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WO2018005964A1 - Glucides modifiés, composition les comprenant et procédés pour les préparer et les utiliser - Google Patents

Glucides modifiés, composition les comprenant et procédés pour les préparer et les utiliser Download PDF

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Publication number
WO2018005964A1
WO2018005964A1 PCT/US2017/040283 US2017040283W WO2018005964A1 WO 2018005964 A1 WO2018005964 A1 WO 2018005964A1 US 2017040283 W US2017040283 W US 2017040283W WO 2018005964 A1 WO2018005964 A1 WO 2018005964A1
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WO
WIPO (PCT)
Prior art keywords
alginate
hydrogel
compound
group
modified
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2017/040283
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English (en)
Inventor
Mark E. Welker
Emmanuel C. Opara
Surya R. BANKS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wake Forest University
Wake Forest University Health Sciences
Original Assignee
Wake Forest University
Wake Forest University Health Sciences
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2017/034748 external-priority patent/WO2018004906A1/fr
Application filed by Wake Forest University, Wake Forest University Health Sciences filed Critical Wake Forest University
Priority to EP17821354.2A priority Critical patent/EP3478725B1/fr
Priority to US16/311,992 priority patent/US10766970B2/en
Priority to CA3029502A priority patent/CA3029502A1/fr
Publication of WO2018005964A1 publication Critical patent/WO2018005964A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/04—Alginic acid; Derivatives thereof

Definitions

  • modified carbohydrates e.g., modified alginate
  • compositions comprising a modified carbohydrate such as hydrogels comprising a modified carbohydrate.
  • methods of preparing and using a modified carbohydrate are also provided.
  • Certain therapeutic and bioactive substances including, but not limited to, (i) medicines, drugs, enzymes, proteins, hormones, and vaccines, (ii) vitamins, minerals, micronutrients and other dietary supplements, (iii) probiotics and other micro-organisms, (iv) cells, cell parts, and/or biological materials, and (v) many other bioactive substances have been found to be vital, therapeutic and necessary for, among other things, the treatment, prevention, and/or inhibition of certain diseases and/or other conditions in humans and animals, the elimination or reduction of pain associated with a wide variety illnesses, diseases and conditions, and/or the general maintenance of good health and well-being in humans and animals, including pets and livestock.
  • the simplest and most cost-effective method for delivering the medicine or other substance to humans and animals is by oral delivery in the form of a pill, capsule, liquid, paste, or other currently available oral delivery method.
  • probiotics are either not alive when they are taken orally (and are therefore completely ineffective for recolonizing the gut with "good” or healthy bacteria), or if alive when taken, are often destroyed in the stomach by stomach acids and enzymatic action, leaving a relatively small amount, if any, of the probiotics that actually make it to the small intestine alive and intact, where they are then able to recolonize the gut with the "good” bacteria, or address certain flora deficiencies as needed.
  • CDI Clostridium difficile infection
  • FMT fecal microbiota transplants
  • opioid derivatives such as oxycodone, hydrocodone, codeine, morphine, fentanyl and others, cause stomach upset, nausea, and/or vomiting.
  • opioid- derived pain medications interact with opioid receptors in the brain and nervous system in order to relieve pain.
  • opioid prescriptions There were about 300 million pain medication prescriptions written in 2016.
  • Vitamin D Vitamin D
  • Coenzyme Q10 Omega-3 fatty acids
  • Omega-3 fatty acids are often sold in the form of fish or Krill oil, or are sold as supplements in a variety of forms.
  • EPA/DHA Omega-3 fatty acids
  • Evidence-based clinical research also strongly suggests these and other dietary supplements should be incorporated into many diets to ensure that sufficient amounts of these critical substances are available for our overall health and well-being.
  • omega-3 fatty acids For example, research has shown that cultures that routinely eat foods with high levels of omega-3 fatty acids demonstrate a variety of health benefits, such as lower levels of depression. Omega-3 fatty acids may also aid in treating the depressive symptoms of bipolar disorder, and may be important for visual and neurological development in infants. When ingested in relatively high doses, it may lower inflammation, which may be important in treating asthma. Other research suggests omega-3 fatty acids may be useful in ameliorating and/or reducing symptoms associated with ADHD in some children, while at the same time enhancing their mental skills. Omega-3 fatty acids may also prove to be useful in the treatment or slowing the progression of Alzheimer's disease and dementia.
  • Vitamin D With respect to Vitamin D, research has shown it can be important in reducing inflammation (by acting on C-Reactive Protein). It is also thought to aid in reducing pain as well as the stress on joints. Vitamin D has also been implicated as a possible source of reducing rheumatoid arthritis, obesity, certain cancers, various heart diseases, and the effects of radiation, while enhancing individuals' mental capacity, the immune system, bone growth, and the proper production of insulin. Although vitamin D can be procured by exposure to sunlight and other ways, vitamin D can also be attained by oral administration in a supplement form.
  • Coenzyme Q 10 it is a substance that helps convert food into energy, is found in almost every cell in the body and it is a powerful antioxidant. It is also critical in fulfilling the energy requirements of different organs such as the liver, heart and kidney. It is soluble in oil and present in most eukaryotic cells such as mitochondria. CoQ 10 is involved in the electron transport chain and participates in aerobic cellular respiration which generates energy. Over ninety percent of the human body's energy is generated this way. CoQ 10 is widely used in numerous applications as an antioxidant. There is also increasing use of CoQ 10 in medical applications like heart disease, eye care, cancer treatment, obesity and Huntington's disease.
  • modified carbohydrate such as a modified alginate or a modified hyaluronic acid.
  • the modified carbohydrate e.g., modified alginate
  • hydrogel comprising a modified carbohydrate (e.g., a modified alginate) of the present invention.
  • the hydrogel may be a chemically modified alginate hydrogel.
  • the hydrogel may comprise a modified carbohydrate that has been prepared by combining an aromatic compound with a carbohydrate (e.g., alginate).
  • the aromatic compound has one or more amines.
  • alginate may be modified using different amines and/or different methods, including: (i) covalently bonding aminoethyl benzoic acid to the carbohydrate (e.g., alginate)backbone, and/or (ii) oxidizing the vicinal diol in the carbohydrate (e.g., alginate) chain to an aldehyde before coupling to aminoethyl benzoic acid.
  • the aromatic compound is dopamine.
  • a chemically modified carbohydrate e.g., modified alginate
  • methods used may be utilized to coat and/or encapsulate at least a portion of one or more bioactive substances, such as, e.g., bioactive substances for oral delivery in humans and/or animals, including, but not limited to: (i) medicines, drugs, enzymes, proteins, hormones, and vaccines, (ii) vitamins, minerals, micronutrients and other dietary supplements, (iii) probiotics and other microorganisms, (iv) cells, cell parts, and/or other biological materials, and/or (v) many other bioactive substances.
  • bioactive substances such as, e.g., bioactive substances for oral delivery in humans and/or animals, including, but not limited to: (i) medicines, drugs, enzymes, proteins, hormones, and vaccines, (ii) vitamins, minerals, micronutrients and other dietary supplements, (iii) probiotics and other microorganisms, (iv) cells, cell parts, and/
  • a hydrogel of the present invention comprises an iodide, such as, but not limited to, potassium iodide, optionally wherein at least a portion of the iodide is coated and/or encapsulated by the hydrogel.
  • an iodide such as, but not limited to, potassium iodide
  • bioactive substance means a substance used by and/or having any biological effect on a living organism, and includes, but is not limited to, prescription and non-prescription medications and drugs, chemicals, chemical compounds, molecules, enzymes, proteins, hormones, vaccines, vitamins, minerals, micronutrients and other dietary supplements, probiotics and other micro-organisms, cells, cell parts (including DNA and RNA), and other biological materials, as well as other bioactive compounds and substances.
  • Another aspect of the present invention relates to a method of protecting a bioactive substance (e.g., a medicine) from attack by an acid and/or an enzyme (e.g., enzymatic action in the stomach) by coating and/or encapsulating at least a portion of the bioactive substance in a modified carbohydrate (e.g., modified alginate) hydrogel of the present invention.
  • a bioactive substance e.g., a medicine
  • an enzyme e.g., enzymatic action in the stomach
  • a modified carbohydrate hydrogel of the present invention upon administration of a hydrogel of the present invention to a subject, when the hydrogel comprising the bioactive substance reaches the small intestine, it may be released into the small intestine by diffusion due to the pH differential, and/or as the hydrogel falls apart, and may thereby increase the overall bioavailability and/or effectiveness of the bioactive substance.
  • This method of encapsulation and oral delivery may eliminate certain problems and/or adverse side effects often associated with the oral delivery of various medicines and other bioactive substances in humans and/or animals. Accordingly, this modified carbohydrate hydrogel, its methods of preparation, and its uses, whereby medicines and other bioactive substances are encapsulated for oral delivery to humans and/or animals, may provide a wide variety of health benefits, while potentially eliminating certain problems and/or adverse side effects often associated with the oral delivery of these medicines and other bioactive substances.
  • a further aspect of the present invention includes various compositions and/or combinations that are micro-encapsulated in a modified carbohydrate (e.g., modified alginate) and/or produced in a size suitable for injection, either by itself, or in combination with liposomes, micelles, and/or nanospheres for, among other things, targeted delivery to a specific site or group of cells in humans and/or animals, such as to a tumor site.
  • a modified carbohydrate e.g., modified alginate
  • nanospheres for, among other things, targeted delivery to a specific site or group of cells in humans and/or animals, such as to a tumor site.
  • a compound of the present is an aromatic compound (e.g., an aromatic compound comprising one or more amines) that is combined with a carbohydrate (e.g., alginate).
  • a carbohydrate e.g., alginate
  • dopamine is combined with alginate.
  • a modified alginate comprises 4-(2-ethylamino)benzoic acid alginate.
  • a modified alginate comprises dopamine modified alginate.
  • a modified alginate comprises an aromatic substituent.
  • the aromatic substituent may be an amine substituent, including, but not limited to, a 4-(2- ethylamino)benzoic acid derivative, a 4-(2-ethylamino)phenolic derivative, a 4-(2- ethylamino)anilinic derivative, or a para (2-ethylamino)toluenic (i.e., (2-ethylamino)4- methylbenzene) derivative, and/or mixtures thereof.
  • the aromatic substituent is a dopamine substituent, including, but not limited to, a 4-(2-ethylamino)phenolic substituent, a 4-(2-ethylamino)benzoic acid substituent, a 4-(2-ethylamino)anilinic substituent, a 4-(2-ethylamino)toluenic substituent, and/or mixtures thereof.
  • a modified alginate of the present invention is a dopamine-modified alginate (DMA), optionally prepared using one and/or two different methods and/or preparations.
  • DMA dopamine-modified alginate
  • a modified alginate of the present invention may be characterized and/or quantified by a ⁇ - ⁇ methodology as described herein, which may quantify the amount of reactant (e.g., an aromatic amine such as, e.g., dopamine) that is incorporated into the alginate backbone.
  • compositions of the present invention may protect the carbohydrate (e.g., alginate)encapsulated compound (e.g., bioactive substance such as medicines) at pH levels that are found in the stomach (e.g., pH of about 1-3), and may make the carbohydrate (e.g., alginate)encapsulated compounds available at pH levels that are found in the intestines (e.g., more basic pH levels of about 7-9).
  • the alkaline environment may allow the carbohydrate (e.g., alginate)compound to be broken down and thus may provide for release of the encapsulated compound.
  • the carbohydrate (e.g., alginate)encapsulated compounds may be protected at acidic pH levels by the carbohydrate (e.g., alginate)coupled to an aromatic amine compound.
  • Fig. 1 shows a graph of the stability of unmodified and benzoic acid-modified alginate under acidic pH condition (pH 1.3).
  • Fig. 2 shows a graph of the stability of unmodified and benzoic acid-modified alginate under neutral-basic pH condition (pH 6.8).
  • Fig. 3 shows images of modified alginate materials under acid versus neutral-basic pH conditions.
  • the transitional phrase “consisting essentially of (and grammatical variants) is to be interpreted as encompassing the recited materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. See, In re Herz, 537 F.2d 549, 551-52, 190 U.S.P.Q. 461, 463 (CCPA 1976) (emphasis in the original); see also MPEP ⁇ 2111.03. Thus, the term “consisting essentially of as used herein should not be interpreted as equivalent to "comprising.”
  • “about X” where X is the measurable value is meant to include X as well as variations of ⁇ 10%, ⁇ 5%, ⁇ 1%, ⁇ 0.5%, or even ⁇ 0.1%» of X.
  • a range provided herein for a measureable value may include any other range and/or individual value therein.
  • a modified carbohydrate of the present invention is a modified alginate or a modified hyaluronic acid.
  • a modified carbohydrate (e.g., a modified alginate) of the present invention comprises at least one structure unit having a structure of Formula I:
  • Y is absent or a Q-C4 alkyl or Ci-C 4 alkenyl
  • R is each independently selected from the group consisting of -H, -OH, -NH 2 , - COOH,
  • each R' is independently selected from the group consisting of unsubstituted or substituted alkyl, alkenyl, alkynyl and aryl;
  • n is from 1 to 1,000,000
  • o 0, 1, 2, 3, 4, or 5.
  • the modified carbohydrate (e.g., a modified alginate) of Formula I has at least one Ri that is selected from the group consisting of -OH, -NH 2 , - COOH, -NO 2 , -CN, -Br, -CI, -F, -C Ce alkylhalide, unsubstituted or substituted -C C 6 alkyl, unsubstituted or substituted -d-C 6 alkenyl, -S0 2 H, -S0 3 H, -COCH 3 , -Si(OH) 3 , -S0 2 NH 2 , - PO(OR') 2 , and -B(OH) 2 , wherein each R' is independently selected from the group consisting of unsubstituted or substituted alkyl, alkenyl, alkynyl and aryl.
  • the modified carbohydrate (e.g., a modified alginate) of Formula I has at least one Ri that is hydrogen. In some embodiments, the modified carbohydrate (e.g., a modified alginate) of Formula I has at least one R] in the para position that is selected from the group consisting of-OH, -NH 2 , -COOH,
  • At least one R ⁇ in a compound of Formula I may have a pKa in a range of about 3 to about 6 or about 4 to about 4.5.
  • at least one Ri may have a pKa of about 3, 3.5, 4, 4.5, 5, 5.5, or 6.
  • one or more functional groups in the modified carbohydrate (e.g., a modified alginate) of Formula I may be protonated or deprotonated, optionally one or more Ri in the modified carbohydrate (e.g., a modified alginate) of Formula I may be protonated or deprotonated.
  • the protonation state (i.e., protonated or deprotonated) of one or more functional groups in the modified carbohydrate (e.g., a modified alginate) of Formula I may depend on the pH of the environment that the modified carbohydrate (e.g., a modified alginate) is exposed to and/or in contact with.
  • a modified carbohydrate (e.g., a modified alginate) of the present invention comprises at least one structure unit having a structure of Formula II:
  • Y is absent or a CrC 4 alkyl or C 1 -C 4 alkenyl
  • Ri is each independently selected from the group consisting of -H, -OH, -NH 2 , - COOH,
  • each R' is independently selected from the group consisting of unsubstituted or substituted alkyl, alkenyl, alkynyl and aryl;
  • n is from 1 to 1,000,000
  • o 0, 1 , 2, 3, 4, or 5.
  • the modified carbohydrate e.g., a modified alginate
  • the modified carbohydrate e.g., a modified alginate
  • Formula II has at least one R] that is selected from the group consisting of -OH, -NH 2 , - COOH, -N0 2 , -CN, -Br, -CI, -F, -Ci-C 6 alkylhalide, unsubstituted or substituted -Ci-C 6 alkyl, unsubstituted or substituted -d-C 6 alkenyl, -S0 2 H, -S0 3 H, -COCH 3 , -Si(OH) 3 , -S0 2 NH 2 , - PO(OR') 2 , and -B(OH) 2 , wherein each R' is independently selected from the group consisting of unsubstituted or substituted alkyl, alkenyl, alkynyl and aryl.
  • the modified carbohydrate (e.g., a modified alginate) of Formula II has at least one R ⁇ that is hydrogen.
  • the modified carbohydrate (e.g., a modified alginate) of Formula II has at least one Ri in the para position that is selected from the group consisting of -OH, -NH 2 , -COOH, -N0 2 , -CN, -Br, -CI, -F, -C C 6 alkylhalide, unsubstituted or substituted -C ⁇ -C alkyl, unsubstituted or substituted -Ci-C6 alkenyl, -S0 2 H, - S0 3 H, -COCH 3 , -Si(OH) 3 , -S0 2 NH 2 , -PO(OR') 2 , and -B(OH) 2 .
  • At least one R ⁇ in a compound of Formula II may have a pKa in a range of about 3 to about 6 or about 4 to about 4.5. In some embodiments, at least one R may have a pKa of about 3, 3.5, 4, 4.5, 5, 5.5, or 6.
  • one or more functional groups in the modified carbohydrate are one or more functional groups in the modified carbohydrate.
  • the protonation state (i.e., protonated or deprotonated) of one or more functional groups in the modified carbohydrate (e.g., a modified alginate) of Formula II may depend on the pH of the environment that the modified carbohydrate (e.g., a modified alginate) is exposed to and/or in contact with.
  • a modified carbohydrate (e.g., a modified alginate) of the present invention may be pH sensitive meaning that the protonation and/or ionic form of at least one functional group (e.g., R in the modified carbohydrate (e.g., a modified alginate) may change over a pH range, such as, e.g., a pH range from about 1, 2, or 3 to about 7, 8, or 9.
  • a pH range such as, e.g., a pH range from about 1, 2, or 3 to about 7, 8, or 9.
  • a modified carbohydrate (e.g., a modified alginate) of the present invention may be pH sensitive and at least one Ri may be a pH sensitive functional group such as, but not limited to, -OH, -NH 2 , -COOH, -S0 2 H, -S0 3 H, -S0 2 NH 2 , -Si(OH) 3 , or -B(OH) 2 .
  • a pH sensitive functional group such as, but not limited to, -OH, -NH 2 , -COOH, -S0 2 H, -S0 3 H, -S0 2 NH 2 , -Si(OH) 3 , or -B(OH) 2 .
  • a modified alginate of the present invention may be a chemically modified alginate.
  • a hydrogel of the present invention comprises a modified alginate of the present invention.
  • a modified alginate may be prepared by combining an aromatic compound with a carbohydrate, wherein the aromatic compound is one or more amines and the carbohydrate is an alginate.
  • the chemical structure of alginate may be modified using different amines and/or different methods, such as, for example: (1) covalently bonding aminoethyl benzoic acid to the alginate backbone, and/or (2) oxidizing the vicinal diol in the alginate chain to an aldehyde before coupling to aminoethyl benzoic acid.
  • the aromatic compound is dopamine.
  • the chemically modified alginate and/or methods of the present invention may be utilized to encapsulate a variety of bioactive substances for oral delivery in humans and/or animals, including, but not limited to: (i) drugs, medicines, enzymes, proteins, hormones, and vaccines, (ii) vitamins, minerals, micronutrients and/or other dietary supplements, (iii) probiotics and/or other microorganisms, (iv) cells, cell parts, and/or other biological materials, and/or (v) other bioactive substances.
  • a bioactive substance e.g., medicine
  • an enzyme e.g., enzymatic action in the stomach
  • encapsulating and/or coating at least a portion of the bioactive substance in a modified alginate hydrogel of the present invention when the encapsulated bioactive substance reaches the small intestine, it may be released into the small intestine by diffusion due to the pH differential, and/or as the hydrogel and/or microcapsule falls apart, which may thereby increase the overall bioavailability and effectiveness of the medicine or other bioactive substance.
  • This method of encapsulation and oral delivery may eliminate certain problems and adverse side effects often associated with the oral delivery of various medicines and other bioactive substances in humans and animals. Accordingly, this novel modified alginate hydrogel, its methods of preparation, and its use to encapsulate medicines and other bioactive substances for oral delivery to humans and/or animals, may provide humans and/or animals with a wide variety of health benefits, while eliminating certain problems and/or adverse side effects often associated with the oral delivery of these medicines and other bioactive substances.
  • compositions and/or combinations may be coated and/or provided in micro-size suitable for injection, either by itself, or in combination with liposomes, micelles, and/or nanospheres, for targeted delivery to a specific site or group of cells in humans or animals, such as a tumor site.
  • an aromatic compound comprising one or more amines may be combined with an alginate to prepare and/or provide a modified alginate of the present invention.
  • the aromatic compound is a dopamine.
  • the modified alginate is 4-(2-ethylamino)benzoic acid modified alginate.
  • the modified alginate is a dopamine modified alginate.
  • a modified alginate of the present invention may comprise a 4- (2-ethylamino)benzoic acid derivative, a 4-(2-ethylamino)phenolic derivative, a 4-(2- ethylamino)anilinic derivative, and/or a para (2-ethylamino)toluenic (i.e., (2-ethylamino)4- methylbenzene) derivative.
  • “Derivative” as used herein refers to a moiety that has been modified (e.g., chemically modified) to remove one or more functional groups (e.g., hydrogen,
  • the methodology used to prepare a modified alginate of the present invention may use N-hydroxysuccinimide (NHS) optionally in conjunction with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to activate a carboxylic acid (or carboxylate) on an alginate, which may allow the primary amine on the aromatic substituent to react with the carboxylate to generate the amide.
  • NHS N-hydroxysuccinimide
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • an alginate may be reacted with one or more reactants selected from the group consisting of 4-(2-aminoethyl)benzoic acid, 4-(2-aminomethyl)benzoic acid, 4-(2-aminoethyl)aniline, (2-ethylamino)4-methyl benzene, 4-(2-aminoacetyl)-benzoic acid, 4- (2-aminoethyl)salicylic acid, and/or 4-(2-aminomethyl)aniline and/or esters thereof.
  • the reactant is not dopamine.
  • the alginate and reactant may be reacted in the presence of N-hydroxysuccinimide (NHS) and/or l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC).
  • NHS N-hydroxysuccinimide
  • EDC l-ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • the alginate and reactant are reacted in the presence of a nitrile such as acetonitrile.
  • the reactant may be incorporated into alginate in an amount of about 1% to about 20% based on the average number of polysaccharide units in the alginate. In some embodiments, the reactant is incorporated into the alginate in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%. In some embodiments, about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the reactant is chemically bond to the alginate, rather than free or trapped within the polymer.
  • Alginate used to prepare a modified alginate of the present invention may be of any type.
  • Alginate is a polysaccharide composed of randomly oriented blocks of monomers of (l-4)-linked ⁇ -D-mannuronic acid (M) and a-L-guluronic acid (G).
  • a modified alginate of the present invention may be prepared and/or formed using an alginate having about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the total number of polysaccharide units be M units or G units.
  • the alginate used to prepare a modified alginate of the present invention may be a natural and/or unmodified alginate.
  • the alginate used to prepare a modified alginate of the present invention may be an oxidized alginate.
  • alginate may have a structure of Formula III:
  • X is hydrogen or a counterion (e.g., sodium, lithium, etc),
  • m is from 1 to 1 ,000,000
  • n is from 1 to 1,000,000.
  • an alginate may be selected to prepare a modified alginate of the present invention in order to provide and/or tune the properties of a hydrogel comprising the modified alginate.
  • the diffusion characteristics and/or diffusion rate may be adjusted and/or tuned for a hydrogel comprising a modified alginate of the present invention by the type of alginate used to prepare the modified alginate.
  • the rate of diffusion in a hydrogel comprising a modified alginate of the present invention may depend on the G fractions of alginate, with the diffusion coefficient increasing at lower G fractions.
  • Measurements of simple physical parameters, such as volume fraction and size, may be used to predict solute transport in a hydrogel of the present invention. These parameters may be controlled based on the alginate concentration and/or composition for sustained release of small amounts of substances (e.g., bioactive substances) encapsulated in the modified alginate. In some embodiments, where the release of readily effective therapeutic levels is desired, it may be beneficial to modify alginate and/or a hydrogel of the present invention to release the encapsulated bioactive substance based on prompt degradation of the alginate and/or hydrogel.
  • substances e.g., bioactive substances
  • One way to achieve this immediate release and enhanced bioavailability of therapeutic molecules encapsulated in alginate hydrogel may be to modify the alginate polymer to degrade based on sensitivity to the basic pH of the small intestine where absorption into the systemic circulation also takes place.
  • a hydrogel of the present invention may degrade when exposed to a basic pH and thereby release at least a portion of the encapsulated substance (e.g., optionally in the small intestine of a subject).
  • the modification of an alginate with a reactant as described herein may shift the pKa of the alginate in solution and may provide sensitivity of the modified alginate and/or a hydrogel comprising the modified alginate to basic pH.
  • alginate e.g., a naturally occurring alginate and/or an oxidized alginate
  • alginate may be covalently and/or noncovalently modified by adding a catechol and/or a pH sensitive functional group to the alginate backbone.
  • modifying a catechol and/or a pH sensitive functional group may be added to the alginate backbone.
  • alginate as described herein may improve the alginate's adhesive properties and/or its rigidity, which may improve performance of the modified alginate as a wound healing aid, surgical adhesive, and/or as a delivery vehicle.
  • a carbohydrate and an aromatic compound may be reacted to generate a polymer that contains both a carbohydrate portion and an aromatic portion.
  • the reaction may proceed as indicated below in Scheme I wherein X is a counterion that allows the carboxylate to make a salt, R ⁇ is each independently selected from substituents such as, but not limited to, -H, -OH, -NH 2 , -COOH,
  • R' is unsubstituted or substituted alkyl, alkenyl, alkynyl, or aryl; ;m is 0 to 3 or 4; n is 1 to 1,000,000; and o is 1 to 3 or 5.
  • a modified alginate of the present invention may comprise two or more different R ⁇ or may comprise two or more of the same Rj. That is, for example, if o is 2, Rj may be two hydroxyls, or alternatively, one of the R s may be hydroxyl and the other Rj may be a halide (or any other substituent identified herein).
  • the reaction as shown in the diagram immediately above may be perfomed using alginates (as the carbohydrate).
  • Alginic acid is a combination of ⁇ -D-mannuronic and a-L- guluronic acids attached with 1 ⁇ 4 linkages.
  • Scheme I is shown with only one type of carbohydrate, it should be understood that the respective sugars in the carbohydrate may be different. Similar to using alginic acid, it should be understood that other types of carbohydrates may be used such as, but not limited to, hyaluronic acid.
  • a modified alginate may be prepared as illustrated in Scheme II, wherein X is hydrogen or a counterion; Y is absent or a Ci-C 4 alkyl or C 1 -C 4 alkenyl; R 1 is each independently selected from the group consisting of -H, -OH, -NH 2 , -COOH, -N0 2 , -CN, -Br, -CI, -F, -Ci-C alkylhalide, unsubstituted or substituted -Ci-C 6 alkyl, unsubstituted or substituted -Ci-C 6 alkenyl, -S0 2 H, -S0 3 H, -COCH 3 , -Si(OH) 3 , - S0 2 NH 2 , -PO(OR') 2 , and -B(OH) 2 , wherein R' is unsubstituted or substituted alkyl, alkenyl, alkyny
  • a modified alginate may be prepared as illustrated in Scheme III, wherein X is hydrogen or a counterion; Y is absent or a C1-C4 alkyl or C 1 -C 4 alkenyl; Rj is each independently selected from the group consisting of -H, -OH, -NH 2 , -COOH, -N0 2 , -CN, -Br, -CI, -F, -Ci-C alkylhalide, unsubstituted or substituted -Ci-C 6 alkyl, unsubstituted or substituted -Ci-C 6 alkenyl, -S0 2 H, -S0 3 H, -COCH 3 , -Si(OH) 3 , - S0 2 NH 2 , -PO(OR') 2 , and -B(OH) 2 , wherein R' is unsubstituted or substituted alkyl, alkenyl, alkyn
  • a modified alginate may be prepared as illustrated in Scheme IV, wherein X is hydrogen or a counterion; Y is absent or a C1-C4 alkyl or C1-C4 alkenyl; Rj is each independently selected from the group consisting of -H, -OH, -NH 2 , -COOH, -N0 2 , -CN, -Br, -CI, -F, -Ci-C 6 alkylhalide, unsubstituted or substituted -Ci-C 6 alkyl, unsubstituted or substituted -C 1 -C 6 alkenyl, -S0 2 H, -S0 3 H, -COCH 3 , -Si(OH) 3 , - S0 2 NH 2 , -PO(OR') 2 , and -B(OH) 2 , wherein R' is unsubstituted or substituted alkyl, alkenyl, alky
  • Periodate oxidized alginate (POA) Periodate oxidized alginate
  • a modified alginate may be prepared as illustrated in Scheme V, wherein X is hydrogen or a counterion; Y is absent or a C 1 -C 4 alkyl or C!-C 4 alkenyl; Rj is each independently selected from the group consisting of -H, -OH, -NH 2 , -COOH, -N0 2 , -CN, -Br, -CI, -F, -C ⁇ -C alkylhalide, unsubstituted or substituted -Ci-C 6 alkyl, unsubstituted or substituted -Ci-C 6 alkenyl, -S0 2 H, -S0 3 H, -COCH 3 , -Si(OH) 3 , - S0 2 NH 2 , -PO(OR') 2 , and -B(OH) 2 , wherein R' is unsubstituted or substituted alkyl, alkenyl, alkenyl,
  • alginic acid is combined with an aromatic as described in Schemes I-V, wherein X is sodium, m is 2, n is between about 500,000 and 1,000,000, o is 2, and the two Ri are both hydroxyls. In some embodiments, the hydroxyls are positioned meta and para to the ethylamine (that is present on the phenyl group).
  • the carbohydrate is alginic acid, X is sodium, m is 2, n is between about 500,000 and 1,000,000, o is 1, and 3 ⁇ 4 is amino or a carboxylate salt (or carboxylic acid).
  • the aromatic substituent that reacts with alginic acid may be 4-aminomethyl benzene sulfonamide. Similar to the reaction shown in Scheme I, when 4-aminomethyl benzene sulfonamide is used for the aromatic substituent, n may be between about 500,000 and 1 ,000,000. In some embodiments, 4- aminomethyl benzene sulfonamide may contain additional substituents (e.g., 1, 2, or more) off the benzene ring, and the substituents may be amino, a carboxylate salt ,and/or a carboxylic acid.
  • additional substituents e.g., 1, 2, or more
  • the reaction between the carbohydrate and an aromatic compound may be performed in a buffer such as, but not limited to, PBS (Phosphate Buffered Saline) and other buffers so long as they don't adversely affect the reaction. Additionally or alternatively, the reaction may take place in a nitrile such as, but not limited to, acetonitrile.
  • a buffer such as, but not limited to, PBS (Phosphate Buffered Saline) and other buffers so long as they don't adversely affect the reaction. Additionally or alternatively, the reaction may take place in a nitrile such as, but not limited to, acetonitrile.
  • linker group sizes e.g., m can be 0 to 3 or 4; Y is absent or a C1-C4 alkyl or alkenyl group
  • maximal microencapsulation and/or coating may occur when the linker group is an ethylene.
  • one or more (e.g., 1, 2, 3, or more) protective groups may be utilized to get the desired reaction to proceed and/or to avoid having a plurality of different reaction processes occurring.
  • protective groups and their chemistry can be found in, for example, Greene's Protective Groups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc., which is hereby incorporated by reference in its entirety.
  • the present invention relates to alginate compounds and methods of preparing said alginate compounds, optionally for encapsulating and/or coating at least a portion of a bioactive substance such as, e.g., a bioactive- substance to be delivered orally or by other means.
  • the modified alginate is an amine-modified alginate.
  • the modified alginate is a dopamine-modified alginate (DMA).
  • DMA dopamine-modified alginate
  • a modified alginate may be characterized and/or quantified by a 'H-NMR methodology, such as, e.g., to quantify incorporation of a reactant (e.g., dopamine) into the alginate backbone.
  • Dopamine i.e., (4-(2-aminoethyl) benzene, 1,2-diol)
  • the linker group may be of a sufficient length to allow microencapsulation of a bioactive substance such as, e.g., medicine, drug, protein, hormone, vaccine, vitamin, mineral, micronutrient and/or other dietary supplement, biological material, probiotic and/or other micro-organism, and/or another bioactive compound and/or substance.
  • a modified alginate of the present invention may comprise a polar group (e.g., the carbohydrate portion) and a hydrophobic portion (e.g., an aromatic benzene ring), which may allow for microencapsulation.
  • a modified alginate of the present invention optionally when provided in a hydrogel of the present invention, may be used for protecting a bioactive substance from attack and/or degradation by an acid/or and an enzyme (e.g., enzymatic action in the stomach), which may enhance the bioavailability and/or effectiveness of the bioactive substance, optionally in the place where they are most useful and/or beneficial (e.g., in the intestines).
  • a modified alginate of the present invention may coat and/or encapsulate at least a portion of a compound (e.g., bioactive substance), and/or may protect the compound at pH levels that are found in the stomach (e.g., pH of about 1-3), but the modified alginate may allow and/or provide for the compound to be made available at the pH levels that are found in the intestines (e.g., more basic pH levels such as about 7-9) as the alkaline environment may allow for the alginate to be broken down, which may allow for access to and/or release of the encapsulated compound.
  • the alginate encapsulated compounds may be protected at acidic pH levels by the modified alginate.
  • the lability of a modified alginate and/or hydrogel of the present invention coating and/or encapsulating a compound may be able to withstand the pH of saliva (generally a pH of about 6.5-7.4).
  • the modified alginate and/or hydrogel may be able to withstand the pH of saliva for a sufficient amount of time such that the modified alginate and/or hydrogel may be able to reach the stomach with at least a portion of the compound (e.g., about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%)) still encapsulated and/or coated.
  • the encapsulated compounds upon prolonged exposure to the pH of the small intestine, the encapsulated compounds may become bioavailable for their intended benefits.
  • a modified alginate of the present invention may be prepared with a method as shown in Scheme VI.
  • two approaches may be performed, optionally simultaneously: 1) formation of amide bonds to existing carboxylic acid groups on the alginate backbone and 2) synthesizing small molecules containing catechol functional groups which may be used as modular additives to other available alginate systems. Some of these small molecules may be covalently linked to alginate and some may interact through noncovalent interactions such as hydrogen bonding. In some embodiments, stiffness and/or adhesiveness of a modified alginate may be improved by up to a factor of three with small molecule additives.
  • a method of the present invention may allow for incorporation of greater amounts of a reactant (e.g., an aromatic amine such as, e.g., dopamine and/or a pH sensitive compound) into the alginate than has been previously reported and/or compared to different methods.
  • a method of the present invention may provide about 1% to about 20% or about 5% to about 15% incorporation of a reactant into alginate, wherein the incorporation percentage is based on the average number of polysaccharide units of the alginate.
  • a reactant e.g., dopamine
  • alginate in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%.
  • the modified alginate contains about 1 of every 25 carboxylates modified, 1 of every 12 carboxylates modified, and 1 of every 8 carboxylates modified, respectively.
  • a cross-linked alginate e.g., a modified alginate of the present invention that is cross-lined.
  • the cross-linked alginate is a cross-linked amine modified alginate.
  • the cross- linked alginate may be used for coating and/or encapsulating a bioactive substance (e.g., medicines, drugs, enzymes, proteins, hormones, vaccines, vitamins, minerals, micronutrients and other dietary supplements, biological materials, probiotics and other micro-organisms, and other bioactive compounds and substances).
  • a modified alginate of the present invention may be produced using a reaction that does not require elevated temperatures.
  • the techniques disclosed herein may enable application of one or more molecular monolayer(s) of a modified alginate (e.g., an amine modified alginate or dopamine modified alginate) on a bioactive substance, which may provide a coating on the bioactive substance.
  • a monolayer may be on the order of nanometers in thickness.
  • a compound and/or coating disclosed herein may enable application of a coating and/or encapsulate that can allow a bioactive substance (e.g., various medicines, drugs, enzymes, proteins, hormones, vaccines, vitamins, minerals, micronutrients and other dietary supplements, biological materials, probiotics and other micro-organisms, and other bioactive substances) to be delivered to and used by a host organism, such as humans, optionally without causing premature rupture of the encapsulated material, for example, in the acidic environment of the stomach.
  • a bioactive substance e.g., various medicines, drugs, enzymes, proteins, hormones, vaccines, vitamins, minerals, micronutrients and other dietary supplements, biological materials, probiotics and other micro-organisms, and other bioactive substances
  • a hydrogel comprising a modified alginate of the present invention.
  • a modified alginate may be present in the hydrogel in an amount of about 0.1% to about 10% w/v of the hydrogel, such as, e.g., about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w/v of the hydrogel.
  • the hydrogel may be cross-linked.
  • the hydrogel is cross- linked with a divalent cation (e.g., calcium).
  • a divalent cation may be present in the hydrogel in an amount of about 0.1 mmol to about 1 mmol.
  • the hydrogel may comprise water or an aqueous solution (e.g., a saline solution) that is optionally buffered.
  • the hydrogel comprises a bioactive substance.
  • the hydrogel may coat and/or encapsulate at least a portion (e.g., about 50%, 60%, 70%, 80%, 90%, or 100%) of the bioactive substance.
  • the bioactive substance is uniformly distributed within the hydrogel.
  • the hydrogel may have an elastic modulus in a range of 1 or 5 kPa to about 15 or 20 kPa.
  • the hydrogel is in the form of a bead, capsule (e.g., microcapsule), food product (e.g., edible treat), pellet, and/or hermetically sealed pouch and/or straw.
  • the hydrogel may be sized for a subject to swallow with or without water.
  • the hydrogel may have at least one dimension in a range of about 100 microns to about 500 microns or about 200 microns to about 400 microns. In some embodiments, the hydrogel may have at least one dimension that is about 300 microns.
  • a biocompatible capsule that comprises a biological material (e.g., a bioactive substance) and a covalently stabilized coating (e.g., a modified alginate coating) which encapsulates the biological material.
  • a biological material e.g., a bioactive substance
  • a covalently stabilized coating e.g., a modified alginate coating
  • the present invention offers unexpectedly superior properties and/or results because of the modification of alginate such as, e.g., attachment of an amine (e.g., dopamine and/or pH sensitive compound, which may result in enhanced adhesiveness of the alginate.
  • modification of alginate such as, e.g., attachment of an amine (e.g., dopamine and/or pH sensitive compound, which may result in enhanced adhesiveness of the alginate.
  • covalent modifications of a polysaccharide may alter the acid-base stability of the polysaccharide, which may be used for drug delivery.
  • Amine and/or dopamine modified alginates may be stable in acid environments similar to the stomach environment and a modified alginate (e.g., a modified alginate pellet) may disintegrate readily in a basic environment similar to the small intestine environment.
  • alginates with varying degrees of amide modification may be provided and/or synthesized, and may be used for acid and base sensitive drug delivery applications.
  • a modified alginate of the present invention may be formulated into microparticles and/or optimized for acid-base stability.
  • a modified carbohydrate formulation and/or microparticle of the present invention may be used as a wound healing aid and/or as a surgical adhesive.
  • a hydrogel of the present invention may provide a barrier to a bioactive substance (e.g., a medicine, drug, enzyme, protein, hormone, vaccine, vitamin, mineral, and/or micronutrient).
  • the hydrogel may coat at least a portion of the bioactive substance and/or encapsulate at least a portion of the bioactive substance.
  • a hydrogel of the present invention comprises a bioactive substance (e.g., potassium iodide) and the hydrogel may prevent and/or reduce degradation and/or oxidation of the bioactive substance.
  • a hydrogel of the present invention may increase the shelf life of a bioactive substance when the hydrogel comprises the bioactive substance (e.g., coats and/or encapsulates at least a portion of the bioactive substance).
  • the shelf life of potassium iodide in liquid or powder form may be increased when incorporated in a hydrogel of the present invention.
  • Shelf life refers to the length of time a bioactive substance maintains a given level of activity in an unopened package stored under recommended storage conditions.
  • shelf life may, for example, be evidenced by the "use by” or “best if used by” date for the product and/or the manufacturer's expiration date of the product (i.e., the "predicted shelf life") and/or the actual product characteristics after the specified period of time (i.e., the "actual shelf life”). Accordingly, the term “shelf life” as used herein should be construed as including both the actual shelf life of the product and the predicted shelf life of the product unless stated otherwise. In some embodiments, shelf life may be determined by extrapolation of data at accelerated temperatures, such as, for example, by using the Arrhenius equation.
  • shelf life may be determined using linear regression analysis, such as, for example, when the kinetics of the bioactive substance degradation is not temperature dependent. In some embodiments, shelf life may be evaluated and/or determined by measuring the bioactive substance, such as, for example, using high pressure liquid chromatography. In some embodiments, the shelf life of a hydrogel comprising a bioactive substance is the time that the bioactive substance in the hydrogel maintains at least about 50% (e.g., at least about 50%, 60%, 70%, 80%, 90%, or more) of a given activity (e.g., the ability to deliver and/or provide a therapeutically effect amount of the bioactive substance) compared to the initial activity of the bioactive substance prior to incorporation into the hydrogel.
  • a given activity e.g., the ability to deliver and/or provide a therapeutically effect amount of the bioactive substance
  • a therapeutically effective amount refers to an amount of a bioactive substance and/or hydrogel that elicits a therapeutically useful response in a subject.
  • a therapeutically effective amount of a hydrogel of the present invention may include delivering a therapeutically effective amount of a bioactive substance (e.g., potassium iodide) present in the hydrogel.
  • a bioactive substance e.g., potassium iodide
  • a packaged hydrogel of the present invention comprises a bioactive substance (e.g., potassium iodide) and has a shelf life of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months or more, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 years or more, or any range and/or individual value therein.
  • a bioactive substance e.g., potassium iodide
  • the terms “increase”, “improve”, and “enhance” refer to an increase in the specified parameter of greater than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175%, 200%, 250%, 300% or more.
  • the terms “decrease”, “inhibit”, and “reduce” refer to a decrease in the specified parameter of about 1%, 2%, 3%», 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • the present invention relates to protecting one or more bioactive substances from the destructive effects of an acid and/or an enzyme (e.g., enzymatic action in the stomach), and/or enhancing the bioavailability and/or effectiveness of these bioactive substances by coating and/or encapsulating them in a modified alginate of the present invention, optionally in a hydrogel of the present invention.
  • an enzyme e.g., enzymatic action in the stomach
  • the present invention relates to encapsulating proteins, hormones, and other bioactive substances in a modified alginate of the present invention, which may protect these bioactive substances from attack and/or degradation by an acid and/or an enzyme (e.g., enzymatic action in the stomach).
  • the bioactive substance may be released in the intestines as a modified alginate micro-capsule falls apart and/or diffuses its contents into the intestines.
  • One such example is encapsulating insulin in the modified alginate in a bioavailable form for oral delivery to protect it from destruction by an acid and/or an enzyme (e.g., enzymatic action in the stomach), so that at least a portion of the insulin may be delivered to the small intestine intact, where it may be released and absorbed into the bloodstream for use by humans or other animals in appropriate amounts.
  • an enzyme e.g., enzymatic action in the stomach
  • the present invention relates to encapsulating drugs, medicines, and other bioactive substances in a modified alginate, such as non-prescription pain medications, which may prevent or reduces these substances from causing stomach upset, nausea, and/or vomiting when taken orally.
  • a modified alginate such as non-prescription pain medications
  • One example is encapsulating aspirin (acetylsalicylic acid) for oral delivery, thereby preventing the release of the acetylsalicylic acid in the stomach, where it often causes stomach upset, nausea, vomiting, and even ulcers (if taken regularly to reduce pain or inflammation).
  • the encapsulated aspirin is released in the small intestine as the modified alginate micro-capsule falls apart and/or diffuses its contents into the intestines, where it is absorbed into the bloodstream to reduce fever, relieve pain, swelling, and inflammation, from conditions such as muscle aches, toothaches, common cold, flu, headaches, and arthritis; prevent blood clots and lower the risk of heart attack, clot-related strokes and other blood flow problems in patients who have cardiovascular disease, or who have already had a heart attack or stroke; and to treat a variety of other conditions in humans and animals.
  • the present invention relates to encapsulating drugs, medicines and other bioactive substances in a modified alginate, such as prescription pain medications, which may prevent or reduce these substances from causing stomach upset, nausea, and/or vomiting when taken orally.
  • a modified alginate such as prescription pain medications
  • opioid-based pain medications such as oxycodone, hydrocodone, codeine, morphine, fentanyl and others. These medications often cause stomach upset, nausea, and/or vomiting when taken orally.
  • the modified alginate may prevent and/or reduce the release of the pain medication in the stomach, where it would normally cause stomach upset, nausea, or vomiting.
  • the encapsulated pain medication may not be released until it reaches the small intestine, where the modified alginate micro-capsule falls apart and/or diffuses its contents into the intestines, where it is absorbed into the bloodstream to reduce moderate to severe pain from a variety of injuries, diseases and other serious or life threatening conditions.
  • the present invention relates to encapsulating opioid-based and other potentially addictive pain medications in a modified alginate for oral delivery, which may provide the medication in a form that cannot easily or readily be separated from the modified alginate, turned into a powder, and/or sold by drug dealers to drug addicts, who inhale, snort or smoke the powder, or liquify it and inject it directly into their veins or arteries.
  • the present invention relates to encapsulating medicines and other bioactive and therapeutic substances in a modified alginate to increase bioavailability, protect the substance from attack, degradation and/or destruction by an acid and/or an enzyme (e.g., enzymatic action in the stomach), and/or make it largely tasteless, odorless and undetectable for oral delivery to animals, including humans, pets and livestock.
  • an acid and/or an enzyme e.g., enzymatic action in the stomach
  • the largely tasteless, odorless, and undetectable micro-capsules containing the medicine or other bioactive substance may be combined with pet food, animal feed, and other foodstuffs the animal finds appealing, so that the animal will readily eat the micro-encapsulated medicine or other bioactive substance, and not reject it or spit it out, as is often the case with any food or other substance that does not smell good or taste good to the animal, which also makes it difficult to administer these therapeutic substances to pets, livestock, and other animals.
  • encapsulation of medicines and other bioactive substances for oral delivery to animals as described herein may (i) increase the bioavailability of the encapsulated medicine or other bioactive substance being ingested, (ii) make it easier to gauge the amount of the bioactive substance that is actually ingested by the animal, (ii) reduce the amount of medicine or other bioactive substance required (dose), since greater bioavailability (i.e., greater efficiency and/or effectiveness of the medicine) often results in a lower dose being required, (iii) eliminate unnecessary anxiety and/or trust issues between the animal and the person administering the medicine or other therapeutic substance, (iv) eliminate the risk of injuries to persons administering the medicines and other bioactive substances to the animal, and/or (v) eliminate the cost and/or expense of having to utilize a veterinarian or other trained professional to administer the medicine or other bioactive substance to the animal.
  • the present invention relates to encapsulating live and/or active probiotics, gut flora, and other "good” or “healthy” micro-organisms in a modified alginate to protect them from attack, degradation, and/or destruction by an acid and/or an enzyme (e.g., enzymatic action in the stomach).
  • the micro-organisms may then be released in the intestines alive and/or intact, where their health and other therapeutic benefits may be fully realized.
  • One example is encapsulating Lactobacillus Casei NCDC 298 in a modified alginate.
  • Encapsulating probiotics may increase their shelf-life and/or shield them from attack, degradation, and/or destruction by an acid and/or an enzyme (e.g., enzymatic action in the stomach) after they are orally ingested.
  • an acid and/or an enzyme e.g., enzymatic action in the stomach
  • the encapsulated probiotics may reach the small intestine, they may be released as the modified alginate falls apart.
  • the probiotics may then be able to recolonize the gut with their "good" bacteria, so that the many health and other therapeutic benefits of the probiotics can be fully utilized and realized.
  • Many other types and strains of probiotics can be encapsulated in a modified alginate for oral delivery to humans and animals.
  • the present invention relates to providing probiotic living cells with a physical barrier against adverse environmental conditions until delivery to the intestines has been accomplished.
  • the proper conditions are a basic pH.
  • the present invention relates to a composition that includes an encapsulated probiotic that has a plurality of health benefits.
  • probiotics are biological entities, delivery of sufficient doses is constantly challenged by inherent factors that might limit their biological activity, including the conditions of growth, processing, preservation, and storage. Specifically, loss of probiotic viability occurs at many distinct stages, including freeze-drying of cells during initial manufacturing, during their preparation (high temperature and high pressure), transportation and storage (temperature fluctuations), and after consumption or in gastrointestinal (GI) track (low pH and bile salts).
  • GI gastrointestinal
  • One of the determined factors for probiotics to have beneficial effects is to maintain the high concentration of viable cells for individuals to uptake.
  • commercial probiotic products are available, many of them lose their viability during the manufacturing process, transport, storage.
  • the present invention relates to a composition which contains a probiotic.
  • compositions of the present invention may be good for those that have cardiovascular issues.
  • the composition of the present invention may be useful at improving the immune health of individuals that consume the composition.
  • the composition of the present invention may comprise both a prebiotic, which may optimize the conditions for any composition, that also contains probiotics.
  • a composition of the present invention may contain one or more probiotic cultures that may include, for example, various species of the genera Bifidobacterium, Lactobacillus and/or propionibacteria such as: Bifidobacterium animalis lactis; Bifidobocterium bifidum; Bifidobacterium breve; Bifidobacterium infantis; Bifidobacterium longum; Lactobacillus acidophilus; Lactobacillus casei; Lactobacillus plantarum; Lactobacillus reuteri; Lactobacillus rhamnosus; Lactobacillus spoogenes and the like.
  • propionibacteria such as: Bifidobacterium animalis lactis; Bifidobocterium bifidum; Bifidobacterium breve; Bifidobacterium infantis; Bifidobacterium longum; Lactobacillus acidophilus; Lactobac
  • a species of yeast Saccharomyces boulardii may also be used as a probiotic.
  • the probiotic cultures include Bifidobacterium lactis BI-04, Bifidobacterium lactis BB-12 (CHN), and L. reuteri (SD 55730-Biogaia).
  • the present invention relates to encapsulating vitamins, dietary supplements, and other bioactive substances in a modified alginate for oral delivery to humans and animals, since certain vitamins, dietary supplements, and other bioactive substances suffer from issues of bioavailability, as well as issues of oxidation and the build- up of toxic peroxides and other substances, among other things.
  • vitamins, dietary supplements, and other bioactive substances suffer from issues of bioavailability, as well as issues of oxidation and the build- up of toxic peroxides and other substances, among other things.
  • These include Omega-3 fatty acids (EPA/DHA), CoQIO, and vitamin D, which current research strongly suggests are important to our overall health and well-being, and should be administered and used to supplement the diets of large numbers of people around the world.
  • the bioavailability of these vitamins, dietary supplements, and other bioactive substances, and their ability to be stored for any length of time, are hampered by oxidation and the build-up of toxic peroxides and other substances. They can also be impacted by the intrinsic properties of the digestive tract, especially the differential pH along the tract. The variable pH from the stomach to the intestine impacts the stability, and thereby the bioavailability, of fat and peptide-based dietary supplements and other pharmaceuticals.
  • Some vitamins and dietary supplements, such as vitamin C, vitamin B3, vitamin A and vitamin D can also cause stomach upset, nausea, and vomiting when taken orally.
  • encapsulation may (i) protect the encapsulated substance from the destructive and/or toxic effects of oxidation while being stored, (ii) prevent or reduce the release of the encapsulated substance in the stomach, where it may cause stomach upset, nausea, or vomiting, (iii) protect the encapsulated substance from attack, degradation, and/or destruction from stomach acids and/or enzymatic action, and/or (iv) prevent at least a portion of the encapsulated substance from being released until it reaches the small intestine, where the micro-capsule may fall apart and/or diffuses its contents into the intestines, where the substance may be absorbed into the bloodstream for its health and other benefits.
  • Vitamin D constitutes a largely unrecognized and serious public health problem.
  • Chronic Vitamin D deficiency adversely affects adequate mineralization of bone and leads to rickets in children and osteomalcia or osteoporosis in adults.
  • Low levels of 25-hydroxyvitamin D, the universal clinical parameter of vitamin D status is associated with an increased risk of cancers, cardiovascular disease, and diabetes, among other diseases.
  • the present invention relates to methods associated with being able to treat cancers, cardiovascular disease, diabetes, and/or other diseases.
  • the present invention may address issues that the dietary supplement and/or pharmaceutical industries have long considered necessary, but have been largely unavailable.
  • the present invention relates to being able to prolong and/or increase the bioavailability of a bioactive substance (e.g., a medicament/dietary supplement) by combining a bioactive substance that is microencapsulated as described herein with the same or different non-microencapsulated medicament.
  • a bioactive substance e.g., a medicament/dietary supplement
  • the medicament/dietary supplement that is not microencapsulated will show bioavailability more rapidly (for example in the acidic stomach) whereas the microencapsulated bioactive substance will not be readily bioavailable until it passes through the acidic stomach. That is, it will be bioavailable once it passes to the more basic conditions of the intestines.
  • the present invention relates to encapsulating cells, cell parts, tissues, and other biological materials in a modified alginate in a micro-size suitable for injection, either by itself, or in combination with liposomes, micelles, and/or nanospheres, for targeted delivery to a specific site or group of cells in humans or animals, such as a tumor site.
  • a composition of the present invention may be used to treat one or more maladies.
  • the functional aspects of the invention may act as an antioxidant and/or treat digestive maladies, cognitive disorders, and/or cardiovascular systems and diseases.
  • the formulations of the present invention may be used to treat eczema.
  • a subject is a human in need of cancer treatment.
  • the present invention relates to methods and compositions comprising a hydrogel comprising a modified alginate of the present invention. The hydrogel may be used to micro-encapsulate a bioactive substance.
  • the hydrogel may be administered orally to humans and other animals in order to treat and/or inhibit a wide variety of diseases, parasites, and other conditions without significant degradation of the bioactive substance by stomach acids and/or enzymatic action and/or with reduced negative side effects such as those that accompany certain medicines when taken orally.
  • the present formulation may comprise a composition that contains one or more stilbenes sufficient to have desired antioxidant effects.
  • the one or more stilbenes present may have beneficial anti-inflammatory effects.
  • the present invention may contain one or more stilbenes that are efficacious in reversing cognitive behavioral deficits.
  • the formulations of the present invention may be effective against Alzheimer's.
  • a composition of the present invention may additionally contain pharmaceutically acceptable salts, solvates, and prodrugs thereof, and may contain antiseptics, astringents, diluents, excipients, carriers, micelles, liposomes, and/or other substances necessary to increase the bioavailability and/or extend the lifetime of the compounds/probiotics present in the composition of the present invention.
  • the present invention is not only directed to compositions but is also directed to formulations, supplements, sweeteners, medicaments, and/or other products and methods of using those products, formulations, supplements, and/or medicaments.
  • a modified alginate is stable under acidic conditions but is labile under basic conditions. In some embodiments, the modified alginate is stable at a pH of between about 1.5 to 3.5, but is labile when the pH increases above 7. In some embodiments, the modified alginate is stable at a pH of about 3 to 5 and labile at a pH above 7. In some embodiments, the modified alginate is stable for at least about 5, 10, or 15 minutes at a pH above 7.
  • a modified alginate optionally in the form of a hydrogel, coats and/or encapsulates a bioactive substance, and has a thickness such that the modified alginate can be exposed to saliva in the mouth and without making the bioactive substance bioavailable until the modified alginate reaches the intestines of an individual administered the modified alginate.
  • the present invention relates to a method of making proteins, micronutrients, dietary supplements and/or probiotics more bioavailable to an individual in need of said proteins, micronutrients, dietary supplements and/or probiotics by administering to said individual said proteins, micronutrients, dietary supplements and/or probiotics encapsulated in a modified alginate of the present invention.
  • the present invention relates to a method of delivering a dietary supplement or probiotic to an individual in need thereof, said method comprising administering to said individual a composition that comprises a modified alginate of the present invention.
  • the present method uses proteins, micronutrients, dietary supplements and/or probiotics that are encapsulated by a modified alginate of the present invention.
  • the present invention relates to a method of treating an individual in need thereof by administering proteins, micronutrients, dietary supplements and/or probiotics to said individual, wherein the proteins, micronutrients, dietary supplements and/or probiotics are encapsulated in a modified alginate, the modified alginate being modified as described above.
  • the method may include treating individuals for depression wherein the method uses as a dietary supplement fish oil that serves as a primary source for omega-3 fatty acids.
  • the method may boost the ability to boost the effects of antidepressants, they also may aid in treating the depressive symptoms of bipolar disorder.
  • the method may be also used for treating visual or neurological problems in infants or aiding visual and neurological development in infants.
  • the method may allow ingestion of omega-3 fatty acids in relatively high doses that may lower inflammation, and may treat asthma.
  • the invention relates to delivering omega-3 fatty acids to individuals, which are useful in ameliorating and/or reducing symptoms associated with ADHD in some children, while at the same time enhancing their mental skills.
  • the invention also relates to the use of omega-3 fatty acids to treat or slow the progression of Alzheimer's disease and/or dementia.
  • the invention relates to a method of using a modified alginate to deliver vitamin D.
  • the method may be used to reduce inflammation (by acting on C- Reactive Protein).
  • the method of delivering vitamin D may aid individuals in reducing pain as well as the stress on joints.
  • the method may also relate to the treatment of or reducing rheumatoid arthritis, obesity, certain cancers, various heart diseases, and the effects of radiation.
  • the method may be used to enhance individuals' mental capacity, the immune system, bone growth, and the proper production of insulin.
  • the present invention relates to a method of administering insulin by using the methods and compositions as disclosed above.
  • the method may be used as a means of keeping the blood sugar level from getting too elevated (hyperglycemia) or too low (hypoglycemia).
  • the method may be able to aid individuals who are unable to effectively produce the correct amount of insulin,
  • the present invention also relates to a method of treating irritable bowel syndrome that allows the modified alginate to encapsulate a medicament that enhances the bioavailability of the medicament in the intestines where the medicament is most needed. Moreover, this would allow the delivery of medicaments that otherwise might be acid labile (that is, these medicaments are able to survive the acidic conditions of the stomach because they are encapsulated).
  • DMA dopamine-modified alginate
  • HBSS Hank's Balanced Salt Solution
  • Omega-3 oil loaded silica nanoparticles were mixed with the DMA.
  • the mixture was then crosslinked by adding CaCl 2 and allowed to sit for about 15 minutes at room temperature until it formed a hydrogel slab.
  • the hydrogel was cut in half to compare the degradation rate in different pH environments. One-half of the hydrogel was placed in a 1 N HCI (pH ⁇ 1), and the other in a bath of Krebs Ringer Solution (pH 7.4) to mimic the highly acidic stomach, and the more neutral gut conditions, respectively.
  • the hydrogel slabs under these two conditions were placed in an incubator at 37°C and an inverted light microscope was used to compare the overall shape, transparency, and release of nanoparticles from the two incubation conditions. Images of the slabs were taken initially, at 1.5 hours and after overnight incubation it was apparent that the neutral pH caused the DMA hydrogel to degrade rapidly, thereby releasing the nanoparticles into the bath. The hydrogel that was placed in the acidic bath remained intact for an additional 2 weeks of follow up.
  • microbeads comprising a modified alginate and a bioactive substance may be used to delay the transit time of the beads in the intestine such that sustained delivery of the bioactive substance may be achieved and/or enhanced therapeutic efficacy.
  • increased stability of the modified alginate microbeads may be achieved by increasing the degree of modification of alginate with the reactant (e.g., dopamine).
  • Modified alginate is dissolved in Hanks Balanced Salt Solution (HBSS) (Sigma) overnight at 4°C.
  • HBSS Hanks Balanced Salt Solution
  • the desired compounds, drugs, or cells are suspended in the alginate and mixed to ensure uniform distribution of the various substances.
  • the suspensions are then loaded into a peristaltic pump, extruded through a 15-gauge needle at a rate of 0.2 ml/min, and droplets of the suspension are received in a bath of calcium chloride (CaCl 2 ) for crosslinking (gelation).
  • CaCl 2 calcium chloride
  • the crosslinked microbeads are then collected and washed twice with HBSS supplemented with 25 mM CaCl 2 .
  • a first method for modifying the alginate degrades slower relative to a second method for modifying the alginate, which can be useful for targeted delivery in the gastrointestinal tract (GIT).
  • GIT gastrointestinal tract
  • the second method has been shown to result in alginate microbeads that fall apart (degrade) within 30 minutes, while microbeads generated from alginate modified by the first method degrade in about 1-2 hours.
  • the two methods are as follows:
  • the alginate (1 mmol equivalent) is dissolved in ultrapure water (Millipore Sigma) with 10% (v/v) isopropanol to about 8 mg/mL.
  • the solution is degassed with N 2 and chilled to about 2-4 DC.
  • a degassed solution of sodium (meta)periodate (0.25M solution) is added based on the desired degree of oxidation intended (at 0.5% oxidation).
  • the mixture is stirred for 48 h in the dark and then dialyzed in ultrapure water until the conductivity was below 2 ⁇ 8 and then dried via lyophilization.
  • the periodate oxidized alginate is dissolved in ultrapure water and methanol (12% v/v).
  • Equivalent moles of amine substituent are added to the solution matching the % oxidized alginate and about 10 mol equivalent of pic-BH 3 (2-picoline-borane).
  • the pH of the mixture is adjusted to about pH 6 using phosphate buffer and the solution is stirred in the dark for 24 h.
  • the sample is dialyzed in 0.1 M NaCl for 12 h followed by dialysis in ultrapure water for 24 h and then lyophilized.
  • Two additional parameters can be changed to further modify the degradation rate of the modified alginate. They are: (1) the type of alginate used, and (2) the alginate concentration. Both LVM (low viscosity mannuronic acid) and LVG (low viscosity guluronic acid) alginate are commonly used for encapsulation, but LVG creates a stronger hydrogel network which slows down the degradation of the modified alginate. Also, increasing the concentration of alginate creates a denser network which slows down the degradation rate. Each of these variables can be adjusted or combined to create a targeted delivery system for the desired compound depending on the mammalian species involved and where and when to deliver the compound of interest.
  • the equine deworming drug Benzimidazole can be micro-encapsulated in the Modified Alginate.
  • Benzimidazole is approximately 1 18.14 g/mol. in powder form. The procedure is as follows.
  • the Benzimidazole should be mixed with the Modified Alginate at approximately 20% w/v (20g/100 mL).
  • the suspension can then be loaded into a peristaltic pump, extruded through a 15-gauge needle at a rate of approximately 0.2 mL/min, and droplets of the suspension are received in a bath of calcium chloride (CaCl 2 ) for crosslinking (gelation).
  • CaCl 2 calcium chloride
  • the crosslinked microbeads are then collected and washed twice with HBSS (Hanks Balanced Salt Solution) supplemented with 25 mM CaCl 2 . There will be approximately 1.693* 10 " mol of Benzimidazole in the 1 mL of alginate.
  • the medication Methylphenidrate can be micro-encapsulated in the Modified Alginate.
  • Methylphenidrate has a molecular weight of 233.31 g/mol in powder form. The procedure is as follows.
  • the Methylphenidrate is mixed with the alginate at 20% w/v (20g/100 mL).
  • the suspension is then loaded into a peristaltic pump, extruded through a 15-gauge needle at a rate of 0.2 mL/min, and droplets of the suspension are received in a bath of calcium chloride (CaCl 2 ) for crosslinking (gelation).
  • CaCl 2 calcium chloride
  • the crosslinked microbeads will then be collected and washed twice with HBSS supplemented with 25 mM CaCl 2 . There will be approximately 8.572*10 "3 mol of Methylphenidrate in the 1 mL of alginate.
  • Oxycodone can be micro-encapsulated in the Modified Alginate.
  • Oxycodone has a molecular weight of 315.364 g/mol in powder form. The procedure is as follows.
  • the Oxycodone can be mixed with the alginate at 20% w/v (20g/100 mL).
  • the suspension is then loaded into a peristaltic pump, extruded through a 15-gauge needle at a rate of 0.2 mL/min, and droplets of the suspension are received in a bath of calcium chloride (CaCl 2 ) for crosslinking (gelation).
  • CaCl 2 calcium chloride
  • the crosslinked microbeads will then be collected and washed twice with HBSS supplemented with 25 mM CaCl 2 . There will be approximately 6.34* 10 "4 mol of Oxycodone in the 1 mL of alginate.
  • the probiotic Lactobacillus Casei NCDC 298 can be micro-encapsulated in the Modified Alginate.
  • the procedure is as follows.
  • the Lactobacillus is cultured overnight in MRS broth then spun down and mixed with the alginate.
  • the suspension is then loaded into a peristaltic pump, extruded through a 15-gauge needle at a rate of 0.2 ml/min, and droplets of the suspension are received in a bath of calcium chloride (CaCl 2 ) for crosslinking (gelation).
  • CaCl 2 calcium chloride
  • the crosslinked microbeads are then collected and washed twice with HBSS supplemented with 25 mM CaCl 2 . There will be approximately 40.0* 10 9 lactobacilli in the 1 mL of alginate.
  • Vitamin E alpha- tocopherol acetate
  • Alpha-tocopherol acetate has a molecular weight of 472.743. The procedure is as follows.
  • the alpha-tocopherol acetate is mixed with the alginate at 20% w/v (20g/100 mL).
  • the suspension is then loaded into a peristaltic pump, extruded through a 15-gauge needle at a rate of 0.2 mL/min, and droplets of the suspension are received in a bath of calcium chloride (CaCl 2 ) for crosslinking (gelation).
  • CaCl 2 calcium chloride
  • the crosslinked microbeads will then be collected and washed twice with HBSS supplemented with 25 mM CaCl 2 . There will be approximately 4.23 * 10 "4 mol of Vitamin E in the 1 mL of alginate.
  • Paroxetine can be micro-encapsulated in the Modified Alginate.
  • Paroxetine has a molecular weight of 374.83 g/mol in powder form. The procedure is as follows.
  • the Paroxetine is mixed with the alginate at 20% w/v (20g/100 mL).
  • the suspension is then loaded into a peristaltic pump, extruded through a T 5-gauge needle at a rate of 0.2 mL/min, and droplets of the suspension are received in a bath of calcium chloride (CaCl 2 ) for crosslinking (gelation).
  • CaCl 2 calcium chloride
  • the crosslinked microbeads will then be collected and washed twice with HBSS supplemented with 25 mM CaCl 2 . There will be approximately 5.33* 10 "4 mol of Paroxetine in the 1 mL of alginate.
  • Acetylsalicylic Acid can be micro-encapsulated in the Modified Alginate.
  • Acetylsalicylic Acid has a molecular weight of 180.157 g/mol in powder form. The procedure is as follows.
  • Acetylsalicylic Acid is mixed with the alginate at 20% w/v (20g/100 mL). The suspension is then loaded into a peristaltic pump, extruded through a 15-gauge needle at a rate of 0.2 mL/min, and droplets of the suspension are received in a bath of calcium chloride
  • Potassium iodide can be micro-encapsulated in the Modified Alginate as a powder and/or as a liquid. Potassium iodide has a molecular weight of 166.0 g/mol in powder form. The procedure can be as follows.
  • Potassium iodide (KI) in powder form is mixed with an alginate in an amount of 20% w/v (20 g of KI/100 mL of alginate) to form a suspension.
  • the suspension is then loaded into a peristaltic pump, extruded through a 15-gauge needle at a rate of 0.2 mL/min, and droplets of the suspension are received in a bath of calcium chloride (CaCl 2 ) for crosslinking (gelation).
  • CaCl 2 calcium chloride
  • the crosslinked microbeads will then be collected and washed twice with HBSS supplemented with 25 mM CaCl 2 .
  • Liquid potassium iodide can be loaded into alginate beads of the present invention using a soaking method.
  • the procedure is as follows. Alginate is loaded into a peristaltic pump, extruded through a 15-gauge needle at a rate of 0.2 mL/min, and droplets of the liquid are received in a bath of calcium chloride (CaCl 2 ) for crosslinking (gelation). The crosslinked microbeads will then be collected and washed twice with HBSS supplemented with 25 mM CaCl 2 . Then, the beads will be soaked in a bath of potassium iodide for about 24 hours. Excess fluid will be aspirated and the beads are allowed to air dry, and then they are ready for use.
  • oral delivery systems for medicines and/or other substances in humans and other animals may be advantageous in that they may provide: (1) protection of the encapsulated substance from destruction and/or degradation by stomach an acid and/or an enzyme (e.g., enzymatic action in the stomach), (2) the elimination and/or reduction of stomach upset, nausea, and/or vomiting caused by certain medicines and other substances when they are introduced into the stomach, (3) a resulting increase in the bioavailability of the substance when it reaches the small intestine, where the contents of the micro-capsule are released into the small intestine through the process of diffusion, or its contents are fully released when the micro-capsule breaks apart in the small intestine due to the pH differential between the stomach and the small intestine, (4) a reduction in the dosage required, since the overall bioavailability of the substance has been increased, (5) the ability to control the rate of release of the substance as it passes through the small intestine by adjusting the chemistry of the aromatic/carbohydrate
  • the present invention has a plurality of uses including, but not limited to, the ability to deliver medicines, drugs, chemicals, proteins, enzymes, probiotics, dietary supplements, and other bioactive substances to humans and other animals, which can be used to treat and/or inhibit diseases, parasites, and/or other conditions in the humans and other animals, eliminate or reduce pain associated with a wide variety illnesses, diseases and conditions, and/or maintain the good health and well-being of humans and other animals, including, but not limited to, the following classes or categories of medicines and other bioactive substances:
  • Oral agents including sulfonylureas, insulin-sensitizers, and insulin;
  • Anticancer drugs and chemotherapeutic agents include sulfonylureas, insulin-sensitizers, and insulin;
  • Anti-hypertensives such as beta blockers and ACE-inhibitors
  • the present invention may be used to eliminate or reduce pain and/or inflammation by administering one or more of the following classes of pain medications to humans and animals without encountering certain negative side effects:
  • Non-prescription pain medications such as nonsteroidal anti-inflammatory drugs, including, but not limited to, aspirin (acetylsalicylic acid), ibuprofen, naproxen, and any combinations thereof.
  • Prescription pain medications such as nonsteroidal anti-inflammatory drugs, including, but not limited to, fenoprofen, flurbiprofen, ketoprofen, oxaprozin, diclofenac sodium, etodolac, indomethacin, ketorolac, sulindac, tolmetin, meclofenamate, mefenamic acid, nabumetone, piroxicam, and any combinations thereof. 3.
  • nonsteroidal anti-inflammatory drugs including, but not limited to, fenoprofen, flurbiprofen, ketoprofen, oxaprozin, diclofenac sodium, etodolac, indomethacin, ketorolac, sulindac, tolmetin, meclofenamate, mefenamic acid, nabumetone, piroxicam, and any combinations thereof.
  • Prescription pain medications such as opioid drugs, including, but not limited to, codeine, fentanyl, hydrocodone, hydrocodone with acetaminophen, hydromorphone, meperidine, methadone, morphine, oxycodone, tapentadol, oxymorphone, buprenorphine, tramadol, oxycodone with acetaminophen, naloxone, and any combinations thereof.
  • opioid drugs including, but not limited to, codeine, fentanyl, hydrocodone, hydrocodone with acetaminophen, hydromorphone, meperidine, methadone, morphine, oxycodone, tapentadol, oxymorphone, buprenorphine, tramadol, oxycodone with acetaminophen, naloxone, and any combinations thereof.
  • the present invention may be used to deliver live probiotics and/or other beneficial micro-organisms to humans and animals for their therapeutic benefits, such as:
  • Probiotic strains and other micro-organisms found in or beneficial to the human microbiome including, but not limited to:
  • Probiotic Strains of the Lactobacillus species of bacterium including, but not limited to, L. acidophilus, L. fermentum, L. plantarum, L. rhamnosus, L. salivarius, L. paracasei, L. gasseri, L. brevis, L. bulgaricus, L. caucasicus, L helveticus, L. lactis, L. casei, and L. reuteri, and any combination thereof.
  • probiotic strains of bacterium found in or beneficial to the human microbiome, including, but not limited to, probiotic strains of bacterium used to treat or combat Clostridium difficile (c. diff), as well as other intestinal diseases or conditions, and any combination thereof.
  • Probiotic strains of bacterium found in or beneficial to the microbiome of other animals, including, but not limited to, dogs, cats, horses, cattle, sheep, pigs, chickens, and includes any combination of those probiotic strains of bacterium.
  • the invention may be used to deliver vitamins, minerals, micro-nutrients, and/or other dietary supplements to humans and animals protected from oxidation and without certain negative side effects, such as:
  • Dietary supplements including, but not limited to, omega-3 fatty acids (EPA/DHA), vitamin D, vitamin Bl, B2, B3, B5, B6, B7, B9, B12, B17, vitamin B complex, alpha lipoic acid, and Coenzyme Q10, among others, and any combinations thereof.
  • EPA/DHA omega-3 fatty acids
  • Equine Dewormers including, but not limited to, omega-3 fatty acids (EPA/DHA), vitamin D, vitamin Bl, B2, B3, B5, B6, B7, B9, B12, B17, vitamin B complex, alpha lipoic acid, and Coenzyme Q10, among others, and any combinations thereof. Equine Dewormers
  • the invention can be used to deliver deworming medicines and other bioactive substances to horses, such as:
  • Benzimidazoles including the generics Fenbendazole and Oxibendazole
  • Macrocyclic Lactones including the generics Ivermectin and Moxidectin
  • Tetrahydropurimidines including the generics Pyrantel Pamoate and Pyrantel Tatrate
  • Isquinoline-pyrozines including the generic Praziquantel
  • the invention can be used to deliver deworming medicines and other bioactive substances to dogs and cats, such as the delivery of:
  • the invention can be used to deliver deworming medicines to other animals, such as:
  • the invention can be used to deliver medicines and other bioactive substances to animals such as:
  • the invention can be used to deliver rodenticides to rodents such as:
  • Chemicals, drugs, compounds, and other substances used to eliminate and/or control rodents or rodent populations including, but not limited to, Warfarin, Chlorphacinone, Diphacinone, Bromadiolone, Difethialone, Brodifacoum, Bromethalin, Cholecalciferol, Zinc phosphide, Strychnine, triptolide, 4-vinylcyclohexene diepoxide, diterpenoid epoxides, ovotoxins, diterpenoid epoxides, and any combinations thereof.
  • Warfarin Chlorphacinone, Diphacinone, Bromadiolone, Difethialone, Brodifacoum, Bromethalin, Cholecalciferol, Zinc phosphide, Strychnine, triptolide, 4-vinylcyclohexene diepoxide, diterpenoid epoxides, ovotoxins, diterpenoid e
  • the alginate microspheres were gelled by calcium crosslinking and each of the two groups of microbeads had one aliquot incubated in different media to mimic the highly acidic stomach (pH ⁇ 3), and another aliquot in a bath of simulated small intestinal fluid (pH >6.8) to mimic the neutral-basic pH gut conditions of this region.
  • Fig. 1 shows the decay curve of the modified alginate over the 3 hours of incubation under the neutral-basic pH conditions during which the unmodified alginate microbeads largely remained intact.
  • Fig. 3 shows that both the modified and unmodified alginate microbeads were equally stable during the 3 -hour incubation in acidic pH.

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Abstract

L'invention concerne des alginates modifiés ainsi que des hydrogels les comprenant. On peut préparer un alginate modifié en faisant réagir un alginate et un composé aromatique (par exemple une amine aromatique) et/ou un composé sensible au pH. Les alginates modifiés, les hydrogels et/ou les procédés de l'invention peuvent être utilisés pour revêtir et/ou encapsuler au moins une partie d'une substance bioactive, éventuellement pour une administration orale chez l'homme et d'autres animaux.
PCT/US2017/040283 2016-07-01 2017-06-30 Glucides modifiés, composition les comprenant et procédés pour les préparer et les utiliser Ceased WO2018005964A1 (fr)

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EP17821354.2A EP3478725B1 (fr) 2016-07-01 2017-06-30 Glucides modifiés, composition les comprenant et procédés pour les préparer et les utiliser
US16/311,992 US10766970B2 (en) 2016-07-01 2017-06-30 Modified carbohydrates, compositions comprising the same, and methods of making and using the same
CA3029502A CA3029502A1 (fr) 2016-07-01 2017-06-30 Glucides modifies, composition les comprenant et procedes pour les preparer et les utiliser

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US201662357741P 2016-07-01 2016-07-01
US62/357,741 2016-07-01
USPCT/US2017/034748 2017-05-26
PCT/US2017/034748 WO2018004906A1 (fr) 2016-07-01 2017-05-26 Hydrogels d'alginate modifiés pour agents thérapeutiques, leur préparation et procédés associés
US15/606,769 2017-05-26
US15/606,769 US20180000743A1 (en) 2016-07-01 2017-05-26 Modified Alginate Hydrogels for Therapeutic Agents, their Preparation and Methods Thereof
US201762519600P 2017-06-14 2017-06-14
US62/519,600 2017-06-14

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US10610280B1 (en) 2019-02-02 2020-04-07 Ayad K. M. Agha Surgical method and apparatus for destruction and removal of intraperitoneal, visceral, and subcutaneous fat
US11213608B2 (en) 2018-08-14 2022-01-04 Wake Forest University Health Sciences Compositions including gelatin nanoparticles and methods of use thereof
US11959095B2 (en) 2016-10-14 2024-04-16 Wake Forest University Health Sciences Compositions, cell constructs, and methods of making and using the same
US11993785B2 (en) 2018-08-07 2024-05-28 Wake Forest University Health Sciences Immersion deposition methods and compositions for use in the same

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11959095B2 (en) 2016-10-14 2024-04-16 Wake Forest University Health Sciences Compositions, cell constructs, and methods of making and using the same
US11993785B2 (en) 2018-08-07 2024-05-28 Wake Forest University Health Sciences Immersion deposition methods and compositions for use in the same
US11213608B2 (en) 2018-08-14 2022-01-04 Wake Forest University Health Sciences Compositions including gelatin nanoparticles and methods of use thereof
US10610280B1 (en) 2019-02-02 2020-04-07 Ayad K. M. Agha Surgical method and apparatus for destruction and removal of intraperitoneal, visceral, and subcutaneous fat
CN110950970A (zh) * 2019-12-12 2020-04-03 江南大学 一种环境响应型葡糖基纳米粒子及其加工方法

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