about 20 mg/kg. Advantageously, the compounds of this invention may be administered several times daily, and other dosage regimens may also be useful.

The compositions may be administered subcutaneously, intramuscularly, colonically, rectally, nasally, orally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations, such as ointments, drops and transdermal patches. Liposomal delivery systems may also be used, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
 

Claim 1 of 10 Claims

1. A formulation comprising a biologically active compound having a chemical structure with hydrogen bonding sites, a first biocompatible, hydrolytically degrading polyarylate with hydrogen bonding sites comprising tyrosine-derived diphenol monomer units, and a second biocompatible polymer that is less hydrophobic than said polyarylate, so that said second polymer degrades hydrolytically to form acidic degradation products that promote the release of said active compound, and wherein said second polymer is selected from the group consisting of a second polyarylate comprising tyrosine-derived diphenol monomer units, a poly(glycolic acid), a poly(lactic acid), a poly(glvcolic acid-co-lactic acid) (PGLA), a polycaprolactone and a poly(hydroxyalkanoic acid).

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.