Patent Application
20250134702
The present invention relates to the fields of contraception and/or prevention of sexually transmitted infections or diseases. Provided are compositions, devices and methods of using aerogels for contraception as well as delivery of drugs.
Contraceptive usage has increased globally, yet 40-45% of pregnancies are unintended. In the United States alone, mistimed, unplanned or unwanted pregnancies result in a total public expenditure of ˜$21 billion per year. These pregnancies are considered high-risk with evidence that both the women and the children experience worse health outcomes than intended pregnancies. Popular contraceptive methods include male/female condoms, female hormone treatments (pills, patches, implants, etc.), and intrauterine devices. Over the past three decades, even though many effective female contraceptive options have been introduced to market, unintended pregnancy rates have remained relatively constant.
A promising strategy to reduce the number of unintended pregnancies and the subsequent societal and family costs is to increase contraceptive options, specifically options available to men. While men make up approximately 50% of the population, they currently only have three contraceptive options available to them: condoms, withdrawal, and vasectomy. When used correctly, condoms can be an effective contraceptive and prophylactic. However, condoms are frequently used incorrectly and are only approximately 85% effective overall and have a low satisfaction rate. Vasectomy is considered permanent and very effective; however, it is difficult to reverse. The withdrawal method is the least effective form of birth control, but from 2002-2015 withdrawal use has doubled while vasectomy (permanent) and condoms (single use at time of need) usage did not significantly increase. No new male contraceptives have been introduced since the vasectomy in the mid-19th century. International and national studies have shown that over half of men would be willing to use new forms of male contraception, yet no new forms of male contraception exist on the market.
Currently, several methods of male contraception are under investigation. These methods can be broken down into two main categories: hormonal and vas-occlusive. (Amory, J. K. Development of Novel Male Contraceptives. Clin. Transl. Sci. 13, 228-237, 2020). Hormonal options such as hormone pills and creams often cause side-effects similar to those observed in female hormonal contraceptives. Some side effects of hormonal male contraceptives include mood swings, depression, and increased risk of suicide. Vas-occlusion has a similar mechanism of action to a vasectomy in that the sperm are prevented from entering into the ejaculatory duct, with the key difference that vas-occlusion does not sever the vessel.
With the advent of novel male contraceptives including hormonal and non-hormonal methods, it is unclear how these male contraceptives will affect the rate of sexually transmitted infections (STIs). One area of interest in public health are multipurpose prevention technologies (MPT), which are combination products that simultaneously provide the user contraception while preventing the contraction of certain STIs. Currently, research on MPTs focus on female patients: for example, intravaginal rings that may deliver antiretroviral drugs for the prevention of HIV. The field lacks a male MPT that provides effective and reversible contraception for men while preventing the contraction of one or more STIs, which may otherwise be referred to as sexually transmitted disease or STDs.
The most publicized vas-occlusive technologies to date are reversible inhibition of sperm under guidance (RISUG) and VASALGEL (pre hydrolyzed RISUG). (Khilwani, B., Badar, A., Ansari, A. S. & Lohiya, N. K. RISUG® as a male contraceptive: journey from bench to bedside. Basic Clin. Androl. 30, (2020); Colagross-Schouten, A., Lemoy, M.-J., Keesler, R. I., Lissner, E. & Vande Voort, C. A. The contraceptive efficacy of intravas injection of VASALGEL for adult male rhesus monkeys. Basic Clin. Androl. 27, 4, 2017.) Both RISUG and VASALGEL are formulations of styrene maleic anhydride (SMA) dissolved in dimethyl sulfoxide (DMSO). Upon injection into the vas deferens (vas), SMA precipitates to coat the inner wall of the vas. The mechanism of action has been reported as both occlusive and spermicidal (depending on the formulation) with the spermicidal action believed to be due to the negative charge present after hydrolysis of the anhydride moieties (Guha, S. K. Biophysical mechanism-mediated time-dependent effect on sperm of human and monkey vas implanted polyelectrolyte contraceptive. Asian J. Androl. 9, 221-227 (2007); Waller, D., Bolick, D., Lissner, E., Premanandan, C. & Gamerman, G. Azoospermia in rabbits following an intravas injection of VASALGEL. Basic Clin. Androl. 26, 6, 2016.) Removal of the SMA from the vas is facilitated by flushing the vas with bicarbonate solution; however, in animal models the sperm lacked acrosomes post-reversal. (Waller, D., Bolick, D., Lissner, E., Premanandan, C. & Gamerman, G. Reversibility of VASALGEL male contraceptive in a rabbit model. Basic Clin. Androl. 27, 2017.)
Another area of interest are compositions and devices for hormonal replacement, such as estrogen, progesterone and/or testosterone replacement therapy (TRT). Currently, TRT involves the implantation of a pellet, which has an extrusion rate of 10% (see Shoskes J J, Wilson M K, Spinner ML. Pharmacology of testosterone replacement therapy preparations. Transl Androl Urol. 2016; 5 (6): 834-843, doi: 10.21037/tau.2016.07.10). Other adverse events of TRT include site infections, bleeding, and fibrosis.
Over the past several decades, hydrogels, which are water-swollen polymer networks, have been applied to a wide variety of biomedical applications including drug delivery. (Li, J. & Mooney, D. J. Designing hydrogels for controlled drug delivery. Nat. Rev. Mater. 1, 1-17, 2016.) Injectable hydrogels have been shown to be biocompatible with the ability to tune the mechanism of gelation, gelation rates, degradation mechanism, degradation rates, pore/mesh size, swelling ratio, and mechanical properties (Bakaic, E., Smeets, N. M. B. & Hoare, T. Injectable hydrogels based on poly(ethylene glycol) and derivatives as functional biomaterials, RSC Adv 5, 35469-35486, 2015; Avery, R. K. et al. An injectable shear-thinning biomaterial for endovascular embolization, Sci. Transl. Med. 8, 365ra156, 2016; Norouzi, M., Nazari, B. & Miller, D. W. Injectable hydrogel-based drug delivery systems for local cancer therapy, Drug Discov. Today 21, 1835-1849, 2016; Staruch, R. M. T., Glass, G. E., Rickard, R., Hettiaratchy, S. P. & Butler, P. E. M. Injectable Pore-Forming Hydrogel Scaffolds for Complex Wound Tissue Engineering: Designing and Controlling Their Porosity and Mechanical Properties, Tissue Eng. Part B Rev. 23, 183-198, 2017; Tan, H. & Marra, K. G. Injectable, Biodegradable Hydrogels for Tissue Engineering Applications, Materials 3, 1746-1767, 2010), thus making them an ideal candidate for the development of a vas-occlusive contraceptive.
Additional efforts in this area include those described in Chinese Patent CN1812746B and Japanese Patent JP5330533B2, and U.S. Pat. No. 6,725,866, which are each hereby incorporated by reference herein in their entireties, but as with any art improvements are needed.
Injectable hydrogels remain ideal candidates for the development of vas-occlusive contraception; however, even small injection volumes (less than 0.25 mL) into the narrow vas deferens lumen can result in long implant lengths. Long implant lengths may in some cases complicate reversal procedures. A need remains for vas-occlusive contraceptive options that provide the benefits of injectable hydrogels, are implantable at consistent, predictable lengths, and are easily removed.
Disclosed are compositions and methods of using one or more aerogel implant, which can be used for example for contraception. The aerogel implants are easily inserted, are highly durable, and are able to last greater than 3 months in vivo, such as up to 3 months or more, including from up to 6 months, up to 1 year, up to 5 years, up to 10 years, up to 20 years, or any time in between. In embodiments, the aerogel implants are configured to be removable to provide reversible contraception.
The accompanying drawings illustrate certain aspects of embodiments of the present invention and should not be used to limit the invention. Together with the written description, the drawings serve to explain certain principles of the invention.
Reference will now be made in detail to various exemplary embodiments of the invention. It is to be understood that the following discussion of exemplary embodiments is not intended as a limitation on the invention. Rather, the following discussion is provided to give the reader a more detailed understanding of certain aspects and features of the invention.
Embodiments of the invention include compositions and methods related to aerogel implants configured to swell in vivo following insertion into a body cavity or lumen, such as a vas deferens or fallopian tube, such as to provide an occlusion. In embodiments, in vivo swelling results in a rehydrated hydrogel implant that is dynamically responsive to vessel contraction. The swelling characteristics are surprising and contribute to low failure rates.
Benefits of the aerogel implant according to embodiments of the invention include several safety features, such as i) precise control of the implant length, which can be customized on a patient-by-patient basis, ii) reduced risk of implant migration due to swelling/axial force, and iii) decreased procedural complexity.
Additional benefits include improved swelling and occlusive properties (less chance of failing) and having a fixed length provides for easier reversal.
With a preformed aerogel implant according to embodiments of the invention, a number of terminal sterilization options can be employed and storage of the implants is more manageable especially with respect to storage requirements, such as not requiring cold chain storage, which increases the potential for non-clinic-based procedures.
As used herein, an “aerogel”, “aerogel implant”, or “lyophilized product” is a hydrogel with air in place of or replacing all or some of the water content of a hydrogel. The “lyophilized product” is an aerogel that is formed by freeze drying a hydrogel.
As used herein, a “hydrogel occlusion” is a hydrogel implant capable of occluding a body cavity or lumen. In embodiments of the invention, an aerogel implant is administered into a body cavity or lumen, forming a hydrogel in situ.
In embodiments, the device or aerogel implant can be formulated for contraception as well as for the delivery of drugs, such as the localized, sustained delivery of drugs over a desired period of time. Examples of intermediate hydrogel formulations that can be used to prepare the aerogel implants and drugs (and other compounds) that can be incorporated therein for delivery can be found in U.S. Patent Publication No. 2022/0175672, which is hereby incorporated herein in its entirety.
In embodiments, the aerogel implants are easily inserted, are highly durable, and are able to last greater than 3 months in vivo, such as up to 3 months or more, including from up to 6 months, up to 1 year, or up to 5 years, or any time in between. In embodiments, the aerogel implants are able to last greater than 5 years in vivo, such as 10 years, 20 years, or more.
In embodiments, the aerogel implants can be prepared by drying hydrogels. In embodiments, hydrogels are prepared and extruded into a mold or tubing with a desired shape and/or diameter. In embodiments, water can be removed by lyophilization while the hydrogels remain in the mold or tubing.
In embodiments, aerogel implants are prepared by removing water from hydrogels through treatment with one or more solvent, such as ethanol. In embodiments, hydrogels are extruded directly into ethanol or another organic solvent. In embodiments, hydrogels are extruded into an aqueous solvent.
In embodiments, following treatment or exposure to the one or more solvent, the hydrogel is exposed to vacuum to remove residual solvent and/or water. Optionally, while under vacuum, the hydrogel is heated to a temperature of up to about 70° C., such as up to about 30° C., 40° C., 50° C., or 60° C.
In embodiments, the hydrogel compositions are prepared by polymerizing one or more type(s) of monomer, macromer, or polymer to form a hydrogel. In embodiments, the hydrogel compositions are prepared from: a first component and a second component capable of combination to form a hydrogel. The resulting hydrogel is then dehydrated, dried, lyophilized and/or otherwise modified to form an aerogel implant.
In embodiments, the aerogel implants formed by drying hydrogels have a moisture content of less than about 25%, such as less than 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 18%, 20%, or 22%. In embodiments, the aerogel implant is partially rehydrated (or not fully dehydrated during aerogel preparation) prior to in vivo insertion, and as such, the aerogel implant comprises up to about 60 wt % water, such as up to about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55% water (or other liquid).
As used herein, the term “component” (also referred to as “biomaterial component”) includes any substance that is capable of forming a hydrogel, aerogel, and/or drug delivery device according to the invention, such as a biomaterial product. For example, a component can include a small molecule, catalyst, peptide, protein, enzyme, nucleotide (or derivatives of), short chains of nucleotides (or derivatives of), long chains of nucleotides (or derivatives of), monosaccharides (or derivatives of), disaccharides (or derivatives of), trisaccharides (or derivatives of), oligo saccharides (or derivatives of), polysaccharides (or derivatives of), monomer, oligomer, macromer, or polymer that can be cross-linked with another component to form a hydrogel, aerogel, and/or drug delivery device according to the invention (e.g., a delivered product or biomaterial product). A component can include a mixture or solution of one or more constituents (e.g., a monomer, macromer, or polymer and a solvent). A component can include such constituents regardless of their state of matter (e.g., solid, liquid or gas). A component can include both active constituents and inert constituents. A constituent may be one or more of a therapeutic agent, an active agent, or drug. For example, in some embodiments, a component can include certain polymers that can form a delivered product, as well as a medicament or other active ingredient. By way of another example, in some embodiments a component can include drugs, including but not limited to, small molecule drugs and biologics. In other embodiments, a component can include certain constituents to impart desired properties to the delivered product, including constituents that facilitate the delivered product being echogenic, radiopaque, radiolucent, or the like.
In embodiments, the components (e.g., monomers, macromers, or polymers) that form the hydrogel, and the aerogel implant formed therefrom, have varied molecular weights, component ratios, concentrations/weight percentages of the components in solvent, and composition of the solvent. Varying any, some, or all of these properties can affect the mechanical, chemical, or biological properties of the device. This includes properties such as, but not limited to, dissolution time, gelation rate/time, porosity, biocompatibility, hardness, elasticity, viscosity, swelling, fluid absorbance, melting temperature, degradation rate, density, reversal time, and echogenicity. Accordingly, one of skill in the art based on this disclosure will know how to “tune” the particular desired features of a hydrogel and/or aerogel to achieve a particular purpose and/or function for a particular application.
In embodiments, the intermediate hydrogel and/or aerogel can be formed by having one or more substances/components/constituents cross-link with one or more of each other, such as macromers.
In embodiments, the aerogel, hydrogel, and/or its macromers can include components including, but not limited to, a polymer backbone, stimuli-responsive functional group(s), and functional groups that enable cross-linking. The functional groups that enable cross-linking can be end groups on the macromer(s). The cross-linking of the macromers may be via bioorthogonal chemistry, such as a Click reaction. In one embodiment, a bioorthogonal reaction is utilized because it is highly efficient, has a quick gelation rate, occurs under mild conditions, and does not require a catalyst.
One example of such reaction is maleimide and thiol. Another type of Click reaction is cycloaddition, which can include a 1,3-dipolar cycloaddition or hetero-Diels-Alder cycloaddition or azide-alkyne cycloaddition, for example. The reaction can be a nucleophilic ring-opening. This includes openings of strained heterocyclic electrophiles including, but not limited to, aziridines, epoxides, cyclic sulfates, aziridinium ions, and episulfonium ions. The reaction can involve carbonyl chemistry of the non-aldol type including, but not limited to, the formation of ureas, thioureas, hydrazones, oxime ethers, amides, and aromatic heterocycles. The reaction can involve carbonyl chemistry of the aldol type. The reaction can also involve forming carbon-carbon multiple bonds, epoxidations, aziridinations, dihydroxylations, sulfenyl halide additions, nitrosyl halide additions, and Michael additions.
Another example of bioorthogonal chemistry is nitrone dipole cycloaddition. The Click chemistry can include a norbornene cycloaddition, an oxanobornadiene cycloaddition, a tetrazine ligation, a [4+1] cycloaddition, a tetrazole chemistry, or a quadricyclane ligation. Other end-groups include, but are not limited to, acrylic, cyrene, amino acids, amine, or acetyl. In one aspect, the end groups may enable a reaction between the polymeric device and the cells lining the tube, duct, tissue, or organ that is being occluded. For example, the devices, compositions, hydrogels and methods of the present invention can include any device, composition, method, hydrogel and/or component/constituent thereof disclosed in any one or more of U.S. Patent Application Publication Nos. 2017/0136143, 2017/0136144, US2018/0028715, US2018/0185096, US2019/0038454, US2019/0053790, US2019/0060513, WO2017/083753, WO2018/139369, WO2019/070632, U.S. Pat. No. 10,155,063, which are each incorporated by reference herein in their entireties.
The macromers or polymers that form the hydrogels (such as the formulations shown in Table 1), which are used in the preparation of the aerogels, according to embodiments of the invention may be one or more of natural or synthetic monomers, polymers, copolymers or block copolymers, biocompatible monomers, polymers, copolymers or block copolymers, polystyrene, neoprene, polyetherether ketone (PEEK), carbon reinforced PEEK, polyphenylene, polyetherketoneketone (PEKK), polyaryletherketone (PAEK), polyphenylsulphone, polysulphone, polyurethane, polyethylene, low-density polyethylene (LDPE), linear low-density polyethylene (LLDPE), high-density polyethylene (HDPE), polypropylene, polyetherketoneetherketoneketone (PEKEKK), nylon, fluoropolymers, polytetrafluoroethylene (PTFE or TEFLON®), TEFLON® TFE (tetrafluoroethylene), polyethylene terephthalate (PET or PETE), TEFLON® FEP (fluorinated ethylene propylene), TEFLON® PFA (perfluoroalkoxy alkane), and/or polymethylpentene (PMP) styrene maleic anhydride, styrene maleic acid (SMA), polyurethane, silicone, polymethyl methacrylate, polyacrylonitrile, poly(carbonate-urethane), poly(vinylacetate), nitrocellulose, cellulose acetate, urethane, urethane/carbonate, polylactic acid, polyacrylamide (PAAM), poly(N-isopropylacrylamide) (PNIPAM), poly(vinylmethylether), poly(ethylene oxide), poly(ethyl (hydroxyethyl) cellulose), polyoxazoline and any of its derivatives (POx), polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) PLGA, poly(ε-caprolactone), polydiaoxanone, polyanhydride, trimethylene carbonate, poly(β-hydroxybutyrate), poly(γ-ethyl glutamate), poly(DTH-iminocarbonate), poly(bisphenol A iminocarbonate), poly(orthoester) (POE), polycyanoacrylate (PCA), polyphosphazene, polyethyleneoxide (PEO), polyethyleneglycol (PEG) or any of its derivatives, linear or multi-armed PEG and any of its derivatives, polyacrylacid (PAA), polyacrylonitrile (PAN), polyvinylacrylate (PVA), polyvinylpyrrolidone (PVP), polyglycolic lactic acid (PGLA), poly(2-hydroxypropyl methacrylamide) (pHPMAm), poly(vinyl alcohol) (PVOH), PEG diacrylate (PEGDA), poly(hydroxyethyl methacrylate) (pHEMA), N-isopropylacrylamide (NIPAM), poly(vinyl alcohol) poly(acrylic acid) (PVOH-PAA), collagen, silk, silk fibroin, sericin, fibrin, gelatin, hyaluron, cellulose, chitin, dextran, casein, albumin, ovalbumin, heparin sulfate, starch, agar, heparin, alginate, fibronectin, keratin, pectin, elastin, ethylene vinyl acetate, ethylene vinyl alcohol (EVOH), polyethylene oxide, PLA or PLLA (poly(L-lactide) or pol (L-lactic acid)), poly(D,L-lactic acid), poly(D,L-lactide), polydimethylsiloxane or dimethicone (PDMS), poly(isopropyl acrylate) (PIPA), polyethylene vinyl acetate (PEVA), PEG styrene, polytetraflurorethylene RFE, TEFLON® RFE, KRYTOX® RFE, fluorinated polyethylene (FLPE), NALGENE®, methyl palmitate, temperature responsive polymers, polycarbonate, polyethersulfone, polycaprolactone, polymethyl methacrylate, polyisobutylene, nitrocellulose, medical grade silicone, cellulose acetate, cellulose acetate butyrate, polyacrylonitrile, poly(lacti de-co-caprolactone (PLCL), and/or chitosan; poly(methyl methacrylate), poly(vinyl alcohol), poly(urethanes) poly(ethylene) poly(siloxanes) or silicones, poly(vinyl pyrrolidone), poly(ethylene-co-vinyl acetate), poly(methyl methacrylate), poly(vinyl alcohol), poly(N-vinyl pyrrolidone), poly(acrylic acid), poly(2-hydroxy ethyl methacrylate), polyacrylamide, poly(methacrylic glycol), poly(ethylene glycol), polyorthoesters, poly(lactide-co-glycolides) (PLGA), polyactide (PLA), polyanhydride, polyglycolides (PGA); polymers formed from radical polymerization such as polystyrene, poly(acrylic acid), poly(methacrylic acid), poly(ethyl methacrylate), poly(methyl methacrylate), poly(vinyl acetate), poly(ethyleneterepthalate), polyethylene, polypropylene, polybutadiene, polyacrylonitrile, poly(vinyl chloride), poly(vinylidene chloride), poly(vinyl alcohol), polychloroprene, polyisoprene, vinyl fluoride, vinylidene fluoride, trifluoroethylene, poly(methyl-α-chloracrylate), poly(ethylvinyl ketone), polymethacroleine, polyaurylmethacryate, poly(2-hydroxyethylmethamilate), poly(fumaronitrile), polychlorotrifluoroethylene, poly(acrylonitrile), polyacroleine, polyacenaphthylene, and branched polyethylene; natural polymers including silk, rubber, cellulose, alginate, wool, amber, keratin, collagen, starch, DNA, and shellac.
In embodiments, one or more drug/therapeutic/active agent can be added to one or more of the substances that cross-link or polymerize to form the hydrogel. For example, if a hydrogel is formed from two macromers, the drug can be loaded to one of the macromers while in solution, while the other macromer does not contain any drug(s) or contains the same drug/therapeutic/active agent, or another drug/therapeutic/active agent. The drug/therapeutic/active agent(s) may be loaded in the same or varying concentrations in the components/constituents used to form the hydrogel.
In embodiments, the aerogel implant or the in vivo hydrogel comprises a composition capable of forming or dissolving within seconds, minutes, hours, weeks, months, or years, such as up to 1, 10, 20, 30, 50, 60 seconds; up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 45, 50 or minutes; or up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours or more; or up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or more; or up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks or more; or up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 months or more; or up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years or more.
Formulations of compositions according to embodiments of the invention are provided in Table 1. In preferred embodiments, the composition comprises one or more polymer comprising polyethylene glycol (PEG), such as a multi-arm PEG (e.g., 4-arm), SMA, or SMAh. The buffer (first column) for example can include any of Acetic Acid-Sodium Acetate (AA), Citric Acid-Sodium Citrate (CA), Citric Acid (0.2)-Phosphate Buffer (0.1) (CP), or Phosphate Buffer (PB), or combinations thereof. The molarity (M) is provided in the second column, which can be adjusted depending on the embodiment. The pH is provided in the third column but can be adjusted for any embodiment to have a pH range of about 4-9. In embodiments (also shown in the first column), the buffer is replaced with a solvent, such as DMSO or acetonitrile (MeCN). The molecular weight (in kDa) is provided in the fourth column but can also be adjusted such that the polymer has a molecular weight within a desired range. The chemistry of the components is provided in the fifth column and can include any of the listed combinations including any one or more functional groups chosen from Thiol (SH), Maleimide (MAL), nitrobenzyl (e.g., o-nitrobenzyl, ONB), Hydrazide (HZ), Isocyanate (IC), Amine (NH), Succinimidyl Glutaraldehyde (SG), Aldehyde (AD), or Epoxide (EP), or combinations thereof. In embodiments, the components include styrene maleic anhydride (SMAh) or styrene maleic acid (SMA), which are prepared by precipitation in aqueous environments (such as neutral to acidic environments). The weight percentage (in solution) is provided in the sixth column and likewise can be adjusted according to particular applications, such as providing a composition comprising a desired polymer with a weight percent of up to 30 wt %, such as from about 1-5 wt %, or from about 2-10 wt %, or from about 3-15 wt %, or from about 10-20 wt %.
In embodiments in which the aerogel comprises a drug, the aerogel is formulated such that the drug is released from the implant over seconds, minutes, hours, weeks, months, or years, such as up to 1, 10, 20, 30, 50, 60 seconds; up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 45, 50 or minutes; or up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours or more; or up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or more; or up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks or more; or up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 months or more; or up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years or more, or any range in between using any of these numbers as endpoints for ranges.
In one embodiment, the molecular weight of the polymers used to form the hydrogels and/or aerogels can be varied from around 1 kDa to 1,000,000 kDa. The molecular weight of the polymer is preferred to be from 10 kDa to 80 kDa. In one example, a high molecular weight can yield small pores in the device and thus, create an effective occlusion. In other embodiments, the polymers can have a weight average molecular weight (Mw) or number-average molecular weight (Mn) ranging from about 1,000 to 1,000,000 Daltons as measured by GPC (gel permeation chromatography) with polystyrene standards, mass spectrometry, or other appropriate methods.
In embodiments, the number average molecular weight (Mn) or the weight average molecular weight (Mw) of polymers of the invention can range from about 1,000 to about 1,000,000 Daltons, such as from about 3,000 to about 60,000 Daltons, or from about 20,000 to about 90,000 Daltons, or from about 150,000 to about 900,000 Daltons, or from about 200,000 to about 750,000 Daltons, or from about 250,000 to about 400,000 Daltons, or from about 300,000 to about 800,000 Daltons, and so on. Further, the degree of polymerization of the polymers in embodiments can range from 1 to 10,000, such as from 50 to 500, or from 500 to 5,000, or from 1,000 to 3,000 Daltons.
The rate of polymerization or depolymerization can be tailored for a particular application and depends on various factors such as compositions, component ratios, concentration/weight percentages, solvent composition, drug composition, drug concentration, pH, temperature, and other factors as previously described.
The molecular weight of substances (e.g., one or more drugs, therapeutics and/or active agents) delivered by the polymer can range from less than 900 Daltons for small molecules to up to 1000 kDa for biologics, for example.
In embodiments, the chain length or degree of polymerization (DP) can have an effect on the properties of the polymers. In the context of this specification, the degree of polymerization is the number of repeating units in the polymer molecule. In embodiments, the polymers include from 2 to about 10,000 repeating units. Preferred are polymers which include from about 5 to 10,000 repeating units, such as from about 10 to 8,000, or from about 15 to 7,000, or from about 20 to 6,000, or from about 25 to 4,000, or from about 30 to 3,000, or from about 50 to 1,000, or from about 75 to 500, or from about 80 to 650, or from about 95 to 1,200, or from about 250 to 2,000, or from about 350 to 2,700, or from about 400 to 2,200, or from about 90 to 300, or from about 100 to 200, or from about 40 to 450, or from about 35 to 750, or from about 60 to 1,500, or from about 70 to 2,500, or from about 110 to 3,500, or from about 150 to 2,700, or from about 2,800 to 5,000, and so on.
If two or more components are used to form the intermediate hydrogel, and as such the aerogel implant, the ratio of the components can be varied. The ratio can be 1:1, 2:1, 1:2, 3:1, 1:3, such as from 1:1 to 1:10, or from 1:2 to 1:20, and so on. For example, a 1:1 ratio allows for the highest degree of cross-linking to occur. The ratio determines the rate of crosslinking and thus, gelation of the hydrogel that is used to form the aerogel implant.
In embodiments, the aerogel implant is implanted into the body part, organ, duct, cavity/space, or lumen using a needle, catheter, or combination thereof. In embodiments, a guide wire (or other means for providing force sufficient to move the aerogel implant through the needle/catheter, such as a plunger, stream of air, fluid etc.) is used during implantation. For occlusion or tissue fillers, the size of the needle or catheter can be chosen based on the estimated size of the body part, organ, duct, cavity/space or lumen from the literature, or determined by imaging the dimensions of the body part, organ, duct, cavity/space or lumen of the subject through ultrasound or other imaging modality. In embodiments, the size of the needle can be between 18 gauge to 34 gauge. In other embodiments, the size of the needle is between 21 gauge and 31 gauge. In other embodiments, the size of the needle is at least 23 gauge, such as between 23 gauge and 29 gauge.
In one embodiment, the weight percent, or concentration of the components in solution, is varied from around 1% to around 50% of the component(s) in solvent. The weight percent of each component can be the same or different, such as from about 1% to 2%, from about 2% to 3%, from about 3% to 4%, from about 4% to 5%, from about 5% to 6%, from about 6%, to 7%, from about 7%, to 8%, from about 8% to 9%, from about 9% to 10%, from about 5-40%, from about 10-35%, from about 15-25%, from about 20-30%, and so on, or any range using these values as endpoints. In another embodiment, the weight percent of the macromer(s) is from about 2.5% to about 35% in the solvent, or from about 6% to about 30%, or from about 7% to about 25%, or from about 8% to about 20%, or from about 10% to about 30%, or from about 10% to about 20%, and so on. The weight percent of each monomer can be the same or different. The weight percent can affect the mechanical and chemical properties of the polymer, such as increasing or decreasing pore size, viscosity, hardness, elasticity, density, and degradation.
The solvent that the component is dissolved in can be aqueous (water-based) or an organic solvent e.g. DMSO, acetonitrile (MeCN), PEG, ethanol, or mixtures thereof. The final composition may contain excipients for purposes such as increased solubility or quicker dissolution rate. The pH of the composition in solution can be varied from 4 to 9, such as from 4 to 5, 5 to 6, 6 to 7, 7 to 8, and 8 to 9. The pH of the solution can affect the gelation time and stability of the macromer in solution.
In one embodiment, the gelation rate and time of formation of the hydrogel varies. Gelation can occur instantaneously, in less than 1 minute, or within 1-10 minutes.
In some embodiments, the aerogel, partially rehydrated hydrogel implant, or rehydrated hydrogel implant is conveyed out of the exit opening of a delivery member into a body part, organ, duct, cavity/space or lumen to at least partially or fully occlude the body part, organ, duct, cavity/space or lumen. In embodiments, the delivery member containing the implant is inserted into the body and a guide wire is used to hold the implant in a desired position while the delivery member is withdrawn, retracted or removed thereby implanting the implant into the body. The guide wire and delivery member can then be removed from the body leaving behind the implant.
In some embodiments, the body part, organ, duct, cavity/space or lumen is chosen from an artery, vein, capillary, vessel, tissue, intra-organ space, lymphatic vessel, a femoral artery, popliteal artery, coronary and/or carotid artery, esophagus, cavity, nasopharyngeal cavity, ear canal, tympanic cavity, sinus, sinuses of the brain, any artery of the arterial system, any vein of the venous system, heart, larynx, trachea, bronchi, stomach, duodenum, ileum, colon, rectum, bladder, kidney, ureter, ejaculatory duct, epididymis, vas deferens, urethra, uterine cavity, vaginal canal, fallopian tube, cervix, duct, bile duct, a hepatic duct, a cystic duct, a pancreatic duct, a parotid duct, organ, a uterus, prostate, organ of the gastrointestinal tract, organ of the circulatory system, organ of the respiratory system, organ of the nervous system, urological organ, subcutaneous space, intramuscular space, or interstitial space.
In one embodiment, the hydrogel implant (e.g., partially rehydrated hydrogel or rehydrated hydrogel) or aerogel implant swells upon contact with one or more fluids inside the body. Swelling allows for the device to secure itself or “lock” within the body part, duct, organ, cavity/space or lumen to form a good occlusion. The device can swell greater than 100%, such as 100-200%, 200-300%, 300-400%, and so on for example up to 2000%. The greater the device swells, the greater the likelihood of the device allowing fluid to travel through, and for hydrostatic pressure to be reduced. Swelling may also allow for the device to properly secure itself within the body part, duct, organ, cavity/space or lumen.
In embodiments, upon implantation of the aerogel implant, a solvent, such as an aqueous solution, is flushed into or onto the body part, organ, duct, cavity/space, or lumen to facilitate rehydrating and/or swelling of the aerogel.
According to another embodiment, the hydrogel, aerogel implant, and/or rehydrated hydrogel implant (includes partially and fully rehydrated hydrogels) includes pores. In embodiments, the pores are homogenous on the surface of the device. The porosity is defined by the properties of the macromers and cross-linking of the macromers. In embodiments, the pore diameter of the formed polymer ranges from 0.001 nm to 3 μm, such as from 0.001 nm to 1 μm. In other embodiments, the pore diameter ranges from 0.01 nm to 100 nm, or from about 1 nm to about 1 μm. In other embodiments, the pore diameter is 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 95, 90, 95, or 100 nm. In other embodiments, the pore diameter is at least the size of an atom (0.5 nm). Specific pore sizes can be targeted to provide an optimum porosity that provides maximum flow of fluid while blocking the flow of sperm cells or ova. In other embodiments, the pores range from 0.1 nm to 2 microns in diameter. In one embodiment, the device is suitable for occlusion of reproductive cells. The pores are less than 3 μm to prevent the flow of sperm. The pores allow for fluid to travel through the implant. The mesh size of the implant/device is small enough to block reproductive cells from traversing through. In embodiments, such as for drug delivery devices/implants, a larger pore size may be desired for quicker release of drug from the implant.
In embodiments, the aerogel implant has a length of up to about 10 cm, such as up to about 1, 2, 3, 4, 5, 6, 7, 8, or 9 cm. In embodiments, the aerogel can be cut to the desired length or the aerogel during the formation of the intermediate hydrogel can be configured to have a desired length. In embodiments, upon implantation, the aerogel swells into a partially or fully re-constituted or rehydrated hydrogel with a length of occlusion produced in a body part, duct, organ, cavity/space or lumen as a result of administering. In embodiments, the length of occlusion ranges from 0.1-10 centimeters in length, including 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0 cm in length, and so on, and any range using any of these values as endpoints. In embodiments, the aerogel implant swells following implantation resulting in a hydrogel occlusion with a length of up to about 5 times the length of the aerogel (prior to swelling), such as up to about 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, or 4.5 times the length of the aerogel prior to swelling.
In embodiments, implants are made by first forming an intermediate hydrogel, then dehydrating the intermediate hydrogel to obtain an aerogel, then implanting the aerogel and allowing the aerogel to rehydrate in vivo to obtain an aerogel implant (e.g., rehydrated intermediate hydrogel), the resulting aerogel implant exhibits a swelling force greater than the intermediate hydrogel would if the intermediate hydrogel was formed directly in vivo without the step of forming an aerogel. In embodiments, the aerogel implant has a swelling force that is between 1-2 times the swelling force of the intermediate hydrogel, or is between 1-10 times, or is between 2-8 times, or is between 3-5 times, or is between 1.5-3 times the swelling force of the intermediate hydrogel. In embodiments, the swelling force of the aerogel implant is in the range of about 2.5 Newtons to 15 Newtons, or from 5 Newtons to 12 Newtons, or from 3-10 Newtons, such as from 3-9 Newtons, or any range using any of these values as endpoints.
In embodiments, the aerogel implant has a diameter of up to about 1 mm, such as up to about 0.05 mm, 0.075 mm, 0.1 mm, 0.15 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm. In embodiments, the aerogel implant swells in vivo following implantation resulting in a hydrogel occlusion (e.g., partially or fully rehydrated hydrogel) with a diameter of up to about 10 times the diameter of the aerogel implant (prior to swelling), such as up to about 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 times the diameter of the aerogel implant prior to swelling. In embodiments, the length of the aerogel implant can be in the range of 0.5 cm to 15 cm. For example, the aerogel implants can have a diameter in the range of about 0.05-1 mm and a length in the range of 0.5-15 cm, such as a diameter of 0.1-0.8 mm and a length of 5-10 cm, or a diameter of 0.3-0.6 mm and a length of 7-15 cm, or a diameter of 0.4-0.5 mm and a length of 5-12 cm.
In one embodiment, the aerogel/hydrogel/device/implant/delivered product does not degrade inside the body in that it is permanent. In another embodiment, the aerogel/hydrogel/device/implant/delivered product degrades partially or fully or is capable of degrading in the body, for example, by way of an endogenous stimulus (e.g., hydrolysis). The degradation rate is slow enough that the device remains an effective occlusion inside the body for greater than three months. According to another embodiment, the device degrades upon application of an exogenous stimulus, for example, by photodegradation (e.g., ultraviolet or infrared exposure), acoustic, and/or enzymatic degradation. Alternatively, or in addition to any of these embodiments, the aerogel implant (e.g., hydrogel/device/delivered product) is configured to have a lifetime that is as long as or longer than the drug/therapeutic agent/active agent release profile.
In some embodiments, the aerogel implant is formed from a composition including a first component and a second component that are each formulated to be crosslinked with the other to form a hydrogel. The first component and the second component are formulated to have an initial storage modulus (initial G′) and an initial loss modulus (initial G″) when initially combined such that a ratio of the initial G″ to the initial G′ is between about 5 and about 100. The first component and the second component are formulated to have a gelation storage modulus (gelation G′) and a gelation loss modulus (gelation G″) at a gelation time after the first component and the second component are combined such that a ratio of the gelation G″ to the gelation G′ is less than about 5, such as less than about 1. In embodiments, the gelation time is less than about 120 seconds. The term “gelation” refers to the transition of the hydrogel components from a soluble polymer of finite branches to a substance with infinitely large molecules. Similarly stated, “gelation” refers to the condition where the gel forms and after the components are combined. Thus, the gelation time refers to the time that it takes for the resulting hydrogel to substantially reach equilibrium.
In some embodiments, the gelation time is less than about 60 seconds, for example, less than about 30 seconds, and in some cases may be instantaneous/immediate. In other embodiments, the gelation time is between about 1 second and 60 seconds. The particular components used to form the hydrogel/device/delivered product can be selected such that the gelation time/rate is “tuned” for the particular application. For example, the components/constituents can be selected to provide for faster or slower gelation times as desired. Alternatively or in addition, the components/constituents used to form the aerogel can be extruded at a rate of up to about 50 mL/min, such as up to about 0.1 mL/min, 0.5 mL/min, 1 mL/min, 1.5 mL/min, 2 mL/min, 2.5 mL/min, 3 mL/min, 4 mL/min, 5 mL/min, 8 mL/min, 10 mL/min, 12 mL/min, 15 mL/min, 17 mL/min, 20 mL/min, 25 mL/min, 30 mL/min, 35 mL/min, 40 mL/min, or 45 mL/min, to provide a desired mechanical property, such as a swelling force in the range of 2.5-15 Newtons, or 2-12 Newtons, or 4-10 Newtons, or a swelling force of the implant that is greater than the swelling force that would result from a hydrogel used to make the aerogel implant.
In some embodiments, the ratio of the gelation G″ to the gelation G′ is less than about 0.2, such as about 0.1. In yet other embodiments, the ratio of the gelation G″ to the gelation G′ is a ratio of up to 1, such as a ratio of up to 0.9, or up to 0.8, or up to 0.7, or up to 0.6, or up to 0.5, or up to 0.4, or up to 0.3, or up to 0.2, or up to 0.1.
In some embodiments, the first component and the second component are formulated to have an initial storage modulus (initial G′) and an initial loss modulus (initial G″) when the first component and the second component are initially combined. A ratio of the initial G″ to the initial G′ is between about 5 and about 100. The first component and the second component are formulated to have a delivered storage modulus (delivered G′) and a delivered loss modulus (delivered G″) when the first component and the second component are conveyed out of the delivery member (e.g., at the delivery time). A ratio of the delivered G″ to the delivered G′ is between about ⅓ and about 3. In some embodiments, the ratio of the initial G″ to the initial G′ is between about 30 and about 5 and the ratio of the delivered G″ to the delivered G′ is between about ⅓ and about 1. In some embodiments, the first component and the second component are formulated to have a gelation storage modulus (gelation G′) and a gelation loss modulus (gelation G″) after the gelation time and a ratio of the gelation G″ to the gelation G′ being less than about 0.2. In some embodiments, the ratio of the gelation G″ to the gelation G′ is about 0.1.
In some embodiments, the first component is at least one of a polyvinyl alcohol, alginate or modified alginate, chitosan or modified chitosan, polyethyleneimine, carboxymethyl cellulose, and/or polyethylene glycol terminated with a bioorthogonal functional group (e.g., amine, thiol, maleimide, azide, activated ester). The second component is at least one of a water or buffer, water or buffer with divalent cations such as calcium, a solution of reduced hyaluronic acid, a solution of polystyrene sulfonate, a solution of gelatin, and/or polyethylene glycol terminated with a bioorthogonal functional group (e.g., amine, thiol, maleimide, azide, activated ester). In some embodiments, polyvinyl alcohol, alginate, chitosan, polyethyleneimine, carboxymethyl cellulose, polyethylene glycol terminated with functional groups, divalent cations, reduced hyaluronic acid, polystyrene sulfonate, or gelatin have a weight percent ranging from about 1 to 30% in solvent. In some embodiments the polysaccharides may be modified with different functional groups. In some embodiments the polysaccharides and proteins may range in molecular weight from 10,000-1,000,000 grams/mole. In some embodiments, the polyvinyl alcohol, polystyrene sulfonate, polyethyleneimine, and polyethylene glycol may be linear, Y-shaped, 3-arm, 4-arm, 6-arm, or 8-arm and range in molecular weight from 1,000-1,000,000 grams/mole.
In some embodiments, the dissolving solution for the polymer component(s) may be aqueous buffers, including any one or more of phosphate, citrate, acetate, histidine, lactate, tromethamine, gluconate, aspartate, glutamate, tartrate, succinate, malic acid, fumaric acid, alpha-ketoglutaric, and/or carbonate. Specific solvents/buffers can include: 1) acetic acid and sodium acetate (AA), 2) citric acid and sodium citrate (CP), 3) citric acid and phosphate buffer (CP), and 4) phosphate buffer (PB), or combinations thereof. Non-aqueous solvents include: dimethyl isosorbide, glycofurol 75, PEG 200, diglyme, tetrahydrofurfuryl alcohol, ethanol, acetone, solketal, glycerol formal, dimethyl sulfoxide, propylene glycol, ethyl lactate, N-methyl-2-pyrrolidone, dimethylacetamide, methanol, isopropanol, 1,4-butanediol, ethyl acetate, toluene, acetonitrile, and combinations thereof. In embodiments, the dissolving solution can include mixtures of aqueous and non-aqueous (e.g., organic) solvents such as a mixture of any one or more of phosphate, citrate, acetate, histidine, lactate, tromethamine, gluconate, aspartate, glutamate, tartrate, succinate, malic acid, fumaric acid, alpha-ketoglutaric or carbonate in combination with any non-aqueous solvent, such as one or more of dimethyl isosorbide, glycofurol 75, PEG 200, diglyme, tetrahydrofurfuryl alcohol, ethanol, acetone, solketal, glycerol formal, dimethyl sulfoxide, propylene glycol, ethyl lactate, N-methyl-2-pyrrolidone, dimethylacetamide, methanol, isopropanol, 1,4-butanediol, ethyl acetate, toluene or acetonitrile.
The molarity of the solutions/solvents/buffers can range for example from 0.01 M to 0.15 M to 0.2 M. In some embodiments, the solution can include a 0.2 M citric acid buffer and can be formulated to have a solution pH of between 4.0 and 6.0. In some embodiments, the pH of the solution can be between 4.0 and 5.25, or about 4.0. In other embodiments, the pH of the solution can be about 5.25, 5.5, 5.75, 6, 6.25, or 6.5. In yet other embodiments, the pH of the solution can be between about 4.5 and about 8 such as a pH of about 5-7, or about 4.5-6.
In embodiments, a first component and a second component can each be a water soluble component (e.g., monomer, macromer, polymer, or the like) that is capable of crosslinking (e.g., with the other component) to form an intermediate hydrogel. In some embodiments, the first component and the second component are formulated such that the resulting intermediate hydrogel has a gelation time of less than 5 minutes. In other embodiments, the first component and the second component are formulated such that the resulting intermediate hydrogel has a gelation time of less than 2 minutes. In other embodiments, the first component and the second component are formulated such that the resulting intermediate hydrogel has a gelation time of less than minute. In yet other embodiments, the first component and the second component are formulated such that the resulting intermediate hydrogel has a gelation time of less than 30 seconds.
In some embodiments, the first component is at least one of a polyvinyl alcohol, alginate or modified alginate, chitosan or modified chitosan, polyethyleneimine, carboxymethyl cellulose, and/or polyethylene glycol terminated with a bioorthogonal functional group (e.g., amine, thiol, maleimide, azide, activated ester). The second component is at least one of a water or buffer, water or buffer with divalent cations such as calcium, a solution of reduced hyaluronic acid, a solution of polystyrene sulfonate, a solution of gelatin, and/or polyethylene glycol terminated with a bioorthogonal functional group (e.g., amine, thiol, maleimide, azide, activated ester). In some embodiments, polyvinyl alcohol, alginate, chitosan, polyethyleneimine, carboxymethyl cellulose, polyethylene glycol terminated with functional groups, divalent cations, reduced hyaluronic acid, polystyrene sulfonate, or gelatin have a weight percent ranging from about 1 to 30% in solvent. In some embodiments the polysaccharides may be modified with different functional groups. In some embodiments the polysaccharides and proteins may range in molecular weight from 10,000-1,000,000 grams/mole. In some embodiments, the polyvinyl alcohol, polystyrene sulfonate, polyethyleneimine, and polyethylene glycol may be linear, Y-shaped, 3-arm, 4-arm, 6-arm, or 8-arm and range in molecular weight from 1,000-1,000,000 grams/mole. The intermediate hydrogel can comprise any combination of the components described herein and can have any of the characteristics as indicated herein. For example, in some embodiments, the formed intermediate hydrogel can be at least 90 percent water. Water can then be removed from the intermediate hydrogel to form the aerogel implant.
In some embodiments, the dissolving solution for the polymer component(s) may be aqueous buffers (pH range 1-14), such as phosphate, citrate, acetate, histidine, lactate, tromethamine, gluconate, aspartate, glutamate, tartrate, succinate, malic acid, fumaric acid, alpha-ketoglutaric, and/or carbonate, or combinations thereof. Non-aqueous solvents include: dimethyl isosorbide, glycofurol 75, PEG 200, diglyme, tetrahydrofurfuryl alcohol, ethanol, acetone, solketal, glycerol formal, dimethyl sulfoxide, propylene glycol, ethyl lactate, N-methyl-2-pyrrolidone, dimethylacetamide, methanol, isopropanol, 1,4-butanediol, ethyl acetate, toluene, acetonitrile, and combinations thereof. In some embodiments, when the polymer component is dissolved, the viscosity of the solution(s) that make up the biomaterial may range from 0.1 to 250,000 cP. The density of the solution may range from 0.1 to 20,000 kg/m3. The temperature during extrusion may range from 2 to 45° C. The pH of the solution(s) may range from 1-14. The ionic strength of the solution(s) may range from 1 nM to 70 M.
In some embodiments, the aerogel is prepared from a biomaterial/hydrogel comprising one or more components. If two components are used to form the biomaterial/hydrogel, then the ratio of the components may be varied such as 1:1, 2:1, 1:2, 3:1, 1:3, 4:1, 1:4, and up to 10:1 or 1:10. The gelation rate of the biomaterial may range from about 0.001 seconds to 60 minutes. The length of the formed biomaterial may range from about 0.1 to 60 cm. The volume of the formed biomaterial may range from about 0.001 to 100 mL.
In some embodiments, the aerogel implant or partially dehydrated or rehydrated hydrogel implant swells within the implantation space to lock or secure its placement. For example, a biomaterial in the form of a hydrogel may swell from about 1.5×-20× its initial volume and/or mass, such as about 2×, 2.5×, 3×, 3.5×, 4×, 4.5×, 5×, 5.5×, 6×, 6.5×, 7×, 7.5×, 8×, 8.5×, 9×, 9.5×, 10×, 10.5×, 11×, 11.5×, 12×, 12.5×, 13×, 13.5×, 14×, 14.5×, 15×, 15.5×, 16×, 16.5×, 17×, 17.5×, 18×, 18.5×, 19×, 19.5× or 20× its initial volume and/or mass. In some embodiments, the implant conforms to the space it is implanted into. In some embodiments, the swelling of the implant does not change volume within the implantation space, or shrinks to conform to a volume of the implantation space.
An intermediate hydrogel (not shown in the figures) is prepared by crosslinking a first polymer comprising PEG and terminated with maleimide functional groups and a second polymer comprising PEG and terminated with thiol functional groups. The components can be extruded as a pre-combination of the components or combined and extruded simultaneously. The intermediate hydrogel in this example was extruded into PTFE tubing of a selected inner diameter to result in an intermediate hydrogel and ultimately an aerogel with a selected outer diameter. In embodiments, the intermediate hydrogel can be extruded through tubing to obtain the desired shape and/or size. Other types of molds can be used and/or the intermediate hydrogel can be formed without a mold. The mold can be selected to control the length and/or the diameter of the intermediate hydrogel and as such the resulting aerogel. The shape of the intermediate hydrogel or the aerogel can be any shape such as a cylinder, triangular prism, or rectangular prism. The intermediate hydrogel or the aerogel can have a cross-section that is any shape, such as circular, rectangular, square, round, etc. The intermediate hydrogel is lyophilized to remove at least about 90% of the moisture, forming aerogel implant 2.
The aerogel implant 2 can be implanted into the body as the lyophilized product, or as a rehydrated hydrogel implant, or as a partially rehydrated hydrogel implant. One benefit of dehydrating the intermediate hydrogel is that aerogel implant 2 prepared in this manner can exhibit an unexpectedly surprising swelling force as compared to implants formed without dehydrating the intermediate hydrogel into an aerogel and rehydrating to form the implant. For contraception and/or occlusion within the body, such as in the vas, a swelling force that is sufficient to enable the implant/device to push against the vas or vessel wall, but which is insufficient to cause harm to the tissue, is highly desired. Implants of the present invention are capable of providing a swelling force that provides for contraceptive efficacy of over 90%, such as over about 95%, 96%, 97%, 98%, 99%, or even approaching 100%, such as 99.9%, 99.8%, 99.7%, 99.6%, 99.5%, 99.4%, 99.3%, 99.2%, 99.1%, for example.
As shown in
An intermediate hydrogel is prepared by crosslinking a first polymer comprising a 4-arm PEG and terminated with maleimide functional groups and a second polymer comprising a 4-arm PEG and terminated with thiol functional groups at a concentration of 20 wt % in 200 mM Citric Acid-Sodium Citrate buffer. The product is then extruded into PTFE tubes, each having a selected internal diameter in the range of 0.5 mm-1.35 mm (0.5 mm, 0.8 mm, 1.0 mm and 1.35 mm). Before crosslinking and extrusion, the starting materials can be prepared as separate polymer/buffer solutions then combined for crosslinking or can be prepared as a single solution. In embodiments, the solution(s) can be prepared separately in advance and stored at −20° C. until crosslinking is to be performed. The PTFE tubes are cured at ambient temperature for approximately 1 hr. The cured products are then sectioned into approximately 5 cm sections. The tube sections are frozen at −80° C., then lyophilized to remove water. The resultant aerogel 5 cm sections (
A two-compartment syringe is used to inject PEG-SH and PEG-MAL to form a hydrogel in PTFE tubing with an internal diameter of about 1.0 mm. In embodiments, the components can be extruded as a pre-combination of the components or combined and extruded simultaneously. A hydrogel is formed from the cross-linked components inside the tubing, which is then sectioned into desired lengths, frozen, and lyophilized (
Following lyophilization, the lyophilized hydrogel is compressed to an outer diameter of about 0.6 mm using a die stamp mold or rolling mill. As shown in
In an embodiment of the invention, the aerogel implants are disinfected and/or desiccated using one or more solvent, such as ethanol.
A 10 cm implant 4 (such as an implant formed via the procedure described in Example 4), is compared to a 10 cm implant disinfected by soaking in 50 mL of ethanol for 24 h. The disinfected implant is then vacuum dried for 72 h to give disinfected implant 5 (
Burst pressures were determined by re-hydrating the aerogel implants.
In
In an embodiment of the invention, an aerogel implant 10 is administered using a delivery kit 100 (
As shown in
At time of delivery, cap 140A is removed and replaced with a catheter 120 or a needle (not shown) as shown in
The catheter 120 or needle is inserted into the body such as a body cavity or lumen, for example a vas deferens or fallopian tube. Cap 140B is removed and guide wire 130 is inserted into the housing 110. The guide wire 130 is used to push the aerogel implant 10 out of the housing 110 and into the catheter 120.
After the aerogel implant 10 is pushed into the catheter 120, the guide wire 130 is removed from the catheter 120, and the catheter 120 is detached from the housing 110. The guide wire 130 is inserted into the catheter 120 and used to hold the aerogel implant 10 in position as the catheter 120 is removed from the body, cavity or body lumen by sliding it out of the body, cavity or body lumen toward a handle of the guide wire 130 (
The term “about” used herein in the context of quantitative measurements means±10%. For example, with a ±10% range, a number average molecular weight (Mn) or the weight average molecular weight (Mw) of “about 1,000 Daltons” can mean a molecular weight in the range of 900-1,100 Daltons.
The present invention has been described with reference to particular embodiments having various features. In light of the disclosure provided above and the claims provided below, it will be apparent to those skilled in the art that various modifications and variations can be made in the practice of the present invention without departing from the scope or spirit of the invention. One skilled in the art will recognize that the disclosed features may be used singularly, in any combination, or omitted based on the requirements and specifications of a given application or design. When an embodiment refers to “comprising” certain features, it is to be understood that the embodiments can alternatively “consist of” or “consist essentially of” any one or more of the features. Any of the methods disclosed herein can be used with any of the compositions disclosed herein or with any other compositions. Likewise, any of the disclosed compositions can be used with any of the methods disclosed herein or with any other methods. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention.
It is noted in particular that where a range of values is provided in this specification, each value between the upper and lower limits of that range, to the tenth of the unit disclosed, is also specifically disclosed. Any smaller range within the ranges disclosed or that can be derived from other endpoints disclosed are also specifically disclosed themselves. The upper and lower limits of disclosed ranges may independently be included or excluded in the range as well. The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is intended that the specification and examples be considered as exemplary in nature and that variations that do not depart from the essence of the invention fall within the scope of the invention. Further, all of the references cited in this disclosure are each individually incorporated by reference herein in their entireties and as such are intended to provide an efficient way of supplementing the enabling disclosure of this invention as well as provide background detailing the level of ordinary skill in the art.
| Number | Date | Country | |
|---|---|---|---|
| 63668151 | Jul 2024 | US | |
| 63595314 | Nov 2023 | US |
