Therapeutic hydrogels
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- VIVOS INC
- Filing Date
- 2026-01-25
- Publication Date
- 2026-08-06
Smart Images
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Abstract
Description
[0001] THERAPEUTIC HYDROGELS
[0002] TECHNCAL FIELD
[0003] The present novel technology relates generally to the preparation and use of reabsorbable therapeutic hydrogel compositions.
[0004] BACKGROUND
[0005] One common approach to the treatment of patients with certain kinds of cancer, such as liver cancer, is to introduce radioactive particles into the patient's circulatory system, wherein the radioactive particles are targeted to the site of the cancer. Specifically, measured amounts of radioactive isotopes are injected into the patient such that they accumulate at the site of the cancer. The lodged particles thus generate a predetermined field of radiation within or proximate to the location of a cancerous tumor. The radioactive isotope is typically selected according to the type of radiation,emitted arid its half-life, such that the radiation has enough range to be destructive to the tumor and proximal tumor margins but does only minimal damage to adjacent healthy tissues and organs and also such that the emission of radiation lasts for only a short, predetermined duration.
[0006] One commonly used radioisotope is yttrium-90, since radioactive yttrium-90 emits 100 percent beta radiation and has a short half-life of 2.67 days. The yttrium-90 is typically incorporated in glass or resin microspheres which are suspended in a liquid medium and introduced via intra-arterial injection. However, the glass or resin formulations and mode of admini stration result in: a) difficulties in achieving a homogeneous distribution of particles within the tumor (and thus not treating the patient with a known and controlled radiation dosage); and b) difficulties in concentrating and sequestering all of the radioisotope at the tumor site allowing significant amounts of the particles to migrate away from the tumor site and deli ver radiation to normal healthy tissues.
[0007] Various means have been employed to incorporate the radioisotopes in microspheres, such as those made of resin or crystalline: ceramic cores with radioactive materials coated thereunto. However, whenever a microsphere comprises a core material having an external surface coating which contains the radioactive isotope there is a risk that the radioactive coating may separate from the under lying microsphere core, Any mechani cal breakage of the coating can release unwanted radioactivity to other parts of the patient’s body, which is highly
[0008] Iundesirable. Further disadvantages are presented by the special handling and precautions that are.necessary to coat a radioactive isotope onto a crystalline ceramic core, or to label or adsorb the isotope onto an ion exchange resin.
[0009] In still another application, mierospheres have been prepared comprising a ceramic material and having a radioactive isotope incorporated into the ceramic material. While the inad vertent release of radioactive isotopes from a radioactive coating i nto other parts of the human body is reduced or eliminated by incorporating the radioisotopes into ceramic spheres, the latter product form is not without its disadvantages. Processing of these ceramic particles is dangerous because potentially volatile radioactivity must be added, to ceramic melts and the microspheres must be produced and sized while radioactive. Such processing steps increase tile likelihood of accidental exposure of personnel and risk radioactive contamination of facilities.
[0010] Some of these drawbacks have been overcome by incorporating stable
[0011]
[0012] in oxide form into glass.microspheres and subsequently exposing them to neutron radiation to activate the to90Y. The mierospheres are then injected into the patient’s hepatic artery, where they may lodge in liver tumor capillaries. Microspheres may end up in normal liver or be transported elsewhere in the body, It is difficult to track and accurately assess where the administered microspheres deposit.
[0013] An approach to overcoming these difficulties is to incorporate the radioactive particles into a hydrogel. Use of bovine serum albumin cross-linked with glutaraldehyde (BioGlue™) as the hydrogel component has been described (see for example W02021084515). Th is approach suffers from the slo w rate of resorption of the hydrogel which can interfere with tissue healing at the site of the excised tumor. It may be that slow resorption of BioGlne™ results from a slow rate of hydrolysis. Incorporation of radioactive particles in a thermogellmg hydrogel has been described (see U. S. Patent No. 12,201,703), Injection of the hydrogel-radioactive particle material provides a localized dosage of radiation to the target tissue.
[0014] Controll ing the rate of reabsorption of the hydrogel remains an important parameter for improving the treatment of solid tumors. Thus, there remains a need for a beter or optimized treatment that is useful in the treatment of cancer or tumor bearing tissue, but which will not release a radioactive coating or isotope, or migrate into other parts of the body of the patient after administration, yet will be reabsorbed (he., biodegrades) in a time frame that avoids interferencewith the heal ing of the tumor site. The present disclosure addresses thi s need.
[0015] It has been surprisingly discovered that hydrogels comprising PLGA-g-PEG polymers wherein the molar ratio of lactate monomers (LA) to glycolate monomers (GA) falls outside of the range: from about 65:35 (LA: GA) to 85:15 (LA: GA) do not have rheological properties useful for forming therapeutic hydrogels for use in warm-blooded patients.
[0016] The descriptions of specific embodiments of the present disclosure are presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present disclosure to the precise forms disclosed, and obviously many modifications and variations are possible considering die above description. The exemplary embodiments are chosen and described to explain the principles of the present disclosure and its practical application for purposes of enabling others who are skilled in the art and making of the product to utilize the present disclosure and various embodiments with various modifications as are suited to the particular use are contemplated.
[0017] DETAILED DESCRIPTION
[0018] For the purpose of promoting an understanding of the princ iples of the novel technology and presenting its currently understood best mode of operation, reference will now be made to the non-limiting embodiments and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the novel technology is thereby intended, with such alterations and further modifications in the illustrated compositions and methods and such further applications of the principles of the novel technology as illustrated therein being contemplated as would normally occur to one skilled in the art to which the novel technology relates.
[0019] As used herein, the recited terms have the following meanings. AU other terms and phrases used in this specification have their ordinary meanings as one of skill in the art would understand. Such ordinary meanings may be obtained by reference to technical dictionaries, such as Hawley’s (i’ondensed Chemical Dictionary 14th Edition, by R. J. Lewis, John Wiley & Sons, New k, N. Y., 2001.
[0020] References in the specification to “one- -embodiment”, “an. embodiment”, etc., indicate that the embodiment described nlay include a particular aspect, feature, structure, moiety, or characteristic, but not every embodiment necessarily includes that aspect, feature,structure, moiety, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred io in other portions of the specificatio. Further, when a particular aspect, feature, structure, moiety, or characteristic is described in connection, with an embodiment; it is within the kno wledge of one skilled in the art to affect or connect such aspect, feature, structure, moiety, or characteristic with other embodiments, whether or not explicitly described.
[0021] The singular forms“a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a drug” includes a plurality of such drags, so that a drug X includes a plurality of drugs X. It is further noted that the claims may be drafted to exclude any optional dement.
[0022] The term “and / or” means any one of the items, any combination of the items, or all of the items with which this term is associated.
[0023] The term “about” can refer to a variation of ±2.5%, ±5%, ±10%, ±20%, or ±25% of the value specified. For an illustrative example, “about.50 percent” can in some embodiments carry a variation from 45 to 55 percent. For integer ranges, the term “about” can include one or two integers greater than and / or less than a recited integer at each end of the range. Unless indicated otherwise herein, the term “about” is intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment. The term about can also modify the end-points of a recited range as discussed above in this paragraph.
[0024] As will be understood by the skilled artisan, all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term “about.” It is also understood that such values inherently contain variability necessarily resulting from the standard deviations found in their respective testing measurements.
[0025] As will be understood by one skilled in the art, all ranges recited herein also encompass any and al l possible sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. A recited range (e.g., weight percentages or carbon groups) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing andenabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-liiniting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art, all language such as “up to”, “at least”, “greater than”, “‘less than”, “more than”, “or more”, and the like, include the number recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio. Accordingly, specific values recited for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents,
[0026] It is to be understood that where items are grouped together in a common manner, such as in a Markush group, the disclosure encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the disclosure encompasses not only the main group, but also the main group absent one or more of the group members. The disclosure therefore envisages the explicit exclusion of any one or more members of a recited group. Accordingly, provisos may apply to any of the disclosed categories or embodiments whereby any one or more of the recited elements, species, or embodiments, may be excluded from such categories or embodiments, for example, for use in an explicit negative limitation.
[0027] The term “contacting” refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change,,e,g., in a sohition, in a reaction mixture, in vitro, or in vivo.
[0028] The terms “inhibit”, “inhibiting”, and “inhibition” refer to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, or group of cells The inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of die treatment or contacting, or compared to the growth or progression that occurs by treatment of a group of cells by a single drug composition.
[0029] As used herein, “gelation temperature” refers to the temperature at which a biodegradable copolymer undergoes thermal gelation, i.e. the tempera tare below which the blockcopolymer is soluble in water and above which the block copolymer undergoes phase transition to increase in viscosity or to form a semi-solid gel. The terms "gelation temperature,’7"thermal gelation temperature,” “'reverse thermal gelation temperature,” and similar terms can be used interchangeably.
[0030] A “polymer solution”, “aqueous solution” and the like, when used in reference to a biodegradable copolymer contained in such solution, refers to a water-based solution having the recited copolymer dissol ved therein at a functional concentration, and maintained at a temperature below the gelation temperature of the block copolymer. It is understood that a polymer solution may refer to a solution, of more than one biodegradable copolymer. " Thermal gelation” is the phenomenon whereby a solution of a block copolymer spontaneously increases in viscosity, and in many instances transforms into a semisolid gel, as the temperature of the solution is increased above the gelation temperature of the copolymer. For example, the term “gel” includes both the semisolid gel state and the high viscosity state that exists above the gelation temperature. When cooled below the gelation temperature, the gel may spontaneously reverse to refonn of revert back to the lower viscosity solution. In many cases, cycling between die solution and the gel may be repeated ad infinitum. because the sol / gel transition does not involve any change in the chemical Composition of the polymer system. It is believed that interactions creating the gel are physical in nature and do not involve the formation or breaking of covalent bonds.
[0031] A “drug delivery system” or “drug delivery composition having thermal gelation properties’” refers to a polymer solation that contains a drug or combination of drugs, where the drug(s) per se can be either dissolved or colloidal), suitable for administration to a warm-blooded animal, which forms a gelled drug depot when the temperature is raised to or above the gelation temperature of the block copolymer.
[0032] A “depot” refers to a drug delivery system following adininistration to a warm¬ blooded animal, which has formed a gel upon the temperature being raised to or above die gelation temperature.
[0033] A “gel” refers to the semi-solid phase that spontaneously occurs as the temperature of the “polymer solution” is raised to or above the gelation temperature of the block copolymer.At temperatures below the gelation temperature the copolymer may be soluble in the water phase and the composition will be a solution.. At temperatures at or above the gelation, temperature the copolymer will solidify to form a gel with the water phase and the composition will be a gel of semi-solid.
[0034] The term “biodegradable” means that the block copolymer can chemically break down or degrade within the body to form nontoxic components under physiological conditions. The terms “resorbable” and “reabsotbable” generally refer to a materia! that is biodegradable. The term ‘ resorption” is used interchangeably with the terms “reabsorption” and “biodegradation” and may include hydrolysis of the thermogel.
[0035] The terms “gel.” “thermal gel,” and “fhermogel” are used interchangeably throughout this disclosure.
[0036] Radiomedicine thermal gels, such as those containing radioactive ', emit a therapeutic intensity and amount of short-range beta radiation that can penetrate tissue to a depth of up to about several millimeters.
[0037]
[0038] is a commonly used radiotherapeutc isotope.<,>0Y is a high-energy beta-emitting isotope with no primary gamma; the maximum energy of the9&Y beta particle is 2.28 MeV with a mean energy of about 0,91 MeV< X’Y has a half-life (t-a) of 64 hours, with 94% of its radiation delivered in approximately 11 days. Typically, the concentration of radioi sotope in the thermal gel and the amount of thermal gel in troduced into a patient is controlled such that they will not emit an excess amount of unwanted radiation that could damage healthy tissue surrounding the target tumor. Thus, the thermal gel composition is typically engineered so that the therapeutic radioisotopes are the only constituent isotopes which emit a significant amount of alpha, beta and / or gamma radiation, and that the radioisotopes have a sufficiently short half-life that the radiation emissions are extinguished after a relatively short period of time, typically on the order o several days to a few months. Desi gning the thermal gel portion of the radiomedi ne thermal gel to have a resorption time that is similar to the time that the radiation emissions of the contained radioisotopes are extinguished (typically 10 half-li ves) provides therapeutic advantages, If the resorption time is too short, the radionuclides / therapeutic agents may be released into surrounding tissue and cause off-target tissue damage. If the resorption rate is too long, healing in the region previously containing the tumor may be inhibited. Elements such as ytrium and phosphorus which have radioisotopes having a half-lifegreater than about two days and less than about 30 days are typically chosen as the constituent elements which emit therapeutic radiation.
[0039] The radiomedicine thermal gels discussed above are thus designed to emit high energy beta particles and / or alpha particles and / or gamma rays that have a relatively short penetration depth in tissue. While tins is desired insofar as it optimizes tumor treatment while minimizing collateral tissue damage, it does pose a detection issue. Thus, it is advantageous to in certain instances introduce a second quanti ty of radioisotope characterized by emissions compatible with Single Photon Emission Computed Tomography (SPECT) r Positron Emission Tomography (PET) techniques that facilitate PET or SPECT imaging of the radiation distribution patterns in the patient and also aid in imaging of where the thermal gels deposit to ensure uniform deposition in and around the tumor site.
[0040] As wi th the treatment thermal gel, the composition of the imaging agent is selected such that the thermal gel emits a sufficient amount of positron emissions to facilitate PET imaging. In other words, the composition of the imaging agent is typically chosen so that its radiation may be tailored to deli ver a radiation profile that is well suited for a particular imaging technique. For instance, when desired for use with PE imaging, the imaging thermal gel will typically include a short-lived positron emitter, such as
[0041]
[0042] (half-life of 12.7 hours) orlsF (half¬ life of 110 minutes) or the like,64Cu and5SF are particularly attractive positron emitters, as they have short half-lives and emit low energy positrons that annihilate with electrons to produce two 511 keV gammas, which facilitates PET imaging. If longer-lived positron emiters are desired,S9Zr (half-life of 78.4 hours) or< 4I (half-life of 4.1 days) or the like may be selected.
[0043] fa most instances, it is desirable to use a thermogel incorporating both treatment radioisotopes and imaging radioisotopes, such as a positron emitter ( like64Cu) along with a beta and gamma emitter (likefeY) or a high-energy beta emitter (like
[0044]
[0045] such that the therapeutic treatment thermogel may themselves be directly imaged and tracked. In one such embodiment, a beta emitter and / or a low' energy gamma emitting nuclide is incorporated along with a positron emitter into the thermogel
[0046] The treatment and imaging thermogel is typically introduced into the patient's body via catheter, injection or the like, gelation rapidly occurs in vivo, and the gel becomes lodged in the cancerous or tumor bearing tissue. It is understood that before die gelling of tiethermogel is complete, the thermogel may fill voids- in tissue left by surgery or enter interstitial portions of the treated tissue. The treatment and imaging thermogel is typically introducedas a liquid medium of sufficient density and viscosity such that the thermogel remains liquid during the administration procedure and gels: rapidly upon introduction into the relati vely warm target tissue.
[0047] The thermal gel has a composition that becomes more: viscous when warmed to a higher temperature. Typically, thermal gel is more fluid at room temperatures and gels to become substantially more viscous, essentially behaving as a solid, at temperatures experienced in vivo. In one embodiment, a PLGA-g-PEG polymer was synthesized having a gelation onset temperature in phosphate buffered saline (PBS) of about 26" C. In one embodiment, the present novel techno logy relates to a method of preparing a radioactive insoluble particle suspension, in this example a radioactive yttrium particle suspension. Non-radioactive yttrium salts such as yttrium chloride, yttrium nitrate, yttrium sulfate, yttrium brom ide and combinations thereof are combined with a soluble salt of radioactive yttrium-90, the latter typically being prepared by chemical separation of90Y from its parent isotope strontium-90 (,’Sr). Non-radioactive yttrium is combined with radioactive9f,Y to provide sufficient mass to yield discrete insoluble yttrium particles due to the vanishingly small masses of9oY required to provide therapeutic doses of radiation.
[0048] The yttrium salts are put into solution and subsequently combined with a solution of soluble phosphates salt(s), such as sodium phosphate, lithium phosphate, potassium phosphate, and combinations thereof, and having a stoichiometric excess of phosphate. The resultant admixture is maintained at a pH in the range of 1.5 to 8. The solutions are agitated, typically with continuous stirring and also rapidly heated in a closed vessel to about 150 degrees Celsius and held for from about one to about ten hours to yield a greater than about 99.99% conversion of soluble ytri m to insoluble YPO4 as well as to achieve a desired particle size distribution, typically less than 2 microns in diameter, more typically in the range of 0.03 ran to 10 u, still more typically in the range of 0,05 um to 3 um, and yet more typically in the range of 0.1 um to 2 um with a median particle size of about 0.2 um. Through careful control of mixing time, temperature, and concentration of the reactants, a specific, desist’d pai tide size distribution and / or particle shape distribution of YPO4 particles suspended may be achieved. Likewise^ oncethe YPO4 particles are formed, the solution may be buffered with saline to achieve neutral pH suitable for direct injection into human or animal tissue.
[0049] Typically, the radioactive panicle suspension has a mean particle size of less than 2 uni. The radioactive particle suspension is typically characterized by at least 90 percent of the total particle volume having generally spherical particles in the range of 0.1 am to 2 tun Typically, the starting concentration of soluble yttrium in the combined solution is in the range of 0.05 to 1.0 niole / liter, more typically in the range of 0.05 to 0.3 mole / liter, and still more typically in the range of 0.08 to 0.3 mole / liter and the stoichiometric excess of phosphate ranges from 10% to 100%. More typically, the starting concentration of soluble yttrium in the combined solution is 0.08 mofes / liter and the stoichiometric excess of ph osphate is in the range of 5% to 100%, more typically about 10%, and still more typically about 25%,
[0050] In other embodiments, the radioactive metal cation is selected from members of the lanthanide series, such as Ce, Sm, Hb, Yb, Lu, and the like, and combinations thereof. In still other embodiments, the radioactive cation is selected from members of t he metals and transition metals, such as Ga, In, Sn, Pb, Ca, Y, Sc, and the like and combinations thereof to yield insoluble or sparingly soluble transition metal phosphate(s). In yet other embodiments, the radioactive cation is selected from members of the alkali metals / alkali earth metals, such as Cs, Ra, Ca, Sr, Ba, and the like and combinations thereof, although these may be combined with insoluble inorganic compounds such as zeolites, as their phosphates may not be sufficiently insoluble. In still other embodiments, the radioactive cation; is selected from members of the Actinide series, such as ”’"!Ac;and in yet other embodiments, the radioactive cation is selected from members of the metals, transition metals, alkali metals, alkali earth metals, the Lanthanides, the Actinides, and combinations thereof. In some embodiments; the radioactive cation is selected from the members of the group incl uding Y, La, Ce, Pr, Pm, Sm, Gd, Tb, Ho, Yb, Ce, Pb, Lu, Ac, Ca, S r, Ba, Ba, Cs, Cu, Tc, P, Sn, lie, Au, and combinations thereof, while the phosphate functional group may include one or more radioi sotopes of phosphorous, such as52P and3P (w ithiP being the stable isotope). In some cases, the functional group may include an iodide wherein the iodide is a radioisotope, such as!
[0051]
[0052] 25Li24I,525I, and / or combinations thereof.
[0053] In operation, the particle suspension is formed by preparing the particle precursor solution of cation (for example, yttrium) salt and sodium phosphate to define an admixture. Theadmixture is then mixed and heated to yield a plurality of ¥POq particles by controlled precipitation, The resulting YPCM particles are rinsed (typically multiple times, more typically three times) with a sterile phosphate buffered saline (PBS) solution and removing or adding PBS to achieve the final desired volume. The pH of the final solution is adjusted, such as by the addition of sodi um hydroxide or the like, and then any excess solution is remo ved or sterile PBS is added to achieve a final desired volume. The YPCri particles are then suspended in a phosphate buffered saline solution at neutral pH, suitable for injection in vivo into human or animal tissue.
[0054] The yttrium phosphate particles are radioactive so as to serve as distributed sources of therapeutic radiation for treating cancerous tumors and other diseases, such as by adding a predetermined amount of soluble radioactive0Y isotope to the particle precursor solution, that becomes homogeneously incorporated into the insoluble yttrium phosphate particle matrix, solubility of less than about IO‘Smole / liter, more typically less than 1O'~' Ksp. The amount of radioactive yttrium (or like cation) is typically from about 100 gCi to 300 mCi; the specific amount needed varies for each patient application, Typically, the yttrium phosphate particle suspension has YPCb panicle concentration in the range of 40 mg / ml to 125 mg / ml to facilitate imaging by x-ray computed tomography after being combined in a ratio of about 1 to 4 to 1 to 10 by volume with biocompatible hydrogel or other suitable liquid carrier solution for injection into human or animal tissue. Again, while the above example focuses on the yttrium cation, the technique may be adapted to accommodate others of the radioisotopes of interest.
[0055] It is well known in radiomedicine that certain types of cancerous tumors may be treated by the localized introduction of shortlived radioisotopes at the tumor site. One effective method of delivering such a radiation treatment is by introducing radioisotopes to the tumor site that emit, gamma or beta radiation at therapeutic levels and intensities and that are suspended or otherwise contained in a thermal gel matrix, the gel being a liquid at room temperature that forms a solid gel upon warming to internal body temperature. The
[0056]
[0057] or like radiotherapeutic radionuclide is typical ly introduced in the form of an insoluble stable oxide, phosphate, or the like, and suspended or dispersed in the thermal gel precursor, shortly before introduction into the patient’s system. Typically, the predetermined radiotherapy treatment element has a short half-life, so that the radiation treatment is relatively short in duration; more typically, the
[0058] Hpredetermined element is selected such that it emits relatively high energy beta particles and / or alpha particles and / or gamma rays. For example,WY has a half-life of 64 hours and emits beta particles with a mean energy of about 930 keV. This technique enjoys the advantage of using a thermally setting gel matrix prepared from stable, non-radioactive materials; the non~radioactive thermal gel may be safely stored for an indefinite period and combined with yttrium~90 or a like radiotherapy treatment element shortly before introduction into a patient’s body.
[0059] Other potential radioisotopes that may be introduced via the thermal gel matrix includeLCs,i25h12!Te,K‘5Pd,U7Sn, and the like, which emit an Auger x-ray upon decay, and beta or beta gamma emitters such as
[0060]
[0061] f> / Cu;U7e,l5,I,!; 7Lu,wRe,ls*Re, and the like. In operation,! JiCs,utI and / ori2;T and the like may be incorporated into the cage structure of a sodalite to yield an insoluble cesium sodalite compound, for example (such as via the hydrothermal synthes is of sodalite with Cs substituting for Na and / or 1 substituting for Cl in the crystal structure); likewise,Uw,Sn may be incorporated as an insoluble Sn apatite compound.
[0062] Still other potential radioisotopes that may be introduced via the thermal gel matrix include alpha-particle emitters such as2i2Pb5223Ra, ^Ac, their respective decay products, and the like. These materials tend to form insoluble or sparingly soluble phosphates, and are thus good candidates for the novel treatments and materials described herein.
[0063] In an embodiment of the disclosure, a radionuclide selected for incorporation into a radio-thermogel may be chosen on the basis of the energy of the radiation em itted by the radionuclide^ Lower energy emitters may be preferred for use when the radio-thermogel is placed in close proximity (about 2 mm, for example) to critical structures that may be damaged. In another embodiment, radionuclides that emit higher energy radiation may useful when placed farther from critical structures (greater than about 2 mm, for example). In another embodiment, a radio-thermogel may comprise both a beta-emitting radionuclide and a gamma-emitting radionuclide. In another embodiment, the radionuclide may be a beta- and gamma-emitter (for example, Lu~i77;Sn~ri7m).
[0064] The thermogels disclosed herein can be combined with a radioactive component with or without one or more therapeutic agents. Such gels can provide a timed-release of the therapeutic agent into surrounding tissue. The timed release of the therapeutic agent may be a result of biodegradation of the.gel.ot by diffusion of the therapeutic agent from the gel to thesurrounding tissue.
[0065] It is believed that hydrolysis of the of the thermal gel may be an important process in the resorption of thermal gels. To develop thermal gels that are capable of gelling after introduction into the tissue being treating and to be resorbed during a therapeutically effective time frame several approaches are possible, hlodification of the synthesis parameters of the thermal gelling polymer and / or modification of the ratios of the polymer backbone constituents (for example the ratios of lactide, glycolide, MPEG, and / br EPEG). It is also possible that mixing thermal gels with different polymeric backbones may provide thermal gel compositions that have gelling behaviors and resorption characteristics that are useful therapeutically. Batches of polymer were syn thesized or combined in order to narro w the condi ti ons necessary to obt ain a gelation temperature below normal body temperature and a hydrolysis rate after gelation consistent with the desired resorption rate. The reaction conditions, polymer composition from Nuclear Magnetic Resonance (NMR) analysis, and gelation properties from dynamic rheology and hydrolysis rates at 37r'C are summarised below
[0066] METHODS EQUIPMENT
[0067] Electric Heating Mantle (Vevor, Model 98-I-A. B-l 000; S / N 2312056090270049)
[0068] Digital Heating Mantle (USA Labs, Model HMSC: 1000ML; S / N 2023010084):
[0069] Freeze drier (HarvestRight)
[0070] Thermo Genesys 150 LTV- Vis spectrophotometer
[0071] Nuclear Magnetic Resonance Spec (NMReady 60e, 60 MHz, N analysis)
[0072] Waters Breeze GPC system (model 1515 isocratic pump, model 2707 autosampler, model 2414 Refractive Index (Rl) detector)
[0073] Rotary evaporator (Scilogex RE 100-Pro)
[0074] Analytical balance (Ohaus + / - 0.1 mg)
[0075] Digital magnetic stirring reactor (Fisher Scientific* Isotemp* Digital St in mg Hotplate, 11-301% 49SHP)
[0076] Refrigerated Circulator (Thermoscientific RTE-7, fill with 50:50 mixture of dei onized water and commercial antifreeze)
[0077] Distillation head (Chemglass, 24 / 40 fittings)Condenser (Chemglass, 24 / 40 fittings, --20 cm long)
[0078] Vacuum distillation adapter (Chemglass, 24 / 40 with barb fiting for tube}
[0079] Inert gas / vacuum ma ifold (Chemglass. barbed)
[0080] Overhead Stirrer (Southwest Science)
[0081] Orbi tal titer plate shaker ( x 4
[0082] Reverse-osmosis water purifier (Cascade Model MK2)
[0083] Deionized water purifier (Easypure II system, Thermoscientific model #07035)
[0084] Orbital agitating incubator (Southwest Science)
[0085] CHARACTERIZATION METHODS
[0086] UV-Vis
[0087] A sample was scanned against a. deionized water (DM20) blank by UV-Vis spectrophotometer ( I’hennofisher, Genesys 150) in the range of 19O-90On. Spectra were collected in Absorbance mode.
[0088] Gel-Permeation Chromatography External Standaid (GPC-ES)
[0089] Samples were analyzed usingGPC against polystyrene standards (external standard). The GPC system consisted of Waters 1515 Isocratic HPLC- pump connected to Wa ters 2707 Autosampler and Waters 2414 Refractive Index Detector. Detector and columns held at 35°C. GPC analysis performed by injecting lOOgL of - 2.0 mg per mL polymer solution dissolved in 2.0 pm filtered tetrahydroforan (THE). A run time of 60 minutes was set with the flow rate of 1ml THF / min, and separation performed by a seri es of three GPC columns. The first column the samples passed through is a Phenomenex column Phenogel 5p 50A 300 x 7.8 mm, the second is Phenomenex column Phenoget 5 1OE4A 300 x7;8, and the last one is Aglient Resipore 300 x 7.5 m 3pm column. These samples were tested against Agilent Technologies EasiCa! PS2 polystyrene standards. These standards were prepared according to manufacturer instructions using 0.2 pm filtered THE Empower software was utilized to calculate number average (Mn) and weight average (Mw) molecular weight as well as pol dispersity index.
[0090] NMRSamples (5 - 10 mg) were dissolved in 0.8 ml of deuterated chloroform (silver foil stabil ized, Aldrich Cat# 416754).
[0091] Processing was performed using ACDLabs Specials. Peaks were selected and integrated to identify peaks at 3.4 ppm (methyl -CH3, 3H)}-3.5 ~ 3.6 ppm (ethylene glycol CH2CH20, 4H), - 4.7-4.0 ppm (glycolide CH2-00, 2H), and 5.1 A3 ppm (lactide CHCH3- (' O, III) and terminal peak (< 'H3-C (,b at 42 ppm which concsponds to the last monomer in the chain though may be either lactide or glyeolide. Notably additional polymer peak was observed at — 1.5-2,0 ppm (lactide CHCH3-G:::O, 3 B) though this was only used for establishing purity (% assigned peaks / total integration). For analysis, the peak integration at 3.4 ppm was fixed as equivalent to 3 hydrogens and each subsequent peak integration was normalized against this to obtain the relative molar ratios of lactide, glycolide, and ethylene glycol. The ratio of glycolide was set to “1” and the ratio of lactide and ethylene glycol was calculated respective w this ratio for composition ratio calculation.
[0092] Gelation, tip-test
[0093] 0.5 L thermogel solution was pipetted into an NMR tube. The tube was submerged into a 'i ’C water bath until gelation occurred. Gelation time was established by pulling the tube from the bath every 10 seconds and conducting a tip test; it was said that gelation had occurred when the hydrogel did not fall or run when the tube -was inverted.
[0094] Rheology
[0095] Samples were tested for gelation by Rheology. Rheology was performed on AR2000 (TA instruments) with 60mm 2 degree cone on a polymer dissolved in phosphate buffered saline (PBS) with stirring at 4°C. Viscosity of the solution at 0.1 (sec*’) and 5°C was measured (1 minute peak hold 5 second test intervals). Rheology was performed by oscillating at constant 6.283 rad / s, 0.1 % strain, in increments of 1 °C ranging from
[0096]
[0097] with 1 minute of temperature equilibration at each point. The resultant GVG" was plotted against temperature. An increase in G and G” with or without accompanying crossover of G’ / G” was taken to indicate onset of gelation with maximum achieved G’ and G” (Pa) noted along with the respective temperature at which this maximum value occurred.EXAMPLE 1. PLGA-G-PEG (LA G 50:50)
[0098] 150 mL anhydrous toluene (TOL) was measured into a 150 L volumetric flask using the following procedure: the flask was sealed with a rubber septum and vacuum purged using an.18G needle attached to a rubber hose When negative pressure was achieved, the needle was removed. One end of a 24 inch double sided 20G cannula needle was inserted through the septa-seal all the way to the bottom of a bottle of anhydrous toluene (Acros cat# 36441-0010), The other end of the cannula was Inserted into the rubber septum of the volumetric flask. Argon was pumped into the bottle of toluene using the 18G needle attached to the rubber hose, causing the toluene to be transferred into the flask without coming into contact with air or moisture. The flask was filled to the 150 mL mark.
[0099] An acetone rinsed, W0°C dried, desiccator cooled 4 ieck lOOOmL RBF with magnetic stirbar was tared. 38.7 g EPEG (Aldrich eat#475696) was slowly pipetted in. The RBF was fared again. 4.5 g mPEG 750 (Acros cat# 192325000) was added into the RBF. Added 150 ml toluene to the flask.. An argon hose was connected to a stopcock attached to the side neck of the RBF and argon was gently pushed through the system (~40ec / ni ) while a vacuum distillation apparatus was assembled. A distillation head was connected to the center neck, rhe condenser temperature on a coolant-recirculator was set to - 10 C. A 500 mL 1 -neck RBF along with a condenser drip-tip plus barbed side arm was attached to the end of the condenser head. The heating mantle's probe was pushed through a thermometer adapter and atached to a side neck in the RBF so that the tip of the probe was submerged in the PEG TOL solution. The last neck was closed with a glass stopper. All atachments were secured with keck clips. The argon line was removed from the stopcock and attached to the barb on the driptip adapter; the stopcock was left open to vent argon. The argon was turned off and the stopcock was closed. Vacuum was applied through the hose atached to the drip-tip adapter. The PEG / TOL solution was set to stir -200 RPM. 'The mantle heal was set to 50<!C. In this manner, the PEGs were vacuum distilled until the toluene appeared to be gone (-4 hour), Afterward, the heat was turned ofl'and the system was allowed to cool to room temperature under continuous vacuum. Once cooled, the system was backflushed with argon. Once pressure inside the system had equalized, the stopcock was opened to facilitate ventilation. Under continuous (-100 cc / min) argon flow, the distillation assembly was removed, keeping the stopcock in the side. neck. Argon flow wasslowed to -25cc / min. Through a funnel in the center neck, added 3 i.46 g D, L-Lactide (Ortec) and 25.31 g Glycolide (Ortec). A syringe was used to add in 6.45 ml. 10% SnOct / TQL (w: v solution. The argon was turned off. The reaction flask was vacuum purged for - 1 hour followed by argon backflush. Through a funnel in the center neck, added 150 ml. anhydrous toluene (drawn from the bottle in the same manner as before). A 9” glass Pasteur pipette was pushed through a thermometer adapter that was installed in the sidemeek, replacing the stopcock, so that the tip of the pipette penetrated to -1.5 inches below the surface of the reaction solution. A reflux condenser topped with a dry-trap was atached to the center neck. Coolant was circulated through the condenser at - KFC. A slow flow of argon was pumped through the pipette (-50 cc / min) with stirring for -20 minutes. The Pasteur pipette.' dapter were removed and replaced with the stopcock. Argon was pumped irt through the stopcock at -20cc / min. The mantle temperature was set to 1140C and stirring was set to a speed which produced a vortex with a visibly deep core and strong movement around the outer edges. Argon was allowed to continue flowing for another hour and then turned off. The reaction was allowed to continue for 24 hours. After 24 hours, the heat was turned off.
[0100] The reaction solution was evaporated under reduced pressure on a rotary evaporator until all toluene appeared to be gone. About 300mL of acetone was added to the reaction flask and placed on room temperature orbital shaker until the material had dissolved. The solution was passed through a qualitati ve filter (Whatman) to remove any insoluble portions, then passed through a 1,2um nylon membrane filter, followed by a O. Sum nylon membrane filter, and finally a 0.45um nylon membrane filter using vacuum filtration. The filtered solution was poured directly into 2L stirring hexane, the resulting solid was collected and then dried under vacuum at 55°C.
[0101] Characierization
[0102] NMR Analysis
[0103] Mnlar contrsbunon ( Methoxy 1 )
[0104] Relative ratio. Target LA: GA,.,., Terminal
[0105] LA GA EG., •, (I X GA Ki)P“>'
[0106] (relative)
[0107]
[0108] 50:50 57 | 56 | 1 10 | 22 1.0: 1: 2.0 | 95% By GPC the Mn was determined to be 2089. the Mw was determined to be 4525,and the polydisjpersity index was determined to be 2.1.7. HNMR was performed and the ratio of components was determined as 1.0:1.0:2.0 (GA: LA EG).
[0109] The polymer was dissolved in water at a concentration of 30% w / v and tested by thermal rheology. The viscosity at 5°C was 0.04460 Pa.s. The Gelation Onset ternperawe was found to be 38.4(,C with a maximum G' of 0.9888 Pa occurring at 44°C and a maximum G” of 2.083 Pa occurring at 43°C.
[0110] EXAMPLE 2. PLGA-G-PEG (LA: GA 65:35)
[0111] Ihe same procedure as described in EXAMPLE 1 was followed with the following amounts of each monomer:
[0112] 38:69g EPEG, 4.5 ig m PEG 750, 39.61g D, L-Lactide, and 17.16g Glycolide. Characterization
[0113] Target EA: GA Molar contribution (Methoxy - 1 ) | Relative ratio Purity LA [ GA EG Terminal 1 (LA: GA: EG)
[0114] (relative)
[0115]
[0116] 65: 35 74 [ 42 116 1 8 ' 1 ^ 7 95%
[0117] By GPC the Mn was determined to be 2255 Da, the Mw was- determined tobe 4800 Da, and the polydispersrty index was determined to be 2.03. HNMR was performed and the ratio of components was determined as 1.0:1.8:2.7 (GA: LA: EG).
[0118] The polymer was dissolved in water at a concentration of 30% w / v and tested by thermal rheology. The viscosity af 5*’C was 0.09056 Pa.s. The Gelation Onset temperature was found to be 30.2*0 with a maximum G’ of 19.21 Pa occurring at 34°C and a maximum G” of 38.50 Pa occurring at 34**0
[0119] EXAMPLE 3. PLGA-G-PEG (LA: GA 75:25)
[0120] The same procedure as described in EXAMPLE I was followed with the fol lowing amounts of each monomer:
[0121] 38.70g EPEG, 4.51g mPEG 750, 45.1 g D-L-Lactide, and I E60g Glyeolide. Characterization
[0122] Target LA: GA Molar contribution (Methoxy ~ 1 ) Relative ratio Purity LA | GA | EG I Tenni nal,(LA: GA: EG) i (relative)
[0123]
[0124] Target 7S:?5 84 | 29 i 107 1 20 2-9: 1 3.7 9-4% jBy GPC the Mn was determined to be 1887 Da, the Mw was determined to be 3828 Da, and the polydispersity index was determined to be 2.03. HNMR was performed and the ratio of components was determined as L0:2,9:3,7 (GA: LA: EG ).
[0125] The polymer was dissolved in water at a concentration of 30% w / v and tested by thermal rheology. The viscosity at 5°C was 0.7123 Pa.s. The Onset temperature was found to be 33°C with a maximum G’ of 6.556 Pa occurring at 36°C and a maximum G;of 17.66 Pa occurring at 36<:‘C.
[0126] EXAMPLE 4. PLGA-G-PEG (LA: GA 85:1 )
[0127] The same procedure asdescribed in EXAMPLE 1 was followed with the following amounts of each monomer:
[0128] 38.69g EPEG, 4.5 Ig mPEG 750, 49,76g D, L-Lactide, arid 7.02g Glycolide Characterization
[0129] Target LA; GA Molar contribution (Methoxy - 1) Relative ratio Purity LA GA EG Terminal (LA: GA: EG)
[0130] (relative)
[0131]
[0132] 85:15) 98 >9 114 19 4,0; 1: 4,7 94° >
[0133] By GPC the Mn was determined to be 1972 Da, the Mw was determined to be 3831 Da, and the polydispersity index was determined to be 1.94. HNMR was performed and the ratio of components was determined as 1. O'4, O:4.7 (GA: LA: EG).
[0134] The polymer was dissolved in water at a concentration of 30% w / v and tested by thermal rheology. The viscosity at 5<?C was 0.04930 Pa.s. The Gelation Onset temperature was found to be 35,0°C with a maximum G’ of 4.258 Pa occurring at 38°C and a maximum G'5of 13.08 Pa occurring at 38!’C.
[0135] EXAMPLE.5. PLA-G-PEG(LA; GA 100:0)
[0136] The same procedure as described in EXAMPLE 1 was followed with the following amounts of each monomer:
[0137] 38.70g EPEG, 4,50g mPEG 750, and 59.10 g D, L-Lactide
[0138] Characterization
[0139] Target LA: G A
[0140]
[0141] *] [Purity
[0142]
[0143] LA: GA EG! Terminal Relative ratio
[0144] (relative) (LA: GA: EG)
[0145]
[0146] 100:0 69 NA 76 NA. NA 94% |
[0147] By GPC the Mn was determined io be 2109 Da, the Mw was determined to be 4369 Da, and the polydispersity index was determined to be 2.07.
[0148] The polymer was dissolved in water at a concentration of 30% w / v and tested by thermal rheology. The viscosity at 5°C was 0.04304 Pa.s. The Gelation Onset temperature was found to be 3O.9°C with a maximum G’ of 1.576 Pa occurring at 42(,C and a maximum G” of
[0149] 1.819 Pa. occurring at 39!’C.
[0150] EXAMPLE 6. MIXTURE COMPOSITION
[0151] A mixture of 75:25 LA: GA and 60:40 LA: GA was physically combined in aqueous solution and tested by rheology
[0152] Sample 1 Concentration Viscosity YiscnSltv 7 Gelation Ma x G’ Max. G ” Gelation in PBS -3120%% Onset time temperature (from tip test) 1 Hydrogel 1 25% (w:v) 0.02236 0.03988 28. UC 10, 69 Pa 20 1-1 Pa 20 blend: equal Pa s Pa.s G IT) (32X’) seconds parts of 30% (w;v) 0.03266 O. O23S3 2K 7 C 12.55 Pa 2391 Pa i 15 (75:25) and Pa.s: Pa.s (32’ C) G2A') seconds (60:40) 35% (w:v) 0.03598 0.01790 29.2°C 14.92 Pa 28 M Pa 10
[0153]
[0154] 1 hydrogels | Pa s Pa,s (32'0 (33' 0 seconds RESORPTION STUDY
[0155] Method
[0156] Hydrogel solutions were prepared from the PLGA-g-PEG polymers at concentrations of "22%, 25%, and 30% (w:v).
[0157] Samples of each -sol utiou were prepared in triplicate as follows: 'Hie botom tip of each dialysis cone (Pur-A-Lyzer Maxi 3500; Sigma-Aldrich cat no PURX35050; lot X0320I3) was cut off. An analytical balance was used to measure the massbf each cartridge. 2ml.. of the i ndicated hydrogels were pipetted into the cartridges, and then the mass of each cartridge / hydrogel was measured. The mass of each empty cartridge was subtracted from the mass of the cartridge / hydrogel in order to determine the mass of the hydrogel. The mass of the hydrogel was multiplied by the actual concentration of the respective hydrogel in order todetermine the beginning mass of polymer in each cartridge. The cartridges were dropped into 50mL centrifuge tubes (Falcon) and then 40 ruL of 37®C DIH2O (measured using a graduated cylinder) was added to each tube. The tubes were placed into 37 ' incubator (no shaking) until gelled (approximately 30 minutes) and then rotation in the incubator was set to 80RPM, At the designated time points, one tube at a time, the cartridges were removed from the tubes and then set aside while the tubes were re-capped and vortexed at high speed for -5 seconds. 5 mL of the liquid from each tube was pipetted into a pre-tared A oz jar (U-Line) and capped loosely; the rest of the liquid was decanted into waste. The cartridges were placed back into the Falcon tubes and 40mL of fresh 37°C DM20 was added. The tubes Were replaced in the incubator with 80 RPM shaking until the next measurement. The jars were lyophilized and then measured on the same analytical balance that was used to measure their tare-mass. The d Ierence between the tare mass and the mass of the lyophi lized jars was multi lied by 8 in order to calculate the mass of polymer that, had eluted (resorbed). The average mass eluted was divided by the average beginning mass for each sample in order to calculate the percent eluted (resorbed). Following the same method, repeated measurements were made at the specified time intervals for a total of 8 weeks. At the end of the 8 weeks, the dialysis cartridges were lyophilized and then measured on an analytical balance in order to obtain the final mass of polymer within each cartridge.
[0158] RESULTS ITe resultant biodegradation / resorption rate was determined gravimeirically Data from weekly media draws: PLGA-g-PEG (IzG 65:35)
[0159] L: G 65:35 22% L: G 65:3525% L; G 65:3530% lumai
[0160] 0,4480g 0,4992g 0.6051g mass
[0161] Cumulative. Cumulative Cmmdative Average mass Average %. Average mass Average % Average mass Average % eluted (g) eluted eluted (g) eluted eluted (g) eluted I day 0,0672 ±0,006 15,00% 6,0533 ±0.041 l6.68% 0.0835 ±0.015 13,79% 3 days 0,0205 ±0.019 19.58% 0.0371 ±0,005 18,11% 0.0341 ±0,024 19.43% 7 days 0.0320 ±0.024 203% 0,0285 ±0.006 23.82% 0.0235 ±0.005 23.31% 10 days 0.0075 ±0.004 28.39% 0.0016 ±0.001 24.15% 0.0123 ±0.005 25.34%
[0162]
[0163] 14 days 0.0080 ±0,006 30 18% 0,0037 *0:006 24.89% 0.0117 ±0.006 27,2:8% 21 days 00117 -10.005 32 80“., 0.0075.-±1.002 26.39% 0.0149 ±0.007 29.75% 28 days 0.0229 ±0,004 37.92% (K0389 ±0.003 34.19% 0,0437 ±0.002 36,97% 35 days 0.0603 ±9,004 51.37% 0.0555 ±0.010 45.30% 0.0757 *0:004 49.49% 42 days 0.0523 ±11.001 63.04% 0.0555 ±0,005 56.41% 0,0603 ±0,005 59.45% 49 days 0.0235 ±0.016 68.27% 0.0499 ±0.004 66.40% 0,0645 ±0.006 70.12% 56 days 0.0261 ±0,002 74.11% 0,0320 ±0.004 72.81% 0,9373 ±0.002 76,28%
[0164]
[0165] Data from weekly media draws: PLGA-g-PEG (L; G 75:25):
[0166] i. / 'G 75:2522%: L: G: 75:25 25% L: G 75:2539% initial
[0167] 0,4438g 0.5000g 0.5997g mass
[0168] Cumulative Cumulative Ctmiulalwe Average mass Average %. Average xiittss Average % zkyerage mass Average % elated (g) eluted eluted (gj ehited ehited (g) ehited 1 day 0,0501 ±0.004 11.30% 0.0325 ±0.017 6,51 % 9.9349 ±0.027 5.83% 3 days 0,0195 ±0.008 15.68% 0,0128 ±0.007 9,07% 9;0101 ±0.909 7.51% 7 days O^192”~±(k002~” o’om ■■■"7152%:%G14F’ ±0’006”'’
[0169] 10 days 0.0043 ±0.006 20,97% 0.0083 ±0.004 13.17%.1.0043 ±0.904 10.58% 14 days 0,0035 ±0.007 21.75% 00072 ±0.002 14,61% 11.0069 ±0,007 11.74% 21 days 0.0069 ±0.005 23.31% 0.0179 ±9.004 18.19%.1.0653 ±0,031 22.63% 28 days 0.0099 ±0:093 25 54% 0.0408 ±0.016 26,35% 0,0552 ±0,017 31.84%, 35 days 0.0376 ±0.007 34.01% 0:0507 ±0.006 36.48%.1,0701 ±0,006 4.153% 42 days 0.0685 ±0.003 49.45% 0.0864 ±0.001 53.76% 0,0939 ±0.009 59.19%, 49 days 0.0456 ±0.003 59.73% 0.0560 Hi. OOU 64.96% 0,0579 ±0.007 68.83% 56 days 0.0467 ±0004 70.24% 90581 ±(1.001 76.59'G 0.0547 ±tj.005 77.95%
[0170]
[0171] Data from weekly media draws PL -g-PEG (L: G 85:15):L-G^:.1522% L: G 85:1525% L: G 85:1530% Initial
[0172] 0,4385g 0,4846g 0,5981 g
[0173] mass
[0174] Cumulative Cumulative Cumulative Average mass Average % Average mass Average; % / Average mass Average % eluted (g) dated eluted, (g) eluted eluted (g) eluted 1 day 6.6866 iO. OH 18.24% 70661 ±6.004 13.65% 00600 ±6.613 W03% 3 days 0.0221 = 0.009 23.29% ±•0099 ±0.008 15.68% 0.0099 ±0.007 11.68% 7 days 0.0144 ±0.001 26.58% 10096 ±0.011 17.66% 00157 ±0005 14.31%: 10 days 0.0067 ±0.002 28 10% 10075 ±0.003 19.20% 00053 ±0005 15.20% 14 days 0.0027 ±0.004 28.70% 3.0051 ±0.005 20.25% 00077 ±0.005 16.50% 21 days 1)0013 ±0.001 29.01% ±0019 ±0002 20.64% 0.0056 ±0003 17.43% 28 days 0.0013 ±0.002 2931% 30024 ±0002 21.13% 0.0088 ±0913 1.8.90% 35 days O OOW H) IMI >9 74% 10075 ±0009 2207% 0.0280 +0027 23.59% 42 days 0.0003 ±0.000 29,80% 90352 ±0051 29.94% 0.0776 ±0036 36.5633 49 days 0.0021 ±0002 30.29% 90372 ±0032 3701% 0.0712 ±6034 48.46% 56 days 0.0080 ±0.00.2 32.11% 0.0.37.1 ±0.011 45.26% 0.0712 ±0009 60.37%
[0175]
[0176] Total mass lost, as calculated by measuring the mass of polymer remaining In the cartridge at the end of the 8-week study.
[0177] Sample / emiceutrat ^initial mass of I final mass of
[0178] ion polymer polymer Total mass tost Total percent lost | 22% 04480g ± 00026g 00304g ± 00013g 0.416g ± 0.0019g 93.21% ±0.25% Z < <) / j _ 1 _ _ _ ™™™i _ _ _ _
[0179] . I 25% 1 0.4992g ± 00049g! 00312g ± 00066a 0.4680g ± 00044g 93.75% ± 1.272'1. lactide j | » ® | ~
[0180] 1 30% 00051g ± 00082g 0.0454g± 00034g 0.5597g ± 0.0061g 92.51% ±0.4936.,i [,,
[0181] i 22'6% 0.4438g? O 0033v 1 00713g -x tH)()64s u.3725g ± dOt)32g 83.95'% ± 1.32% _ _ i. — (
[0182] f"?', 1 25% i 0.5000g ± 00075a | 0.0500g ± 00439g 0.4499g ± 00462g 89.97% ± 8.77% lactide j | |
[0183] | 30% 0.5997g ± 00018g 00754g ± 00095g 0.5242g ± 00109g 87.42% ± 1,61% | 22% | 0.4385g ± 00039g | 0.2569g ± 0.0051g 04816 g ± 6.0076g 41,40% ± 1,37%
[0184]
[0185] >5%
[0186] 85% 0.4846g 1 0,6305g 0.2875g r (i 016Og ti ling; 0 f )4?8g 40.41 % ± 6.53% lactide 30% (> 5981 g. t 0.< H»33g 0.3226g x 0,0163g U.2755g.>■ 0 1 > 166g 46.07% ± 2.74%
[0187]
[0188] Resoprtion Test NMR
[0189] Example NMR properties of eluted materials for PLGA-g-PEG (LAiG 75:25) as calculated from NMR
[0190] Sample Molar contribution (Methoxy ~ 1) Relative ratio
[0191] LA GA EG Terminal (I, A: GA: EG)
[0192] (relative)
[0193] 2 hours 3 1 52 8 5, 1; 1: 93,7
[0194] 1 day 9 2 124 16 4.5: 1: 64.8
[0195] 2 days 17 5 1 16 18 3.5; 1: 23 X
[0196] 3-7 days 29 8 83 2 3.8: 1; 10.7
[0197] 8 days 48 13 83 36 3 6; 1; 6.4
[0198] 9 day s 22 6 31 12 3.4 ■ 1 ■ 4.9
[0199] 10 days 34 1 1 48 19 3 1: 1 - 4.4
[0200] 1 1 days 24 7 32 13 3.3: 1: 4.3
[0201] 12-14 days. 1*. n 49. 23. 3.5; I: 4.5
[0202] 15 days 12 4 17 8 3.4: 1; 4.6
[0203] 16 days 44 12 61 30 3.6; 1; 5.0
[0204] 17 days! O 6 2h 16 3 2 • i 4 <;
[0205] 18 days 15 4 j S _ _ 1 1 _ ) 3 4 1 4 0
[0206] 19-21 days 44 13 42 26 3 5 1 3 4
[0207] “ndays 22 6 30 14 3.4; 1; 4.6
[0208] 23 days 30:T:30 17 3.6: 1: 3.6
[0209] 24 days 2 i: 7 19 12 3 1: 1: 2.8
[0210] 25 days 21 7 19 12 3.1: 1: 2.8
[0211] 26-28 days 25:7 43 17 3.4: 1: 5,8
[0212] 29 days 27 8 38 16 3.2: 1: 4.5
[0213] 30 days 29 9, 33 16: 3.2: 1: 3.7
[0214] 31-37 days 51 14 49 37 3.6; 1: 3.4
[0215] 38-43 days 38 H 74 38 3.4; 1; 6.8
[0216] 44-51 days 45 14 78 313 3.3: 1: 5.6
[0217]
[0218] 52-58 days m L. 32 83 263 3.8; 1: 2.6
[0219] The NMR results, although varied in composition, were consistent with the resultant released materials being lactic acid, glycolic acid, poly(etliylene glycol) and various compositions of oligomers of said compounds. Thi s may indica te bioeompatibility of theresorption by-products as all these components are well tolerated by the human body.
[0220] Several non-limiting embodiments of the disclosure are described in the following clauses.
[0221] 1. A biodegradable thermogel suspension that forms a gel at a temperature of about 20°C to about 40ftC comprising:
[0222] one or more PLG A-g-PEG polymers, which are synthesized under conditions substantially free of water molecules and oxygen molecules, then dissolved in an aqueous buffer solution;
[0223] wherein the molar ratio of lactate monomer ( LA) to glyeolate monomer (GA) in the one or more PEG A-g-PEG polymers is individually from about 65:35 to about 85: 15; and wherein the biodegradable thermogel biodegrades with a half-life of from about 1 day to about 365 days or about TO to about 50 days.
[0224] 2. 'Hie biodegradable thermogel of clause I. wherein the biodegradable thermogel comprises a single PLGA-g-PEG polymer.
[0225] 3. The biodegradable thermogel of clause I or 2, wherein the molar ratio of LA: GA.is about. 65:35.
[0226] 4. The biodegradable thermogel of clause 1 or 2, wherein the molar ratio of I.. A: GA is about 75:25.
[0227] 5. The biodegradable thermogel of clause 1 or 2, wherein the molar ratio of LA: G is about 85: 15.
[0228] 6. The biodegradable thernrogel of any one of the preceding biodegradable thermogel clauses, wherein the ratio of EPEG+mPEG toPLGA in the one or more PLGA-g-PEG polymers is individually from 1:99 to 99 1 or about 1:1 to about 1:2.
[0229] 7. The biodegradable thermogel of any one of the prec eding biodegradable thermogel clauses wherein, the ratio of mPEG to EPEG in the one or more PLGA-g-PEG polymers is individually from 1:99 to 99: 1, or about 1:8 to about 1:10
[0230] 8; The biodegradable thermogel suspension of any one of the preceding biodegradable thermogel clauses, wherein the one or more PLGA-g-PEG polymers have a weight average molecule weight (Mw) of about 100 Da to about 10,000 Da or about 500 Da to about 8000 Da, or about 1000 Da to about 7000, or about 1500 Da to about 5000 Da,9. The biodegradable thermog l suspension of any one of the preceding biodegradable thennogel clauses, wherein the one or more PLGA-g-PEG polymers independently have a number average molecule weight ( n) of about 100 Da to about 10,000 Da or about 500 Da to about 8000 Da, or about 1000 Da to about 7000, or about 1500 Da to about 5000 Da.
[0231] 10. The biodegradable thermogel suspension of any one of the preced ing biodegradable thermogel clauses, wherein the weight of the one or more PEG A-g~PEG polymers is in the range of about 15 t% to about 40 wt% or about 20 wi% to about 35 wt% in aqueous buffer solution.
[0232] 11. The biodegradable thermogel suspension of any one of the preceding biodegradable thermogel clauses, wherein the thermogel suspension has a pH between 1.5 and 8.0.
[0233] 12. A biodegradable radioactive thermogel suspension that forms a gel at a temperature of about 209C to about 40°-C comprising:
[0234] one or more PLGA-g-PEG polymers, which are synthesized under conditions substantially free of water molecules and oxygen molecules., then dissolved in an aqueous buffer solution;
[0235] wherein the molar ratio of lactate monomer to glycolate rnonomer in the one or more PLGA-g-PEG polymers is individually from about 65:35 to about 85: 15; and
[0236] a plurality of chemically isolated radioacti ve particles suspended in the thermogel, wherein each chemically isolated radioactive particle includes a cation and a functional group;
[0237] wherein the plurality of chemically isolated radioactive particles are betw een 0.03 pm and 10 gm in diameter;
[0238] wherein the chemically isolated radioactive particles have water solubility of less than 1 x ILL'1mole' liter; and
[0239] wherein the biodegradable radioactive thermogel biodegrades with a half-life of from about 1 day to about 365 days or about 10 to about 50 days.
[0240] 13. The biodegradable radioactive thermogel suspension of clause 12, wherein the biodegradable radioactive thermogel comprises a single PLGA-g-PEG polymer.
[0241] 14. The biodegradable radioactive thermogel of clause 1 or 2, wherein the.molar ratio of LA: GA is about 65:35.
[0242] 15. The biodegradable radioactive thermogel of clause 1 or 2, wherein the molar ratio of LA: GA is about 75:25.
[0243] 16. The biodegradable radioacti ve thermogel of clause I or 2, wherein the: molar ratio of LAr A is about 85:15.
[0244] 17. The biodegradable radioactive thermogel of any one of the preceding biodegradable radioactive thermogel clauses wherein the ratio of EPEGHnPEG to PLGA the one or more PLGA g-PEG polymers is individually from 1;99 to 99; 1 or from about 1: 1 to about 1:2.
[0245] 18. The biodegradable radioactive thermogel of any one of the preceding biodegradable radioacti ve thermogel clauses, wherein, the ratio of tnPEG to EPEG in the one or more PLGA-g-PEG polymers is individually from 1:99 to 99:1.
[0246] 19. The biodegradable radioacti ve thermogel suspension of any one of the preceding clauses wherein the one or more polymers have a weight average molecule weight (Mvv) of about 100 Da to about 10,000 Da or about 500 Da to about 8000 Da, or about 1000 Da to about 7000, or about 1500 Da to about 5000 Da,
[0247] 20. The biodegradable radi oactive thermogel suspension of any one of the preceding biodegradable radioactive thermogel clauses, wherein the one or more polymers have a number average molecule weight I Mn) of aboutl 00 Da to about 10,000 Da or about 500 Da to about 8000 Da, or about 1000 Da to about 7000, or about 1500 Da to about 5000 Da.
[0248] 1. The biodegradable radi oactive thermogel suspension of any one of the preceding biodegradable radioactive thermogel clauses, wherein the radioactive particles are combined with the thermogel to yield a final concentration of thennogelliug polymer in the range of about 15 wt% to 40 t% in aqueous buffer solution.
[0249] 22. The biodegradable radioactive thermogel suspension of any one of the preceding biodegradable radioactive thermogel clauses, wherein the biodegradable radioactive thennogel suspension has a pH between 1.5 and 8.0.
[0250] 23. The biodegradab le radioactive thermogel suspension of any one of the preceding biodegradable radioactive thermogel clauses wherein the cation is selected from the group consisting of Y, La, Ce, Pt; Pm, Sm, Gd, Tb Ho, Yb, Cs, Pb, Lu, Ac, Cd, Sr, Ba, Ra, Cu,Tc, Pd, Sft, Re, Au. and combinations thereof; an wherein the functional group includes phosphorous isotopes selected from the group consisting of ^P, '2P, ’’P, and combinations thereof.
[0251] 24. The biodegradable radioacti ve thermogel suspension of any one of the preceding biodegradable radioactive thermogel clauses, wherein the cation is selected from the group consisting of Y, Ho, Yb, Ce, Pb, Pd, Cs, Ac, Sm, Lu, Sc, €a, Sr, Ba, and combinations thereof
[0252] 25. The biodegradable radioactive thermogel suspension of any one of the preceding biodegradable radioactive thermogel clauses, wherein the functional group includes isotopes selected from the group consisting ofjSP,..32P, ^
[0253]
[0254] P,12T,!241,!25I, and combinations thereof,
[0255] 26. The biodegradabl e radioactive thermogel suspension of any one of the preceding biodegradable radioactive thermogel clauses, wherein the cation is
[0256]
[0257] and the functional group is a phosphate, wherein the phosphorus of the phosphate inc ludes one or more isotopes selected from the group consisting of3!P,42P, and;;P.
[0258] 27. The biodegradable radioactive thermogel suspension of c lause 26, wherein the phosphorus of the phosphate is
[0259]
[0260] at its natural abundance.
[0261] 28. The biodegradable radioactive thermogel suspension of any one of the preceding biodegradable radioactive thermogel clauses, wherein the chemically isolated radioactive particle concentration is in the range of 3 mg / inl to 100 mg / ml.
[0262] 29. The biodegradable radi oactive thermogel suspension of any one of the preceding biodegradable radioactive thermogel clauses, wherein the chemically isolated radioactive particles provide a dosage of between 30 aCi and 300 mCi.
[0263] 30. The biodegradable radioactive fhermoge I suspension of any one of the preceding biodegradable radioactive thermogel clauses wherein the functional group is selected from the group consisting of apatite, sodalite, iodide, hydride, and combinations thereof
[0264] 3.1, The biodegradable radioacti ve thermogel of any one of the preceding biodegradable radioactive thermogel clauses, wherein the radioactive particles emit radiation with an energy of about 0.01 MeV to about 6 MeV
[0265] 32. The biodegradable radi oactive thermogel of any one of the precedingbiodegradable radioactive thermogel clauses, wherein the radioactive particles emit beta radiation and gamma radiation.
[0266] 33. Hie biodegradable radioactive thennogel of any one of the preceding biodegradable radioactive thermogel clauses, wherein the gelled biodegradable Radioactive thermogel biodegrades with a half-life of biodegradation of about the same as the half-life of the radioactive particles.
[0267] 34. The biodegradabl e radi oactive thennogel of any one of the preceding biodegradable radioactive diemiogel clauses, wherein the gelled biodegradable radioactive thermogel biodegrades with a hall-life of about 5 days tb about 90 days.
[0268] 35. The biodegradable radioactive thermogel of any one of the preceding biodegradable radioactive thermogel clauses, further comprising a therapeutic agent selected from the group consisting of antibodies, small interfering RNAs (siRNAs), imaging agents, metallic nanoparticles, anti-cancer agents, radiosensitizers, hormones, antibiotics, analgesics, anti-infla matory agents, imnnmoactivators, growth factors, gene therapy agents, oligonucleotides, antisense nucleotides, peptides, and proteins, enzyme inhibitors, chelators, nanocarriers, probiotics, photodynamic therapy agents, mioroRNA (miRNA), cytokines, neurotransmitter modulators, antioxidants, biomimetic peptides, exosomes, sensory modulation agents, aptamers, medicinal compounds, and combinations thereof
[0269] 36, A therapeutic depot formed when the biodegradable radioactive thermogel of any one of the preceding biodegradable radioactive thermogel clauses forms a gel after administration to a warm-blooded, patient.
Claims
What is claimed:L A biodegradable thermogel suspension that forms a gel at a temperature of about 20 'C to about 40°C comprising:one ©r more PLGA-g-PEG polymers, which are synthesized under conditions substantially free of water molecules and oxygen molecules, then dissolved in an aqueous buffer solution;wherein the molar ratio of lactate monomer (LA) to glycolate monomer (GA) in the one or more ELGA-g-PEG polymers is individually from about 65:35 to about 85: 15; and wherein the biodegradable thennogel biodegrades with a. half-life of from about I day to about 365 days or about 10 to about 50 days.
2. " Hie biodegradable thermogel of claim 1, wherein the biodegradable thermogel comprises a single PLGA-g-PEG polymer.
3. The biodegradable thermogel of claim 1, wherein rhe ratio of EPEG‘mPEG to PLGA in the one or more PEG A-g~PEG polymers is individually from 1:99 to 99:1.
4. The biodegradable thermogel of claim 3, wherein the ratio of EPEG+mPEG to PLGA in the one or more PLGA-g-PEG polymers is individually from about 1:1 to about 1:2.
5. The biodegradable thermogel of claim 1 wherein, the ratio of mPEG to EPEG in the one or more PLGA-g-PEG polymers is individually from 1:99 to 99:1.
6. The biodegradab le thermogel of claim 5 wherein, the rati o of mPEG to EPEG in the one or more PLGA-g-PEG polymers is individually from about 1:8 to about 1:10.
7. The biodegradable thennogel suspension of claim I, wherein the one or more PLGA-g-PEG polymers have a weight average molecule weight (Mw) of about 100 Da to about 10,000 Da or about 500 Da to about 8000 Da, or about 1000 Da to about 7000 Da, or about 1500 Da to about 5000 Da.
8. The biodegradable thennogel suspension of claim 1, wherein the one or more PLGA-g-PEG polymers independently have a number average molecule weight (Mn) of about 100 Da to about 10,000 Da or about 500 Da to about 8000 Da, or about 700 Da to about 7000 Da, or about 1000 Da to about 5000 Da9. The biodegradable thermogel suspension of claim 1, wherein the weight of the one or more PLGA-g-PEG polymers is in the range of about 15 wt% to about 40 wt% or about 20 wt% to about 35 wt% in aqueous buffer solution.
10. The biodegradable thermogel suspension of claim 1, wherein the thermogel suspension has a pH between 1.5 and 8.0;11. A. biodegradable radioactive thermogel suspension that forms a gel at a temperature of about 20°C to about 40°C comprising;one or more P GA-g’PEG polymers, which are synthesized under conditions substantially free of water molecules and oxygen molecules, dissolved in an aqueous buffer solution;wherein the molar ratio of lactate monomer to glycolate monomer in the one or more PLGA-g-PEG polymers is individually from about 65:35 to about 85:15; anda plurality of chemically isolated radioactive particles suspended in the thermogel, wherein each chemically isolated radioactive particle includes a cation and a functional group;wherein the plurality of chemically isolated radioactive particles are between 0.03 μm and 10 μm in diameter;wherein the chemically isolated radioactive particles have water solubility of less than 1 x 10-6mole / liter; andwherein the biodegradable radioactive thermogel biodegrades with a half-life of from about 1 day to about 365 days, or about 10 days to about 50 days.
12. The biodegradable radioactive thermogel suspension of claim 11, wherein the biodegradable radioactive thermogel comprises a single PLGA-g-PEG polymer.
13. The biodegradable radioactive thermogel of claim 11, wherein the ratio of EPEG+mPEG to PLGA in the one or more PLGA-g-PEG polymers is individually from 1:99 to 99:1.
14. The biodegradable radioactive thermogel of claim 13, wherein the ratio of EPEG+mPEG to PLGA in the one or more PLGA-g-PEG polymers is individually from about 1:1 to about 1:2.
15. The biodegradable radioactive thermogel of claim 11, wherein, the ratio of mPEG to EPEG in the one or more PLGA-g-PEG polymers is from 1:99 to 99:
116. The biodegradable radioactive thermogel of claim 1'5, wherein, the ratio of mPEG to EPEG in the one or more PLGA-g-PEG polymers is individually from about 1:8 to about 1:10.
17. The biodegradable radioacti ve thermogel suspension of claim 11, wherein the one or more polymers have a weight average molecule weight (Mw) of about 100 Da to about 10,000 Da or about 500 Da to about 8000 Da, or about 1000 Da to about 7000, or about 1500 Da to about 5000 Da.
18. The biodegradable radioactive thermogel suspension of claim 11, wherein the one or more polymers have a number average molecule weight (Mn) of about 100 Da to about 10,000 Da or about 500 Da to about 8000 Da, or about 700 Da to about 7000 Da, or about 1000 Da to about 5000 Da.
19. The biodegradable radioactive thermogel suspension of claim 11, wherein the radioactive particles are combined with the thermogel to yield a final concentration of thermogelling polymer in the range of about 15 wt% to 40 wt% in aqueous buffer solution.
20. The biodegradable radioactive thermogel suspension of claim 11, wherein the biodegradable radioactive thermogel suspension has a pH between 1.5 and 8.0,21. The biodegradable radioactive thermogel suspension of claim 1 wherein the cation is selected from the group consisting of Y, La, Ce, Pr, Pm, Sm, Gd, Tb, Ho, Yb, Cs, Pb, Lu, Ac, Ca, Sr, Ba, Ra, Cu, Tc, Pd, Sn, Re, Au, and combinations thereof; and wherein the functional group includes phosphorous isotopes selected from the group consisting of35P,KP, ■’P, and combinations thereof22. The biodegradable radioactive thermogel suspension of claim 21, wherein the cation is selected from, the group consisting of Y, Ho, Yb, Ce, Pb, Pd, Cs, Ac, Sm, Lu, Sc, Ca, Sr, Ba, and combinations thereof.
23. The biodegradable radioactive thermogel suspension of claim 11, wherein the functional group includes isotopes selected from the group consisting of31P,32P,33P,123I,124I,125I, and combinations thereof24. The biodegradable radioactive thermogel suspension of claim 11, wherein the cation is90Y and the functional group is a phosphate, wherein the phosphorus of the phosphate includes one or more isotopes selected from the group consisting of31P,32P, and33P.
25. The biodegradable radioactive themiogel suspension of claim 20, wherein the phosphorus of the phosphate is31P at its natural abundance.
26. The biodegradable radioactive thermogei suspension of claim 1 L, wherein the chemically isolated radioactive particle concentration is in the range of 3 mg / ml to 100 mg / ml.
27. The biodegradable radioactive thermogei suspension of claim 11, wherein the chemically isolated radioacti ve particles provide a dosage of between 30 μCi and 300 mCi.
28. The biodegradable radioactive thermogei suspension of claim 11 wherein the functional group is selected from the group consisting of apatite, sodalite, iodide, hydride, and combinations thereof.
29. The biodegradable radioactive thermogei of claim 11, wherein the radioactive particles emit radiation with an energy of about 0.01 MeV to about 6 MeV30. 'Hie biodegradable radioactive thermogei of claim 11, wherein the radioactive particles emit beta radiation and gamma radiation.
31. The biodegradable radioactive thermogei of claim 11. wherein the gelled biodegradable radioactive thermogei biodegrades with a half-life of biodegradation of about the same as the half-live of the radioactive particles.
32. The biodegradable radioactive thermogei of any of claim 11, wherein the gelled biodegradable radioactive thermogei biodegrades with a half-life of bout 5 days to about 90 days.
33. The biodegradable radioactive thermogel of claim 11, further comprising a therapeutic agent selected from the group consisting of antibodies, small interfering RNAs (siRNAs), imaging agents, metallic nanoparticles, anti-cancer agents, radiosensitizers, hormones, antibiotics, analgesics, anti-inflammatory agents, immunoactivators, growth factors, gene therapy agents, oligonucleotides, antisense nucleotides, peptides, and proteins, enzyme inhibitors, chelators, nanocarriers, probiotics, photodynamic therapy agents, micro R As (miRNAs), cytokines, neurotransmitter modulators, antioxidants, biomimetic peptides, exosomes, sensory modulation agents, aptamers, medicinal compounds, and combinations thereof34. A therapeutic depot formed when the biodegradable radioactive thermogeiof claim 11 forms a gel after introduction into a patient.