WO2014165566A1 - Compositions de particules hydrophiles, procédés de production, et utilisations dans la gestion alimentaire et les troubles de la digestion - Google Patents

Compositions de particules hydrophiles, procédés de production, et utilisations dans la gestion alimentaire et les troubles de la digestion Download PDF

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WO2014165566A1
WO2014165566A1 PCT/US2014/032626 US2014032626W WO2014165566A1 WO 2014165566 A1 WO2014165566 A1 WO 2014165566A1 US 2014032626 W US2014032626 W US 2014032626W WO 2014165566 A1 WO2014165566 A1 WO 2014165566A1
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particles
particle
certain embodiments
polyalkoxys
protein
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PCT/US2014/032626
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W. Robert Taylor
Daiana Weiss
Niren Murthy
Xinghai Ning
Abhinav Acharya
Xuli FENG
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Emory University
Georgia Tech Research Corporation
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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A61K38/443—Oxidoreductases (1) acting on CH-OH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
    • C12Y101/03—Oxidoreductases acting on the CH-OH group of donors (1.1) with a oxygen as acceptor (1.1.3)
    • C12Y101/03004—Glucose oxidase (1.1.3.4)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
    • C12Y101/03—Oxidoreductases acting on the CH-OH group of donors (1.1) with a oxygen as acceptor (1.1.3)
    • C12Y101/03009—Galactose oxidase (1.1.3.9)
    • 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

Definitions

  • Glucose oxidase also referred to as notatin, is an enzyme that catalyzes the breakdown of glucose to gluconolactone and hydrogen peroxide. Gluconolactone hydrolyzes to gluconic acid.
  • the enzyme utilizes a cofactor, flavin adenine dinucleotide (FAD). Hydrogen peroxide produced by glucose oxidase kills certain bacteria. Because of this property glucose oxidase has been reported as an antibacterial agent, e.g., in toothpaste, and as a food and beverage preservative. Although oral toxicity is low, intravenous administration of glucose oxidase is toxic at certain levels. See Broom et al., Brit. J. Pharmacol, (1946), 1, 225.
  • glucose oxidase is often utilized in sensors for detecting glucose levels. See Bankar et al, Biotechnology Advances, 2009, 27: 489-501, and Wong et al, Appl Microbiol Biotechnol, 2008,
  • Nakamoto reports a glucose sensor with gel-immobilized glucose oxidase and gluconolactonase. See U.S. Patent 5,082,786.
  • Glucose oxidase in an aqueous solution is generally unstable and loses activity over time. See U.S. Patents 7,892,801, 7,892,536, and 6,312,687.
  • This disclosure relates to hydrophilic particles, compositions, processes of production, and uses in dietary management and digestive disorders.
  • the particle comprises a protein coated in a hydrophilic polymer comprising monomers with branched polyalkoxys, such as but not limited to, polyethylene glycol.
  • the protein is a glucose oxidase, galactose oxidase, lipase, other digestive enzyme, or combinations thereof.
  • compositions comprising particles disclosed herein are used to reduce blood glucose levels or prevent elevated blood glucose levels in a subject.
  • the disclosure relates to particle disclosed herein that have a size of about 1 to 10 micrometers or 2 to 8 micrometers.
  • the disclosure relates to processes for preparing particles disclosed herein comprising mixing a protein and branched polyalkoxys with a polyalkoxy crosslinker in an oil and water solution under conditions such that a polymer of monomers with branched polyalkoxys is formed around the protein to form a particle.
  • the branched polyalkoxys comprise azide groups or alkyne groups.
  • the polyalkoxy crosslinker comprises azide groups or alkyne groups.
  • the solution further comprises an ionic or nonionic surfactant, such as but not limited to, sorbitan monooleate.
  • the method further comprises the step of separating the oil in the solution from the particles to provide a composition comprising hydrated particles. In certain embodiments, the method further comprises the step of removing water from the hydrated particles. Typically, water is removed from the particles by the steps of freezing the particles and reducing the surrounding air pressure under conditions such that frozen water in the particles sublimate.
  • the disclosure relates to compositions comprising particles disclosed herein. In certain embodiments, the disclosure relates to dietary supplements comprising particles of disclosed herein. In certain embodiments, the disclosure relates to pharmaceutical compositions comprising particles of disclosed herein and a
  • the disclosure relates to methods of treating or preventing hyperglycemia comprising administering a pharmaceutical composition disclosed herein to a subject in need thereof.
  • the subject is diagnosed with diabetes.
  • particles disclosed herein are used as preservative or antibacterial agent.
  • the disclosure relates to methods of treating or preventing a bacterial infection comprising administering an effective amount of a pharmaceutical composition disclosed herein to a subject in need thereof.
  • the disclosure relates to methods of treating or preventing a digestive disorder or condition comprising administering a dietary supplement or pharmaceutical composition disclosed herein to a subject in need thereof.
  • Figure 1 illustrates (A) Chemical structures of the monomer and cross linker for making microgel. (B) Schematic representation of the preparation of microgel through the copper free click chemistry based reverse phase process.
  • Figure 2 shows data on particle size distribution of redispersed microgel measured by danamic light scattering (DLS).
  • DLS danamic light scattering
  • Figure 3 shows data on (A) absorbance spectra of different sources G ox encapsulated microgel at different time points (B) enzymatic kinetics of different sources G ox
  • Figure 4 shows data on reduction of blood glucose levels with the intake of glucose oxidase containing particles in conjunction with a high starch meal. Two different preparations of the particles are presented.
  • Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.
  • polyalkoxy refers to a polymer containing alkoxy monomers, such as but not limited to, ethoxy, methoxy, propoxy, and combinations thereof.
  • a typical polyalkoxy is polyethylene glycol.
  • Smaller size polyalkoxy polymers typically contain repeating monomers of 3 or more alkoxy monomers having terminal crosslinking groups. Larger polymers typically contain additional functional groups due coupling the smaller size polyalkoxys together during formation.
  • the smaller size polyoxylates are crosslinked together by the reaction of azides with alkynes to form a nitrogen containing heterocycles; however, other crosslinking groups are
  • polyalkoxys may be terminated with vinyl groups which can be linked together by radical initiated polymerization optionally including other vinyl containing monomers.
  • the terms “prevent” and “preventing” include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity is reduced.
  • treat and “treating” are not limited to the case where the subject (e.g., patient) is cured and the condition or disease is eradicated. Rather,
  • embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays conditions or disease progression.
  • treatment that merely reduces symptoms, and/or delays conditions or disease progression.
  • combination with when used to describe administration with an additional treatment means that the agent may be administered prior to, together with, or after the additional treatment, or a combination thereof.
  • protein and “polypeptide” refer to compounds comprising amino acids joined via peptide bonds and are used interchangeably.
  • An “enzyme” is a protein that has catalytic activity.
  • amino acid sequence is recited herein, it refers to an amino acid sequence of a protein molecule.
  • terms such as “polypeptide” or “protein” are not meant to limit the amino acid sequence to the deduced amino acid sequence, but include post-translational modifications of the deduced amino acid sequences, such as amino acid deletions, additions, and modifications such as glycolsylations and addition of lipid moieties.
  • sequence identity refers to the number of exactly matching residues (expressed as a percentage) in a sequence alignment between two sequences of the alignment. As used herein, percentage identity of an alignment is calculated using the number of identical positions divided by the greater of the shortest sequence or the number of equivalent positions excluding overhangs wherein internal gaps are counted as an equivalent position.
  • polypeptides GGGGGG and GGGGT have a sequence identity of 4 out of 5 or 80%.
  • the polypeptides GGGPPP and GGGAPPP have a sequence identity of 6 out of 7 or 85%.
  • Percent "similarity” is used to quantify the similarity between two sequences of the alignment. This method is identical to determining the identity except that certain amino acids do not have to be identical to have a match. Amino acids are classified as matches if they are among a group with similar properties according to the following amino acid groups: Aromatic - F Y W; hydrophobic-A V I L; Charged positive: R K H; Charged negative - D E; Polar - S T N Q.
  • variant when used in reference to a polypeptide refer to an amino acid sequence that differs by one or more amino acids from another, usually related polypeptide.
  • the variant may have "conservative" changes, wherein a substituted amino acid has similar structural or chemical properties.
  • conservative amino acid substitutions refers to the interchangeability of residues having similar side chains.
  • a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur-containing side chains is cysteine and methionine.
  • Preferred conservative amino acids substitution groups are: valine-leucine- isoleucine, phenylalanine -tyrosine, lysine-arginine, alanine-valine, and asparagine- glutamine. More rarely, a variant may have "non-conservative" changes (e.g., replacement of a glycine with a tryptophan). Similar minor variations may also include amino acid deletions or insertions (in other words, additions), or both. Guidance in determining which and how many amino acid residues may be substituted, inserted or deleted without abolishing biological activity may be found using computer programs well known in the art, for example, DNAStar software. Variants can be tested in functional assays. Certain variants have less than 10%, and preferably less than 5%, and still more preferably less than 2%> changes (whether substitutions, deletions, and so on).
  • this disclosure relates to proteins or enzymes, such as but not limited to, glucose oxidase, galactose oxidase, lipases or other digestive enzymes, containing microgel particles.
  • the particles can decompose glucose and prevent its absorption from the gastrointestinal tract.
  • the microgel particles are formulated from a combination of branched and linear PEG derivatives that contain either terminal alkynes or azides as crosslinking groups. See Fig. 1.
  • glucose oxidase is encapsulated in the microgels via an inverse emulsion procedure.
  • micron sized microparticles which can protect the glucose oxidase from enzymatic degradation within the stomach and intestines, but has a pore size that allows glucose to diffuse inside.
  • the microparticles are designed to be ingested orally along with a meal. Although it is not intended that embodiments of this disclosure be limited by any particular mechanism, it is believed that once in the intestines the glucose from the meal will diffuse into the particles and get converted into glucoronic acid, which will not be absorbed and will also not be toxic via its metabolism within bacteria. Data herein indicates that glucose oxidase containing particles can suppress glucose uptake in mice. See Figure 4.
  • the disclosure relates to particles disclosed herein comprising glucose oxidase.
  • Glucose oxidase also known as notatin, is an enzyme that catalyzes the breakdown of glucose and oxygen to gluconolactone and hydrogen peroxide. Gluconolactone hydrolyzes to gluconic acid.
  • the commonly studied glucose oxidase homologs are derived from Aspergillus and Penicillium fungi.
  • the fungal enzyme is a dimer containing two FAD cofactors.
  • the mature enzyme typically contains peptide of about 583 amino acids preceded by a presequence of about 22 amino acids.
  • Known enzyme sequences typically have about or greater than 30% sequence identity or about or greater than 50% sequence similarity to each other.
  • a glucose oxidase refers to an enzyme capable of catalyzing the conversion of glucose to gluconolactone comprising a glycosylated or unglycosylated polypeptide from Aspergillus niger having SEQ ID NO: 1 :
  • the disclosure relates to particles disclosed herein comprising lipases or other digestive or pancreatic enzymes or combinations thereof.
  • Lipases are intestinal enzymes produced by the pancreas that breaks down fats. Cystic fibrosis is associated with decreased pancreatic lipase production. Dietary supplementation with lipases is a treatment for patients with cystic fibrosis. A number other diseases and conditions are also sometimes ameliorated by supplementation of their diet with lipases and other digestive or pancreatic enzymes such as colipase, amylases, proteases, papain, and pepsin. Lipases belong to a family of proteins with similar structure including pancreatic triglyceride lipase (PTL, triacylglycerol acylhydrolase, EC 3.1.1.3) and its close
  • pancreatic triglyceride lipase related proteins 1 and 2 which have about 60% or greater identity and about 80% or greater similarity.
  • the proteins have a globular N- terminal domain containing the catalytic site, and a beta-sandwich C-terminal domain.
  • the C-terminal domain includes a colipase-binding site. See Winkler et al., Nature 343 (6260), 771-774 (1990) and Low, J Lipid Res, 2002, 43(12):2007-16.
  • a lipase refers to an enzyme capable of hydrolyzing long-chain acyl-triglycerides into di- and monoglycerides, comprising a glycosylated or unglycosylated polypeptide having SEQ ID NO: 2:
  • compositions comprising particles disclosed herein, e.g., comprising glucose oxidase, galactose oxidase, or a combination of the two enzymes, are used to reduce blood glucose levels or prevent elevated blood glucose levels in a subject.
  • the disclosure relates to methods of preventing hyperglycemia comprising administering a pharmaceutical composition disclosed herein to a subject in need thereof.
  • the subject is diagnosed with diabetes or heightened blood sugar levels, e.g., type I, type II, prediabetes, or gestational diabetes.
  • Diabetes refers to a metabolic diseases resulting in high blood sugar levels.
  • Insulin is a protein produced by the pancreas that signals cells to absorb glucose from the blood. Diabetes may be the result of a pancreas that does not produce sufficient insulin, typically diagnosed as type I diabetes. If cells stop responding to typical levels of insulin, i.e., insulin resistance, this results in high blood sugar levels. This condition is typically diagnosed as type II diabetes. Prediabetes is diagnosed when blood glucose levels are higher than normal but not high enough for a diagnosis of type 2 diabetes. Higher than normal blood glucose levels sometimes occur during pregnancy, a condition diagnosed as gestational diabetes.
  • insulin and pharmaceutically acceptable derivatives are typically use as a substitute.
  • this disclosure relates to methods of treating or preventing diabetes with nutritional supplements and pharmaceutical compositions comprising particles disclosed herein administered or ingested in combination with insulin and pharmaceutically acceptable insulin derivatives, such as but not limited to, insulin lispro, insulin aspart, insulin glulisine, prompt insulin zinc, isophane insulin, neutral protamine Hagedorn (NPH), insulin zinc, extended insulin zinc insulin, insulin glargine, insulin detemir, or combinations thereof.
  • insulin lispro insulin aspart, insulin glulisine, prompt insulin zinc, isophane insulin, neutral protamine Hagedorn (NPH), insulin zinc, extended insulin zinc insulin, insulin glargine, insulin detemir, or combinations thereof.
  • this disclosure relates to methods of treating or preventing diabetes with nutritional supplements and pharmaceutical compositions comprising particles disclosed herein administered or ingested in combination with anti-diabetic agents, such as but not limited to, metformin, glyburide, glimepiride, glipizide, acarbose, miglitol, voglibose, pioglitazone, rosiglitazone, or combinations thereof.
  • anti-diabetic agents such as but not limited to, metformin, glyburide, glimepiride, glipizide, acarbose, miglitol, voglibose, pioglitazone, rosiglitazone, or combinations thereof.
  • the disclosure relates to methods of preventing weight gain or reducing weight comprising ingesting an effective amount of a dietary supplement disclosed herein.
  • particles disclosed herein are used as a preservative or antibacterial agent.
  • the disclosure relates to methods of treating or preventing a bacterial infection comprising administering an effective amount of a pharmaceutical composition disclosed herein to a subject in need thereof.
  • the disclosure relates to methods of treating or preventing a digestive disorder or condition comprising administering a dietary supplement or pharmaceutical composition disclosed herein to a subject in need thereof.
  • the digestive disorder or condition is selected from cystic fibrosis, celiac disease, or dyspepsia.
  • Cystic fibrosis is caused by a genetic defect in the protein cystic fibrosis
  • transmembrane conductance regulator which regulates digestive fluids and mucus resulting problematic digestion and breathing. It is typically diagnosed by genetic testing or when a newborn infant fails to pass feces. Patients are chronically treated with one or more antibiotics to prophylactically suppress infection. In certain embodiments, this disclosure contemplates treating someone with cystic fibrosis by administering particles disclosed herein, e.g., comprising lipases, in combination with antibiotics, tobramycin, colistin, aztreonam, ciprofloxacin, azithromycin or combinations thereof.
  • particles disclosed herein e.g., comprising lipases, in combination with antibiotics, tobramycin, colistin, aztreonam, ciprofloxacin, azithromycin or combinations thereof.
  • Dyspepsia or indigestion after a meal has many different causes, such as, ulcers, gastric reflux disease, stomach cancer, gastroparesis, stomach infections, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, chronic pancreatitis, and thyroid disease.
  • Ulcerative colitis is a disease of the colon typically characterized by ulcers.
  • Ulcerative colitis is sometime treated with sulfasalazine and mesalazine.
  • this disclosure contemplates treating someone with dyspepsia by
  • particles disclosed herein e.g., comprising lipases
  • 5- aminosalicylic acid containing drugs such as but not limited to, sulfasalazine or mesalazine.
  • a subject with chronic symptom of mucosal damage caused by stomach acid coming up from the stomach into the esophagus is often diagnosed with gastroesophageal reflux disease. Treatment is sometimes with medications such as proton pump inhibitors, H 2 receptor blockers or antacids.
  • this disclosure contemplates treating someone with dyspepsia by administering particles disclosed herein, e.g., comprising lipases, in combination with proton pump inhibitors, H 2 receptor blockers, antacids, omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, ilaprazole, ranitidine, sucralfate, calcium carbonate, bicarbonate, or combinations thereof.
  • particles disclosed herein comprising lipases, in combination with proton pump inhibitors, H 2 receptor blockers, antacids, omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, ilaprazole, ranitidine, sucralfate, calcium carbonate, bicarbonate, or combinations thereof.
  • Crohn's disease is an autoimmune disease associated with the gastrointestinal tract. It is sometimes treated with anti -inflammatory or immune suppressant drugs. In certain embodiments, this disclosure contemplates treating someone with dyspepsia by
  • particles disclosed herein e.g., comprising lipases, in combination with antiinflammatory drugs, immune suppressant drugs, hydrocortisone, prednisone, azathioprine, 6-mercaptopurine, methotrexate, infliximab, adalimumab, certolizumab, natalizumab, abatacept, belatacept, or combinations thereof.
  • subject may be in need of treatment because the subject is diagnosed with, exhibiting symptoms of, or at risk of a disease or condition disclosed herein.
  • the disclosure relates to compositions comprising particles disclosed herein. In certain embodiments, the disclosure relates to dietary supplements comprising particles of disclosed herein. In certain embodiments, the disclosure relates to pharmaceutical compositions comprising particles of disclosed herein and a
  • a dietary supplement refers to composition to supplement the diet in a physical form for ingestion, such as a pill, capsule, tablet, powder or liquid form that is not a drug.
  • this disclosure relates to dietary supplements comprising particles disclosed herein optionally in combination other ingredients of a dietary supplement such as a vitamin, a mineral, an herb, a botanical, an amino acid, a concentrate, metabolite, constituent, or extract.
  • compositions for use in the present disclosure typically comprise an effective amount of particles and a suitable pharmaceutical acceptable carrier.
  • the preparations may be prepared in a manner known per se, which usually involves mixing the at least one particle according to the disclosure with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds.
  • the particles may be formulated as a
  • composition comprising at least one particle and at least one
  • the pharmaceutical preparations of the disclosure are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • unit dosages will contain between 0.01 and 1000 mg, and usually between 0.01 and 50 mg, of the proteins in the particles of the disclosure, e.g., about 0.01, 0.1, 0.5, 1, 10, 25, 50, 10, 20, 30 or 40 mg of protein per unit dosage.
  • the particles will generally be administered in an "effective amount", by which is meant any amount of particles that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered.
  • an effective amount will usually be between 0.01 to 100 mg of protein per kilogram body weight of the patient per day, more often between 0.01 and 50 mg, such as between 1 and 25 mg, for example about 0.1, 0.5, 1, 5, 10, 2, 5, 10, 15, 20 or 25 mg of protein, per kilogram body weight of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses.
  • the amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated.
  • the particles may be mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as pill, tablets, coated tablets, capsules, aqueous, alcoholic, or oily solutions.
  • suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch.
  • the preparation may be carried out both as dry and as moist granules.
  • Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.
  • Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof.
  • Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms.
  • these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
  • compositions may be extended release formulations.
  • Typical extended release formations utilize an enteric coating.
  • Enteric coatings prevent release of medication before it reaches the small intestine.
  • Enteric coatings may contain polymers of polysaccharides, such as maltodextrin, xanthan, scleroglucan dextran, starch, alginates, pullulan, hyaloronic acid, chitin, chitosan and the like; other natural polymers, such as proteins (albumin, gelatin etc.), poly-L-lysine; sodium poly(acrylic acid); poly(hydroxyalkylmethacrylates) (for example poly(hydroxyethyl methacrylate) ); carboxypolymethylene (for example CarbopolTM); carbomer; polyvinyl pyrrolidone; gums, such as guar gum, gum arabic, gum karaya, gum ghatti, locust bean gum, tamarind gum, gellan gum, gum tragacanth,
  • CHEC carboxymethylhydroxyethylcellulose
  • HPMC hydroxypropylmethyl-cellulose
  • HPEC hydroxypropylethylcellulose
  • Na CMC sodium carboxymethylcellulose
  • Certain of the above-mentioned polymers may further be crosslinked by way of standard techniques.
  • UV-vis absorption spectra were taken on a JASCO V-550 spectrophotometer, Dynamic light scattering (DLS) were measured with Zetasizer Nano ZSP (Malvern Instruments Ltd, UK).
  • the particle size was determined by dynamic light scattering using a ZetaSizer Nano ZS instrument.
  • Enzymatic assay of the activity of the microgel encapsulated glucose oxidase was measured according to the standard procedure provided by Sigma- Aldrich online. Briefly, a reaction cocktail (0.17 mM o-Dianisidine and 1.72% (w/v) Glucose Solution) and
  • Peroxidase (POD, 60 Purpurogallin units/ml) was prepared in DI water, and the microgel encapsulated glucose oxidase solution was diluted in cold sodium acetate buffer (50 mM, pH 5.1), reaction cocktail (2.9 ml) and POD (0.1 mL) was added to a cuvette, then 0.1 mL of either buffer (blank) or the above microgel solution was added to the cuvette. The absorption in 500 nm (A500nm) was measured continuously for six minutes, and the enzymatic activity was calculated by the following equations:
  • 7.5 Millimolar extinction coefficient of oxidized o-Dianisidine at 500nm

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des particules hydrophiles, des compositions, des procédés de production, et des utilisations dans la gestion alimentaire et les troubles de la digestion. Dans certains modes de réalisation, la particule comprend une protéine revêtue dans un polymère hydrophile comprenant des monomères ayant des polyalcoxy ramifiés, tels que mais sans y être limités, le polyéthylène glycol. Typiquement, la protéine est une glucose oxydase, une galactose oxydase, une lipase, d'autres enzymes digestives, ou des combinaisons de celles-ci. Dans certains modes de réalisation, les compositions comprenant des particules décrites dans la description sont utilisées pour réduire les taux de glycémie ou empêcher des taux de glycémie élevés chez un sujet.
PCT/US2014/032626 2013-04-03 2014-04-02 Compositions de particules hydrophiles, procédés de production, et utilisations dans la gestion alimentaire et les troubles de la digestion WO2014165566A1 (fr)

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WO2016059654A1 (fr) * 2014-10-16 2016-04-21 Giuseppe Baricco Utilisation de glucose oxydase pour la prise en charge, la prévention et le traitement de troubles intestinaux
WO2019136168A1 (fr) 2018-01-03 2019-07-11 Penn State Research Foundation Compositions de glucose oxydase utilisées comme anticonvulsivant chez le nouveau-né
WO2022261166A1 (fr) * 2021-06-08 2022-12-15 President And Fellows Of Harvard College Systèmes et procédés de réduction du sucre et/ou de production de fibres pour des aliments et d'autres applications

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016059654A1 (fr) * 2014-10-16 2016-04-21 Giuseppe Baricco Utilisation de glucose oxydase pour la prise en charge, la prévention et le traitement de troubles intestinaux
WO2019136168A1 (fr) 2018-01-03 2019-07-11 Penn State Research Foundation Compositions de glucose oxydase utilisées comme anticonvulsivant chez le nouveau-né
EP3735262A4 (fr) * 2018-01-03 2021-09-29 Penn State Research Foundation Compositions de glucose oxydase utilisées comme anticonvulsivant chez le nouveau-né
US11666640B2 (en) 2018-01-03 2023-06-06 Penn State Research Foundation Glucose oxidase compositions as a neonate anticonvulsant
WO2022261166A1 (fr) * 2021-06-08 2022-12-15 President And Fellows Of Harvard College Systèmes et procédés de réduction du sucre et/ou de production de fibres pour des aliments et d'autres applications

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