Traceable oral formulations and uses thereof

Abstract

The disclosure relates to solid oral formulations and their use. More specifically, the disclosure relates to compositions, methods and uses of solid oral formulations comprising a core- shell structure, with an active pharmaceutical ingredient, a radio-opaque tracer and a composition, which, following contact with a bodily fluid, becomes mucoadhesive.

Description

TRACEABLE ORAL FORMULATIONS AND USES THEREOFBACKGROUND

[0001] The disclosure is directed to solid oral formulations and their use. More specifically, the disclosure is related to compositions, methods and uses of solid oral formulations comprising a core-shell structure, with an active pharmaceutical ingredient, a radio-opaque tracer and a composition, which, following contact with a bodily fluid, becomes mucoadhesive.

[0002] The major limiting factor in delivering the appropriate tumoricidal dose of radiation is toxicity to normal tissue in adjacent organs. This issue is highlighted by solid tumors of the abdomen and pelvis, such as pancreatic and prostate adenocarcinoma, which often cannot achieve tumoricidal doses without significant morbidity to the gastrointestinal (GI) tract. For example, pancreatic cancer often occurs in the head of the pancreas, which shares blood supply with the duodenum - a radiosensitive portion of the intestinal tract. Tumors of the pancreatic head require doses that exceed 77 Gy to achieve local control, an often impossible endeavor to administer safely, because the adjacent duodenum can only tolerate a maximum of 50 Gy without causing bleeding ulcers or perforation. Unfortunately for patients with unresectable pancreatic cancer, there are no effective treatments that specifically protect the GI tract from this radiotoxicity, and thus ablative radiotherapy in non-resectable pancreatic cancer is currently impractical.

[0003] It was found previously, that certain orally administered cytoprotectant compounds accrete preferentially in the radiation-sensitive tissues adjacent to the target organ, allowing, under certain circumstances, achieving a much higher dose of radiation.

[0004] However, in order to ensure the therapeutically effective accretion of the cytoprotectant API in the tissue adjacent to the radiated organ prior to the commencement of radiation, it is necessary to be able to ascertain the amount and location of the cytoprotectant API.SUMMARY

[0005] In an exemplary implementation, provided is a pharmaceutical composition of a solid oral drug delivery system comprising: a core or a plurality of mini cores (interchangeable withcore sub-units), or core sub-units (in other words, beads, pellets, mini-tabs, powder and the like, each) comprising: an active pharmaceutical ingredient (API), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof; a radio-opaque contrast tracer; and a bio-adhesive composition; with or without a subcoating comprising polymer; and an outer lag-time coating comprising A pH depended coating polymer such as an acid resistant pharmaceutically acceptable coating polymer.

[0006] In another exemplary implementation, provided herein is a method of determining the onset for irradiating a predetermined location on at least one of: a first tissue, and a first organ, the at least one of the first tissue, and the first organ are each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to radiation, the method comprising: administering to the patient an oral composition comprising: a core or a plurality of mini cores (interchangeable with core sub-units) (in other words, beads, pellets, mini-tabs, powder and the like, each) comprising: an active pharmaceutical ingredient (API), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof a radio-opaque tracer, and a bio-adhesive composition; sub-coating comprising a polymer; and an outer lag-time coating comprising coating the sub coated core with A pH depended coating polymer such as an acid resistant pharmaceutically acceptable coating polymer; using an imaging device, imaging the at least one of: the adjacent second tissue, and the adjacent second organ, each adjacent to the predetermined location sought to be irradiated in the at least one of: the first tissue, and the first organ; detecting the radio-opaque contrast tracer in a location on the at least one of: the adjacent second tissue, and the adjacent second organ, adjacent to the predetermined location sought to be irradiated; and upon detecting the radio-opaque contrast tracer commencing irradiation of the predetermined location of the at least one of: the first tissue, and the first organ.

[0007] In yet another exemplary implementation, provided herein is the use of an oral composition comprising: a core or a plurality of mini cores (interchangeable with core sub-units) (in other words, beads, pellets, mini-tabs, powder and the like, each) comprising: an active pharmaceutical ingredient (API), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof a radioopaque contrast tracer; and a bio-adhesive composition; optionally a sub-coating comprising polymer; and an outer lag-time coating comprising a pH depended coating polymer such as anacid resistant pharmaceutically acceptable coating polymer for the process of determining the onset for irradiating a predetermined location of at least one of: a first tissue, and a first organ, the first tissue, and the first organ each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to radiation.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The features of the methods for selectively accreting a radioprotectant in a radiationsensitive healthy tissue and / or organ, prior to exposure of an adjacent tissue and / or organ to otherwise toxic radiation, will become apparent from the following detailed description when read in conjunction with the drawings, which are exemplary, not limiting, and wherein like elements arc numbered alike in several figures and in which:

[0009] FIG. 1, shows the release profile of a certain exemplary implementation of the solid oral pharmaceutical composition disclosed; and

[0010] FIG. 2A, is a schematic representation of the solid oral pharmaceutical composition, with FIG. 2B illustrating a core comprised of multiple components;

[0011] FIG. 3 A, shows the release profile of the API from an exemplary implementation of the composition, with FIG. 3B, showing the release profile of the radio-opaque contrast tracer.

[0012] FIG. 4, depicts time series for dissolution;

[0013] FIG. 5, depicts the accretion of the API along the duodenum;

[0014] FIG. 6, is a schematic of the gut sections;

[0015] FIG. 7A, illustrates the fractional API concentration in each of the zones described in FIG. 5, and FIG. 7B illustrates the fractional concentration of adsorbed API, relative to the total amount of adsorbed API in the gut;

[0016] FIG. 8, shows the release profile of oral API from another exemplary implementation of the composition of Example III; and

[0017] FIG. 9A shows a comparative dissolution profile in acid and buffer media, with FIG. 9B, illustrating the dissolution profile of the compositions in FIG. 9A, in pH 5.8 media.

[0018] 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 describedin 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

[0019] The disclosure relates in one exemplary implementation to compositions, methods and uses of solid oral formulations comprising a core-shell structure, or a plurality of mini cores (interchangeable with core sub-units) (in other words, beads, pellets, mini-tabs, powder and the like, each) with an active pharmaceutical ingredient (API), or a prodrug or a pharmaceutically acceptable salt thereof; a radio-opaque tracer and a composition, which, following contact with a bodily fluid, becomes mucoadhesive.

[0020] Pancreatic cancer requires a biologically equivalent dose of more than 77 Gy to have a clinical (tumoricidal) benefit. Currently, this is not practicable for most pancreatic tumors unless they are in a location that is at least 1cm away from the bowel wall. In addition to the use of oral WR-2721 for improving the outcomes for pancreatic cancer patients, a similar strength Gy may be required for other abdominal or pelvic cancers that cannot be treated definitively with radiation due to GI toxicity, such as hepatobiliary tumors, retroperitoneal sarcomas, or metastatic disease within the abdomen.

[0021] Accordingly and in an exemplary implementation, provided herein is a pharmaceutical composition of a solid oral drug delivery comprising: a core or a plurality of mini units comprising: an effective amount of an active pharmaceutical ingredient, or prodrug or a pharmaceutically acceptable salt thereof; a radio-opaque contrast tracer; and a bio-adhesive composition; with or without a sub-coating comprising polymer; and an outer lag-time coating comprising a pH depended coating polymer such as an acid resistant pharmaceutically acceptable coating polymer.

[0022] In an exemplary implementation, the API is the prodrug S-2-(3- aminopropylamino)ethyl dihydrogen phosphorothioate (hereinafter WR-2721) having the formula:given orally at a predetermined time before radiation. Following delayed disintegration, in certain exemplary implementation, if formulated as a pro-drug, the pro-drug is rapidly activated by the endogenous digestive enzymes in the duodenum and jejunum to its active 2-[(3- Aminopropyl) amino] ethanethiol dihydrochloride (hereinafter WR-1065). It is noted, that the prodrug API includes also 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:

[0023] Due to the increased expression of non-tissue specific alkaline phosphatase in the intestine, enterally activated form of WR-2721 would accumulate in high concentrations in the intestines and provide selective localized radioprotection with fewer systemic side effects. This can be useful during radiation for pancreatic cancer, since the duodenum and jejunum arc doselimiting organs preventing ablative treatments. The disclosure shows that oral WR-2721 is an effective radioprotector against otherwise lethal doses of radiation directed to the upper abdomen. Furthermore, demonstrated herein is the fact that the drug is well tolerated and accretes its active metabolite, WR-1065, in significantly higher levels in the GI tract compared to the serum, liver or spontaneous pancreatic tumors. Since the oral dosage form does not get absorbed into the blood stream, the ingested material remains on the duodenum’s walls, protecting the organ from radiation (see e.g., FIG.s 4, 6A, 6B). Such a localization effect is not accessible by IV administration of WR-2721.

[0024] 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. Also, as used herein, the term “accrete” and its grammatical derivatives e.g., “accretive” or “accretivly”, refer in an exemplary implementationto the gradual increase in concentration of the active metabolite in the target tissue and / or organ that is to be radiation-protected.

[0025] In an exemplary implementation, the API 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-drug 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 drug conjugate (active form).

[0026] The oral 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.

[0027] In several tissue / organ imaging technologies (e.g., X-ray and computed tomography (CT), positron emission tomography (PET) and single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), ultrasound imaging, optical imaging) the contrast in the generated image may be enhanced by introducing into the zone being imaged an agent (a “contrast agent”), which affects the organ or the methodology being used to increase the contrast between the imaged organ / tissue and its surrounding. For example, in MRI, the contrast agent is operable to affect the spin re-equilibration (e.g., time) characteristics of nuclei (the “imaging nuclei” which generally are protons and more especially water protons) which are responsible for the resonance signals from which the images are generated.

[0028] The enhanced contrast thus obtained enables particular organs or tissues (e.g. blood, blood vessel walls, the small intestine walls, the large intestine walls and the like lumen walls) to be visualized more clearly by increasing or by decreasing the brightness of the image of the particular organ or tissue relative to that of its surroundings. MRI employs a magnetic field, radio frequency energy and magnetic field gradients to make images of the body. The contrast or signal intensity differences between tissues mainly reflect the Tl (longitudinal) and T2 (transverse) relaxation values and the proton density (effectively, the free water content) of the tissues. In changing the signal intensity in a region of a patient by the use of a contrast agent, several possible approaches are available. For example, a contrast medium can be used to change either the Tl, the T2 or the proton density of the tissue containing the contrast agent. As used herein the term “contrast” refers to the relative difference of signal intensities in two adjacent regions of an image. Image contrast is heavily dependent on the chosen imaging technique (i.e., TE, TR, TI), and is associated with such parameters as proton density and Tl or T2 relaxation times. For example, the pharmaceutical; composition, using the radio-opaque contrast tracer can be imaged after administration using MRI, whereby post disintegration and release of the core, the radio-opaque contrast tracer will be discharged for example, in the duodenum providing the necessary contrast for imaging using MRI. Accordingly, the radio-opaque contrast tracer used in the pharmaceutical compositions, methods and uses disclosed herein, can be, for example, zirconium oxide, aluminum oxide, barium sulphate, sodium amidotrizoate, meglumine amidotrizoate, sodium diatrizoate, sodium calcium edetate, lodixanol, or triphenyl bismuth, diatrizoate (see e.g., FIG.3), metrizoate, iothalamate, ioxaglate, iopamidol, iohexol, ioxilan, iopromide, iodixanol, iobitridol, ioversol, or a composition comprising one or more of the foregoing. In an exemplary implementation, the radio-opaque contrast tracer comprises about NET 3% (w / w tablet).

[0029] In the context of the disclosure, the term “radio-opaque agent” refers to any substance or agent which blocks, absorbs, scatters, or reflects any radiation outside the visible light spectrum, including, but not limited to. X-rays (in the wavelength range of 0.01 to 10 nm), beta rays (e.g., having velocities of about 35,000 to 180,000 miles per second), gamma rays (having an energy in the range of 104to 107eV), radiation used in radiation therapy (e.g., therapy to treat cancer), and other harmful radiation (such as that resulting from nuclear disasters and nuclear weapons). Suitable radio-opaque agents include, but are not limited to, those comprisingplatinum, gold, silver, bismuth, mercury, lead, barium, calcium, zinc, aluminum, iron, gallium, iodine, tungsten, and any combination of any of the foregoing. Other suitable radio-opaque agents include, but are not limited to, those commercially available as radio-opaque agents for medical uses, such as ionic and nonionic intravenous radiocontrast agents, diagnostic barium and gastrographin preparations, and gallium preparations.

[0030] In an exemplary implementation, the radio-opaque tracer can be selected based on its (i.e., the tracer’s) affinity to the tissue sought to be protected. In other words, while in certain implementations, the radio-opaque tracer’s function is to provide indication of the tablet (or core sub-units, e.g., pellets, mini-tablets etc.) disintegration and the targeted release of the API, in certain additional, or alternative implementations, the radio-opaque tracer can function as an indicator of the API coverage of the area sought to be irradiated. Furthermore, depending on the radio-opaque tracer used, the interference with the irradiation, or potentially damaging effects of the radio-opaque tracer in focusing absorption of radiation to the protected tissuc / organ, will dictate a radio-opaque tracer that has lower affinity to the tissue / organ sought to be protected. In the context of the disclosure, the term “binding affinity” refers to the strength of the binding of a single radio-opaque tracer to a tissue / organ site. Binding affinity depends on the closeness of stereochemical fit between single radio-opaque tracer to a tissue / organ site, on the size of the area of contact between them, on the distribution of charged and hydrophobic groups, etc.

[0031] Furthermore, the core further comprises the 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 API to a wall of a body lumen, such as the duodenum and jejunum. Furthermore, with typically only 25 cm in duodenum length, drugs taken by oral administration always go quickly through the duodenum. Therefore, the bio-adhesive 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 duodenum, or jejunum), following the calculated lag in release, and to facilitate intimate contact of the dosage form with the underlying duodenum 1 inside surface to improve and enhance the efficacy of the therapeutically effective amount of the API. 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 theability 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 Jim 14; 1J(6): 748-64. doi: 10.1002 / mabi.201000388.Epub 2010 Dec. 27]. In an exemplary implementation, the bioadhesive 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. In an exemplary implementation, the bio-adhesive compositions comprises between about NET 2% (w / w tablet).

[0032] The core in the compositions disclosed used in the methods described is coated with a sub-coating of a polymer, and with enteric coating referring to a polymer which is preferentially soluble in the less acid environment of the intestine relative to the more acid environment of the stomach. The sub-coat consequently lying beneath the outer lag-time coating comprising the acid-resistant, pharmaceutically acceptable coating polymer. Suitable sub-coat materials include Hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC) or polyvinyl alcohol (PVA)

[0033] The Functional coating may be an essentially conventional coating material, for example, polymers that can be dissolved at pH value of no less than 5.0. The polymer can be, for example poly(methacrylic acid-co-ethylacrylate, poly(methacylilc acid-co-methyl methacrylate), poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3 , cellulose acetate phthalate, cellulose acetate succinate, methyl cellulose phthalate, methylhydroxy propylcellulose phthalate, ethyl hydroxycellulose phthalate, poly(vinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl aerylate-methacrylic acid copolymer, and methacrylate- methacrylic acid-octyl acrylate copolymer, and / or enteric polymers such as cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethyl hydroxy cellulose phthalate, polyvinyl acetate phthalate, styrene-maleic mono-ester copolymer, methacrylic acid methyl methacrylate copolymer methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, etc. These may be used either alone or in combination, or together with other polymers than those mentioned above. The Functional coating may also include insolublesubstances which are neither decomposed nor solubilized in living bodies, such as alkyl cellulose derivatives such as ethyl cellulose, crosslinked polymers such as styrene-divinylbenzene copolymer, polysaccharides having hydroxyl groups such as dextran, cellulose derivatives which are treated with bifunctional crosslinking agents such as epichlorohydrin, dichlorohydrin, 1, 2-, 3, 4-diepoxybutane, etc. The enteric Functional coating may also include starch and / or dextrin. For example, the enteric-coating materials are the pharmaceutically acceptable methacrylic acid copolymer which are copolymers, anionic in character, based on methacrylic acid and methyl methacrylate, for example having a ratio of free carboxyl groups: methyl-esterified carboxyl groups of 1:>3, e.g. around 1:1 or 1:2, and with a mean molecular weight of 135,000.

[0034] Such Functional polymers are sold under the trade name Eudragit™, such as the Eudragit L series e.g. Eudragit L 12.5™, Eudragit L 12.5P™, Eudragit L100™, Eudragit L 1 GO- 55™, Eudragit L-30™, Eudragit L-30 D-55™, the Eudragit S™ series e.g. Eudragit S 12.5, Eudragit S 12.5P™, Eudragit SI 00™, the Eudragit NE™ series e.g. Eudragit NE 30D™, the Eudragit RL™ series, e.g. Eudragit RL 12.5™, Eudragit RL 100™, Eudragit RL PO™, Eudragit RL 30D ™, and the Eudragit RS™ series e.g. Eudragit RS 12.5™, Eudragit RS 100™, Eudragit RS PO™, and Eudragit RS 30D™. Furthermore, some of these polymers are known and sold as enteric polymers, for example having a solubility in aqueous media at pH 5.5 and above, such as the commercially available “EUDRAGIT” (Trade Mark) enteric polymers, such as “Eudragit L100-55” (Trade Mark) or OPADRY® Enteric (94 Series) i.e. a cationic polymer synthesised from dimethylaminoethyl methacrylate. Furthermore, some of these polymers are known and sold as enteric polymers, for example having a solubility in aqueous media at pH 5.0 and above, such as the commercially available Functional polymers are sold under the trade name OPADRY Enteric-91 series. OPADRY Enteric-91 series the enteric Functional coating may also include Polyvinyl Acetate Phthalate (Phthalavin enteric coating polymer, PVAP).

[0035] Moreover, may be used either alone or with a plasticizer. Such coatings are normally applied using a liquid medium, and the nature of the plasticizer depends upon whether the medium is aqueous or non-aqueous. Aqueous plasticizers include propylene glycol or “Citroflex” or Citroflex A2” (Trade Marks) (mainly triethyl citrate or acetyl triethyl citrate). Non-aqueous plasticizers include these, and also diethyl and dibutyl phthalate and dibutyl sebacate. The quantity of plasticizers included will be apparent to those skilled in the art. The enteric coating may also include an anti-tack agent such as talc, silica or glyceryl monostearate. The quantity ofplasticizers and anti-tack agent may be generally conventional to the art. Typically the coating may include around 10-40 wt. % plasticizer and up to around 50 wt. % of anti-tack agent, e.g. 2- 20 wt. % of anti-tack agent.

[0036] Enteric coating may be applied to the core by dissolving or suspending the enteric coating materials in a suitable medium, such as water, ethanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, etc. or mixtures thereof, and the resultant solution or suspension may be sprayed on the core to coat them, followed by drying sufficiently with an airflow and screening. In addition, in certain exemplary implementations, an over-coat is also applied. Suitable over-coat materials include copolymers of methacrylic acid and methyl methacrylate, and hydroxypropyl methyl cellulose. The over-coat may be of the same material as the entericcoat. Typically, such coatings may be applied by known techniques of aqueous film coating, using known unit operations.

[0037] In an exemplary implementation, and as illustrated in FIG. 1, the pharmaceutical composition exhibits a dissolution of not less than 85% of the API within 30 minutes as measured with a paddle apparatus with or without sinker at 75 - 100 revolutions per minute over 30 minutes in 150-900 ml, 500 mL of aqueous buffered solution at a pH of 5.5- pH 6.0.However, the pharmaceutical composition exhibits a dissolution of not more than 10% of the API after 2 hours in 0.1N HC1. Moreover, the pharmaceutical composition exhibits a dissolution of not more than 10% of the API in 150-900 ml, or 500 mL of aqueous 0.1 N HC1 at 37°C, as measured with or without sinker with a paddle apparatus at 75rpm during 120 minutes, followed not less than 85% of the API over additional 30 minutes at 75 rpm in 500 mL of aqueous buffered solution at a pH of 5.5 at 37°C. The pharmaceutical composition exhibits a dissolution of not more than 10% of the API after 2 hours in 0.1N HC1. Moreover, the pharmaceutical composition exhibits a dissolution of not more than 10% of the API in 150-900 ml, or 500 mL of aqueous 0.1 N HC1 at 37°C, as measured with or without sinker with a paddle apparatus at lOOrpm during 120 minutes, followed not less than 85% of the API over additional 30 minutes at 100 rpm in 500 mL of aqueous buffered solution at a pH of 5.8 at 37°C.

[0038] These compositions may also contain excipients such as fillers disintegrant, flowing agent, gliadents, binders, wetting agents, lubricants, and / or antioxidants addition, the oral compositions provided herein may also comprise an acceptable buffering agent mixture (e.g., tris buffer, phosphate buffer, and the like); a sweetening agent; and / or at least one flavor agent.

[0039] Actual dosage levels of the active ingredients in the pharmaceutical compositions provided herein, can be varied so as to obtain an amount of the active ingredient or the prodrug (e.g., WR-2721) that is effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound provided herein, can employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs compounds (e.g., oxaliplatin, irinotecan, fluorouracil, leucovorin, gemcitabine in the case of metastatic pancreatic cancer), and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors and their combination.

[0040] In an exemplary implementation, the compositions disclosed arc used in the methods described. Accordingly, provided herein is a method of determining the onset for irradiating a predetermined location on at least one of: a first tissue, and a first organ, the at least one of the first tissue, and the first organ are each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to radiation, the method comprising: administering to the patient an oral composition comprising: a core or a plurality of mini cores (interchangeable with core sub-units) (in other words, beads, pellets, mini-tabs, powder and the like, each) comprising: an active pharmaceutical ingredient (API), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof, a radioopaque tracer, and a bio-adhesive composition; an optional sub-coating comprising a polymer; and an outer lag-time coating comprising coating the sub coated core with an acid resistant pharmaceutically acceptable coating polymer; using an imaging device, imaging the at least one of: the adjacent second tissue, and the adjacent second organ, each adjacent to the predetermined location sought to be irradiated in the at least one of: the first tissue, and the first organ; detecting the radio-opaque contrast tracer in a location on the at least one of: the adjacent second tissue, and the adjacent second organ, adjacent to the predetermined location sought to be irradiated; and upon detecting the radio-opaque contrast tracer commencing irradiation of the predetermined location of the at least one of: the first tissue, and the first organ.

[0041] In certain exemplary implementations, the core can be customized for the intended protection, by incorporating into the core a plurality of beads, mini tablets and / or pellets and / or powder comprising the API compositions disclosed or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof a radio-opaque contrast tracer; and a bio-adhesive and the pH depended polymer such as enteric coating. It is noted, that the mini tablets beads, and / or pellets, and / or mini-tablets used can have an enteric coating that can be configured to release the API with the mucoadhesive such that the API will be released over a larger area of the organ / tissue sought to be protected. In an exemplary implementation, the multi-particles’ core can be customized ad-hoc by the physician to obtain optimal coverage of the area to be protected. As illustrated in FIG.s 2A, and 2B, the core can have API 100, with contrast agent 200 and enteric coating 300. An additional or alternative configuration is illustrated in FIG. 2B, where the core comprises multiple particles, where Functional or enteric coating 301 , 302, 303 all have different composition and / or thickness, configured when release, to cause API 100 to be released over a predetermined area length at a predetermined location e.g., along the duodenum.

[0042] 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 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 hydroxysubstituted 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 alky 1-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] ethanethiol dihydrochloride (hereinafter WR-1065), having a basic functional group, such as an amino functional group, and a pharmaceutically acceptableinorganic or organic acid. Suitable acids can be, but are not limited to, hydrogen sulfate, citric acid, 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.

[0043] In the context of the disclosure, the language “at least one of: a first tissue, and a first organ” (in other words, first tissue and / or organ) is intended to describe the tissue and / or organ where the tumor sought to be irradiated is located. Conversely, the language “at least one of : an adjacent second organ, and an adjacent second tissue” is intended to describe the tissue and / or organ that are prohibitively sensitive to irradiation and are adjacent to the tumor location. For example, the first organ would be the pancreas head, and the second tissue would be the duodenum wall. Similarly, the first organ can be the prostate in the second organ can be the GI tract.

[0044] In an exemplary implementation, the tissues sensitive to radiation is the duodenum and / or jejunum. For example, given as conventionally fractionated therapy, typical limits for maximum radiation dose to the duodenum are thought to be about 50 Gray ( Gy) to one-third of the organ or 40 Gy to the entire organ, with recent guidelines recommending that only 195 cm3of small bowel receive >45 Gy. Conversely, as disclosed herein, biologically effective doses in (large) excess of 55 Gy may be necessary to achieve a high probability of tumor control.

[0045] Using, for example, MRI, or X-ray devices, the location and disintegration of the pharmaceutical composition can be monitored and upon release of the radio-opaque tracer, it is assumed the mucoadhesive composition has been activated and will “smear” on the wall of the adjacent organ and / or tissue in close proximity to the target tumor, where accretion can take place and cytoprotection maximized. At that point irradiation can then commence.

[0046] As indicated, the step of commencing irradiation comprises: using fractionated stereotactic body radiation therapy, exposing the predetermined location on the at least one of the first tissue, and the first organ, to between 1 and about 5 irradiation fractions. Accordingly and in an exemplary implementation, the step of exposing the at least one tissue and one organ to a therapeutically effective radiation dose comprises using stereotactic body radiation therapy (SBRT), administrating to the patient a total radiation dose of between about 5 Gy, and about 16Gy per fraction for a total of between one and five fractions (25-80 Gy), which would be a total BED10 of 37.5 Gy- 208 Gy in three to five fractions or an D2EQ of 31.25 Gy to 173.3 Gy on three to five fractions.D2 equivalent (D2EQ) = Dl(a / p + dl) / (a / p + d2) (Equ. 1) where D2 = equivalent total dose, Dl = initial total dose, dl = initial dose I fraction and d2 = wanted dose / fraction

[0047] In stereotactic body radiation therapy (SBRT), a single or limited number of focused, high dose radiation fractions are configured to be delivered to the tumor, which enables the delivery of ablative doses to the tumor and immediately adjacent tissues. In an exemplary implementation, SBRT can be an alternative to resection when a critical structure, which precludes its surgical resection, is presented. Moreover, in another exemplary implementation, the methods disclosed further comprise treatment planning using, for example, respiratory- correlated cone-beam computed tomography (4D-CT), with abdominal compression to limit the respiratory-associated movement of tumor during the step of delivering the fractionated radiation. In certain exemplary implementations, fiducial markers are used during the course of treatment to actively track tumor movement.

[0048] Likewise, and in yet another exemplary implementation, provided herein is use of a composition comprising: a core, or a plurality of mini cores (interchangeable with core sub-units) (in other words, beads, pellets, mini-tabs, powder and the like, each) with comprising: an active pharmaceutical ingredient (API), or prodrug or a pharmaceutically acceptable salt thereof; a radio-opaque contrast tracer; and a bio-adhesive composition; an optional sub-coating comprising polymer; and an outer lag-time coating comprising a pH depended polymer such as an acid resistant pharmaceutically acceptable coating polymer for the process of determining the onset for irradiating a predetermined location of at least one of: a first tissue, and a first organ, the first tissue, and the first organ each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to radiation.

[0049] 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 thesingular 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). 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.EXAMPLESExample I. APT / Tracer release profile

[0050] Using the methods disclosed herein, the release profile of the API, in this case, amifostine, and the radio-opaque contrast tracer were measured. As illustrated in FIG.s 3 A and 3B the release profiles of API and tracer are similar when stored at 5°C, indicating that their release is controlled solely by the coating system’s structure. Therefore, the addition of the contract agent to the tablets is operable for tracing the tablet progression in Duodenum and API release and accretion along the duodenum.Example II. Animal Studies: duodenal disintegration testing of oral dosagePurpose• To visually track the product movement by methylene blue trail and X Ray visualisation.• To determine the concentration and spread of amifostine in the duodenum by bioanalytical sampling the duodenal wallsTest System DetailsSpecies : PigNumber : 2Age : 2 monthsWeight : 54 KgGender : FemaleMaterials and methodsTest ItemAmifostine 125mg with methylene blue coated tabletsCoating %3.6%HusbandryAnaesthetised : 2 hours after dose providedFeed : Fasted for x hours prior to activityExperimental DesignTable 1: Experimental Design StructureDose AdministrationThe tablet was administered to the fasted pig orally with 250ml water (eq. to glass of water).After 2 hours the pig was anaesthetizedThe animal was placed on the bed in a slightly vertical position if possible, simulating (as much as possible), natural patient posture.Following dissection, the pig stomach and duodenum have undergone X-Ray to determine the location of the tablet.After 2 hours the tablet was still located in the stomach and did not disintegrated means the coating was highly effective.A different wetted* coated tablet was placed directly into the duodenum.^Tablet preparationThe tablet that have soaked for 2 hours, at a temperature of 37°C of a 0.1N HC1 / gastric fluid (PH 1.2) and than directly placed in the duodenum andPlacement of the tabletThe placement of the softened tablet will be undertaken by a selected product which will gently place the tablet in the correct position.ObservationWhilst the product is in the duodenum, it was X-Rayed to track the disintegration of the coated tablet. Endoscopic assessments was undertaken to visualize the tablet disintegrated and the methylene blue which was included in the core tablet formulation was dissolution release (trail),SacrificeSacrifice was done as per the EC and animal handling requirements. The animal was sacrificed 30 -45min after the coated tablet disintegrate and dissolved .Removal of animal partsThe following elements was removed after sacrifice of the animalDuodenumSmall intestine Jejunum, ileumDuodenal fluidJejunum, ileum fluidMethod of removalDuodenumThe duodenum was resected and removed, tied off and marked to show the ends of the duodenum and the position within the animal. It was labelled with the proximal and distal segments and the segment closest to the pancreas was noted.Jejunum and ileumAs per duodenum above.FluidThe fluid was taken out from each organ and was labelled (X ml, Organ name)..Storage for bioanalysisLabellingThe removed products was labelled, to identify• Part being stored• Which animal the pail comes from• Date and time of sacrifice, removal and storageStorage conditionThe duodenum and other removed elements was placed in storage at -20°C / -80°C within x timeframe of removal.Transport of bioanalytical samplesBioanalytical samples are to be maintained at -20 or -80 °C during transport.Bioanalytical sectioning for analysisAfter thawing of the sample, the duodenum was sliced vertically to separate the proximal and distal sections. These were then be cut into predetermined portions over the relevant duodenal sections.Summary of activityAnimals received the coated tablets containing GMP Amifostine with contrast medium and colorant (methylene blue) - lot # 015-106.The activity had 2 phases i. One coated tablet (no pre-treatment with HC1) was administered to the pig orally. The pig was subsequently anaesthetised, and visualisation of the tablet dissolution was undertaken via X-ray and Endoscopy. Due to the tablet being stuck behind food remnants in the stomach (undigested straw), after 2 hours in the stomach the pill was placed in the duodenum manually via an endoscope attachment. ii. One coated tablet (pre-treated with HC1) was placed in the duodenum using the endoscope attachment. The disintegration of the tablets was visualised using X-ray.RESULTSTable 2: Timed observation of disintegration in gut.

[0051] Timed results of the release are shown in FIG. 4. As depicted via X-ray imaging, full disintegration is achieved over a 30 minutes period (14:28-14:58). At 16:35 the sow duodenum was dissected and the accretion of amifostine on the duodenum’s wall was quantified. Results are depicted in FIG. 5.

[0052] Results were as follows: i. 3.4% coating tablet does not disintegrate at 37°C in 0. IN HC1, but does in the duodenum within 30min, similarly to in-vitro results. ii. Diatrizoate is effective as a radio-opaque tracer. iii. The green coating seen in duodenum (see e.g., FIG. 5, bracketed area) are the result of methylene blue which was released from the tablet core and mixed with yellow gastric fluids. iv. WR-1065 Concentration is higher near duodenum (la>lb, 2a>2b, etc), see e.g., FIG.s 6, and 7B. v. Under the tested conditions, 20% of WR-1065 is absorbed on duodenum walls, 80% remains in the duodenal fluid.Example III

[0053] The compositions were reformulated to affect the release most of the API (>50%) in areas la (the duodenal cap) -2a (the superior duodenal flexure 602) of the duodenum 600 past the pylorus 601 (see e.g., FIG. 6), to improve the protection of the pancreas head 610.

[0054] To achieve the desired profile, two formulations were made having a similar core and different coating:Table 3: Cores Formulation for #034-149-200, and #034-44-200 Amifostine (API)

[0055] The sub coating used in the tablet formulation is provided in Table 4:Table 4: Sub coating composition of #034-44-200 core

[0056] The sub-coating composition for composition #034-149-200 is provided in Table 5.Table 5 Sub coating composition of #034-149-200 core

[0057] The enteric coating composition for composition #034-44-200 is provided in Table 6.Table 6: Enteric coating composition of #034-44-200 formulation

[0058] The enteric coating composition for composition #034-149-200 is provided in Table7.Table 7: Enteric coating composition of #034-149-200 formulationCoating systemOpadry Enteric* is a proprietary mixture of: poly(vinyl acetate phthalate), TiOz, purified stearic acid, and triethyl citrate sold under the COLORCORN™ brand name.Methodology:Equipment• Dissolution tester Varian 705DS equipped with Distec Syringe Pump and Evolution 4300 Dissolution Sampler• Spectrophotometer• Analytical balance• pH meter• Hot plate with magnetic stirrer• Dissolution 20 p filters, Dissolution Accessories, Cat. No.PSFIL020-01-1000Dissolution ParametersDissolution Medium #1 : 0. IM HC1Dissolution Medium #2: Citrate buffer pH 5.8Apparatus II PaddleRate: 100 rpmVolume: 500 mLTemperature: 37°CDissolution Medium #1 2 hoursDissolution Medium #2 10 minutesSpectrophotometrySpectrophotometer UV-1700Absorbance at WL=825Cuvette, 10 mm light pathSolution PreparationMedia 1 (stomach simulation): Mix 25 mL of HC1 37% with 3 L water.Media 2 (Post pylorus simulation): Mix 480 mL of 0.1M Citric acid with 2520 mL of 0.1M Sodium Citrate and adjust pH to 5.8 with IN NaOH or IN HC1.Preparation of Ammonium molybdate 2.5% solution: Dissolve 2.5 g of Ammonium molybdate (VI) tetrahydrate in lOOmL of water.Preparation of Ammonium molybdate 2.5% solution: Dissolve 2.5 g of Ammonium molybdate (VI) tetrahydrate in lOOmL of water.Preparation of Sulfuric acid 1 M solution: Mix 2.8 mL of Sulfuric acid with 47.2mL waterStandard Preparation:Stock standard solution: Accurately weigh 20 mg of Amifostine Standard in 20.0mL volumetric flask. Dissolve the content in water and complete to the volume with water. The resulting concentration of Amifostine is about 1 mg / mLWorking standard solution: Place 2.5mL of Stock standard solution in 50.0 mL volumetric flask and complete to the volume with water. The resulting concentration of Amifostine is about 0.05mg / mLPreparation of Standard solution for analysis: 2.0 ml of Amifostine Working standard solution were transferred into 20 mL volumetric flask, where about 10 ml of water were admixed. 4 mL of IM Sulfuric acid was added, as well as 0.4 mL of 2.5% Ammonium molybdate, and 0.4 mL of1% Ascorbic acid. The mixture was completed to 100% of the volume with water, where the open flask was heated in a boiling water bath for 15 min then cooled.Preparation of the samples after dissolution for analysis: 0.2 ml of the sample solution was transferred into 20.0 mL volumetric flask, for further preparation for analysis.Dissolution Test: Six dissolution vessels were filled with 500 mL of dissolution media, and the temperature of dissolution media was verified at 37 °C before starting the dissolution test. Previously weighed tablets were placed in each vessel. Stirring was initiated at a rate of 100 rpm for tablets with 100-200 mg Amifostine or at 150 rpm for tablets with 300 mg Amifostine. Then 5 ml was withdrawn from the dissolution media of each vessel through 20 pm filter at the specified time point for UV-VIS analysis in the spectrophotometer.ResultsAbsorbance of the Amifostine standard and each sample solutions was measured at 825 nm against water.% dissolution was measured using the Equation 2:, _ ■ ASm Dis-Conc.Std-DF nn . rnr r .%Dissolution = - 100 (EQU 2)Amifostine labeled amount-ASt. wherein:Cone, st is a working standard concentration in mg / mLWst is weight of Amifostine standard, mgAst is absorbance of Amifostine working standard solutionAsm diss is absorbance of Amifostine in each dissolution sampleVst is volume of flask for stock standard solution preparation, 20.0 mLV medium is volume of dissolution medium, 500 mLF is the standard purity factorDF is dilution factor for after sampling preparation (DF=100)\[00059J As illustrated in FIG. 8, formulation #034-149-200, comprising 3.47% Opadry enteric coating with micronized talc, clearly shows over 80% dissolution of the API within 3 minutesfollowing exposure to media 2, configured to emulate the conditions past the pylorus within the duodenum, namely 5.8 pH.

[0060] As shown further in Figures 9A-9B, when expose sequentially to conditions emulating the stomach, the oral tablet maintains the API for a period of 120 minutes, and only once exposed to the 5.8 pH of media 2, does the API release (see e.g., FIG. 9A) over 50% over 3 minutes as illustrated in FIG. 9B (for #034-44 formulation using Eudragit enteric coating), or over 80% over the same time period (for #034-149 formulation using Opadry enteric coating).

[0061] Accordingly and in an exemplary implementation, provided herein is a pharmaceutical composition of a solid oral drug delivery comprising: a single unit core, or plurality of core units, each comprising: an active pharmaceutical ingredient (API), a prodrug or a pharmaceutically acceptable salt thereof; a radio-opaque contrast tracer; and a bio-adhesive composition; an outer coating comprising a pH depended polymer, pharmaceutically acceptable coating polymer, configured for a predetermined dissolution lag-time; and optionally, a subcoating comprising polymer, wherein (i) the API or pro-drug, or its pharmaceutically acceptable salt is a cytoprotectant pro-drug or a drug composition, (ii) the cytoprotectant pro-drug or a drug composition comprises at least one of: ergotamine, amifostine, pyridoxine, Amifostine thiol (WR- 1065) (iii) comprising S-2-(3-amino propylamino) ethyl dihydrogen phosphorothioate, its active 2- [(3 -Aminopropyl) amino]ethanethiol dihydrochloride (WR-1065), or their pharmaceutically accepted salt, wherein (iv) the single unit core, or plurality of core units (in other words, particles comprising the API, which together can be adjusted for strength and dosage that is implementation, pathology, radiation, relrease profile etc. - specific) are in the form of single unit core being at least one of: a tablet, a capsule or plurality of core units in the form of: a pellet, a bead, a mini-tablet, and a granulated powder, wherein (v) the radio-opaque contrast tracer is: Diatrizoate Sodium, zirconium oxide, aluminum oxide, barium sulphate, sodium amidotrizoate, meglumine amidotrizoate, sodium diatrizoate, sodium calcium edetate, lodixanol, or triphenyl bismuth, or a composition comprising one or more of the foregoing, (vi) the radioopaque contrast tracer (ROCT) has a lower affinity to a tissue affected by the API, than the API itself (ROCT<AP1), or, as meeded (vii) the radio-opaque contrast tracer has a higher affinity to a tissue affected by the API, than the API (ROCT>API), wherein (viii) the bio-adhesive composition is adapted to form the bio-adhesive upon mixing with a body fluid (interchangeable with liquid), the bio-adhesive configured to adhere the API to a wall of a body lumen, (ix) thebody fluid is at least one of: a gastrointestinal fluid, and a Duodenum fluid, for example, (x) the bio-adhesive composition is comprised of hydroxylpropyl cellulose (HPC) , hydroxypropyl methylcellulose (HPMC), Hypromellose, starch, polyvinylpyrollidone (PVP), xanthan gum, or a composition comprising one or more of the foregoing, wherein (xi) the acid resistant pharmaceutically acceptable coating polymer is a copolymer comprised of monomers of methyl acrylate, methyl acetate and methyl methacrylate, their oligomers, copolymers or Polyvinyl Acetate Phthalate (Phthalavin enteric coating polymer, PVAP) terpolymers, configured to release the API at pH of NLT 4.5, for example, between pH of 4.5 and 5.8, or between pH of 5.2 and pH of 5.8, or for example, (xii) ) pH of 5.0, pH of 5.5, pH of 5.8 wherein (xiii) the outer lag time coating further comprises an acid resistant enteric polymer and thermodynamically compatible plasticizer (in other words, a plasticizer exhibiting a slope of over 30 degrees when plotting the reduced osmotic pressure against the plasticizer’s fractional concentration i.e. (— -2-) C / C2 where C2 is the fractional concentration of the plasticizer and ,Tis the osmotic pressure), (xiv) the enteric polymer being, for example at least one of; monomers of a methyl acrylate, methyl acetate and methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), or a combination comprising one or more of the foregoing, wherein (xv) the thermodynamically compatible plasticizer is: triethyl citrate (TEC), diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutyl sebecate, castor oil, or a plasticizer composition comprising one or more of the foregoing, wherein (xvi) the pharmaceutical composition exhibits a dissolution of not less than 75% release of the radioopaque contrast tracer within 30 minutes as measured with a paddle apparatus with or without sinker at 75 (75-100) revolutions per minute or 100 (75-100) revolutions per minute or basket apparatuses over 30 minutes in 150 mL- 900ml of aqueous buffered solution at a pH of about 5.5, for example pH between 5.2 and pH of 5.8, or buffered solution at a pH of about 5.8 wherein (xvii) the pharmaceutical composition exhibits a dissolution of not more than 20% release of the API in 150 mL-900ml of aqueous 0.1 N HC1 at 37 °C, as measured with a paddle apparatus at 75 ((50 -100)rpm or 100 (75-100) revolutions per minute or basket with NMT 100 rpm during 120 minutes, followed not less than Average of 75% of the API over additional 30 minutes at 75 (50 -100)rpm or 100 (75-100) revolutions per minute in 150-900 mL of aqueous buffered solution ata pH of 5.5 or a pH of 5.8 at 37°C, (xviii) configured to release no less than 80% of the API within 3 minutes of passing through the pylorus, as well as (xix) release no less than 80% of the API within 3 within region la-2a ( in other words, no further than the superior duodenal flexure) of the duodenum.

[0062] In another exemplary implementation, provided herein is a method of determining the onset for irradiating a predetermined location on at least one of: a first tissue, and a first organ, the at least one of the first tissue, and the first organ are each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to radiation, the method comprising: administering to the patient an oral composition comprising: single unit core or plurality of core units, each (core, or core sub unit) comprising: an active pharmaceutical ingredient , prodrug (API), or a pharmaceutically acceptable salt thereof, a radio-opaque tracer, and a bio-adhesive composition; optionally, sub-coating comprising a polymer; and non-optionally, an outer lag-time coating comprising coating the sub coated core with an acid resistant pharmaceutically acceptable coating polymer configured for a predetermined dissolution lag-time; using an imaging device, imaging the at least one of: the adjacent second tissue, and the adjacent second organ, each adjacent to the predetermined location sought to be irradiated in the at least one of: the first tissue, and the first organ; detecting the radio-opaque contrast tracer in a location on the at least one of: the adjacent second tissue, and the adjacent second organ, adjacent to the predetermined location sought to be irradiated; and upon detecting the radio-opaque contrast tracer commencing irradiation of the predetermined location of the at least one of: the first tissue, and the first organ, wherein (xx) the step of commencing irradiation of the predetermined location of the at least one of: the first tissue, and the first organ, is preceded by a step of detecting dissipation of the radioopaque contrast tracer, wherein (xxi) the radio-opaque contrast tracer has a lower affinity (xxii), or higher affinity to the at least one of: the second tissue, and the second organ, than the API, (xxiii) the radio-opaque contrast tracer is: zirconium oxide, aluminum oxide, barium sulphate, sodium amidotrizoate, meglumine amidotrizoate, sodium diatrizoate, sodium calcium edetate, lodixanol, or triphenyl bismuth, , metrizoate, iothalamate, ioxaglate, iopamidol, iohexol, ioxilan, iopromide, iodixanol, iobitridol, ioversol, or a.or a combination comprising one or more of the foregoing, wherein (xxiv) the API or its pharmaceutically acceptable salt is a cytoprotectant prodrug or a drug composition, (xxv) the cytoprotectant pro-drug or a drug composition comprisesat least one of: ergotamine, amifostine, 2-[(3-Aminopropyl)amino]ethanethiol dihydrochloride (hereinafter WR-1065), and pyridoxine, (xxvi) the API is a pro-drug, or a drug composition comprising 2-(3- aminopropylamino)ethylsulfanylphosphonic acid , its active 2-[(3- Aminopropyl) amino] ethanethiol dihydrochloride (WR-1065) or its pharmaceutically accepted salt, wherein (xxvii) the plurality of core (sub-) units are in the form of at least one of: a pellet, a bead, a mini-tablet, and a granulated powder, wherein (xxviii) the bio-adhesive composition is adapted to form the bio-adhesive upon mixing with a body fluid, the bio-adhesive configured to adhere the API to a wall of a body lumen, (xxix) the body fluid is gastrointestinal fluid, or Duodenum fluid, (xxx) the bio-adhesive composition comprises: hydroxypropyl cellulose (HPC) , hydroxypropylmethylcellulose (HPMC), Hypromellose, starch, polyvinylpyrollidone (PVP), xanthan gum, lectin-agglutinin conjugate, or a composition comprising one or more of the foregoing, wherein (xxxi) the enteric polymer is a methyl acrylate, methyl acetate and methyl methacrylate copolymer, hydroxypropyl mcthylccllulosc phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), or a combination comprising one or more of the foregoing, wherein (xxxii) the acid resistant pharmaceutically acceptable coating polymer comprises an enteric polymer and a thermodynamically compatible plasticizer, wherein (xxxiii) the enteric polymer is: methacrylic acid-methyl methacrylate copolymer, methacrylic acid ■■ ethyl acrylate copolymer, a methyl acrylate, methyl acetate and methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate pthalate (CAP), polyvinyl acetate phthalate (PVAP), or a combination comprising one or more of the foregoing, (xxxiv) the thermodynamically compatible plasticizer is: triethyl citrate (TEC), diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutyl sebecate, castor oil, or a plasticizer composition comprising one or more of the foregoing, wherein (xxxv) the pharmaceutical composition exhibits a dissolution of not less than 85% of the API within 30 minutes as measured with a paddle apparatus with or without sinker at 75 revolutions per minute in 150 mL-900ml of aqueous buffered solution at a pH of 5.5, or additionally or alternatively (xxxvi) the pharmaceutical composition exhibits a dissolution of not more than 10% of the API in 150 mL- 900ml of aqueous 0.1 N HC1 at 37°C, as measured with a paddle apparatus at 75 rpm during 120 minutes, followed not less than 85% of the API over additional 30 minutes at 75 rpm in 150 mL- 900ml of aqueous buffered solution at a pH of 5.5 at 37°C, or additionally or alternatively the pharmaceutical composition exhibits a dissolution ofnot less than 85% of the API within 30 minutes as measured with a paddle apparatus with or without sinker at 100 revolutions per minute in 150 mL-900ml of aqueous buffered solution at a pH of 5.8, or additionally or alternatively (xxxvi) the pharmaceutical composition exhibits a dissolution of not more than 10% of the API in 150 mL- 900ml of aqueous 0.1 N HC1 at 37°C, as measured with a paddle apparatus at 100 rpm during 120 minutes, followed not less than 85% of the API over additional 30 minutes at 100 rpm in 150 mL- 900ml of aqueous buffered solution at a pH of 5.8 at 37°C, wherein, in the method (xxxvii) the step of commencing irradiation comprises: using fractionated stereotactic body radiation therapy, exposing the predetermined location on the at least one of the first tissue, and the first organ, to between 1 and about 5 irradiation fractions, (xxxviii) the fractionated stereotactic body radiation therapy is configured to expose the predetermined location on the at least one of the first tissue, and the first organ, to a total radiation dose of between about 15 Gy and about 208 Gy, wherein (xxxix) the at least one of: the second tissue, and the second organ is at least one of: a gastrointestinal tract, duodenum, jejunum, small intestine, large intestine, rectum, esophagus, stomach, bladder, and urinary tract, while (xl) the at least one of: the first tissue, and the first organ is a pancreas, a prostate, a liver, a gallbladder, and adrenal gland, a kidney, the retroperitneum, a lymph node, a uterus, a testicle, an ovary, or a combination comprising one or more of the foregoing.

[0063] In yet another exemplary implementation, provided herein is a use of an oral composition comprising: single unit core or plurality of core sub-units, each (core unit or subunits) comprising: an active or prodrug pharmaceutical ingredient (API), or a pharmaceutically acceptable salt thereof; a radio-opaque contrast tracer; and a bio-adhesive composition; optionally a sub-coating comprising polymer; and an acid resistant pharmaceutically acceptable coating polymer configured for a predetermined dissolution lag-time for use in the process of determining the onset for irradiating a predetermined location of at least one of: a first tissue, and a first organ, the first tissue, and the first organ each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to radiation, wherein (xli) the radio-opaque contrast tracer has a lower affinity, or (xlii) higher affinity, to the at least one of: the second tissue, and the second organ, than the API, (xliii) the radio-opaque contrast tracer is: Diatrizoate Sodium, zirconium oxide, aluminum oxide, barium sulphate, sodium amidotrizoate, meglumine amidotrizoate, sodium diatrizoate, sodium calcium edetate, Todixanol, or triphenyl bismuth, ,metrizoate, iothalamate, ioxaglate, iopamidol, iohexol, ioxilan, iopromide, iodixanol, iobitridol, ioversol or a composition comprising one or more of the foregoing, wherein (xliv) the API or its pharmaceutically acceptable salt is a cytoprotectant pro-drug or a drug composition, comprising (xlv) at least one of: ergotamine, amifostine, 2- [(3 -Aminopropyl)amino] ethanethiol dihydrochloride (WR-1065), and pyridoxine, such as (xlvi) S-2-(3-amino propylamino) ethyl dihydrogen phosphorothioate, its active 2-[(3-Aminopropyl)amino]ethanethiol dihydrochloride (WR-1065) or its pharmaceutically accepted salt, wherein (xlvii) the plurality of core sub-units are in the form of at least one of: a pellet, a bead, a mini-tablet, and a granulated powder, wherein (xlviii) the bio-adhesive composition is adapted to form the bio-adhesive upon mixing with a body fluid, the bio-adhesive configured to adhere the API to a wall of a body lumen, (il) the body fluid is gastrointestinal fluid, or duodenum fluid or intestinal fluid, wherein (1) the bioadhesive composition is comprised of hydroxylpropyl cellulose (HPC) , hydroxyl propyl mcthylccllulosc (HPMC), Hypromcllosc, starch, polyvinylpyrollidonc (PVP), xantlian gum, or a composition comprising one or more of the foregoing, wherein (li) the acid resistant pharmaceutically acceptable coating polymer is a copolymer comprised of: methacrylic acid - ethyl acrylate copolymer methyl acrylate, methyl acetate and methyl methacrylate, their oligomers, copolymers or terpolymers, configured to release the API at pH of 5.5, and / or the acid resistant pharmaceutically acceptable coating polymer is a copolymer comprised of: polyvinyl acetate phthalate (PVAP) configured to release the API at pH of 5.0, wherein (lii) the outer lag time coating comprises an enteric polymer and a thermodynamically compatible plasticizer, wherein (liii) the enteric polymer is: methacrylic acid - ethyl acrylate copolymer, a methyl acrylate, methyl acetate and methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate pthalate (CAP), polyvinyl acetate phthalate (PVAP), or a combination comprising one or more of the foregoing, (liv) the thermodynamically compatible plasticizer is: triethyl citrate (TEC) diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutyl sebecate, castor oil, or a plasticizer composition comprising one or more of the foregoing, the use (Iv) configured to release no less than 85% of the API within 30 minutes of dissolution at PH of 5.5 of the solid oral pharmaceutical composition, or (Ivi) no less than 80% of the API within 3 minutes of dissolution at PH of 5.8 of the solid oral pharmaceutical composition, wherein (Ivii) the step of commencing irradiation comprises: using fractionated stereotactic body radiationtherapy, exposing the predetermined location on the at least one of the first tissue, and the first organ, to between 1 and about 5 irradiation fractions, (Iviii) the fractionated stereotactic body radiation therapy is configured to expose the predetermined location on the at least one of the first tissue, and the first organ, to a total radiation dose of between about 15 Gy and about 208 Gy, wherein (lix) the at least one of: the second tissue, and the second organ is at least one of: a gastrointestinal tract, duodenum, jejunum, small intestine, large intestine, rectum, esophagus, stomach, bladder, and urinary tract, while (lx) the at least one of: the first tissue, and the first organ is a pancreas, a prostate, a liver, a gallbladder, and adrenal gland, a kidney, the retroperitneum, a lymph node, a uterus, a testicle, an ovary, or a combination comprising one or more of the foregoing.

[0064] While in the foregoing specification the pharmaceutical compositions, and their methods of use have been described in relation to certain preferred exemplary implementations, and many details arc 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

What is claimed:

1. A pharmaceutical composition of a solid oral drug delivery comprising: a. a single unit core, or plurality of core units, each comprising: i. an active pharmaceutical ingredient (API), a prodrug or a pharmaceutically acceptable salt thereof; ii. a radio-opaque contrast tracer; and iii. a bio-adhesive composition; b. an outer coating comprising a pH depended polymer, pharmaceutically acceptable coating polymer, configured for a predetermined dissolution lag-time; and c. optionally, a sub-coating comprising polymer. d. optionally, a plasticizer e. optionally, an anticaking agent2. The pharmaceutical composition of claim 1, wherein the API or pro-drug, or its pharmaceutically acceptable salt is a cytoprotectant pro-drug or a drug composition.

3. The pharmaceutical composition of claim 2, wherein the cytoprotectant pro-drug or a drug composition comprises at least one of: ergotamine, amifostine, Amifostine thiol- amifostine, 2- [(3-Aminopropyl)amino]ethanethiol dihydrochloride (hereinafter WR-1065) and pyridoxine.

4. The pharmaceutical composition of claim 3, comprising S-2-(3-amino propylamino) ethyl dihydrogen phosphorothioate, its active 2- [(3 -Aminopropyl) amino]ethanethiol dihydrochloride (WR-1065), or their pharmaceutically accepted salt.

5. The pharmaceutical composition of claim 1, wherein the plurality of core units are in the form of at least one of: a pellet, a bead, a mini-tablet, and a granulated powder.

6. The pharmaceutical composition of claim 2, wherein the radio-opaque contrast tracer is: Diatrizoate Sodium, zirconium oxide, aluminum oxide, barium sulphate, sodium amidotrizoate, meglumine amidotrizoate, sodium diatrizoate, sodium calcium edetate, lodixanol, or triphenyl bismuth, or a composition comprising one or more of the foregoing.

7. The pharmaceutical composition of claim 6, wherein the radio-opaque contrast tracer has a lower affinity to a tissue affected by the API, than the API.

8. The pharmaceutical composition of claim 6, wherein the radio-opaque contrast tracer has a higher affinity to a tissue affected by the API, than the API.

9. The pharmaceutical composition of claim 1, wherein the bio-adhesive composition is adapted to form the bio-adhesive upon mixing with a body fluid, the bio-adhesive configured to adhere the API to a wall of a body lumen.

10. The pharmaceutical composition of claim 9, wherein the body fluid is at least one of: a gastrointestinal fluid, and a Duodenum fluid.

11. The pharmaceutical composition of claim 9, wherein the bio-adhesive composition is comprised of hydroxylpropyl cellulose (HPC) , hydroxypropylmethylcellulose ( HPMC), Hypromellose, starch, polyvinylpyrollidone (PVP), xanthan gum, or a composition comprising one or more of the foregoing.

12. The pharmaceutical composition of claim 1, wherein the acid resistant pharmaceutically acceptable coating polymer is a copolymer comprised of Polyvinyl Acetate Phthalate (PVAP) configured to release the APT at pH of NLT 5.0.

13. The pharmaceutical composition of claim 1, wherein the acid resistant pharmaceutically acceptable coating polymer is a copolymer comprised of methyl acrylate, methyl acetate and methyl methacrylate, their oligomers, copolymers or terpolymers, configured to release the API at pH of NLT 5.5.

14. The pharmaceutical composition of claim 1, wherein the outer lag time coating further comprises an acid resistant enteric polymer and thermodynamically compatible plasticizer.

15. The pharmaceutical composition of claim 14, wherein the enteric polymer is: a methyl acrylate, methyl acetate and methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate pthalate (CAP), polyvinyl acetate phthalate (PVAP), or a combination comprising one or more of the foregoing.

16. The pharmaceutical composition of claim 14, wherein the thermodynamically compatible plasticizer is: triethyl citrate (TEC), diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutyl sebecate, castor oil, or a plasticizer composition comprising one or more of the foregoing.

17. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition exhibits a dissolution of not less than 75% release of the radio-opaque contrast tracer within 30 minutes as measured with a paddle apparatus with or without sinker at 75 (75-100) revolutions per minute or basket apparatuses over 30 minutes in 150 mL- 900ml of aqueous buffered solution at a pH of about 5.5.

18. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition exhibits a dissolution of not more than 20% release of the API in 150 mL-900ml of aqueous 0.1 N HC1 at 37°C, as measured with a paddle apparatus at 75 ((50 -100)rpm or basket with NMT 100 rpm during 120 minutes, followed not less than Average of 75% of the API over additional 30 minutes at 75 rpm in 150-900 mL of aqueous buffered solution at a pH of 5.5 at 37°C.

19. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition exhibits a dissolution of not more than 10% release of the API in 150 mL-900ml of aqueous 0.1 N HC1 at 37°C, as measured with a paddle apparatus at 100 rpm or basket with NMT 100 rpm during 120 minutes, followed not less than Average of 75% of the API over additional 30 minutes at 100 rpm in 150-900 mL of aqueous buffered solution at a pH of 5.8 at 37°C.

20. The composition of claim 1, configured to release no less than 80% of the API within 3 minutes of passing through the pylorus.

21. The composition of claim 1, configured to release no less than 80% of the API within 3 within region la-2a of the duodenum.

22. A method of determining the onset for irradiating a predetermined location on at least one of: a first tissue, and a first organ, the at least one of the first tissue, and the first organ are each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to radiation, the method comprising: a. administering to the patient an oral composition comprising: i. single unit core or plurality of core sub-units, each comprising: an active pharmaceutical ingredient , prodrug (API), or a pharmaceutically acceptable salt thereof, a radioopaque tracer, and a bio-adhesive composition; ii. optionally, sub-coating comprising a polymer; and iii. non-optionally, an outer lag-time coating comprising coating the sub coated core with an acid resistant pharmaceutically acceptable coating polymer configured for a predetermined dissolution lag-time; b. using an imaging device, imaging the at least one of: the adjacent second tissue, and the adjacent second organ, each adjacent to the predetermined location sought to be irradiated in the at least one of: the first tissue, and the first organ;c. detecting the radio-opaque contrast tracer in a location on the at least one of: the adjacent second tissue, and the adjacent second organ, adjacent to the predetermined location sought to be irradiated; and d. upon detecting the radio-opaque contrast tracer commencing irradiation of the predetermined location of the at least one of: the first tissue, and the first organ.

23. The method of claim 22, wherein the step of commencing irradiation of the predetermined location of the at least one of: the first tissue, and the first organ, is preceded by a step of detecting dissipation of the radio-opaque contrast tracer.

24. The method of claim 22, wherein the radio-opaque contrast tracer has a lower affinity to the at least one of: the second tissue, and the second organ, than the API.

25. The method of claim 22 wherein the radio-opaque contrast tracer has a higher affinity to the at least one of: the second tissue, and the second organ, than the API.

26. The method of claim 22 wherein the radio-opaque contrast tracer is: zirconium oxide, aluminum oxide, barium sulphate, sodium amidotrizoate, meglumine amidotrizoate, sodium diatrizoate, sodium calcium edetate, lodixanol, or triphenyl bismuth, , metrizoate, iothalamate, ioxaglate, iopamidol, iohexol, ioxilan, iopromide, iodixanol, iobitridol, ioversol, or a.or a combination comprising one or more of the foregoing.

27. The method of claim 24, wherein the API or its pharmaceutically acceptable salt is a cytoprotectant pro-drug or a drug composition.

28. The method of claim 27 wherein the cytoprotectant pro-drug or a drug composition comprises at least one of: ergotamine, amifostine, 2-[(3-Aminopropyl)amino]ethanethiol dihydrochloride (hereinafter WR-1065), and pyridoxine.

29. The method of claim 28, wherein the API is a pro-drug, or a drug composition comprising 2-(3- aminopropylaminojethylsulfanylphosphonic acid , its active 2-[(3-Aminopropyl) amino] ethanethiol dihydrochloride (WR-1065), or its pharmaceutically accepted salt.

30. The method of claim 22, wherein the plurality of core sub-units are in the form of at least one of: a pellet, a bead, a mini-tablet, and a granulated powder.

31. The method of claim 22, wherein the bio-adhesive composition is adapted to form the bioadhesive upon mixing with a body fluid, the bio-adhesive configured to adhere the API to a wall of a body lumen.

32. The method of claim 31, wherein the body fluid is gastrointestinal fluid, or Duodenum fluid.

33. The method of claim 31, wherein the bio-adhesive composition comprises: hydroxypropyl cellulose (HPC) , hydroxypropylmethylcellulose (HPMC), Hypromellose, starch, polyvinylpyrollidone (PVP), xanthan gum, lectin- agglutinin conjugate, or a composition comprising one or more of the foregoing.

34. The method of claim 22, wherein the enteric polymer is a methyl acrylate, methyl acetate and methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), or a combination comprising one or more of the foregoing.

35. The method of claim 22, wherein the acid resistant pharmaceutically acceptable coaling polymer comprises an enteric polymer and a thermodynamically compatible plasticizer.

36. The method of claim 34, wherein the enteric polymer is: methacrylic acid-mcthyl methacrylate copolymer, methacrylic acid - ethyl acrylate copolymer, a methyl acrylate, methyl acetate and methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate pthalate (CAP), polyvinyl acetate phthalate (PVAP), or a combination comprising one or more of the foregoing.

37. The method of claim 35, wherein the thermodynamically compatible plasticizer is: triethyl citrate (TEC), diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutyl sebecate, castor oil, or a plasticizer composition comprising one or more of the foregoing.

38. The method of claim 22, wherein the pharmaceutical composition exhibits a dissolution of not less than 85% of the API within 30 minutes as measured with a paddle apparatus with or without sinker at 75 revolutions per minute in 150 mL-900ml of aqueous buffered solution at a pH of 5.5.

39. The method of claim 22, wherein the pharmaceutical composition exhibits a dissolution of not more than 10% of the API in 150 mL- 900ml of aqueous 0.1 N HC1 at 37°C, as measured with a paddle apparatus at 75 rpm during 120 minutes, followed not less than 85% of the API over additional 30 minutes at 75 rpm in 150 mL- 900ml of aqueous buffered solution at a pH of 5.5 at 37°C.

40. The method of claim 22, wherein the pharmaceutical composition exhibits a dissolution of not more than 10% of the API in 150 mL- 900ml of aqueous 0.1 N HC1 at 37°C, as measured with a paddle apparatus at 100 rpm during 120 minutes, followed not less than 85% of the API over additional 30 minutes at 100 rpm in 150 mL- 900ml of aqueous buffered solution at a pH of 5.8 at 37°C.

41. The method of claim 22, wherein the step of commencing irradiation comprises: using fractionated stereotactic body radiation therapy, exposing the predetermined location on the at least one of the first tissue, and the first organ, to between 1 and about 5 irradiation fractions.

42. The method of claim 39, wherein the fractionated stereotactic body radiation therapy is configured to expose the predetermined location on the at least one of the first tissue, and the first organ, to a total radiation dose of between about 15 Gy and about 208 Gy.

43. The method of claim 22, wherein the at least one of: the second tissue, and the second organ is at least one of: a gastrointestinal tract, duodenum, jejunum, small intestine, large intestine, rectum, esophagus, stomach, bladder, and urinary tract.

44. The method of claim 22, wherein the at least one of: the first tissue, and the first organ is a pancreas, a prostate, a liver, a gallbladder, and adrenal gland, a kidney, the retroperitneum, a lymph node, a uterus, a testicle, an ovary, or a combination comprising one or more of the foregoing.

45. Use of an oral composition comprising: single unit core or plurality of core sub-units, each comprising: an active or prodrug pharmaceutical ingredient (API), or a pharmaceutically acceptable salt thereof; a radio-opaque contrast tracer; and a bio-adhesive composition; optionally a sub-coating comprising polymer; and an acid resistant pharmaceutically acceptable coating polymer configured for a predetermined dissolution lag-time for use in the process of determining the onset for irradiating a predetermined location of at least one of: a first tissue, and a first organ, the first tissue, and the first organ each being adjacent to at least one of : an adjacent second organ, and an adjacent second tissue, wherein each of the adjacent second organ, and the adjacent second tissue is sensitive to radiation.

46. The use of claim 43, wherein the radio-opaque contrast tracer has a lower affinity to the at least one of: the second tissue, and the second organ, than the API.

47. The use of claim 45, wherein the radio-opaque contrast tracer has a higher affinity to the at least one of: the second tissue, and the second organ, than the API.

48. The use of claim 45, wherein the radio-opaque contrast tracer is: Diatrizoate Sodium, zirconium oxide, aluminum oxide, barium sulphate, sodium amidotrizoate, meglumine amidotrizoate, sodium diatrizoate, sodium calcium edetate, lodixanol, or triphenyl bismuth, , metrizoate, iothalamate, ioxaglate, iopamidol, iohexol, ioxilan, iopromide, iodixanol, iobitridol, ioversol or a composition comprising one or more of the foregoing.

49. The use of claim 45, wherein the API or its pharmaceutically acceptable salt is a cytoprotectant pro-drug or a drug composition.

50. The use of claim 49, wherein the cytoprotectant pro-drug or a drug composition comprises at least one of: ergotamine, amifostine, 2-[(3-Aminopropyl)amino]ethanethiol dihydrochloride (WR-1065) ,and pyridoxine.

51. The use of claim 50, wherein the API or its pharmaceutically acceptable salt is a pro-drug or a drug composition comprising S-2-(3-amino propylamino) ethyl dihydrogen phosphorothioatc, its active 2-[(3-Aminopropyl)amino]cthancthiol dihydrochloridc (WR-1065) or its pharmaceutically accepted salt.

52. The use of claim 45, wherein the plurality of core sub-units are in the form of at least one of: a pellet, a bead, a mini-tablet, and a granulated powder.

53. The use of claim 45, wherein the bio-adhesive composition is adapted to form the bioadhesive upon mixing with a body fluid, the bio-adhesive configured to adhere the API to a wall of a body lumen.

54. The use of claim 53, wherein the body fluid is gastrointestinal fluid, or duodenum fluid or intestinal fluid.

55. The use of claim 45, wherein the bio-adhesive composition is comprised of hydroxylpropyl cellulose (HPC) , hydroxypropylmethylcellulose (HPMC), Hypromellose, starch, polyvinylpyrollidone (PVP), xanthan gum, or a composition comprising one or more of the foregoing.

56. The use of claim 45, wherein the acid resistant pharmaceutically acceptable coating polymer is a copolymer comprised of: methacrylic acid - ethyl acrylate copolymer methyl acrylate, methyl acetate and methyl methacrylate, their oligomers, copolymers or terpolymers, configured to release the API at pH of 5.5.

57. The use of claim 45, wherein the acid resistant pharmaceutically acceptable coating polymer is a copolymer comprised of: Polyvinyl Acetate Phthalate (PVAP), configured to release the API at pH of 5.0.

58. The use of claim 45, wherein the outer lag time coating comprises an enteric polymer and a thermodynamically compatible plasticizer.

59. The use of claim 58, wherein the enteric polymer is: methacrylic acid - ethyl acrylate copolymer, a methyl acrylate, methyl acetate and methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate pthalate (CAP), polyvinyl acetate phthalate (PVAP), or a combination comprising one or more of the foregoing.

60. The use of claim 59, wherein the thermodynamically compatible plasticizer is: triethyl citrate (TEC) diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutyl sebecate, castor oil, or a plasticizer composition comprising one or more of the foregoing.

61. The use of claim 45, configured to release no less than 85% of the API within 30 minutes of dissolution at PH of 5.5 of the solid oral pharmaceutical composition.

62. The use of claim 45, configured to release no less than 80% of the API within 3 minutes of dissolution at PH of 5.8 of the solid oral pharmaceutical composition.

63. The use of claim 45, wherein the step of commencing irradiation comprises: using fractionated stereotactic body radiation therapy, exposing the predetermined location on the at least one of the first tissue, and the first organ, to between 1 and about 5 irradiation fractions.

64. The use of claim 63, wherein the fractionated stereotactic body radiation therapy is configured to expose the predetermined location on the at least one of the first tissue, and the first organ, to a total radiation dose of between about 15 Gy and about 208 Gy.

65. The use of claim 64, wherein the at least one of: the second tissue, and the second organ is at least one of: a gastrointestinal tract, duodenum, jejunum, small intestine, large intestine, rectum, esophagus, stomach, bladder, and urinary tract.

66. The use of claim 64, wherein the at least one of: the first tissue, and the first organ is a pancreas, a prostate, a liver, a gallbladder, and adrenal gland, a kidney, the retroperitneum, a lymph node, a uterus, a testicle, an ovary, or a combination comprising one or more of the foregoing.

Images