Irradiation protection compositions and uses

Abstract

The disclosure relates to compositions for use in protecting the rectum from adverse effects of high-dose radiation. More specifically, the disclosure is related to methods and uses of suppositories operable for radial targeted delivery of compositions of radioprotectants to a predetermined radial position adjacent an organ or a tissue sought to be irradiated in a subject in need thereof.

Description

Docket No. XPH0005PCTIRRADIATION PROTECTION COMPOSITIONS AND USESBACKGROUND

[0001] The disclosure is generally directed to pharmaceutical delivery systems for radiation therapy protection. More specifically, the disclosure is directed to suppository formulations designed for radially directed, sustained release delivery of cytoprotectant agents to protect rectal tissue and adjacent organs from radiation damage during external beam radiation therapy, particularly in the treatment of pelvic cancers such as prostate cancer.

[0002] Radiation therapy remains a primary treatment modality for various pelvic cancers, including prostate, cervical, and rectal malignancies. During external beam radiation therapy, the rectum and surrounding healthy tissues are at significant risk of radiation-induced injury due to their proximity to the target tumor. Conventional protective approaches include careful treatment planning, dose fractionation, and physical spacing techniques such as hydrogel spacer injection between the prostate and rectum. Pharmacological cytoprotection has been explored through systemic administration of radioprotective agents like amifostine; however, systemic delivery often results in dose-limiting toxicides, inadequate local concentrations at the target site, and poor patient tolerance.

[0003] Existing local delivery methods for cytoprotectants face multiple technical challenges. Conventional suppositories provide omnidirectional drug release, resulting in unnecessary exposure of unaffected rectal regions and suboptimal drag concentrations at the specific tissue area requiring protection. The lack of directional control in drug delivery means that cytoprotectant distribution cannot be aligned with the radiation field geometry. Furthermore, rapid dissolution and clearance of traditional suppository formulations prevent sustained therapeutic levels throughout fractionated radiation treatment courses. Current mucoadhesive formulations provide some retention improvement but still lack the spatial precision needed for targeted radioprotection.

[0004] Clinical dose constraints for rectal protection typically require maintaining the volume of rectum receiving 70 Gy (V70) below 20% and the volume receiving 50 Gy (V50) below 50%, constraints that are challenging to achieve without compromising tumor coverage.Docket No. XPH0005PCTThese stringent requirements underscore the need for improved protective strategies that can work synergistically with modem radiation delivery techniques.

[0005] There remains an unmet need for a pharmaceutical delivery system that can provide sustained, directionally controlled release of cytoprotectant agents specifically to rectal regions at highest risk of radiation injury. Such a system must maintain therapeutic drug concentrations throughout multiple radiation fractions while minimizing systemic exposure and off-target effects. The ability to spatially orient the drug release to match the radiation field geometry, combined with sustained release kinetics compatible with fractionated therapy schedules, represents a critical gap in current radiation oncology practice. The compositions, methods of use and combination therapies disclosed herein address certain shortfalls of the current state of affairs.SUMMARY

[0006] In an exemplary implementation, provided is generally, enemas, foams, gels or cylindrical, elongated suppository, each configured for radially directed, sustained and / or immediate release delivery of cytoprotectant, the suppository defining a longitudinal axis, a distal end and a proximal end, the suppository comprised of. a core; with bio-adhesive polymers and a cytoprotectant pro-drug or the drug composition dispersed (radially) asymmetrically or dispersed symmetrically or dissolved in a dual, different release profile layers within the core; an intermediate layer surrounding the core; and an external layer, wherein the cytoprotectant prodrug or the drug composition is encapsulated within a plurality of nanoparticles adapted, sized and configured to sustainably release the cytoprotectant.

[0007] In another exemplary implementation, provided herein is a method of protecting a portion of the rectum from radiation damage during radiation therapy of a tissue or an organ in a subject in need thereof, using a generally cylindrical, elongated suppository configured for radially directed delivery of cytoprotectant sustained and or immediate release, the method comprising: inserting the distal end of the suppository for radially directed cytoprotectant sustained and or immediate release to a rectum of a subject in need thereof to a predetermined depth within the rectum; rotating the suppository position directing the release of the cytoprotectant to the portion sought to be irradiated; validating the location of the distal end;Docket No. XPH0005PCTvalidating the radially directed position of the suppository; and exposing the organ or the tissue sought to be irradiated to ablative radiation.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The features of the methods and uses of suppositories operable for radial targeted delivery of compositions of radioprotectants to a predetermined radial position adjacent an organ or a tissue sought to be irradiated in a subject in need thereof, will become apparent from the following detailed description when read in conjunction with the drawings, which are exemplary, not limiting, not necessary to scale, and wherein like elements are numbered alike in several figures and in which:

[0009] FIG. 1, is a schematic of a male pelvic anatomy in a sagittal view;

[0010] FIG. 2, is a schematic of a female pelvic anatomy in a top view; and

[0011] FIG. 3A, is a X-Z cross section of the suppository operable for radial targeted delivery of compositions of radioprotectants to a predetermined radial position on the rectal wall, adjacent an organ or a tissue sought to be irradiated in a subject in need thereof, with FIG. 3B being a top view of the multilayered suppository, while FIG. 3C being an X-Y cross section thereof and FIG. 3D, illustrates an alternative configuration of the dispersed (or dissolved) particulates in a half-shell configuration.

[0012] While the disclosure is amenable to various modifications and alternative forms, specifics thereof have been shown by way of example in the figures and will be further described in detail hereinbelow. It should be understood, however, that the intention is not to limit the disclosure to the particular exemplary implementations described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives.DETAILED DESCRIPTION

[0013] The disclosure relates to pharmaceutical dosage forms for localized cytoprotection of rectal epithelium and submucosa during pelvic radiation therapy. Radiation-induced proctitis incidence is related to radiation dose, area of exposure, method of delivery, and use of cytoprotective agents, with treatment doses ranging from 45-50 Gray (Gy) for adjuvant therapyDocket No. XPH0005PCTto up to 90 Gray for definitive gynecological malignancy treatment. Ionizing radiation causes double-strand DNA breaks, protein denaturation, and lipid peroxidation through oxygen-free radical generation, leading to mucosal ulceration, vascular telangiectasia, and fibrotic changes in rectal tissue. Conventional systemic cytoprotectants suffer from inadequate site-specific delivery, resulting in suboptimal radioprotection of healthy rectal mucosa while attempting to preserve radiosensitivity of tumor cells. The disclosure addresses this limitation by providing a suppository configured for sustained, radially-directed cytoprotectant release directly to target tissues, achieving therapeutic concentrations at the radiation field interface while minimizing systemic exposure and maintaining spatial precision necessary for protecting normal tissue adjacent to treatment volumes.

[0014] In an exemplary implementation as illustrated schematically in FIG.s 3A-3C, provided herein is a multi-layered suppository formulation designed for radially directional, sustained and / or immediate release of cytoprotectants to protect the rectal walls from radiation of tissues and organs during high-dose radiation therapy for pelvic (non-rectal) cancers. This composition is configured to provide localized protection to healthy tissues adjacent to the tumor site while allowing effective radiation treatment of the cancerous tissue.

[0015] As indicated, provided is a suppository composition comprised of a multi-layered structure to achieve radially directional drug release. In an exemplary implementation, the core 100 (see e.g.. FIG. 3A, 3C) of the suppository is composed of a hydrophobic base, such as cocoa butter or a synthetic hard fat like Witepsol H15, which is adapted sized and configured to provide structural integrity and allows for slow melting at body temperature. These suppositories can be composed of. but not limited to, cocoa butter, coconut oil, glycerinated gelatin, hydrogenated vegetable oils and hard fats, polyethylene glycols (PEGs) and fatty acid esters of PEG. With a combination of these excipient bases, suppositories have fallen into one of two major types: lipophilic based or hydrophilic based. The lipophilic fat-based suppositories melt at body temperature to release drug to the body.

[0016] Dispersed within this core is the cytoprotectant, such as amifostine or its active metabolite WR-1065, encapsulated in biodegradable polymeric nanoparticles HOi made for example, from biodegradable polymer, such as PLGA. These nanoparticles are configured to provide sustained release of the cytoprotectant over an extended period (from several hours to several days. Furthermore, The cytoprotectant pro-drug or active drug composition is uniformlyDocket No. XPH0005PCTdispersed or molecularly dissolved within the core matrix at concentrations ranging from between about 5% and about 40% (w / w) by weight, depending upon therapeutic requirements and solubility characteristics. Sucralfate adheres to mucosal cells and stimulates prostaglandin production, producing cytoprotective effects, while it can form a protective barrier at the injury site and reduce damage caused by enzymes and defecation. Alternative cytoprotectant agents include misoprostol analogs exhibiting protective effects through enhanced mucosal blood flow, or antioxidant compounds capable of scavenging radiation-induced reactive oxygen species. The pro-drug formulation enables enzymatic or pH-dependent conversion to active moieties within the rectal microenvironment, optimizing local bioavailability while reducing systemic distribution. Dispersion within the core ensures initial burst release upon suppository insertion, followed by sustained liberation as the core matrix progressively dissolves or erodes under physiological conditions. This element interfaces functionally with surrounding layers to establish multi-phasic release kinetics appropriate for prolonged radioprotection during fractionated radiation therapy schedules

[0017] As indicated, the core comprises a pharmaceutically acceptable matrix material exhibiting structural integrity sufficient to maintain dimensional stability during manufacturing, storage, and initial phases of rectal insertion. Suitable core materials comprise hydrophobic bases such as triglycerides, medium-chain fatty acid esters, or cocoa butter derivatives with melting points between about 34 °C and about 37 °C, ensuring body-temperature-responsive dissolution. Alternatively, hydrophilic polymeric matrices incorporating polyethylene glycols with molecular weights ranging from between about 1000 Daltons to 6000 Daltons can provide controlled erosion characteristics. The core as adapted and sized to measure between aboy 15mm and about 30mm in length along the longitudinal axis and between about 8 mm and about 12 mm in diameter, conforming to standard adult rectal dosing geometries. The core is configured to function as the primary structural scaffold, providing mechanical support during insertion while serving as a reservoir for controlled cytoprotectant dispersion. Upon exposure to rectal temperature and moisture, the core undergoes phase transition or matrix erosion, initiating drug release kinetics predetermined by base composition and polymer selection.

[0018] In an exemplary implementation, the cytoprotectant pro-drug or active composition is incorporated within one or more discrete layers exhibiting asymmetric spatial distribution relative to the longitudinal axis (see e.g., FIG. 3A). This asymmetric configuration is adapted,Docket No. XPH0005PCTsized and configured to direct preferential drug release toward specific anatomical regions, particularly the anterior rectal wall adjacent to radiation-sensitive structures. Layer thickness can range from between about 0.5 mm., and about 3 mm., with drug loading ranging e.g., between 10% and about 50% w / w within each layer. The asymmetric geometry can be achieved through e.g.; sequential molding, compression layering, or 3-dimensional printing techniques that precisely control spatial drug distribution. Functionally, this design element enables directional pharmacokinetics, concentrating cytoprotectant delivery to tissues experiencing maximal radiation exposure while minimizing drug deposition in less affected regions. The layers may further incorporate rate-controlling polymers including hydroxypropyl methylcellulose, carbopol, or poloxamers that modulate dissolution and diffusion kinetics. Upon rectal insertion, body temperature and mucosal fluid penetration cause selective layer swelling and erosion, establishing concentration gradients that drive radial drug migration toward target epithelium

[0019] When present, the intermediate layer surrounds the core, forming a concentric barrier between the core reservoir and external environment. This layer typically comprises polymeric materials with controlled permeability characteristics, including cellulose derivatives with hydroxypropyl or ethyl substituents, or synthetic copolymers exhibiting pH-responsive swelling behavior. Layer thickness can be configured to range from between about 0.2mm. and about 1.5 mm., sufficient to provide temporal delay in core drug release without excessive diffusion resistance. The intermediate layer can be configured to function as a rate-limiting membrane, converting immediate core drug liberation into extended-release kinetics suitable for maintaining therapeutic concentrations over 6 to 12 hours. Manufacturing integration involves dip-coating, spray-lay ering, or compression-molding the intermediate material onto the pre-formed core. Tolerance specifications maintain layer uniformity within plus-or- minus 15 % to ensure reproducible pharmacokinetic performance. This element can be configured to interact with the core through diffusion-controlled mass transfer and with external layers through sequential erosion mechanisms.

[0020] In another exemplary implementation, the external (outer) layer, when incorporated, can be configured to provide immediate mucosal contact upon insertion, delivering initial cytoprotectant doses while protecting inner formulation components from premature moisture exposure during handling. Common external materials can be, for example; water-soluble polymers such as polyvinyl alcohol, and / or low-molecular- weight polyethylene glycol thatDocket No. XPH0005PCTrapidly dissolve upon rectal contact. The cytoprotectant pro-drug or active composition can be encapsulated within nanoparticles ranging from between about 50 nanometers (nm) and about 500 nm in diameter, optimized for enhanced epithelial penetration and sustained intracellular release.

[0021] The outer layer 300 of the suppository can likewise be optionally formulated with a pH-responsive polymer, such as Eudragit S100. and configured to dissolves at pH levels above 6.5, corresponding to the colonic environment. This outer layer helps to target the release of the cytoprotectant to the desired area of the colon.

[0022] To achieve radially directional drug release, the suppository is designed with an asymmetric distribution of the cytoprotectant-loaded nanoparticles (see e.g., lllj, 112p, 113q within the core 100. A higher concentration of nanoparticles, and / or nanoparticles containing higher concentration of the cytoprotectant 11 Ij can be positioned towards the side of the suppository that will face the tissue undergoing radiation. This asymmetric distribution can be achieved during the manufacturing process by using a specialized mold and controlled cooling techniques.

[0023] In certain exemplary implementations, the nanoparticle composition used in the formulations disclosed, can comprise, e.g.; biodegradable polymers such as poly-lactic-co-glycolic acid, chitosan derivatives, or solid lipid matrices that undergo enzymatic or hydrolytic degradation. With increasing PLGA molecular weight, particle size gradually increases while drug loading and release significantly decrease.

[0024] Furthermore, surface functionalization with mucoadhesive moieties or targeting ligands can be configured to enhance rectal tissue retention and cellular uptake. The nanoparticles are adapted through, for example; size fractionation, surface charge modification, and polymer selection to achieve release half-lives between about 4 and about 24 hours.Encapsulation can be used in certain implementations to protect labile cytoprotectants from oxidative degradation while facilitating controlled liberation through, for example; diffusion, polymer erosion, or stimuli-responsive mechanisms. Emulsification- solvent evaporation is the most common method for preparing PLGA particle formulation, with other methods including spray-drying, phase separation, microfluidics, and nanoprecipitation. The nanoparticles can be configured to disperse throughout external or asymmetric layers, establishing in certainDocket No. XPH0005PCTexemplary implementations, a depot that can be configured to continuously liberate cytoprotectant as radiation fractions are delivered over multi- week treatment courses.

[0025] Accordingly and in another exemplary implementation illustrated schematically in FIG.s 3A-3C, provided herein is a generally cylindrical, elongated suppository 10 configured for radially directed delivery of cytoprotectant sustained release, defining a longitudinal axis XL, a distal end 102 and a proximal end 101. the suppository 10 comprising: a core 100; a cytoprotectant pro-drug or the drug composition 500 dispersed asymmetrically within the core; an intermediate layer 200 surrounding the core; and an external layer 300, wherein the cytoprotectant pro-drug or the drug composition is encapsulated within a plurality of nanoparticles HOi adapted, sized and configured to sustainably release the cytoprotectant.

[0026] In an exemplary implementation, the method for forming this radially specific, controlled-release suppository involves several steps. First, the cytoprotectant is encapsulated in nanoparticles of a biodegradable polymer using, for example duplex emulsion solvent evaporation technique (W / O / W, O / W / O depending on the hydrophobicity of the active pharmaceutical ingredient (API)). These nanoparticles can then be mixed with the molten hydrophobic core material in a precise ratio and distribution to create the asymmetric core (see e.g., FIG.s 3A, 3C, 3D). The core mixture is partially cooled in a specially designed mold that allows for directional solidification. Next, the thermosensitive and mucoadhesive polymer blend is prepared and carefully layered around the partially solidified core. This is followed by the application of the pH-responsive outer layer using a dip-coating process. The entire suppository is then allowed to fully solidify under controlled temperature conditions to maintain the desired structure and API distribution. In certain exemplary implementations, the mucoadhesive polymer blend, or composition, can be dispersed within the core.

[0027] Alternatively, as illustrated in FIG. 3D, the core can be comprised of a configuration of the dispersed (or dissolved) particulates being in a half- shell configuration, thereby providing directed controlled delivery of the cytoprotectant.

[0028] The resulting suppository is designed to be inserted into the rectum with a specific orientation, ensuring that the side with the higher concentration of cytoprotectant-loaded nanoparticles faces the tissues undergoing exposure to the radiation. Upon insertion, the outer pH-responsive layer dissolves as it reaches the colonic environment, exposing the mucoadhesiveDocket No. XPH0005PCTlayer. This layer then adheres to the rectal mucosa and forms a gel, providing localized retention of the suppository.

[0029] As the hydrophobic core slowly melts, it releases the cytoprotectant-loaded nanoparticles. The asymmetric distribution of these nanoparticles results in a higher concentration of the cyto protectant being released towards the targeted tissues. The biodegradable nanoparticles HOi provide sustained release of the cytoprotectant, offering prolonged protection during the course of radiation therapy. This formulation approach allows for the targeted, radially directional delivery of cytoprotectants to portions of the rectal wall adjacent to non-rectal tumors undergoing radiation therapy. The sustained release profile and localized delivery minimize systemic exposure to the cytoprotectant, potentially reducing side effects while maximizing the protective effect on healthy tissues.

[0030] In an exemplary implementation, the cytoprotectant pro-drug or the drug composition comprises at least one of: ergotamine, amifostine, Amifostine thiol- amifostine, 2-[(3-Aminopropyljamino] ethanethiol dihydrochloride (hereinafter WR- 1065) and pyridoxine.

[0031] In another exemplary implementation, the cytoprotectant pro-drug is the prodrug S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (hereinafter WR-2721) having the formula:given via the nasal tube before radiation, whereby, the pro-drug is rapidly activated by endogenous digestive enzymes in, for example, the duodenum and jejunum to its active 2-[(3-Aminopropyl) amino] ethane thiol dihydrochloride (hereinafter WR- 1065). It is noted, that the prodrug can also include its free mono-base or di-base conjugate, devoid of the respective HC1 and any other pharmaceutically acceptable salt formation once passage into or through the duodenum, as well as metabolite having the formula:Docket No. XPH0005PCT

[0032] An “effective amount” of a subject compound, with respect to the pharmaceutical compositions, methods and uses, refers to an amount of the cytoprotective pro-drug in a preparation which, when applied as part of a desired dosage regimen (dose, formulation, frequency), prevents from bringing about, e.g., a negative change in rate of survival of a cell according to clinically acceptable standards.

[0033] In an exemplary implementation, the pro-drug is WR-2721. As used herein, the term “pro-drug” refers to a pharmacologically inactive form of a compound that undergoes biotransformation prior to exhibiting its pharmacological effect(s). A pro-drag is one that is converted in vivo by a subject after administration into a pharmacologically active form of the compound in order to produce the desired pharmacological effect. After administration to the subject, the pharmacologically inactive form of the compound is converted in vivo under the influence of biological fluids and / or enzymes into a pharmacologically active form of the compound. Although metabolism occurs for many compounds primarily in the liver and / or kidney, almost all other tissues and organs, especially the lung, are able to carry out varying degrees of metabolism. Pro-drug forms of compounds can be utilized, for example, to improve bioavailability, mask unpleasant characteristics such as bitter taste, alter solubility for intravenous use, or to provide site- specific delivery of the compound. Reference to a compound herein includes pro-drug forms of a compound and the drag conjugate (active form).

[0034] The dosage forms of WR-2721 can be also be a part of a composition comprising salt of a chelating agent selected from the group consisting of EDTA, EGTA, citrate and therapeutically acceptable salts thereof. A preferred formulation can be made with the pharmacologically required dose of WR-2721 being between about 50 mg / unit of dosage form and about 2000 mg / unit dosage form or NMT 2000mg / dosage form unit for example, between about 125 mg / and about 750 mg or about 250 mg.

[0035] Furthermore, and as indicated, in certain exemplary implementations, the suppository can further comprises an intermediate layer of a bio-adhesive composition (interchangeable with ‘mucoadhesive composition), which is adapted to form the bio-adhesive upon mixing with a body fluid, the bio-adhesive configured to adhere the cytoprotectant pro-drug or the drag composition to a radial portion of the wall of a body lumen, such as the rectum wall. The bioadhesive is, in an exemplary implementation, a mucoadhesive polymer composition, configured to prolong the residence time of the dosage form at the site of absorption (e.g., the rectum wall),Docket No. XPH0005PCTfollowing the calculated lag in release, and to facilitate intimate contact of the dosage form (e.g., the cytoprotectant-loaded nanoparticles) with the underlying inside surface of the rectum (see e.g.. FIG. 1) to improve and enhance the efficacy of the therapeutically effective amount of the API.

[0036] In the context of the disclosure, the term “bio-adhesive”, or “mucoadhesive” denotes a compound exhibiting an affinity for a mucosal surface. Mucoadhesive polymers are typically polymers having hydrogen bonding groups. See e.g. http: / / en.wikipedia.org / wiki / Bioadhesive#Mucoadhesion. “Mucoadhesion is the ability of materials to adhere to mucosal membranes in the human body and provide a temporary retention”. “Excellent mucoadhesive properties are typical for hydrophilic polymers possessing charged groups and / or non-ionic functional groups capable of forming hydrogen bonds with mucosal surfaces.” [Macromol Biosci. 2011 lim 14; 11(6): 748-64. doi: 10.1002 / mabi.201000388.Epub 2010 Dec. 27], In an exemplary implementation, the bio-adhesive composition is a mucoadhesive composition that is comprised of hydroxylpropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC).Hypromellose, starch, polyvinylpyrollidone (PVP), xanthan gum, thiolated chitosan, or a composition comprising one or more of the foregoing, or for example, chitosan, polyoxyethylene-polyoxypropylene block polymer (poloxamer 407), carboxypolymethylene (carbopol), Hydroxypropyl Methylcellulose (HPMC), hydroxylpropyl cellulose (HPC) , Hypromellose, starch, polyvinylpyrollidone (PVP), xanthan gum, or a mucoadhesive composition comprising one or more of the foregoing.

[0037] In an exemplary implementation the plurality of nanoparticles adapted sized and configured to affect sustained release of the API are formed of a biodegradable polymer selected from the group comprising: poly(lactic-co-glycolic acid) (PLGA), Polycaprolactone (PCL), PolyQactic acid) (PLA), gelatin, or a biodegradable polymer composition comprising one or more of the foregoing.

[0038] When considering synthetic hard fats for use as suppository bases for the core, several options are available in addition to Witepsol H15. These include Fattibase, Wecobee, Hard Fat Mixed Fatty Acid Glycerides (Adeps Solidus), Suppocire, and Hydrokote. For example, Witepsol Hl 5, a synthetic hard fat produced through direct esterification of glycerol and fatty acids from sustainable vegetable sources, meets pharmacopoeial requirements. Likewise, Fattibase is a preblended base composed of triglycerides from palm, palm kernel, and coconutDocket No. XPH0005PCToils, designed to mimic cocoa butter's melting characteristics without polymorphism issues (crystalline form phase transition). Wecobee, derived from coconut oil triglycerides, can likewise offer various types with different melting points. Hard Fat Mixed Fatty Acid Glycerides are blends of glycerol esters can also be used, primarily consisting of stearic, palmitic, and oleic acids, available in different types with varying melting points. Moreover, Suppocire a synthetic triglyceride mixture designed for consistent melting properties, and Hydrokote, manufactured by ABITEC, formulated for stable and consistent melting characteristics can both be used as well. These synthetic hard fats offer advantages such as consistent melting points, lack of polymorphism, and compatibility with a wide range of active pharmaceutical ingredients, making them suitable alternatives to traditional cocoa butter-based suppositories. Accordingly, an in an exemplary implementation, the core used in the suppositories used in the therapies and procedures disclosed is comprised of a hydrophobic composition comprising: cocoa butter, a synthetic hard fat selected from the group consisting of: Witepsol H15, Fattibase, Wecobee, Suppocire, or Hydrokote, or a hydrophobic composition comprising one or more of the foregoing.

[0039] In certain exemplary implementations, and as illustrated in FIG, 3B, the generally cylindrical, elongated suppository configured for radially directed delivery of cytoprotectant sustained release further defining a longitudinal axis XL, wherein the plurality of nanoparticles 1 lOi are distributed at axially even concentration and radially forming a gradient having a radial peak concentration (see e.g. FIG. 3C). As illustrated in FIG. 3B, the external layer 300 further comprises a visual marking of the radial peak concentration, providing a fiducial to the physician of where to “aim” the suppository. See e.g., FIG. 2, where the direction of the suppository for cervical cancer irradiation, can be different than that for ovarian cancer.

[0040] In an exemplary implementation, the suppositories disclosed are used in the methods provided. Accordingly, provided herein is a method of protecting a portion of the rectum from radiation damage during radiation therapy of a tissue or an organ in a subject in need thereof, using a suppository adapted for radially directed cytoprotectant sustained release having a proximal end and a distal end, the method comprising: inserting the distal end 102 of the suppository 10 for radially directed cytoprotectant sustained release to a rectum of a subject (see e.g.. FIGs 1, 2) in need thereof to a predetermined depth within the rectum; rotating the suppository position (see e.g., FIG. 3B) directing the release of the cytoprotectant to the portionDocket No. XPH0005PCTsought to be protected from irradiation; validating the location of the distal end; validating the radially directed position of the suppository; and exposing the organ or the tissue sought to be irradiated to ablative radiation. Furthermore, the step of rotating the suppository position comprising radially aligning the marking 350 with the tissue or organ sought to be irradiated.

[0041] To reiterate, the insertion step involves advancing the distal end of the suppository into the rectum to a predetermined depth that positions the radially directed release zone adjacent to the rectal segment requiring protection. The predetermined depth correlates with the radiation treatment plan and the anatomical location of the organ receiving ablative therapy. For example, in prostate irradiation, depths can be maintained at between about 6 cm., and about 10 cm., from the anal verge and position the suppository at the mid-to-upper rectum (see e.g., FIG. 1), where dose spillover is maximal. For cervical or rectal cancer treatments, depths can be adjusted according to computed tomography (CT)-based treatment planning coordinates.

[0042] The insertion can performed, e.g.; with the patient positioned consistently with radiation therapy positioning protocols, typically supine with reproducible immobilization.Depth markings on the suppository or insertion applicator can be used to provide tactile or visual confirmation of the predetermined depth. Furthermore, the suppository's geometry, typically bullet-shaped with a tapered distal end measuring about 2 grams (g.) for adults, can be used to facilitate insertion and retention at the designated depth. The formulation's melting point, can ensure the suppository maintains structural integrity during insertion but softens appropriately at physiological rectal temperature to initiate cytoprotectant release.

[0043] Following insertion to the predetermined depth, the suppository undergoes rotational adjustment to align the radially directed release sector (see e.g., 11 Ij, FIG. 3C), toward the specific portion of the rectal wall requiring protection from irradiation. This rotational positioning exploits the asymmetric release architecture (see e.g., FIG.l), directing cytoprotectant liberation toward the anterior rectal wall when protecting against prostate radiation, or toward lateral rectal walls depending upon the radiation beam geometry and dose distribution patterns identified in the treatment plan. The rotation can be performed through e.g.; gentle manipulation of the proximal end while the distal end remains at the predetermined depth.

[0044] Consequently, rotational positioning can for example, be configured to take into consideration the radiation beam entry angles, dose- volume histogram projections showing rectal segments receiving threshold doses, and anatomical variations specific to the individual patient.Docket No. XPH0005PCTFor example, for intensity-modulated radiation therapy employing multiple beam angles, the rotation can be configured to direct cytoprotectant release toward the rectal segment receiving the highest cumulative dose. External anatomical landmarks or patient-specific positioning instructions derived from simulation imaging guide the rotational adjustment. The suppository design may incorporate asymmetric cross-sectional geometry (see e.g., FIG. 3C) or orientation markers (see e.g., FIG. 3B) that correlate rotational position with external references or natural fiducials (e.g., the prostate).

[0045] In certain exemplary implementations, validation of the axial, distal end location can be used to ensure the suppository has reached and remains at the predetermined depth prior to radiation delivery. This validation can employ e.g., imaging modalities including computed tomography, magnetic resonance imaging, or ultrasound capable of visualizing the suppository within the rectal anatomy. In yet another exemplary implementation, the suppository may further incorporate radiopaque elements such as, for example; barium sulfate, bismuth subcarbonate, and / or iodinated compounds, each dispersed within the base material, rendering the suppository visible on kilovoltage or megavoltage imaging systems. Concentration ranges of between about 10%, and about 30% (w / w), can be used to provide adequate radiographic contrast without compromising suppository mechanical properties.

[0046] Similarly, validation of the radially directed position can be used to confirm that the asymmetric release sector (see e.g., FIG.s 3B-3C) is oriented correctly to deliver cytoprotectant toward the rectal portion requiring protection. This validation can rely upon, for example; imaging-based identification of radiopaque orientation markers, asymmetric suppository geometry, markings on the suppository, or distinct radiographic signatures corresponding to the cytoprotectant-loaded sector versus the non-, or less loaded sector (where spatial asymmetry is by gradients, rather than sectors). The markers may comprise small metallic seeds, different radiopaque material concentrations between sectors, or suppository shape asymmetries visible on axial computed tomography slices.

[0047] Alternatively, the suppository geometry itself provides sufficient tissue-air contrast for visualization on cone beam computed tomography performed as part of image-guided radiation therapy workflows. The validation confirms that the distal end position corresponds within 5 millimeters of the planned position, as deviations beyond this threshold may result in inadequate cytoprotectant delivery to the intended rectal segment. Digital measurement toolsDocket No. XPH0005PCTintegrated within radiation therapy treatment planning systems enable rapid comparison between the observed suppository position and the predetermined position specified in the treatment plan. Any detected positioning discrepancies prompt suppository repositioning before proceeding to radiation delivery

[0048] Additionally, or alternatively, radial validation process can further involve acquiring axial images through the suppository-containing rectal segment and analyzing the rotational orientation relative to the anterior-posterior or left-right axes. Treatment planning systems can be used to enable superimposition of the observed suppository orientation onto dose distribution overlays, confirming alignment between the radially directed release vector and the rectal segment within high-dose regions. Angular tolerances of ±30° can be used to ensure adequate directional specificity, while simultaneously accommodating practical positioning limitations.

[0049] Moreover, and following successful validation of both depth (axial), and rotational positioning, the target organ or tissue is exposed to ablative radiation therapy. Ablative radiation doses, typically ranging from between about 36 Gy and about 81 Gy delivered in fractionated schedules or stereotactic body radiation therapy regimens, achieve tumoricidal effects on target tissues. The term “ablative” encompasses both conventionally fractionated regimens delivering between about 1.8 Gy / fraction and about 2 Gy / fraction over multiple weeks and hypofractionated regimens delivering larger fractions over abbreviated treatment courses (e.g., between about 17 Gy / fraction and 50 Gy / fraction). The sustained cytoprotectant release initiated upon suppository insertion is configured to continue throughout the radiation delivery interval.

[0050] The temporal relationship between suppository insertion and radiation beam delivery accounts for the release kinetics and tissue penetration characteristics of the selected cytoprotectant. In an exemplary implementation, for formulations exhibiting initial burst release followed by sustained zero-order kinetics, or pseudo-zero-order kinetics, insertion can occur 15 to 60 minutes before radiation to establish therapeutic tissue concentrations. The radiation therapy can then proceed according to standard quality assurance protocols including daily image guidance, while the positioned suppository remains in place providing continuous directional cytoprotectant delivery. Post-treatment, the suppository may be retained or expelled naturally, with any residual cytoprotectant continuing to provide post-exposure radioprotection during the cellular repair interval.Docket No. XPH0005PCT

[0051] Accordingly, the method disclosed can integrate seamlessly with contemporary radiation therapy workflows employing image guidance and adaptive treatment planning. The suppository insertion, positioning, and validation steps can take place in the treatment room immediately before each radiation fraction, analogous to rectal balloon spacer protocols but providing pharmacological rather than purely physical protection. For patients undergoing daily fractionated radiation, a fresh suppository can be inserted each treatment day, ensuring consistent cytoprotectant delivery throughout the treatment course. The relatively brief insertion and validation procedures, requiring e.g., between about 5 min. and about 10 min, minimally extend overall treatment time.

[0052] The method can prove particularly advantageous for patients where physical rectal displacement strategies are contraindicated, including for example; those with postprostatectomy anatomy, pelvic surgical adhesions, or anatomical variations precluding spacer placement. The directional release capability enables customization to patient-specific dose distributions, addressing asymmetric radiation dose patterns common in complex treatment plans. Treatment planning systems may further model the anticipated spatial distribution of cytoprotectant diffusion from the directed release sector, integrating pharmacokinetic predictions into biological dose calculations and normal tissue complication probability estimates, thereby optimizing both radiation dose prescriptions and suppository positioning parameters

[0053] In yet another exemplary implementation, and as indicated herein, the suppositories disclosed can be used as combination with other procedures, such as the use of rectal spacers in prostate cancer radiotherapy has shown promise in further reducing rectal toxicity by physically separating the prostate from the anterior rectal wall. For example, such procedure, is a minimally invasive procedure designed to reduce the radiation exposure to the rectum during external beam radiation therapy for prostate cancer.

[0054] The procedure involves the injection of a hydrogel spacer between the prostate and the rectum to create a physical separation between these organs. Initially, the patient is prepared for the procedure, which may include stopping blood-thinning medications and performing an enema to clear the rectum if necessary. The area behind the scrotum is numbed with a local anesthetic to reduce discomfort during the procedure. General or regional anesthesia can also be used depending on the patient's preference and medical condition.Docket No. XPH0005PCT

[0055] A side-fire transrectal ultrasound (TRUS) probe with a stand-off balloon is inserted into the rectum to provide ultrasound guidance. The probe is adjusted to obtain optimal ultrasound coupling with the anterior rectal wall. An 18G x 15cm needle is attached to a syringe containing saline and inserted approximately 1-2 cm above the anal opening. The needle is angled to reach the perirectal fat between the anterior rectal wall and the prostate. The needle is advanced through the rectourethralis muscle to the perirectal fat at the mid-gland level of the prostate. The correct needle position is confirmed in both sagittal and axial ultrasound views.

[0056] Small amounts of saline are injected to hydrodissect the space between the Denonvilliers’ fascia and the anterior rectal wall. Aspiration is performed to ensure the needle is not intravascular. The saline syringe is disconnected from the needle, and the hydrogel delivery system is attached. The hydrogel is formed by mixing two solutions in situ by mixing two solutions, the Precursor and the Accelerator. The Precursor solution is formed through the mixing of the Diluent solution (e.g., Trilysine buffer solution) with the PEG powder. The Accelerator solution is a salt buffer solution. When mixed together (the Precursor and the Accelerator) as they pass through a static mixer before being injected through the needle, the solutions cross-link to form a soft hydrogel.

[0057] Under continuous ultrasound guidance, the hydrogel is injected into the space between the prostate and the rectal wall in a smooth, uninterrupted manner. The entire syringe contents are injected without stopping.

[0058] The procedure, carries several risks and potential complications. These include pain and discomfort at the injection site, which is typically temporary, as well as bleeding, infection, and local inflammatory reactions. Urinary retention, fecal urgency, and rectal mucosal damage, including ulcers and necrosis, can also occur. There is a risk of needle injury to the bladder, rectum, or prostate, and incorrect hydrogel placement can occur in a small %age of cases, potentially leading to lateral hydrogel formation or displacement of cancer cells. Intravascular injection of air, fluid, or hydrogel is a rare but serious complication. The benefits of the procedure are significant. It creates a physical separation of about 1 cm between the prostate and the rectum, reducing the radiation dose to the rectal wall during external beam radiation therapy. Clinical trials have shown a 66% improvement in bowel bother in men who undergone the procedure compared to those who did not. The procedure is minimally invasive and can be performed in an outpatient setting, allowing patients to quickly resume their normal activities.Docket No. XPH0005PCT

[0059] Accordingly and in yet another exemplary implementation, provided herein is a use of a suppository for radially directed cytoprotectant sustained release a minimally invasive procedure configured to reduce the radiation exposure to a rectum of a subject in need thereof during external beam radiation therapy for prostate cancer, by injecting a hydrogel spacer between the prostate and the rectum thereby creating a physical separation. In an exemplary implementation, the use comprises: administering a local anesthesia a scrotum of the subject: inserting the distal end of the suppository for radially directed cytoprotectant sustained release to the rectum of a subject in need thereof to a predetermined depth within the rectum; rotating the suppository position directing the release of the cytoprotectant to the portion adjacent the prostate of the subject; inserting to the rectum of the subject a side-fire transrectal ultrasound (TRUS) probe with a stand-off balloon; into the scrotum, inserting a needle operably coupled a syringe containing a saline solution about 1.5 cm above an anal opening of the subject, wherein the needle is configured to reach a perirectal fat located between an anterior rectal wall and the prostate of the subject; advancing the needle through a rectourethralis muscle of the subject to the perirectal fat at a mid-gland level of the prostate; by injecting a predetermined amount of saline, hydrodissecting the space between a Denonvilliers’ fascia and an anterior rectal wall of the subject; decoupling the needle from the syringe; coupling the needle to a static mixer in fluid communication with a hydrogel composition; and injecting the hydrogel composition into the space between the prostate and the rectal wall. Furthermore, the precursor solution and / or the accelerator solution further comprises a cytoprotectant pro-drug or a drug composition comprising: ergotamine, amifostine, Amifostine thiol- amifostine, 2-[(3- Aminopropyl) amino] ethane thiol dihydrochloride (hereinafter WR-1065). pyridoxine or a drug composition comprising one or more of the foregoing.

[0060] In the context of the disclosure, the term “sustained release”, refers to a drug delivery system designed to release an API at a predetermined and controlled rate over an extended period. This approach aims to maintain therapeutically effective levels of the drug in the body for a prolonged duration, typically reducing dosing frequency and minimizing fluctuations in drug concentration. The term “Controlled rate” used throughout the specification shall apply to dosage forms, matrices, particles, coatings, portions thereof, or compositions that alter the release of an active ingredient in any manner. Types of controlled release include burst, modified, prolonged, sustained, extended, delayed, their combination and the like.Docket No. XPH0005PCT

[0061] The mechanism for the sustained release of the cytoprotectants disclosed herein, can be achieved through various methods. In an exemplary implementation the active ingredient is dispersed or encapsulated within a biodegradable polymer matrix. As the polymer degrades over time, it allows for the gradual release of the drug. This process can be tailored to achieve specific release profiles by selecting appropriate polymers and adjusting formulation parameters. One of the primary mechanisms for sustained release from biodegradable polymers is diffusion in moving boundaries. In this process, the drug molecules slowly migrate through the polymer matrix and into the surrounding environment as the polymer swells and degrades. The rate of diffusion is influenced by factors such as the polymer's molecular weight, crystallinity, and hydrophobicity, as well as the size and solubility of the drug molecules. By carefully selecting and modifying these properties, the diffusion rate and, consequently, the drug release profile can be controlled, for example, such that each group of nanoparticles 11 Ij, 112p, and 113q can each release the API at a different profile.

[0062] Additionally or alternatively, biodegradable polymer erosion can be used to create the sustained release profile desired. As the polymer matrix comes into contact with biological fluids, it begins to degrade through hydrolysis or enzymatic breakdown. This erosion process can occur on the surface of the polymer (surface erosion) or throughout the bulk of the material (bulk erosion). The choice of polymer and its degradation characteristics significantly influence whether surface or bulk erosion predominates, which in turn affects the drug release kinetics.

[0063] In certain exemplary implementations, a combination of diffusion and erosion mechanisms contribute to the overall sustained release profile. Initially, drug release is be primarily driven by diffusion, while erosion becomes more dominant as the polymer degrades over time. This interplay between diffusion and erosion results in certain circumstances, in complex release profiles that can be fine-tuned to meet specific therapeutic needs.

[0064] For radio cytoprotectants. which are often used to protect healthy tissues from radiation damage during cancer treatments, sustained release formulations can be particularly beneficial. These formulations can help maintain therapeutically effective levels of the cytoprotectant in the body throughout the course of radiation therapy, thereby reducing side effects and improving treatment outcomes.

[0065] The choice of biodegradable polymer for such applications takes into consideration the desired release profile, as well as other factors, such as, for example, biocompatibility and theDocket No. XPH0005PCTpotential interactions between the polymer, the radio cytoprotectant, and the biological environment.

[0066] Each biodegradable polymer used in the compositions and methods disclosed has unique properties that influence drug release, degradation rate, and biocompatibility. For example, the nanoparticles are composed of PLGA whereby release rates are controlled through adjustments in the ratio between lactic acid and glycolic acid.

[0067] Encapsulation techniques are used in yet another exemplary implementation, to achieve the desired sustained release profiles. Methods such as (fast) solvent evaporation, spray drying, and hot melt extrusion are commonly employed to incorporate drugs into polymer matrices, effectively creating polymer glasses. The choice of technique affect in certain implementations, the distribution of the drug within the polymer, the morphology of the resulting nanoparticles, and the release characteristics of the formulation.

[0068] In the context of the disclosure, the term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable nontoxic acids and bases, including inorganic and organic acids and bases. The term “pharmaceutically acceptable salt” also refers to a salt prepared from an API (API), referring to the cytoprotectant pro-drug or the drug in the composition having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to. hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)-amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N- (hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)-amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. Moreover, the term “pharmaceutically acceptable salt” also refers to a salt prepared from the API, e.g., amifostine, 2-[(3-Aminopropyl) amino] ethane thiol dihydrochloride (hereinafter WR-1065), having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid. Suitable acids can be, but are not limited to, hydrogen sulfate, citricDocket No. XPH0005PCTacid, acetic acid, oxalic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0069] The terms “first.” “second,” and the like, herein do not denote any order, quantity, or importance, but rather are used to denote one element from another. The terms “a”, “an” and “the” herein do not denote a limitation of quantity, and are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The suffix “(s)” as used herein is intended to include both the singular and the plural of the term that it modifies, thereby including one or more of that term (e.g., the tumor(s) includes one or more tumor).

[0070] Reference throughout the specification to “one exemplary implementation”, “another exemplary implementation”, “an exemplary implementation”, and so forth, means that a particular element (e.g., feature, structure, and / or characteristic) described in connection with the exemplary implementation is included in at least one exemplary implementation described herein, and may or may not be present in other exemplary implementations. In addition, it is to be understood that the described elements may be combined in any suitable manner in the various exemplary implementations.

[0071] Accordingly and in an exemplary implementation, provided herein is a generally cylindrical, elongated suppository configured for radially directed, sustained release delivery of cytoprotectant, defining a longitudinal axis, a distal end and a proximal end, the suppository comprising, a core; a cytoprotectant pro-drug or the drug composition dispersed or dissolved within the core; a cytoprotectant pro-drug or the drug composition dispersed asymmetrically or dissolved in one or more layers optionally an intermediate layer surrounding the core; and optionally an external layer, wherein the cytoprotectant pro-drug or the drug composition is encapsulated within a plurality of nanoparticles adapted, sized and configured to sustainably release the cytoprotectant, wherein (i) the core is comprised of a hydrophobic base, (ii) the core further comprises a mucoadhesive polymer composition, the suppository (iii) comprising the intermediate layer surrounding the core (iv). comprising the external layer, wherein (v) the cytoprotectant pro-drug or the drug composition comprises, ergotamine, amifostine, AmifostineDocket No. XPH0005PCTthiol- amifostine, 2-[(3-Aminopropyl)amino]ethanethiol dihydrochloride (hereinafter WR- 1065), pyridoxine or a cytoprotectant drug composition comprising one or more of the foregoing, wherein (vi), the plurality of nanoparticles are formed of a biodegradable polymer selected from the group comprising, poly(lactic-co-glycolic acid) (PLGA), Polycaprolactone (PCL), Poly(lactic acid) (PLA), gelatin, or a biodegradable polymer composition comprising one or more of the foregoing, (vii) while the intermediate layer is comprised of a mucoadhesive polymer blend comprising, chitosan, polyoxyethylene-polyoxypropylene block polymer (poloxamer 407), carboxypolymethylene (carbopol), Hydroxypropyl Methylcellulose (HPMC), hydroxylpropyl cellulose (HPC) , Hypromellose, starch, polyvinylpyrollidone (PVP), xanthan gum, or a mucoadhesive composition comprising one or more of the foregoing, wherein (viii) the plurality of nanoparticles are distributed at axially even concentration and radially forming a gradient having a radial peak concentration, wherein (ix) the external layer further comprises a visual marking of the radial peak concentration, and wherein (x) the core is comprised of a hydrophobic composition comprising, cocoa butter, hydrogenated vegetable oils, and hard fats, a synthetic hard fat selected from the group consisting of, Witepsol H15, Fattibase, Wecobee, Suppocire, or Hydrokote, or a hydrophobic composition comprising one or more of the foregoing.

[0072] In another exemplary implementation, provided herein is a method of protecting a portion of the rectum from radiation damage during radiation therapy of a tissue or an organ in a subject in need thereof, using a suppository for radially directed cytoprotectant sustained release having a proximal end and a distal end, the method comprising, inserting the distal end of the suppository for radially directed cytoprotectant sustained release to a rectum of a subject in need thereof to a predetermined depth within the rectum; rotating the suppository position directing the release of the cytoprotectant to the portion sought to be protected from irradiation; validating the location of the distal end; validating the radially directed position of the suppository; and exposing the organ or the tissue sought to be irradiated to ablative radiation, wherein (xi) the organ or tissue sought to be protected is a duodenum, a jejunum, a large intestine, a small intestine, a pancreas, a uterus, a prostate, an ovary, or a bladder, (xii) the step of exposing the organ or the tissue sought to be irradiated to ablative radiation comprises, using fractionated stereotactic body radiation therapy, exposing the organ or the tissue sought to be irradiated to between 1 and about 5 irradiation fractions, wherein (xiii) the core is comprised of a hydrophobic base, (xiv) the core further comprises a mucoadhesive composition (xv), wherein theDocket No. XPH0005PCTcytoprotectant pro-drug, the drug composition, or its pharmaceutically acceptable salt, each comprises, ergotamine, amifostine, Amifostine thiol- amifostine, 2-[(3- Aminopropyl) amino] ethane thiol dihydrochloride (hereinafter WR-1065). pyridoxine or a drug composition comprising one or more of the foregoing, wherein (xvi) the suppository comprises, a core; a cytoprotectant pro-drug or the drug composition dispersed asymmetrically within the core; optionally an intermediate layer surrounding the core; and optionally an external layer, wherein the cytoprotectant pro-drug or the drug composition is encapsulated within a plurality of nanoparticles adapted, sized and configured to sustainably release the cytoprotectant, (xvii) the plurality of nanoparticles are formed of a biodegradable polymer selected from the group comprising, poly(lactic-co-glycolic acid) (PLGA), Polycaprolactone (PCL), PolyQactic acid) (PLA), gelatin, or a biodegradable polymer composition comprising one or more of the foregoing, wherein (xviii) the intermediate layer is comprised of a mucoadhesive polymer blend comprising, chitosan, polyoxyethylene-polyoxypropylene block polymer (poloxamer 407), carboxypolymethylene (carbopol), Hydroxypropyl Methylcellulose (HPMC), hydroxylpropyl cellulose (HPC) , Hypromellose, starch, polyvinylpyrollidone (PVP), xanthan gum, or a mucoadhesive composition comprising one or more of the foregoing, and (xix), further defining a longitudinal axis, wherein the plurality of nanoparticles are distributed at axially even concentration and radially forming a gradient having a radial peak concentration, wherein (xx) the external layer further comprises a visual marking of the radial peak concentration, (xxi) wherein the core is comprised of a hydrophobic composition comprising, cocoa butter, a synthetic hard fat selected from the group consisting of, Witepsol H15, Fattibase, Wecobee, Suppocire, or Hydrokote, or a hydrophobic composition comprising one or more of the foregoing, and wherein (xxii) the step of rotating the suppository position comprising radially aligning the marking with the tissue or organ sought to be irradiated.

[0073] In yet another exemplary implementation, provided herein is a use of a suppository for radially directed, controlled release delivery of a cytoprotectant in a minimally invasive procedure configured to reduce the radiation exposure to a rectum of a subject in need thereof during external beam radiation therapy for prostate cancer, by injecting a hydrogel spacer between the prostate and the rectum thereby creating a physical separation, wherein (xxiii) the suppository comprises, a core; a cytoprotectant pro-drug or the drug composition dispersed asymmetrically within the core; optionally an intermediate layer surrounding the core; andDocket No. XPH0005PCToptionally an external layer, wherein the cytoprotectant pro-drug, the drug composition, or an acceptable pharmaceutical salt thereof is encapsulated within a plurality of nanoparticles adapted, sized and configured to sustainably release the cytoprotectant, wherein (xxiv) the plurality of nanoparticles are formed of a biodegradable polymer selected from the group comprising, poly(lactic-co-glycolic acid) (PLGA), Polycaprolactone (PCL), PolyQactic acid) (PLA), gelatin, or a biodegradable polymer composition comprising one or more of the foregoing, (xxv) the core further comprises a mucoadhesive composition, wherein (xxvi) the suppository further comprises an intermediate layer, wherein (xxvii) the intermediate layer is comprised of a mucoadhesive polymer blend comprising, chitosan, polyoxyethylenepolyoxypropylene block polymer (poloxamer 407), carboxypolymethylene (carbopol), Hydroxypropyl Methylcellulose (HPMC), hydroxylpropyl cellulose (HPC) , Hypromellose. starch, polyvinylpyrollidone (PVP), xanthan gum, or a mucoadhesive composition comprising one or more of the foregoing, further (xxviii) comprising an external layer, (xxix) the external layer is a pH responsive layer, configured to dissolve at pH of no less than 7.0. and (xxx), further defining a longitudinal axis, wherein the plurality of nanoparticles are distributed at axially even concentration and radially forming a gradient having a radial peak concentration, wherein (xxxi) the external layer further comprises a visual marking of the radial peak concentration, wherein (xxxii) the core is comprised of a hydrophobic composition comprising, cocoa butter, a synthetic hard fat selected from the group consisting of. Witepsol H15, Fattibase. Wecobee, Suppocire. or Hydrokote, or a hydrophobic composition comprising one or more of the foregoing, wherein (xxxiii) the cytoprotectant pro-drug the drug composition or its pharmaceutically acceptable salt comprises, ergotamine, amifostine. Amifostine thiol- amifostine, 2-[(3-Aminopropyl)amino]ethanethiol dihydrochloride (hereinafter WR-1065), pyridoxine or a drug composition comprising one or more of the foregoing, wherein (xxxiv) the minimally invasive procedure configured to reduce the radiation exposure to the rectum during external beam radiation therapy for prostate cancer, by injecting a hydrogel spacer between the prostate and the rectum to create a physical separation therebetween comprises, administering a local anesthesia a scrotum of the subject, inserting to the rectum of the subject a side-fire transrectal ultrasound (TRUS) probe with a stand-off balloon; into the scrotum, inserting a needle operably coupled a syringe containing a saline solution about 1.5 cm above an anal opening of the subject, wherein the needle is configured to reach a perirectal fat located between an anterior rectal wall and theDocket No. XPH0005PCTprostate of the subject; advancing the needle through a rectourethralis muscle of the subject to the perirectal fat at a mid-gland level of the prostate; by injecting a predetermined amount of saline, hydrodissecting the space between a Denonvilliers’ fascia and an anterior rectal wall of the subject; decoupling the needle from the syringe; coupling the needle to a static mixer in fluid communication with a hydrogel composition; injecting the hydrogel composition into the space between the prostate and the rectal wall; removing the TRUS probe from the rectum; inserting the distal end of the suppository for radially directed, controlled release delivery of a cytoprotectant to the rectum of a subject in need thereof to a predetermined depth within the rectum; and rotating the suppository position directing the release of the cytoprotectant to the portion adjacent the prostate of the subject, wherein (xxxv) the hydrogel composition comprises a precursor solution and an accelerator, (xxxvi) the precursor solution and / or the accelerator solution further comprises a cytoprotectant pro-drug or a drag composition comprising, ergotamine, amifostine, Amifostine thiol- amifostine, 2-[(3-Aminopropyl)amino]ethanethiol dihydrochloride (hereinafter WR-1065), pyridoxine or a drug composition comprising one or more of the foregoing.

[0074] While in the foregoing specification the methods of use have been described in relation to certain preferred exemplary implementations, and many details are set forth for purpose of illustration, it will be apparent to those skilled in the art that the disclosure is susceptible to additional exemplary implementations and that certain of the details described in this specification and as are more fully delineated in the following claims can be varied considerably without departing from the basic principles of this invention.

Claims

Docket No. XPH0005PCTWhat is claimed:

1. A generally cylindrical, elongated suppository configured for radially directed, sustained release delivery of cytoprotectant, defining a longitudinal axis, a distal end and a proximal end, the suppository comprising:a) a core;b) a cytoprotectant pro-drug or the drug composition dispersed or dissolved within the core;c) a cytoprotectant pro-drug or the drug composition dispersed asymmetrically or dissolved in one or more layersd) optionally an intermediate layer surrounding the core; ande) optionally an external layer, wherein the cytoprotectant pro-drug or the drug composition is encapsulated within a plurality of nanoparticles adapted, sized and configured to sustainably release the cytoprotectant.

2. The suppository of claim 1, wherein the core is comprised of a hydrophobic base.

3. The suppository of claim 1, wherein the core further comprises a mucoadhesive polymer composition.

4. The suppository of claim 1, comprising the intermediate layer surrounding the core.

5. The suppository of claim 1, comprising the external layer.

6. The suppository of claim 1, wherein the cytoprotectant pro-drug or the drug composition comprises: ergotamine, amifostine. Amifostine thiol- amifostine, 2-[(3-Aminopropyl)amino]ethanethiol dihydrochloride (hereinafter WR-1065), pyridoxine or a drug composition comprising one or more of the foregoing.

7. The suppository of claim 1, wherein the plurality of nanoparticles are formed of a biodegradable polymer selected from the group comprising: poly(lactic-co-glycolic acid) (PLGA), Polycaprolactone (PCL), Poly(lactic acid) (PLA). gelatin, or a biodegradable polymer composition comprising one or more of the foregoing.

8. The suppository of claim 4, wherein the intermediate layer is comprised of a mucoadhesive polymer blend comprising: chitosan, polyoxyethylene-polyoxypropylene block polymer (poloxamer 407), carboxypolymethylene (carbopol), Hydroxypropyl MethylcelluloseDocket No. XPH0005PCT(HPMC), hydroxylpropyl cellulose (HPC) , Hypromellose, starch, polyvinylpyrollidone (PVP), xanthan gum, or a mucoadhesive composition comprising one or more of the foregoing.

9. The suppository of claim 1, wherein the plurality of nanoparticles are distributed at axially even concentration and radially forming a gradient having a radial peak concentration.

10. The suppository of claim 7, wherein the external layer further comprises a visual marking of the radial peak concentration.

11. The suppository of claim 1, wherein the core is comprised of a hydrophobic composition comprising: cocoa butter, hydrogenated vegetable oils, and hard fats, a synthetic hard fat selected from the group consisting of: Witepsol H15, Fattibase, Wecobee, Suppocire, or Hydrokote, or a hydrophobic composition comprising one or more of the foregoing.

12. A method of protecting a portion of the rectum from radiation damage during radiation therapy of a tissue or an organ in a subject in need thereof, using a suppository for radially directed cytoprotectant sustained release having a proximal end and a distal end, the method comprising:a) inserting the distal end of the suppository for radially directed cytoprotectant sustained release to a rectum of a subject in need thereof to a predetermined depth within the rectum;b) rotating the suppository position directing the release of the cytoprotectant to the portion sought to be protected from irradiation;c) validating the location of the distal end;d) validating the radially directed position of the suppository; ande) exposing the organ or the tissue sought to be irradiated to ablative radiation.

13. The method of claim 12, wherein the organ or tissue sought to be protected is a duodenum, a jejunum, a large intestine, a small intestine, a pancreas, a uterus, a prostate, an ovary, or a bladder.

14. The method of claim 12, wherein the step of exposing the organ or the tissue sought to be irradiated to ablative radiation comprises: using fractionated stereotactic body radiation therapy, exposing the organ or the tissue sought to be irradiated to between 1 and about 5 irradiation fractions.

15. The method of claim 12, wherein the core is comprised of a hydrophobic base.Docket No. XPH0005PCT16. The method of claim 12, wherein the core further comprises a mucoadhesive composition.

17. The method of claim 12, wherein the cytoprotectant pro-drug, the drag composition, or its pharmaceutically acceptable salt, each comprises: ergotamine, amifostine, Amifostine thiol-amifostine, 2-[(3-Aminopropyl)amino]ethanethiol dihydrochloride (hereinafter WR- 1065), pyridoxine or a drag composition comprising one or more of the foregoing.

18. The method of claim 12, wherein the suppository comprises:a) a core;b) a cytoprotectant pro-drug or the drug composition dispersed asymmetrically within the core;c) optionally an intermediate layer surrounding the core; andd) optionally an external layer, wherein the cytoprotectant pro-drug or the drug composition is encapsulated within a plurality of nanoparticles adapted, sized and configured to sustainably release the cytoprotectant.

19. The method of claim 18, wherein the plurality of nanoparticles are formed of a biodegradable polymer selected from the group comprising: poly(lactic-co-glycolic acid) (PLGA), Polycaprolactone (PCL), Poly (lactic acid) (PLA), gelatin, or a biodegradable polymer composition comprising one or more of the foregoing.

20. The method of claim 18, wherein the intermediate layer is comprised of a mucoadhesive polymer blend comprising: chitosan, polyoxyethylene-polyoxypropylene block polymer (poloxamer 407), carboxypolymethylene (carbopol), Hydroxypropyl Methylcellulose (HPMC), hydroxylpropyl cellulose (HPC) , Hypromellose, starch, polyvinylpyrollidone (PVP), xanthan gum, or a mucoadhesive composition comprising one or more of the foregoing.

21. The method of claim 20, further defining a longitudinal axis, wherein the plurality of nanoparticles are distributed at axially even concentration and radially forming a gradient having a radial peak concentration.

22. The method of claim 21, wherein the external layer further comprises a visual marking of the radial peak concentration.

23. The method of claim 18 wherein the core is comprised of a hydrophobic composition comprising: cocoa butter, a synthetic hard fat selected from the group consisting of: WitepsolDocket No. XPH0005PCTHl 5, Fattibase, Wecobee, Suppocire, or Hydrokote, or a hydrophobic composition comprising one or more of the foregoing.

24. The method of claim 22, wherein the step of rotating the suppository position comprising radially aligning the marking with the tissue or organ sought to be irradiated.

25. A use of a suppository for radially directed, controlled release delivery of a cytoprotectant in a minimally invasive procedure configured to reduce the radiation exposure to a rectum of a subject in need thereof during external beam radiation therapy for prostate cancer, by injecting a hydrogel spacer between the prostate and the rectum thereby creating a physical separation.

26. The use of claim 25, wherein the suppository comprises:a) a core;b) a cytoprotectant pro-drug or the drug composition dispersed asymmetrically within the core;c) optionally an intermediate layer surrounding the core; andd) optionally an external layer, wherein the cytoprotectant pro-drug, the drug composition, or an acceptable pharmaceutical salt thereof is encapsulated within a plurality of nanoparticles adapted, sized and configured to sustainably release the cytoprotectant.

27. The use of claim 26, wherein the plurality of nanoparticles are formed of a biodegradable polymer selected from the group comprising: poly(lactic-co-glycolic acid) (PLGA), Polycaprolactone (PCL), Poly(lactic acid) (PLA), gelatin, or a biodegradable polymer composition comprising one or more of the foregoing.

28. The use of claim 26, wherein the core further comprises a mucoadhesive composition.

29. The use of claim 26, wherein the suppository further comprises an intermediate layer.

30. The use of claim 29, wherein the intermediate layer is comprised of a mucoadhesive polymer blend comprising: chitosan, polyoxyethylene-polyoxypropylene block polymer (poloxamer 407), carboxypolymethylene (carbopol), Hydroxypropyl Methylcellulose (HPMC), hydroxylpropyl cellulose (HPC) , Hypromellose, starch, polyvinylpyrollidone (PVP), xanthan gum, or a mucoadhesive composition comprising one or more of the foregoing.

31. The use of claim 26, comprising an external layer.

32. The use of claim 31, wherein the external layer is a pH responsive layer, configured to dissolve at pH of no less than 7.0.Docket No. XPH0005PCT33. The use of claim 26, further defining a longitudinal axis, wherein the plurality of nanoparticles are distributed at axially even concentration and radially forming a gradient having a radial peak concentration.

34. The use of claim 31, wherein the external layer further comprises a visual marking of the radial peak concentration.

35. The use of claim 26 wherein the core is comprised of a hydrophobic composition comprising: cocoa butter, a synthetic hard fat selected from the group consisting of: Witepsol H15, Fattibase. Wecobee, Suppocire, or Hydrokote, or a hydrophobic composition comprising one or more of the foregoing.

36. The use of claim 26, wherein the cytoprotectant pro-drug the drug composition or its pharmaceutically acceptable salt comprises: ergotamine, amifostine, Amifostine thiol-amifostine, 2-[(3-Aminopropyl)amino]ethanethiol dihydrochloride (hereinafter WR- 1065), pyridoxine or a drug composition comprising one or more of the foregoing.

37. The use of claim 25, wherein the minimally invasive procedure configured to reduce the radiation exposure to the rectum during external beam radiation therapy for prostate cancer, by injection of a hydrogel spacer between the prostate and the rectum to create a physical separation therebetween comprises:a) administering a local anesthesia a scrotum of the subject;b) inserting to the rectum of the subject a side-fire transrectal ultrasound (TRUS) probe with a stand-off balloon;c) into the scrotum, inserting a needle operably coupled a syringe containing a saline solution about 1.5 cm above an anal opening of the subject, wherein the needle is configured to reach a perirectal fat located between an anterior rectal wall and the prostate of the subject; d) advancing the needle through a rectourethralis muscle of the subject to the perirectal fat at a mid-gland level of the prostate;e) by injecting a predetermined amount of saline, hydrodissecting the space between a Denonvilliers’ fascia and an anterior rectal wall of the subject;f) decoupling the needle from the syringe;g) coupling the needle to a static mixer in fluid communication with a hydrogel composition;Docket No. XPH0005PCTh) injecting the hydrogel composition into the space between the prostate and the rectal wall;i) removing the TRUS probe from the rectum;j) inserting the distal end of the suppository for radially directed, controlled release delivery of a cytoprotectant to the rectum of a subject in need thereof to a predetermined depth within the rectum; andk) rotating the suppository position directing the release of the cytoprotectant to the portion adjacent the prostate of the subject.

38. The use of claim 36, wherein the hydrogel composition comprises a precursor solution and an accelerator.

39. The use of claim 38, wherein the precursor solution and / or the accelerator solution further comprises a cytoprotectant pro-drag or a drag composition comprising: ergotamine, amifostine, Amifostine thiol- amifostine, 2-[(3-Aminopropyl)amino]ethanethiol dihydrochloride (hereinafter WR-1065). pyridoxine or a drug composition comprising one or more of the foregoing.

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