WO2025054598A2 - Implant sous-cutané biodégradable pour l'administration d'agents thérapeutiques d'une manière pulsatile contrôlée ou prolongée - Google Patents

Implant sous-cutané biodégradable pour l'administration d'agents thérapeutiques d'une manière pulsatile contrôlée ou prolongée Download PDF

Info

Publication number
WO2025054598A2
WO2025054598A2 PCT/US2024/045833 US2024045833W WO2025054598A2 WO 2025054598 A2 WO2025054598 A2 WO 2025054598A2 US 2024045833 W US2024045833 W US 2024045833W WO 2025054598 A2 WO2025054598 A2 WO 2025054598A2
Authority
WO
WIPO (PCT)
Prior art keywords
therapeutic agent
subject
reservoirs
reservoir
cap
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/045833
Other languages
English (en)
Other versions
WO2025054598A3 (fr
Inventor
Thanh Duc NGUYEN
Parbeen SINGH
Nicole E. NELSON
Tra T. VINIKOOR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Connecticut
Original Assignee
University of Connecticut
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Connecticut filed Critical University of Connecticut
Publication of WO2025054598A2 publication Critical patent/WO2025054598A2/fr
Publication of WO2025054598A3 publication Critical patent/WO2025054598A3/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0097—Medicinal compositions released by microdevices, e.g. microelectromechanical systems [MEMS], microdevices comprising chips or microdevices on silicon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin

Definitions

  • 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.
  • NSAIDs non-opioid pain medication
  • NSAIDs non-opiate and non-steroid anti-inflammation drugs
  • ASA Aspirin
  • acetylsalicylic acid e.g., lidocaine as local anesthesia
  • 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 muco
  • bnAbs broadly neutralizing antibodies
  • ART antiretroviral therapy
  • 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.
  • Controlled drug releasing vehicles with easy administration could be a promising strategy to overcome these kinds of problems.
  • very few systems have been reported as an alternative vehicle for delivery of therapeutic molecules.
  • hydrogels and microneedles have been employed to deliver antibodies.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the body of the implant is formed from polylactic acid (PLA) and the caps are formed from poly(lactic-co-glycolic) acid (PLGA).
  • the biodegradable polymer combined with the therapeutic agent is poly(lactic-co-glycolic) acid (PLGA).
  • the biodegradable polymer combined with the therapeutic agent is poly vinyl alcohol (PVA) or the carrier is a saccharide such as sugar or trehalose.
  • 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.
  • 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.
  • 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.
  • PLGA poly(lactic-co- glycolic) acid
  • 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.
  • 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.
  • the drug or therapeutic agent may be a drug, a protein, a hormone, or a vaccine.
  • FIG. 1 is an abstraction depicting steps for fabrication of a subcutaneous implant according to aspects of the disclosure
  • 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;
  • 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;
  • 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;
  • 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
  • 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;
  • 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
  • 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
  • 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.
  • Figure 10 is a perspective longitudinal sectional view of a subcutaneous implant combining features of the implants illustrated in Figures 5 and 9.
  • 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.
  • 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.
  • 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.
  • 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.
  • “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.
  • compositions of the disclosure 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.
  • 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).
  • 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.
  • 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.
  • nonmammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • “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.
  • “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.
  • 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).
  • PLGA poly lactic-co-glycolic acid
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PCL polycaprolactone
  • 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.
  • poly lactic acid PLA
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the implants 10 can be used for animal care.
  • the implant is entirely constructed of biodegradable materials, eliminating the need for removal procedures.
  • 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.
  • 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.
  • 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.
  • 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.
  • release profde refers to a rate of release of a drug from each of the reservoirs, or collectively from a biodegradable implant 10.
  • 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.
  • a “sustained” release refers to a substantially continuous release of drugs over a long period of time from three days to several months.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the polymer encapsulating the drug will fully degrade and release whatever contents of the drug remain.
  • 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.
  • 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.
  • a hydrophilic polymer such as polyvinyl alcohol (PVA)
  • PVA polyvinyl alcohol
  • a carrier such as sugar
  • a polymer such as PLGA
  • the drug or therapeutic agent can combined with a polymer such as PLGA that degrades slowly and predictably in the presence of body fluids.
  • 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.
  • a library of varying delay times can be selected with differently formulated PLGA caps.
  • 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.
  • 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.
  • 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.
  • Figures 2 and 3 illustrate master molds used to form silicone molds from polydimethylsiloxane (PDMS) for different implant bodies 12.
  • PDMS polydimethylsiloxane
  • One commercially available material suitable for molds in the disclosed fabrication methods is DOW SYLGARDTM 184 SILICONE ENCAPSULANT CLEAR 3.9 KG KIT. The description for that material is listed as follows: SYLGARDTM 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.
  • PDMS Polydimethylsiloxane
  • 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.
  • 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.
  • Polylactic acid also known as poly(lactic acid) or polylactide (PLA or PLLA)
  • PLA or PLLA polylactide
  • C3H4O2 backbone formula
  • 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.
  • 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.
  • 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).
  • BSA protein
  • IgG and anti-HIV antibodies 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.
  • 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.
  • 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.
  • 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.
  • the zero point on the X axis is the date on which the implant is implanted and begins to be exposed to body fluids.
  • 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.
  • 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.
  • PLGA Poly Lactic Glycolic Acid
  • 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.
  • pulses of drug release produced an accumulation of drug over time (Fig. 8).
  • this system can be used to deliver the various therapeutic drugs in a pulsatile manner.
  • the therapeutic agent can be combined with a biodegradable polymer selected to slow release of the therapeutic agent.
  • a biodegradable polymer selected to slow release of the therapeutic agent.
  • 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.
  • Figure 5 illustrates a representative example of a biodegradable, subcutaneous implant 10 according to aspects of the disclosure.
  • 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.
  • 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.
  • FIG. 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the articles “a,” “an,” and “the” are intended to mean that there are one or more of the elements.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Anesthesiology (AREA)
  • Medical Informatics (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Materials For Medical Uses (AREA)
  • Media Introduction/Drainage Providing Device (AREA)
  • Medicinal Preparation (AREA)

Abstract

Un implant sous-cutané comprend un corps formé à partir d'un polymère biodégradable et définissant une pluralité de réservoirs, chaque réservoir ayant une ouverture. Chaque réservoir contient une quantité prédéterminée d'agent thérapeutique, ou une quantité prédéterminée d'une combinaison d'agent thérapeutique et de polymère ou d'excipient biodégradable. Un capuchon recouvre l'ouverture d'au moins l'un de la pluralité de réservoirs, le capuchon comprenant un polymère biodégradable formulé pour se dégrader lors de l'exposition au tissu du sujet, permettant au contenu du réservoir encapsulé d'être libéré dans le tissu d'un sujet à un moment prédéterminé après insertion de l'implant sous-cutané sous la peau d'un sujet. Le corps, l'agent thérapeutique, la combinaison d'un agent thérapeutique et d'un polymère ou d'un excipient biodégradable, et ledit capuchon se dissolvent dans le temps, éliminant le besoin de retirer l'implant. Le corps de l'implant peut être constitué essentiellement d'un polymère biodégradable et ne contient pas ou ne comprend pas d'agent thérapeutique. Le contenu du ou des réservoirs capsulés ne peut pas fuir du réservoir jusqu'à un temps prédéterminé.
PCT/US2024/045833 2023-09-08 2024-09-09 Implant sous-cutané biodégradable pour l'administration d'agents thérapeutiques d'une manière pulsatile contrôlée ou prolongée Pending WO2025054598A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363581323P 2023-09-08 2023-09-08
US63/581,323 2023-09-08

Publications (2)

Publication Number Publication Date
WO2025054598A2 true WO2025054598A2 (fr) 2025-03-13
WO2025054598A3 WO2025054598A3 (fr) 2025-05-08

Family

ID=94924451

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/045833 Pending WO2025054598A2 (fr) 2023-09-08 2024-09-09 Implant sous-cutané biodégradable pour l'administration d'agents thérapeutiques d'une manière pulsatile contrôlée ou prolongée

Country Status (1)

Country Link
WO (1) WO2025054598A2 (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN156886B (fr) * 1981-08-22 1985-11-30 Council Scient Ind Res
EP0706353A1 (fr) * 1993-07-02 1996-04-17 Materials Evolution and Development USA, Inc. Systeme implantable s'appliquant a la regulation du developpement cellulaire
EP2111482A2 (fr) * 2007-02-13 2009-10-28 Cinvention Ag Dispositifs médicaux à réservoirs étendus ou multiples
US20160022570A1 (en) * 2014-07-25 2016-01-28 Robert W. Adams Medical implant

Also Published As

Publication number Publication date
WO2025054598A3 (fr) 2025-05-08

Similar Documents

Publication Publication Date Title
US6997909B2 (en) Low profile combination device for gastrostomy or jejunostomy applications having anti-granuloma formation characteristics
US20240197986A1 (en) Multi-stage biodegradable drug delivery platform
CN1165294C (zh) 具有多层结构的控释制剂
Kleiner et al. Evolution of implantable and insertable drug delivery systems
US20150045764A1 (en) Silk reservoirs for drug delivery
CN101854922A (zh) 用于减轻、预防或治疗疼痛和炎症的具有不同释放曲线的长效制剂
Graham et al. Polymeric inserts and implants for the controlled release of drugs
JP2005517653A (ja) Ｘ線不透過性徐放性医薬器具
JP7719066B2 (ja) 組織インターフェースコンポーネントを製造するための方法
CN102917693B (zh) 释放特征不同的植入装置及制造和使用该装置的方法
Bermudez et al. Challenges and opportunities in polymer technology applied to veterinary medicine
WO2025054598A2 (fr) Implant sous-cutané biodégradable pour l'administration d'agents thérapeutiques d'une manière pulsatile contrôlée ou prolongée
ES3056905T3 (en) Orally implantable drug delivery device
Kumar et al. Microneedle for wound healing and dermal application
HK1247846A1 (zh) 具有内芯凸起部的芯鞘型植入装置
US20180207328A1 (en) Implantable Compositions for Pain Management
CN220327790U (zh) 一种人工耳蜗载药电极
RU104458U1 (ru) Микроконтейнер полимерный с лекарственным веществом, обеспечивающий местное пролонгированное противоопухолевое действие
RU103294U1 (ru) Микроконтейнер полимерный с лекарственным веществом, обеспечивающий местное пролонгированное противотуберкулезное действие
Laracuente Development of a Methacrylated Poly (Glycerol Sebacate) Platform for the Sustained Release of Small Molecule Therapeutics
RU103296U1 (ru) Микроконтейнер полимерный с лекарственным веществом, обеспечивающий местное пролонгированное гемостатическое действие

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24863778

Country of ref document: EP

Kind code of ref document: A2