WO2025054598A2

WO2025054598A2 - Biodegradable subcutaneous implant for delivery of therapeutics in a controlled pulsatile or sustained manner

Info

Publication number: WO2025054598A2
Application number: PCT/US2024/045833
Authority: WO
Inventors: Thanh Duc NGUYEN; Parbeen SINGH; Nicole E. NELSON; Tra T. VINIKOOR
Original assignee: University of Connecticut
Current assignee: University of Connecticut
Priority date: 2023-09-08
Filing date: 2024-09-09
Publication date: 2025-03-13
Anticipated expiration: 2026-03-08
Also published as: WO2025054598A3

Abstract

A subcutaneous implant comprises a body formed from a biodegradable polymer and defining a plurality of reservoirs, each reservoir having an opening. Each reservoir contains a pre-determined quantity of therapeutic agent, or pre-determined quantity of a combination of therapeutic agent and biodegradable polymer or carrier. A cap covers the opening of at least one of the plurality of reservoirs, the cap comprising a biodegradable polymer formulated to degrade upon exposure to the tissue of the subject, permitting the contents of the capped reservoir to be released into the tissue of a subject at a predetermined time after the subcutaneous implant is inserted beneath the skin of a subject. The body, therapeutic agent, combination of therapeutic agent and biodegradable polymer or carrier, and said cap dissolve over time, eliminating the need to remove the implant. The body of the implant may consist essentially of a biodegradable polymer and does not contain or include a therapeutic agent. The contents of the capped reservoir or reservoirs cannot escape from the reservoir until a predetermined time.

Description

BIODEGRADABLE SUBCUTANEOUS IMPLANT EOR DELIVERY OE THERAPEUTICS IN A CONTROLLED PULSATILE OR SUSTAINED MANNER

BACKGROUND OF THE INVENTION

1. Field of the Invention

[0001] The invention disclosed herein relates to medical devices, and in particular to implantable devices for periodic delivery of therapeutics.

2. Description of the Related Art

[0002] The most common methods used to administer therapeutic drugs, hormones and vaccines to human and animal subjects are oral administration in the form of liquids or pills (or feed additives for animals), and injection. It is also known to deliver drugs, therapeutics, hormones and vaccines to human and animal subjects using microneedle patches applied to the skin or implants inserted beneath the skin. It is well-known that the method of administration impacts the effectiveness of the treatment. Oral administration is impacted by absorption through the digestive tract, with some materials broken down by digestive acids and enzymes, or difficulty in being absorbed in the digestive tract. Injection is an expensive form of delivery, and many subjects fear needles. Microneedles, while effective at delivering drugs, hormones, and vaccines, are limited in terms of dose or capacity. Known implantable devices also lack flexibility in terms of the pattern of delivery, with a burst or slow sustained release being the typical delivery profile.

[0003] Some drugs, vaccines, or therapies require delivery of therapeutics to a subject over an extended period of time and at different concentrations or rates of delivery. One example is administration of non-opioid pain medication such as steroids (e.g., dexamethasone), non-opiate and non-steroid anti-inflammation drugs (NSAIDs) such as Aspirin (ASA or acetylsalicylic acid) and others (e.g., lidocaine as local anesthesia) to treat chronic pain in patients with arthritis. Oral administration of these drugs such as NSAIDs unfortunately causes significant side-effects on the gastrointestinal (GI) tract (stomach bleeding, stomach ulcers with cancer risks etc.), which stem from direct contact between these drugs and gastric mucosa. Additionally, many drugs such as dexamethasone or NSAIDs have short lifetimes and some drugs (e.g., ASA) exhibit a low bioavailability in oral use, thereby requiring daily administrations with a large dose, making the side effects on the Gl tract even more severe. [0004] Another example are broadly neutralizing antibodies (bnAbs) that have emerged as an excellent alternative or adjuvant to antiretroviral therapy (ART) in treating HIV/AIDS. bnAbs uniquely target and bind to the HIV envelope as the virus seeks to enter new target cells or is expressed by previously infected cells. Besides suppressing the virus, bnAbs may induce additional T- cell immunomodulatory effects as seen for other forms of immunotherapy. As such, antibody treatments are being explored as partners for long acting antiretrovirals for use in therapy or prevention of HIV infection. Although combination ART using bnAbs is highly effective, it requires lifelong medication. In addition, the delivery of antibodies into the human body faces many other challenges including the short plasma half-lives of the bnAbs, and low patient compliance to the antibody administrations. To maintain the efficacy of these antibodies, these formulations go through cold chain process which enhances the burden of cost to patients. Specifically, the effective therapies of mAb require frequent longitudinal administrations of relatively large doses. The most common mode of administration, intravenous infusion, is associated with pain, high cost, discomfort, and repeated travel. In addition, it causes lots of stress in medical facilities and patients in resource-constrained areas.

[0005] Further, many vaccines require multiple doses spaced apart over a period of days or weeks. In addition to the challenges of administering vaccines via injection, effectiveness is reduced when subjects do not receive the complete regimen of vaccine doses or receive the doses at times outside the recommended schedule.

[0006] Controlled drug releasing vehicles with easy administration could be a promising strategy to overcome these kinds of problems. However, very few systems have been reported as an alternative vehicle for delivery of therapeutic molecules. Notably, hydrogels and microneedles have been employed to deliver antibodies. Unfortunately, these technologies suffer from significant limitations for the delivery period (only for a short time for both delivery methods), a large injection volume (for hydrogel), and small loading capacity (for microneedles). Further, the tiny drug volume of the microneedles is still a significant limiting factors for antibody therapy. So far, there has been limited studies, and no FDA approved products available for controlled and sustained release of antibodies from degradable biopolymers.

[0007] Implantable drug delivery devices are an effective drug delivery method that can enhance the patient compliance with minimal side-effects. Subcutaneous bioimplants can act as a potential tool where traditional delivery methods are unsuitable. These implants avoid the first pass metabolism by allowing the direct absorption of drugs, hormones, or vaccines in systemic circulation and thus increase the bioavailability and bioaccumulation of the therapies being delivered.

[0008] Thus, what are needed are subcutaneous implants and methods of fabricating subcutaneous implants capable of delivering therapeutics over a broad range of delivery profiles and over an extended period of time.

SUMMARY

[0009] A disclosed subcutaneous implant comprises a body formed from a biodegradable polymer and defining a plurality of reservoirs, each reservoir having an opening. Each reservoir contains a pre-determined quantity of therapeutic agent, or pre-determined quantity of a combination of therapeutic agent and biodegradable polymer or carrier. A cap covers the opening of at least one of the plurality of reservoirs, the cap comprising a biodegradable polymer formulated to degrade upon exposure to the tissue of the subject, permitting the contents of the capped reservoir to be released into the tissue of a subject at a predetermined time after the subcutaneous implant is inserted beneath the skin of a subject. The body, therapeutic agent, combination of therapeutic agent and biodegradable polymer or carrier, and said cap dissolve over time, eliminating the need to remove the implant. The body of the implant may consist essentially of a biodegradable polymer and does not contain or include a therapeutic agent. The contents of the capped reservoir or reservoirs cannot escape from the reservoir until a predetermined time.

[0010] The caps covering one or more of the reservoirs may include a first cap comprising a first biodegradable polymer formulated to permit the contents of a first reservoir to begin release into the tissue of a subject at a predetermined first time and a second cap comprising a second biodegradable polymer formulated to permit the contents of a second reservoir to begin release into the tissue of a subject at a predetermined second time. The first and second times may be different times after insertion of the implant. One or more of the reservoirs may not include a cap, allowing the reservoir(s) without a cap to begin release of its contents into the tissue of a subject immediately upon insertion of the implant beneath the skin of the subject.

[0011] One or more of the reservoirs contain a combination of a therapeutic agent and a biodegradable polymer formulated to degrade in the presence of the tissue of the subject, thereby releasing the therapeutic agent over a predetermined period of time between three days and several months after the combination of therapeutic agent and biodegradable polymer are exposed to the tissue of the subject. In some embodiments, at least one of the reservoirs contains a therapeutic agent alone or a combination of a therapeutic agent and polymer or carrier, the therapeutic agent or combination of therapeutic agent and polymer or carrier formulated to release into the tissue of the subject over a predetermined period of time between one hour and two days after the therapeutic agent or combination of therapeutic agent and polymer or carrier are exposed to the tissue of the subject.

[0012] In some embodiments, the body of the implant is formed from polylactic acid (PLA) and the caps are formed from poly(lactic-co-glycolic) acid (PLGA). In some embodiments the biodegradable polymer combined with the therapeutic agent is poly(lactic-co-glycolic) acid (PLGA). In some embodiments the biodegradable polymer combined with the therapeutic agent is poly vinyl alcohol (PVA) or the carrier is a saccharide such as sugar or trehalose.

[0013] The disclosure includes a method for delivering a drug or therapeutic agent to a subject with a subcutaneous implant, the method including forming a body of a subcutaneous implant from a biodegradable polymer, the body defining a plurality of reservoirs, each reservoir having an opening. Each said reservoir is loaded with a pre-determined quantity of a therapeutic agent, or pre-determined quantity of a combination of a therapeutic agent and biodegradable polymer or carrier. At least one of the plurality of reservoirs is covered with a cap comprising a biodegradable polymer formulated to degrade over a predetermined period of time after exposure to the tissue of the subject. The subcutaneous implant is inserted beneath the skin of a human or animal subject and releases the drug or therapeutic agent into the body of the subject in a pattern defined by the presence and formulation of a cap for each reservoir, combined with the formulation of the drug and/or polymer or carrier in each reservoir. The body, therapeutic agent and biodegradable polymer or carrier and cap dissolve over time and are absorbed by the subject.

[0014] The caps are configured of biodegradable polymer selected to degrade over a predetermined period of time, permitting the contents of the capped reservoir to begin to be released into the tissue of the subject after the predetermined time. In some embodiments, the step of covering at least one of the plurality of reservoirs includes forming a cap from poly(lactic-co- glycolic) acid (PLGA), said PLGA formulated to degrade over a predetermined period of time after exposure to the tissue of the subject.

[0015] In some embodiments, the step of loading each said reservoir includes combining the therapeutic agent with poly(lactic-co-glycolic) acid (PLGA) to release the therapeutic agent over a period of between three and several months. Alternatively, the drug or therapeutic agent may be combined poly vinyl alcohol (PVA) or a saccharide to release the therapeutic agent over a period of between one hour and two days.

[0016] The drug or therapeutic agent may be a drug, a protein, a hormone, or a vaccine.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The features and advantages of the invention are apparent from the following description taken in conjunction with the accompanying drawings in which:

[0018] FIG. 1 is an abstraction depicting steps for fabrication of a subcutaneous implant according to aspects of the disclosure;

[0019] FIG. 2 is a perspective view of a rigid mold suitable for forming a silicone mold used to form the body of an embodiment of a subcutaneous implant with multiple reservoirs for small quantity drug delivery according to aspects of the disclosure;

[0020] FIG. 3 is a perspective view of a rigid mold suitable for forming a silicone mold used to form the body of an embodiment of a subcutaneous implant with multiple reservoirs for large quantity drug delivery according to aspects of the disclosure;

[0021] FIG. 4 is a perspective view of an embodiment of a subcutaneous implant defining four reservoirs and illustrating a cap covering one of the reservoirs according to aspects of the disclosure;

[0022] FIG. 5 is a perspective longitudinal sectional view of an embodiment of a subcutaneous implant with four reservoirs, each having a predetermined sustained release profile according to aspects of the present disclosure;

[0023] FIG. 6 is a graph depicting average drug loading capacity of subcutaneous implants according to aspects of the disclosure formed, where SubQ 1 represents the drug payload capacity of an implant with multiple small reservoirs formed using the mold of Figure 3, and SubQ 2 represents the drug payload capacity of an implant with four large reservoirs formed using the mold of Figure 4;

[0024] FIG. 7 is a graph depicting release kinetics from different reservoirs of a subcutaneous implant where the time to release is defined using differently formulated PLGA caps according to aspects of the disclosure;

[0025] FIG. 8 is a graph depicting accumulative pulsatile drug release from a subcutaneous implant over a 24 day period according to aspects of the disclosure;

[0026] FIG. 9 is a perspective longitudinal sectional view of a subcutaneous implant with four reservoirs, each having a predetermined pulsatile release profile according to aspects of the present disclosure; and

[0027] Figure 10 is a perspective longitudinal sectional view of a subcutaneous implant combining features of the implants illustrated in Figures 5 and 9.

DETAILED DESCRIPTION OF THE INVENTION

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0029] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not. Further, it should further be noted that the terms “first,” “second,” and the like herein do not denote any order, quantity, or relative importance, but rather are used to distinguish one element from another. [0030] As used herein, the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.

[0031] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9-1.1. Other meanings of“about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.

[0032] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. All ranges disclosed herein are inclusive of the endpoints, and the endpoints are independently combinable with each other. Each range disclosed herein constitutes a disclosure of any point or sub-range lying within the disclosed range.

[0033] As used herein, the terms “providing”, “administering,” and “introducing,” are used interchangeably herein and refer to the placement of the compositions of the disclosure into a subject by a method or route which results in at least partial localization of the composition to a desired site. The compositions can be administered by any appropriate route which results in delivery to a desired location in the subject. [0034] A “subject” or “patient” may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein. Likewise, patient may include either adults or juveniles (e.g., children). Moreover, patient may mean any living organism, preferably a mammal (e.g., human or non- human) that may benefit from the administration of compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non- human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of nonmammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0035] As used herein, “treat,” “treating” and the like mean a slowing, stopping or reversing of progression of a disease or disorder when provided a composition described herein to an appropriate control subject. The terms also mean a reversing of the progression of such a disease or disorder to a point of eliminating or greatly reducing the cell proliferation. As such, “treating” means an application or administration of the compositions described herein to a subject, where the subject has a disease or a symptom of a disease, where the purpose is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease or symptoms of the disease.

[0036] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting of the true scope of the invention disclosed herein. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Since many modifications, variations, and changes in detail can be made to the described examples, it is intended that all matters in the preceding description and shown in the accompanying figures be interpreted as illustrative and not in a limiting sense.

[0037] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention or any embodiments unless otherwise claimed. [0038] Disclosed herein are methods and apparatus for providing unsupervised periodic or sustained release of therapeutics to a subject. The term therapeutics or therapeutic agent as used in this application is intended to mean any drug, protein, hormone, or vaccine useful in treating any disorder, disease, or condition in an animal or human subject. Examples of therapeutic agents discussed in the application are by way of example and are not to be considered limiting of the scope of the disclosed biodegradable implants.

[0039] The term “biodegradable polymer” as used in this application means polymers that break down over time in the body of a human or animal subj ect. The most widely accepted biodegradable polymers are chitosan, alginate, poly lactic-co-glycolic acid (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL). These biodegradable polymers have great biocompatibility, non-toxicity, and mechanical strength which makes them suitable for the fabrication of the disclosed subcutaneous implants.

[0040] Figure 1 illustrates one example of a subcutaneous implant 10 configured to deliver antiHIV antibodies into the body of a human subject in pulses or bursts separated by predetermined time periods from several days to several months. In some embodiments, poly lactic acid (PLA) is used to fabricate a subcutaneous implant having a thin, elongated rod-like body 12. The body 12 of the implant may, for example, have a length of approximately 4 cm and a width and height of approximately 2 mm. This form of implant can be easily inserted beneath the skin of a human or animal subject. As described in greater detail below, the subcutaneous implant 10 is constructed from biodegradable materials selected to provide pulses of one or more therapeutic agents or periods of sustained release of one or more therapeutic agents into the body of a human or animal subject. The disclosed implants 10 can be configured to provide a wide range of release profiles useful in the treatment of a variety of chronic conditions, disorders, diseases, or administration of vaccines or immunotherapies.

[0041] The body 12 of the disclosed subcutaneous implant defines a plurality of reservoirs 14 that can be filled with a therapeutic agent by itself or with a therapeutic agent combined with a biodegradable polymer or carrier. Each reservoir 14 may be covered with a cap 18 constructed of a biodegradable polymer such as PLGA to delay release of the contents of the capped reservoir. PLGA can be selected in a range of formulations that degrade predictably in the body of a subject, so differently formulated PLGA caps can be used to provide different delay periods. Each reservoir 14 can be adapted to release contents (e g., therapeutics) at different time points in a pulsatile manner. Moreover, different drug release profdes can be incorporated into a single implant 10 by selecting different materials for the cap 18 and combining the therapeutic agent with different biodegradable polymers or carriers before filling the reservoir 14.

[0042] The disclosed subcutaneous implant 10 is biodegradable and therefore offers (1) highly effective, long acting, and convenient delivery of therapeutic agents which can provide a great relief to the patients who need regular doses typically delivered via injection or other delivery methods. Therapeutic agents compatible with the disclosed implants 10 include anti -HIV antibodies, antiviral drugs, growth hormone, diabetes, antibiotics, vaccines etc. Furthermore, the implants 10 can be used for animal care. (2) The implant is entirely constructed of biodegradable materials, eliminating the need for removal procedures. (3) Due to its ability to perform sustained (mixture of PLGA or other polymer+drug) or multi-burst/pulsatile release, the disclosed implant 10 reduces the number of injections that patients need, and the associated discomfort and travel needed to receive medication. (4) This is a delivery device for drugs used to treat diabetics, delivery of birth-control hormones, blood pressure drugs, antibiotics, growth hormones, and vaccines etc. A single implantable device can be configured to provide two or more doses of therapeutic agent separated by delays of days or weeks, which will improve patient compliance with treatment requiring doses at specific times.

[0043] Embodiments of the subcutaneous implant 10 are efficient for modulating drug release according to a profile (from sustained release to a pulsatile release) for prolonged time periods. End users may include (1) patients with HIV, diabetes, and blood pressures and other chronic conditions, (2) pharmaceutical companies, (3) veterinary applications; (4) research; and (4) biomedical companies. The term “sustained release” as used in this application means release at a substantially constant rate over a period of three to thirty days, or several months. The term “pulsatile release” as used in this application means release over a period of one hour to two days. The rate of release of therapeutic agent in a pulsatile release profile will typically be substantially higher than the rate of release of therapeutic agent in a sustained release profile. The disclosed subcutaneous implants 10 can be configured to deliver one or more therapeutic agents in a range of release profiles, including mixed releases of two or more therapeutic agents where the release profiles of the two or more therapeutic agents can be the same or different. [0044] Generally, as discussed herein, the term “release profde” refers to a rate of release of a drug from each of the reservoirs, or collectively from a biodegradable implant 10. For example, a “pulsatile” release generally refers to a substantially periodic release of the drug which takes place over a relatively short period of time from one hour to two days. Generally, a “sustained” release refers to a substantially continuous release of drugs over a long period of time from three days to several months. According to aspects of the disclosure, a pulsatile release profde will have a higher rate of release of a drug or therapeutic agent from a reservoir 14 than the rate of drug or therapeutic agent release from a reservoir 14 in a sustained release profde. A sustained release profde generally does not exhibit bursts of higher dose delivery and is characterized by a nearly constant rate of release. Additionally, it should be recognized that release profdes may be characterized according to well-known kinetics and descriptions, such as “zero order” release profdes. A device having a "zero-order release", maintains a constant release rate until exhaustion of drug in the device. In reservoir systems such as the disclosed biodegradable implants 10, the drug or therapeutic agent is surrounded by polymeric matrices. Drug release is mediated by diffusion through the surrounding polymeric matrices. Zero-order release is maintained because a constant concentration gradient of drug is kept in the polymeric matrices as long as the reservoir contains a saturated solution and sufficient excess solid drug. Additionally, other release kinetics, such as “first order” may be used. Release kinetics may be described by well-known equations characterizing transport and elimination. In some instances, release kinetics may be characterized by relationships particular to any one or more of the embodiments of the biodegradable implant. As techniques for developing such relationships are known, release kinetics are therefore not discussed further herein. As used herein, the term “programmed” (and conjugations thereof) generally refer to compositions, methods of construction and other techniques for fabrication that are designed to produce a desired release profile.

[0045] One example of a biodegradable polymer that can be used for the cap 18 and/or in combination with a drug or therapeutic agent in the reservoir 14 of a disclosed biodegradable implant 10 is PLGA. PLGA is a biodegradable aliphatic polyester-based polymer that comprises a synthetic copolymer of lactic acid (a-hydroxy propanoic acid) and glycolic acid (hydroxy acetic acid). PLGA degrades by bulk degradation. In bulk degradation, which is defined as degradation that occurs throughout the whole material equally while maintaining the structure's original shape, pores form in the PLGA polymer that eventually create channels through which the drug diffuses out. Some embodiments of the disclosed biodegradable implants have a near zero-order release due to the Fickian diffusion that results from the bulk degradation of the PLGA cap and/or matrix that holds the drug within the reservoir. The drug leaves the reservoir 14 through the channels/pores in the matrix due to a concentration gradient. Eventually, the polymer encapsulating the drug will fully degrade and release whatever contents of the drug remain.

[0046] According to aspects of the disclosure, there are two primary factors contributing to the release profile from a particular reservoir 14 of the disclosed biodegradable implants 10: 1) the presence and configuration of a cap 18 on the reservoir 14, and 2) the composition of the drug and any carrier or polymer in the reservoir 14. In some disclosed embodiments, at least one reservoir 14 does not include a cap 18, in which case the drug and/or carrier or polymer in the reservoir 14 are immediately exposed to body fluids of the subject upon insertion of the implant 10. A reservoir 14 may also be capped with a hydrophilic polymer or material soluble in water such as sugar, which cap 18 will dissolve rapidly upon insertion of the implant 10. Release of a drug or therapeutic agent from an uncapped reservoir or a reservoir capped with a soluble material will begin immediately or almost immediately upon insertion of the implant 10, as shown in Figures 7 and 8. Alternatively, a reservoir 14 may be capped with PLGA caps 18 formulated to degrade over a predetermined period of time. PLGA caps provide a delay between insertion of the implant and exposure of the contents of the reservoir 14 to fluids in the human or animal subject. Release of a drug or therapeutic agent from a reservoir 14 is controlled by adding the drug or therapeutic agent to the reservoir 14 by itself, with a hydrophilic polymer such as polyvinyl alcohol (PVA), a carrier such as sugar, or combining the drug or therapeutic agent with a polymer such as PLGA that degrades slowly after exposure to body fluids. In the disclosed biodegradable implants 10, an uncapped reservoir 14 filled with a drug by itself or a drug or therapeutic agent in combination with a hydrophilic polymer or carrier such as sugar, will begin release immediately (or very soon after) insertion of the implant, and the release will be relatively rapid. If immediate, sustained release of a drug or therapeutic agent is desired, the drug or therapeutic agent can combined with a polymer such as PLGA that degrades slowly and predictably in the presence of body fluids. In some of the disclosed embodiments, a reservoir capped with PLGA will be exposed to body fluids of a subject only after the PLGA cap has degraded. Degradation of the PLGA cap provides a delay before any drug or therapeutic agent can be released from a reservoir 14, where the duration of the delay can be selected by using different PLGA formulations as discussed below. According to aspects of the disclosure, a library of varying delay times can be selected with differently formulated PLGA caps.

[0047] The quantity of drug or therapeutic agent released from a reservoir per unit of time can be controlled by fabricating the reservoir with different drug concentrations. For a reservoir 14 configured for pulsatile or sustained release, a higher concentration of drug or therapeutic agent in the reservoir 14 will produce a higher quantity or dose per unit of time. It will be apparent that by choosing whether or not to cap a reservoir 14, the type and formulation of a cap 18, the formulation of the contents of a reservoir 14, and the concentration of drug or therapeutic agent in the reservoir 14 allow the disclosed biodegradable implants 10 to provide a wide range of release profiles including immediate burst/pulse release, delayed burst/pulse release, immediate sustained release, and delayed sustained release. A single biodegradable implant 10 may be constructed to produce one or more of these release profiles and may be loaded with one or more drugs and/or therapeutic agents. Thus, combination therapies are possible, delivering a first drug or therapeutic agent at one or more predetermined times after insertion and in one or more release profiles, and delivery of a second drug or therapeutic agent at one or more predetermined times after insertion and in one or more release profiles. For example, a first drug or therapeutic agent can be delivered with an immediate, sustained release profile, while a second drug or therapeutic agent can be delivered with a delayed pulsatile release profile.

[0048] Figures 2 and 3 illustrate master molds used to form silicone molds from polydimethylsiloxane (PDMS) for different implant bodies 12. One commercially available material suitable for molds in the disclosed fabrication methods is DOW SYLGARD™ 184 SILICONE ENCAPSULANT CLEAR 3.9 KG KIT. The description for that material is listed as follows: SYLGARD™ 184 silicone elastomer, transparent, two-part encapsulant, with good flame resistance. The base polymer, in this case the Polydimethylsiloxane (PDMS) component, is mixed with a curing agent which cross-links the PDMS polymer and turns it into a solid. In the context of this disclosure, the solid becomes the PDMS negative mold.

[0049] The PDMS negative molds are replicated from the master molds and used to mold PLA. The master mold of Figure 2 defines an implant body 12 having 24 small reservoirs with a combined drug payload of approximately 60 mg as shown in Figure 6. The master mold of Figure 3 defines an implant body 12 four elongated reservoirs with a combined drug payload of approximately 100 mg. After preparation of a silicone negative mold from the master molds, polylactic acid (PLA) is heated to its melting temperature of 200°C under vacuum and poured into the silicone negative mold. After cooling the molds at room temperature, implant bodies constructed of PLA are removed from the silicone molds.

[0050] Polylactic acid, also known as poly(lactic acid) or polylactide (PLA or PLLA), is a thermoplastic polyester with backbone formula (C3H4O2)n or [-C(CH3)HC(=O)O-]n, formally obtained by condensation of lactic acid C(CH3)(OH)HCOOH with loss of water (hence its name). It can also be prepared by ring-opening polymerization of lactide [-C(CH3)HC(=O)O-]2, the cyclic dimer of the basic repeating unit.

[0051] PLA degrades in the body of human or animal subjects into innocuous lactic acid, making it suitable for use as medical implants in the form of anchors, screws, plates, pins, rods, and mesh. Depending on the type used, it breaks down inside the body within 6 months to 2 years. This gradual degradation is desirable for a support structure, because it gradually transfers the load to the body (e.g., to the bone) as that area heals. The strength characteristics of PLA (also referred to as PLLA) implants are well documented. Other biodegradable materials may be used to form the body of the biodegradable implant. In the context of the disclosed biodegradable implants, the PLA body defines reservoirs that can be filled with a payload comprising a drug/therapeutic agent alone, a drug or therapeutic agent with a biodegradable polymer or carrier such as sugar or trehalose. The body 12 of the biodegradable implant 10 is a support structure and container but degrades over a time period longer than the intended release profile of the biodegradable implant, and so does not play a role in release of the drug or therapeutic agent.

[0052] Drug loading capacity of the implant bodies 12 were evaluated by using different types of molecules including protein (BSA), and antibodies (IgG and anti-HIV antibodies). The drug loading data showed that the implant body 12 with four large reservoirs 14 has ~ 40% high drug loading capacity as compared to the implant body 12 with 24 small reservoirs, as shown in Figure 6. The size and shape of the implant body 12, and the number and shape of reservoirs 14 defined by the implant body 12 are not limited to the disclosed examples and can be tailored for different therapeutic agents and purposes.

[0053] According to aspects of the disclosure, at least some of the reservoirs 14 are capped to delay release of therapeutic agent from the capped reservoirs. In some embodiments, caps 18 are formed from PLGA selected to degrade in the body of a human or animal subject over a predetermined period of time. The PLGA caps prevent release of therapeutic agent from a capped reservoir until the cap 18 has degraded sufficiently to expose the contents of the reservoir 14 to the body fluids of the human or animal subject. Differently formulated PLGA caps can be used to provide different periods of delay between doses of a therapeutic agent.

[0054] Figures 7 and 8 illustrate the release profiles of therapeutic agents from a six-reservoir subcutaneous implant according to aspects of the disclosure. The first reservoir is either uncapped or capped with a saccharide such as sugar that will rapidly dissolve when exposed to body fluids. The caps for the remaining five reservoirs are made from PLGA selected to degrade at different rates, resulting in release from the six reservoirs at different times over a period of 24 days. In this example, the first reservoir was capped with a saccharide such as sugar or trehalose, resulting in immediate release of the contents of the first reservoir. The cap for the second reservoir was constructed of PLGA (1 : 1) (15kDa and 30kDa) and degraded to release the contents of the second reservoir beginning at approximately day 7. The cap for the third reservoir was constructed of PLGA (1 :3) (15kDa and 30kDa) and degraded to release the contents of the third reservoir beginning at approximately day 9. The cap for the fourth reservoir was constructed of PLGA having a molecular weight in the range of (30kDa-45 kDa) and degraded to release the contents of the fourth reservoir beginning approximately at day 11. The cap for the fifth reservoir was constructed of PLGA having a molecular weight in the range of (45-54kDa) and degraded to release the contents of the fifth reservoir beginning approximately on day 14. The cap for the sixth reservoir was constructed PLGA having a molecular weight in the range of 60-65 kDa and degraded to release the contents of the sixth reservoir beginning approximately on day 21. In the graphs of Figures 7 and 8, the zero point on the X axis is the date on which the implant is implanted and begins to be exposed to body fluids.

[0055] In this example, the contents of the reservoirs 14 were formulated for burst or pulsatile release, where the therapeutic agent contents of each reservoir 14 are released rapidly over a period of one hour to two days. The contents of a reservoir 14 can be released rapidly if the drug is deposited in the reservoir 14 by itself or with a hydrophilic polymer such as PVA that dissolves rapidly in water or with a carrier such as sugar which also dissolves readily in water. [0056] A drug or therapeutic may be combined with a polymer by dissolving a polymer with the desired drug or therapeutic agent and then precipitating the combined polymer and drug out of solution through a simple precipitation reaction or via slow solvent evaporation, also known as “co-precipitation.” An example of a suitable polymer is Poly Lactic Glycolic Acid (PLGA), and examples of suitable solvents include tetrahydrofuran, acetone, ethyl acetate and chlorinated solvents. The solvent is then removed either by evaporation, lyophilization or another suitable technique, leaving behind the solid drug-loaded polymer material, which can be loaded into the reservoir.

[0057] The release kinetic mechanism was checked with a BSA protein assay kit. The capped reservoirs were able to release the drugs in a pulsatile manner (Fig. 7), with a delay between pulsed releases. Moreover, pulses of drug release produced an accumulation of drug over time (Fig. 8). Overall, this system can be used to deliver the various therapeutic drugs in a pulsatile manner.

[0058] If the treatment calls for release of therapeutic agent over an extended period of time, or sustained release of the therapeutic agent, the therapeutic agent can be combined with a biodegradable polymer selected to slow release of the therapeutic agent. For example, mixing the therapeutic agent with PLGA of different molecular weights will produce a sustained release of the therapeutic agent over a period of time from three to thirty days or up to several months when reservoirs 14 are also capped with PLGA. PLGA with heavier molecular weight degrades more slowly and produce a sustained release over a longer period than PLGA with lower molecular weights. PLGA is used as an example of a biodegradable polymer useful for combination with a therapeutic agent in a reservoir to produce sustained release of a therapeutic agent, but the disclosed subcutaneous implants 10 are not limited to using PLGA for this purpose.

[0059] Figure 5 illustrates a representative example of a biodegradable, subcutaneous implant 10 according to aspects of the disclosure. In this example, the body 12 of the implant 10 is constructed from PLA and defines four elongated reservoirs 14. Each of the four reservoirs 14 has a PLGA cap 18 formulated to delay exposure of the contents of the reservoir 14 by a predetermined period of time. Further, each of the reservoirs 14 contains a combination of drug and PLGA, where the drug is released slowly from the reservoir 14 providing a sustained release. The embodiment of Figure 5 provides a series of delayed, sustained release profiles from the four reservoirs. It will be apparent that the PLGA formulation of each cap 18 may be selected to provide a predetermined delay period. The formulation of PLGA used in the reservoirs 14 may also be selected to define a sustained release of the drug over a predetermined period of time. Concentration of drug in each reservoir 14 may be selected to provide a desired dose per unit time in a sustained release profile. The caps 18 may all be differently formulated to produce four different delay periods. Some of the caps may be the same, so the contents of more than one reservoir is exposed to body fluids at the same time. Such an arrangement could be used to provide a large initial sustained release of a drug, followed by later, smaller sustained releases of the drug.

[0060] Figure 9 illustrates an embodiment of a biodegradable, subcutaneous implant 10 configured to produce delayed pulsatile releases of a drug or therapeutic agent. The body 12 of the implant is constructed of PLA and defines four elongated reservoirs 14 of the same size, but reservoirs of different size are within the scope of the disclosure. Each of the reservoirs 14 is capped with a PLGA cap 18 selected to provide a predetermined delay before the reservoir 14 is exposed to body fluids and begins to release the drug or therapeutic agent into the human or animal subject. In this embodiment, each of the reservoirs 14 is filled with a combination of drug and hydrophilic polymer to produce a pulsatile release of the drug. An alternative to the hydrophilic polymer is a saccharide such as sugar or trehalose. The caps 18 may be different and selected to produce a sequence of pulsatile releases separated by a predetermined delay. Alternatively, one or more of the caps 18 may be the same as another cap 18, producing a large pulse of drug at a desired time following insertion of the implant 10. Concentration of the drug in each reservoir 14 may be the same or different, depending upon the quantity or dose of the drug desired in each pulsed release.

[0061] Figure 10 illustrates an embodiment of a biodegradable subcutaneous implant 10 that combines different capping and reservoir formulations to produce a combination of release profiles. The body 12 of the implant is constructed of PLA and defines four elongated reservoirs 14. Three of the reservoirs 14 are capped with a PLGA cap 18, while the fourth reservoir 14 is not capped or is capped with a rapidly dissolvable cap of sugar. In this example, two of the reservoirs 14 are configured to produce a sustained release profile by combining the drug with a polymer such as PLGA. Two of the reservoirs 14 are configured to produce a pulsatile release profile by combining the drug with a hydrophilic polymer that will dissolve rapidly upon exposure to body fluids. One of the reservoirs 14 is not capped or is capped with a rapidly dissolving sugar cap. In this embodiment, the uncapped reservoir will produce an immediate pulsed release of the drug. The capped pulsatile release reservoir will produce a delayed pulsed release of the drug, with the delay determined by formulation of the PLGA cap 18. The capped sustained release reservoirs will produce delayed sustained release of the drug, with the delay determined by formulation of the PLGA cap 18. The dose and rate of drug release from each reservoir 14 is determined by selection of the drug concentration in the reservoir and selection of the hydrophilic or PLGA polymer combined with the drug in the reservoir. This embodiment of a biodegradable subcutaneous implant 10 can produce a combination of immediate pulsed release, delayed pulsed release, and delayed sustained release of one or more drugs or therapeutic agents without further intervention after insertion of the implant into a subject.

[0062] All statements herein reciting principles, aspects, and embodiments of the disclosure, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents as well as equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure.

[0063] Various other components may be included and called upon for providing for aspects of the teachings herein. For example, additional materials, combinations of materials and/or omission of materials may be used to provide for added embodiments that are within the scope of the teachings herein. Adequacy of any particular element for practice of the teachings herein is to be judged from the perspective of a designer, manufacturer, seller, user, system operator or other similarly interested party, and such limitations are to be perceived according to the standards of the interested party.

[0064] In the disclosure hereof any element expressed as a means for performing a specified function is intended to encompass any way of performing that function including, for example, a) a combination of circuit elements and associated hardware which perform that function or b) software in any form, including, therefore, firmware, microcode or the like as set forth herein, combined with appropriate circuitry for executing that software to perform the function. Applicants thus regard any means which can provide those functionalities as equivalent to those shown herein. No functional language used in claims appended herein is to be construed as invoking 35 U.S.C. §112(f) interpretations as “means-plus-function” language unless specifically expressed as such by use of the words “means for” or “steps for” within the respective claim. [0065] When introducing elements of the present invention or the embodiment(s) thereof, the articles “a,” “an,” and “the” are intended to mean that there are one or more of the elements. Similarly, the adjective “another,” when used to introduce an element, is intended to mean one or more elements. The terms “including” and “having” are intended to be inclusive such that there may be additional elements other than the listed elements. The term “exemplary” is not intended to be construed as a superlative example but merely one of many possible examples.

Claims

CLAIMS What is claimed is:

1. A subcutaneous implant (10) comprising: a body (12) formed from a biodegradable polymer and defining a plurality of reservoirs (14), each reservoir having an opening (16); a pre-determioned quantity of therapeutic agent, or pre-determined quantity of a combination of therapeutic agent and biodegradable polymer or carrier within each said reservoir; and a cap (18) covering the opening (16) of at least one of said plurality of reservoirs (14), said cap (18) comprising a biodegradeable polymer formulated to degrade upon exposure to the tissue of the subject, permitting the contents of the at least one of said plurality of reservoirs to be released into the tissue of a subject at a predetermined time after the subcutaneous implant (10) is inserted beneath the skin of a subject, wherein the body (12), therapeutic agent, combination of therapeutic agent and biodegradable polymer or carrier, and said cap (18) dissolve over time.

2. The subcutaneous implant of claim 1, wherein the body (12) consists essentially of a biodegradable polymer and does not contain or include a therapeutic agent.

3. The subcutaneous implant of claim 1, wherein the contents of the at least one of the plurality of reservoirs (14) cannot escape from the reservoir (14) until the predetermined time.

4. The subcutaneious implant of claim 1, comprising: a first cap (18) covering a first of said plurality of reservoirs, said first cap (18) comprising a first biodegradable polymer formulated to permit the contents of the first reservoir to begin release into the tissue of a subject at a predetermined first time; and a second cap (18) covering a second of said plurality of reservoirs, said second cap (18) comprising a second biodegradable polymer formulated to permit the contents of the second reservoir to begin release into the tissue of a subject at a predetermined second time, wherein the predetermined second time is different from the predetermined first time.

5. The subcutaneous implant of claim 1, wherein at least one of the reservoirs (14) does not include a cap and the contents of the at least one of the reservoirs (14) without a cap begins to release its contents into the tissue of a subject immediately upon insertion of the implant (10) beneath the skin of the subject.

6. The subcutaneous implant of claim 1, wherein at least one of the reservoirs (14) contains a combination of a therapeutic agent and a biodegradable polymer formulated to degrade in the presence of the tissue of the subject, thereby releasing the therapeutic agent over a predetermined period of time between three days and several months after the combination of therapeutic agent and biodegradable polymer are exposed to the tissue of the subject.

7. The subcutaneous implant of claim 1, wherein at least one of the reservoirs (14) contains a therapeutic agent alone or a combination of a therapeutic agent and polymer or carrier, said therapeutic agent or combination of therapeutic agent and polymer or carrier formulated to release into the tissue of the subject over a predetermined period of time between one hour and two days after the therapeutic agent or a combination of therapeutic agent and polymer or carrier are exposed to the tissue of the subject.

8. The subcutaneous implant of claim 1, wherein the body (12) is formed from polylactic acid (PLA) and the caps (18) are formed from poly(lactic-co-glycolic) acid (PLGA).

9. The subcutaneious implant of claim 6, wherein the biodegradable polymer combined with the therapeutic agent is poly(lactic-co-glycolic) acid (PLGA).

10. The subcutaneous implant of claim 7, wherein the biodegradable polymer combined with the therapeutic agent is poly vinyl alcohol (PVA) or the carrier is a saccaride.

11. A method for delivering a therapeutic agent to a subject with a subcutaneous implant (10), said method comprising: forming a body (12) of a subcutaneous implant from a biodegradable polymer, said body (12) defining a plurality of reservoirs (14), each reservoir having an opening (16); loading each said reservoir (14) with a pre-determined quantity of a therapeutic agent, or pre-determined quantity of a combination of a therapeutic agent and biodegradable polymer or carrier; covering at least one of the plurality of reservoirs (14) with a cap (18), said cap comprising a biodegradable polymer formulated to degrade over a predetermined period of time after exposure to the tissue of the subject; and inserting the subcutaneous implant (10) beneath the skin of a subject, wherein the cap degrades over said predetermined period of time after exposure to the tissue of the subject, permitting the contents of the at least one of said plurality of reservoirs to begin to be released into the tissue of the subject after said predetermined time, wherein the body (12), therapeutic agent, combination of therapeutic agent and biodegradable polymer or carrier, and said cap (18) dissolve over time and are absorbed by the subject.

12. The method of claim 12, wherein said step of forming a body (10) comprises molding said body from polylactic acid (PLA).

13. The method of claim 12, wherein said step of covering at least one of the plurality of reservoirs comprises: forming a cap (18) from poly(lactic-co-glycolic) acid (PLGA), said PLGA formulated to degrade over a predetermined period of time after exposure to the tissue of the subject, allowing the contents of the at lest one of the plurality of reservoirs to begin being released into the subject.

14. The method of claim 12, wherein said step of loading each said reservoir (14) comprises: combining the therapeutic agent with poly(lactic-co-glycolic) acid (PLGA) to release the therapeutic agent over a period of between three days and several months; or combining the therapeutic agent with poly vinyl alcohol (PVA) or a saccharide to release the therapeutic agent over a period of between one hour and two days.

15. The method of claim 12, wherein the therapeutic agent is a drug, a protein, a hormone, or a vaccine.