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WO2005113008A1 - Delivrance d'agents permettant d'ameliorer l'absorption mucosale d'agents therapeutiques - Google Patents

Delivrance d'agents permettant d'ameliorer l'absorption mucosale d'agents therapeutiques Download PDF

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Publication number
WO2005113008A1
WO2005113008A1 PCT/KR2005/001359 KR2005001359W WO2005113008A1 WO 2005113008 A1 WO2005113008 A1 WO 2005113008A1 KR 2005001359 W KR2005001359 W KR 2005001359W WO 2005113008 A1 WO2005113008 A1 WO 2005113008A1
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Prior art keywords
acid
agent
delivery agent
charged
composition
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Ceased
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PCT/KR2005/001359
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English (en)
Inventor
Youngro Byun
Hyuntae Moon
Seulki Lee
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MEDIPLEX CORP
Mediplex Corp Korea
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MEDIPLEX CORP
Mediplex Corp Korea
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Priority claimed from US10/851,477 external-priority patent/US7906137B2/en
Application filed by MEDIPLEX CORP, Mediplex Corp Korea filed Critical MEDIPLEX CORP
Priority to JP2007526975A priority Critical patent/JP4717071B2/ja
Priority to EP05764770A priority patent/EP1765406A4/fr
Publication of WO2005113008A1 publication Critical patent/WO2005113008A1/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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • the present invention relates to compositions for delivering biologically active agents, particularly therapeutic agents.
  • the compositions comprise a synthetic delivery agent that facilitates oral delivery of the biologically active agent and that may also be used in connection with other routes of delivery.
  • the invention also relates to methods for the preparation and administration of such compositions.
  • Oral delivery would be the route of choice for administering many biologically active agents to animals, including humans, but for barriers that interfere with efficient absorption of these agents.
  • biologically active peptides such as insulin, calcitonin, growth hormone, and glucagon-like-peptide-1; polysaccharides and mu- copolysaccarides including, but not limited to, heparin and haparinoids; antibiotics; and other organic substance.
  • GI gastrointestinal
  • bioactive agents Due to the hydrophilicity of many bioactive agents, such bioactive agents typically exhibit low bioavailability. Chemical modification of a native bioactive agent can result in an increase o f lipophilicity, however, such modification imposes high costs for preparing and purifying the final product. If a delivery agent could increase lipophilicity of a native bioactive agent by simple mixing with the bioactive agent, it would allow increased bioavailability and would also provide a simplicity of preparation and low cost.
  • Typical delivery agents do not interact with bioactive agents under physiological conditions. This is why a significant amount of felivery agent and/or enhancer are usually needed to deliver the bioactive agent. Increasing the ability of a delivery agent to interact with a bioactive agent would allow more effective delivery at much lower concentrations of delivery agent.
  • Maintaing or controlling the effective charge of a bioactive agent is crucial for increasing permeability of a bioactive agent through membranes. If a delivery agent could control the net charge of a bioactive agent by simple mixing of the delivery agent and the bioactive agent, it would allow more deffective delivery of the bioactive agent.
  • a high aggregation state of a bioactive agent results in low bioavailability after oral administration. If a delivery agent could alter the aggregation state of a bioactive agent, it would allow more effective delivery.
  • compositions and methods for delivery of bioactive agents wherein degradation and inactivation are inhibited, solubility problems are reduced, interaction of bioactive agents and delivery agents is increased, electrostatic charge is controlled, lipophilicity of bioactive agents is increased, and aggregation state of bioactive agents is altered, would be a significant advancement in the art.
  • compositions and methods for delivery of bioactive agents wherein solubility problems are reduced and interaction of bioactive agents and delvery agents is increased.
  • compositions and method for delivery of bioactive agnets wherein electrostatic charge of the bioactive agents can be controlled.
  • compositions and methods for delivery of bioactive agents wherein the aggregation state of bioactive agents can be altered.
  • a delivery agent for delivery of a biologically active agent to a warm-blooded animal comprising (a) a hydrophobic moiety selected from the group consisting of bile acids, sterols, derivatives of such bile acids and sterols, and small hydrophobic molecules having molecular weights of less than about 500 daltons and (b) a hydrophilic moiety covalently bonded to the hydrophobic moiety, wherein the hydrophilic moiety is positively charged, negatively charged, or a salt.
  • Illustrative hydrophilic moieties according to the present invention include -amino acids, such as lysine, arginine, histidine, aspartic acid, or glutamic acid; dipeptides or tripep tides; and hydrophilic small molecules having a molecular weight of about 100 to about 3000.
  • the delivery agent ahs a molecular weight of about 400 to about 4000 daltons.
  • N ⁇ -deoxycholyl-L-lysine-methylester is an illustrative delivery agent according to the present invention.
  • Another illustrative embodiment of the invention comprises a composition comprising a mixture of a biologically active agent and a delivery agent, wherein the delivery agent comprises (a) a hydrophobic moiety selected from the group consisting of bile acids, sterols, derivatives of such bile acids and sterols, and small hydrophobic molecules having a molecular weight of less than about 500 daltons and (b) a hydrophilic moiety covalently bonded to the hydrophobic moiety, wherein the hydrophilic moiety is positively charged, negatively charged, or a salt thereof.
  • the delivery agent comprises (a) a hydrophobic moiety selected from the group consisting of bile acids, sterols, derivatives of such bile acids and sterols, and small hydrophobic molecules having a molecular weight of less than about 500 daltons and (b) a hydrophilic moiety covalently bonded to the hydrophobic moiety, wherein the hydrophilic moiety is positively charged, negatively charged, or
  • Illustrative biologically active agents include human growth hormone, recombinant human growth hormone, bovine growth hormone, porcine growth hormone, growth hormone-releasing hormone, alpha- interferon, beta-interferon, gamma-interferon, interleukin-1, interleukin-2, insulin, porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor (IGF), insulin-like growth factor- 1 (IGF-1), glucagon-like peptide- 1 (GLP-1), heparin, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, pentasaccharide, calcitonin, salmon calcitonin, eel calcitonin, human calcitonin, erythropoietin, atrial naturetic factor, antigens, monoclonal antibodies, somatostatin, protease inhibitor, a
  • Insulin, low molecular weight heparin, and calcitonin are especially illustrative of biologically active agents that can be delivered according to the present invention.
  • Excipients, diluents, disintegrants, lubricants, plasticizers, colorants, and mixtures thereof can also be added to the present compositions.
  • Another illustrative embodiment of the invention comprises a dosage form for delivery of a biologically active agent to a warm-blooded animal, the dosage form comprising a mixture of the biologically active agent and a delivery agent, wherein the delivery agent comprises (a) a hydrophobic moiety selected from the group consisting of bile acids, sterols, derivatives of such bile acids and sterols, and small hydrophobic molecules having a molecular weight of less than about 500 daltons and (b) a hydrophilic moiety covalently bonded to the hydrophobic moiety, wherein the hydrophilic moiety is positively charged, negatively charged, or a salt thereof.
  • the delivery agent comprises (a) a hydrophobic moiety selected from the group consisting of bile acids, sterols, derivatives of such bile acids and sterols, and small hydrophobic molecules having a molecular weight of less than about 500 daltons and (b) a hydrophilic moiety covalently bonded to the hydro
  • FIG. 1. shows a representation of N ⁇ -deoxycholyl-L-lysine-methylester.
  • FIGS. 2A and 2B show effects of N ⁇ -deoxycholyl-L-lysine-methylester/insulin complexes on blood glucose levels (FIG. 2A; measured by ONETOUCH glucose monitoring card) and plasma insulin levels (FIG.
  • Type I diabetic rats 42 U/kg human insulin (O); 42 U/kg human insulin + 0.75 mg/kg N ⁇ -deoxycholyl-L-lysine-methylester (•); 42 U/kg human insulin + 1.5 mg/kg N ⁇ - deoxycholyl-L-lysine-methylester ( ⁇ ); 42 U/kg human insulin + 3.0 mg/kg N ⁇ - deoxycholyl-L-lysine-methylester (D).
  • FIG. 3 shows the effect of N ⁇ -deoxycholyl-L-lysine-methylester/insulin complex on blood glucose levels at various times before and after administration of 1.5 g/kg of glucose (arrow) in an oral glucose tolerance test (OGTT) : 42 U/kg human insulin in PBS (•); 42 U/kg human insulin + 1.5 mg/kg N ⁇ -deoxycholyl-L-lysine-methylester (O).
  • OGTT oral glucose tolerance test
  • FIG. 4 shows stability of N ⁇ -deoxycholyl-L-lysine-methylester/insulin (O) toward enzymatic degradation in comparison with native insulin (•).
  • FIG. 5 shows change of aggregation state of insulin by increasing dose of delivery carrier, N ⁇ -deoxycholyl-L-lysine-methylester : 0.18 mM insulin (•); 0.18 mM insulin + 0.18 mM N ⁇ -deoxycholyl-L-lysine-methylester (O); 0.18 mM insulin + 0.37 mM N ⁇ - deoxycholyl-L-lysine-methylester (T); 0.18 mM insulin + 0.55 mM N ⁇ - deoxycholyl-L-lysine-methylester (V); 0.18 mM insulin + 0.37 mM N ⁇ - deoxycholyl-L-lysine-methylester (T); 0.18 mM insulin + 27 mM N ⁇ -de- oxycholyl-L-lysine-methylester ( ⁇ ); 0.18 mM insulin + 37 mM N ⁇ -de- oxycholyl-L-ly
  • FIG. 6 shows the effect of N ⁇ -deoxycholyl-L-lysine-methylester on the concentration of low molecular weight heparin (LMWH) in the plasma after oral administration, as measeured by antiFXa assay: 20 mg/kg LMWH (O); 20 mg/kg of LMWH + 20 mg/kg of N ⁇ -deoxycholyl-L-lysine-methylester (•).
  • LMWH low molecular weight heparin
  • a dosage form comprising a biologically active agent includes reference to a dosage form comprising two or more of such biologically active agents
  • reference to “an -amino acid” includes reference to two or more of such ⁇ -amino acids
  • reference to “the positively charged group” includes reference to two or more of such positively charged groups.
  • bile acids means natural and synthetic derivatives of the steroid, cholanic acid, including, without limitation, chlic acid, deoxycholic acid, chen- odeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isoursode oxycholic acid, lagodeoxycholic acid, glycocholic acid, tautocholic acid, gly- codeoxycholic acid, glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid, and hyodeoxycholic acid.
  • sterols means alcohols structurally related to the steroids including, without limitation, cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, and ergocalciferol.
  • modified peptide means a synthetic dipeptide or tripeptide that contains positively or negatively charged functional groups that may induce electrostatic interaction within an active agent and also increase solubility of the delivery agent. Protecting groups may be used to avoid unwanted side reactions, as would be known to those skilled in the art, and also to increase efficiency of delivery of the therapeutic agent. Esters of peptides, and the like, are also considered modified pep tides.
  • small chemicals or “small molecules” means chemicals having a molecular weight of about 100 to about 3000 and that contain charged functional groups with appropriate salts.
  • “pahrmaceutically acceptable” refers to materials and compositions that are physiologically tolerable and do not typically produce an allergic or similar untowar reaction, such as gastric upset, dizziness and the like, when administered to a human.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government of listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and, more particularly, in humans.
  • ⁇ ективное amount means an amount of a drug or pharmacologically active agent that is nontoxic but sufficient to provide the desired local or systemic effect and performance at a reasonable benefit/risk ratio attending any medical treatment.
  • diluents are inert substances added to increase the bulk of the formulation to make a tablet a practical size for compression.
  • Commmonly used diluents include calcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar, silica, and the like.
  • disintegrators or “disintegrants” are substances that facilitate the breakup or disintegration of tablets after administration.
  • Materials serving as disintegrants have been chemically classified as starches, clays, celluloses, algins, or gums.
  • Other disintegrators include methylcellulose, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp, cross-linked polyvinylpyrrolidone, carboxymethylcellulose, and the like.
  • lubricants are materials that perform a number of function in tablet manufacture, such as improving the rate of flow of the tablet granulation, preventing adhesion of the tablet material to ther surface of the dies and punches, reducing interparticle friction, and facilitating the ejection of the tablets from the die cavity.
  • Commonly used lubricants include talc, magnesium stearate, calcium stearate, stearic acid, and hydrogenated vegetable oils. Typical amounts of lubricants range from about 0.1% by weight to about 5% by weight.
  • coloring agents or “colorants” are agents that give tablets a more pleasing appearance, and in addition help the manufacturer to control the product during its preparation and help the user to identify the product.
  • Any of the approved certified water-soluble FD&C dyes, mixtures thereof, or their corresponding lakes may be used to color tablets.
  • a color lake is the combination by adsorption of a water- soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.
  • flavoring agents are agents for masking the objectionable taste of therapeutic agents. Flavoring agents vary considerably in their chemical structure, ranging from simple esters, alcohols, and aldehydes to carbohydrates and complex volatile oils. Synthetic flavors of almost any desired type are now available.
  • Bioly active agents suitable for use in the present invention include, but are not limited to, proteins, polypeptides, peptides, hormones, polysaccarides, lipids, other organic compounds, and particularly compounds that by themselves do not pass through the gastrointestinal mucosa and/or are susceptible to chemical and/or enzymatic cleavage by acids and enzymes in the gastro-intestinal tract, or any combination thereof.
  • biologically active agents include, but are not limited to, the following, including synthetic, natural or recombinant sources thereof: growth hormones, including human growth hormones (hGH), recomninant human growth hormone (rhGH), bovine growth hormones, and porcine growth hormones; growth hormone-releasing hormones; interferons, including alpha-, beta-, and gamma-in- terferons; interleukin- 1 ; interleukin-2; insulin, including porcine, bovine, human, and human recombinant insulins, optionally comprising counter ions such as sodium, zinc, calcium, and ammonium ions; insulin-like growth factor, including IGF-1; heparin, including unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, and unltra low molecular weight heparin including penta-saccharide; calcitonin, including
  • An illustrative delivery agent according to the present invention comprises a hydrophobic moiety covalently coupled to a hydrophilic moiety.
  • the hydrophobic moiety comprises a bile acid residue, a sterol residue, or a hydrophobic small molecule.
  • the hydrophobic moiety (a) increase lipophilicity of the therapeutically active agent after ionic bonding of the delivery agent and the therapeutically active agent, thereby forming a complex, (b) assists in forming a particulate structure of the complex by providing the hydrophobic portion of the complex, (c) deaggregates highly aggregated protein forms, and (d) may be recognized by certain transporters, such as a bile acid transporter, thus facilitating absorption of the complexes.
  • the bydrophilic moiety comprises, without restriction, modified peptides, small charged molecules, spermidine derivatives, and chelating agents, such as ethylenediaminetetraacetic acid (EDTA) and diethyllenetriaminepentaacetic acid (DTPA).
  • EDTA ethylenediaminetetraacetic acid
  • DTPA diethyllenetriaminepentaacetic acid
  • the hydrophilic moiety can be positively charged, negatively charged, and/or zwitterionic.
  • the hydrophilic moiety provides the charged portion of the delivery agent, thereby providing for electrostatic interaction with the therapeutically active agent, (b) increasing solubility of the delivery agent by forming salt forms, and (c) being recognized by certain transporters, such as di- and tri- peptide transporters, thus facilitating absorption of the complexes.
  • Modified peptides may be recognized by di- and tri-peptide transporters (PEPT1 and PEPT2), which may mediate the efficient absorption of a wide variety of oral peptide-like drugs in the small intestine.
  • PEPT1 and PEPT2 di- and tri-peptide transporters
  • Delivery agents prepared by conjugation of a bile acid and a midified peptide may be recognized by a peptide transporter and also by a bile acid transporter, which may mediate the efficient absorption of a wide variety of delivery agent/biologically active agent complexes in the gastrointestinal (GI) membrane.
  • GI gastrointestinal
  • An illustrative cationic delivery agent according to the present invention if water soluble and positively cahrged.
  • cationic delivery agents that can be used in the invention include, but also not limited to, agents having the formula
  • X is the hydrophobic moiety comprising a bile acid or sterol residue or a small hydrophobic molecule having a molecular weight of less than about 500 daltons
  • Y is the hydrophilic moiety comprising a positively charged molecule, for example, without limitation, positively charged ⁇ -amino acids (Lys, Arg, and His); di- or tri- peptides that contain Lys, Arg, or His; polyamines, such as spermidine and spermine; and positively charged alkyl chain derivatives; or any combination thereof, wherein the positive charge is provided by an appropriate functional group, such as primary, secondary, tertiary, and/or quaternary amines with an appropriate salt, and R is the appropriate functional group, for example, without limitation, -OCH , -OCH CH , -OH, - O " Na + , -SO " , or NH with an appropriate salt.
  • an appropriate functional group such as primary, secondary, tertiary, and
  • An illustrative anionic delivery agent according to the present invention is water soluble and negatively charged.
  • anionic delivery agents that can be used in the invention include, but are not limited to, agents having the formula
  • X is the hydrophobic moiety comprising a bile acid or sterol residue or a small hydrophobic molecule having a molecular weight of less than about 500 daltons
  • Y' is the hydrophilic moiety comprising a negatively charged molecule, for example, without limitation, negatively charged ⁇ -amino acids (Glu and Asp); di- or tri- peptides that contain Glu or Asp; negatively charged chelating agents, such as DTPA or EDTA; or any combination thereof, wherein the negative charge is provided by an appropriate functional group, such as -COOH or -SO " with an appropriate salt, and R is an appropriate salt, and R is an appropriate functional group, for example, without limitation, -OCH , -OCH CH , -OH, O Na + , -SO , or NH . 3 2 3 3 2
  • the delivery agents are made by conjugating the hydrophobic and hydrophilic moietis to each other.
  • either the hydrophobic moiety or the hydrophilic moiety can be activated and then reacted to the other moiety.
  • An illustrative example of such a strategy is forming a succinimido derivative of a bile acid and then reacting the activated bile acid with an amine group of an ⁇ -amino acid, dipeptide, or tripeptide to form the conjugate.
  • activating a hydrophilic moiety or hydrophobic moiety is activating a carboxylic acid group with thionyl chloride to form an acid chloride and then reacting the acid chloride with reactive amines, alcohols, thiols, Grignard reagents, and the like to form amide, ester, thioester, ketone, or other bonds linking the conjugate.
  • sulfonic acid groups can also be activated with thionyl chloride to form sulfonyl chloride groups, which can then be reacted with amines, alcohols, and the like to form sulfonamide, sulfonate ester, or other bonds.
  • Patent No. 5,618,433 describes formation of such bonds.
  • Either the hydrophobic moiety or the hydrophilic moiety may be adapted to contain reactive -NH , -OH, -SH, or MgX moieties according to methods well known in the art to facilitate bonding of the hydrophobic moiety to the hydrophilic moiety.
  • linkers such as heterobifunctional linkers, may be used to conjugate the hydrophobic and hydrophilic moieties to each other. Such linkers are well known in the art and are commercially available.
  • compositions of the present invention may include one or more bioactive agents.
  • the delivery agents of the present invention may be used by simply mixing them with the selected bioactive agent prior to administration. Such mixtures may be prepared by mixing an aqueous solution of the delivery agent with an aqueous solution of the active ingredient, just prior to administration.
  • the delivery agent and the bioactive agent can be admixed during the formulation process.
  • the solution may optionally contain pharmaceutically acceptable additives.
  • Stabilizing additives may be incorporated into the delivery agent solution. With some active agents, the presence of such additives promotes the stability and dis- persiblility of the agent in solution.
  • the stabilizing additives may be used at a concentration ranging between about 0.1 and 50% (w/v), illustratively about 1% (w/v).
  • Suitable, but non-limiting, examples of stabilizing additives include propylene glycol, TweenTM surfactants, gelatin, methyl cellulose, polyethylene glycol, and organic solvents such as dimethylsulfoxide (DMSO), alcohols, carboxylic acids, and salts thereof.
  • the amount of bioactive agent used in a dose is an amount effective to accomplish the purpose of the particular bioactive agent. Such an effective amount can readily be determined by a person skilled in the art.
  • the amount in the composition typically is a pharmacologically or biologically effective amount. However, the amount can be less than a pharmacologically or biologically effective amount when the composition is used in a dosage unit form, such as a solid, a capsule, a tablet, or a powder, an emulsion, or a liquid, because the dosage unit form may contain a multiplicity of delivery agent or bioactive agent compositions or may contain a divided pharmacologically or biologically effective amount.
  • the total effective amounts can then be administered in cumulative units containing, in total, pharmacologically or biologically active amount of biologically or pharmacologically active agent.
  • the total amount of bioactive agent to be used can be determined by those skilled in the art. However, because the presently disclosed delivery agents provide efficient delivery, lower amounts of biologically active agent than those used in prior dosage unit forms or delivery systems may be administered to the subject, while still achieving the same blood levels and biological effects.
  • the amount of delivery agent in the present composition is an amount effective for delivery of a selected bioactive agent, which can be determined without under experimentation for any particular delivery agent or bioactive agent by methods known to those skilled in the art.
  • the amount of delivery agent in a composition according to the present invention will be an amount effective for delivery of the bioactive agent by the selected route of delivery.
  • Dosage unit forms can also include excipients, diluents, disintegrants, lubricants, coloring agents, flavoring agents, and mixture thereof.
  • compositions or dosage unit forms preferably is oral, intracolonic, or intraduodenal.
  • compositions of the present invention are useful in orally administrating active agents, especially those that are not ordinarily orally deliverable.
  • the delivery compositions of the present invention may also include one or more enzyme inhibitors.
  • enzyme inhibitors include, but are not limited to, compounds such as actinonin, H. Umezawa et al., Production of actinonin, an inhibitor of aminopeptidase M, by actinomycetes, 38 J. Antibiot. (Tokyo) 1629-1630 (1985), or epiactinonin and derivatives thereof.
  • compositions of the subject invention are useful for administering biologically active agnets to animals, including humans.
  • the system is particularly advantageous for delivering biologically active agents that would otherwise be destroyed or rendered less effective by conditions encountered before the bioactive agent has reached its target zone (i.e. the area in which the bioactive agent of the delivery composition are to be released) ann within the body of the animal to which they are administered.
  • target zone i.e. the area in which the bioactive agent of the delivery composition are to be released
  • the invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various other dmbodiments, modifications, and equivalents thereof, which after reading the description herein, may suggest themselves to those skilled in the art without departing from the spirit of the present invention.
  • the resulting succinimi- dodeoxycholate (230 mg, 0.48 mmol) was then reacted with the primary amine group of N ⁇ -tBOC-Lys-OCH (150 mg, 0.58 mmol) in dimethylformamide (10 ml) containing triethyl amine (200 D, 1.7 mmol) for 12 h at room temperature. After reaction, the mixture was diluted with ethylacetate (30 ml) and successively washed with 10 ml of 0.5 N HC1, distilled water, 0.5 N NaOH, and distilled water. The organic phase was dried against magnesium sulfate and evaporated to dryness.
  • the protected ⁇ -amine group of the lysine residue was deprotected by mixing with trifluoroacetic acid/ dichloromethane (50/50, v/v) for 2 h at room temperature.
  • the reaction volume was minimized by evaporation under reduced pressure, and the product was previpitated against cold diethyl ether and dried under reduced pressure.
  • the dried product was then dissolved in distilled water and purified through a Sep-Pak C18 column (Waters, Milford, Massachusetts). Finally, purified N ⁇ -deoxychoyl-L-lysine-methylester (DCK; FIG. 1) was lyophilized and obtained as a white powder.
  • DCK N ⁇ -deoxychoyl-L-lysine-methylester
  • An oral insulin formulation was prepared by mixing of human insulin and an illustrative delivery agent according to the present invention, i.e., N ⁇ - deoxychoyl-L-lysine-methylester, which was prepared according to the procedure of Example 1.
  • Zinc human insulin was dissolved in a small volume of 5 mmol/1 HC1 and diluted with PBS (10 mM, pH 7.4) to a final concentration 42 U/ml as a stock solution.
  • the delivery agent was dissolved in PBS (1.5 mg/ml).
  • Insulin complexes were prepared by addition of a predetermined dose of delivery agent solution to insulin solution while vortexing. Insulin complexes were then orally administered to rats in liquid form using a gavage needle.
  • mice Female Sprague-Dawley rats (230 ⁇ 250g) were housed in stainless steel metabolic cages and fed with rodent chow. After an initial 3-day acclimation period, the rats were fasted for 12 h before inducing diabetes mellitus. Streprozotocin (STZ) solution (60 mg/ml) was freshly prepared in acetate buffer (pH 4.5) and used within 1 h. After the baseline blood glucose level was determined, rats were injected intraperitonally (i.p.) with STZ at 60 mg/kg. Five days after STZ treatment, rats with a fasted plasma glucose level greater than 300 mg/dl were selected as diabetic rats for further investigations.
  • STZ Streprozotocin
  • the diabetic rats were fasted overnight for 12 h and then were orally administered insulin, insulin with delivery agent, or placebo (PBS) in PBS solution (10 mM, pH 7.4) using a gavage needle. Each group was reanomized based on their average body weights and fasting blood glucose levels. The insulin dose was fixed (42 U/kg, equivalent to 1.5 mg/kg), but the amount of delivery agent ranged varied among 0.75, 1.5 and 3 mg/kg.
  • the treated rats were kept in metabolic cages, with free access to water only. Blood samples were collected from the ocular orbital at predetermined time points (0. 30, 60, 120, 180, 240, 300, and 360 min).
  • the blood glucose levels were determined immediately from fresh samples using a ONETOUCH blood glucose monitoring system, and the hypoglycemic effect was expressed as mg/dl (FIG. 2A).
  • Plasma insulin was measured by a Coat-A-TubeTM human insulin RIA kit (Diagnostic Products, Los Angeles, California) according to the supplier's instructions, and results were expressed as ⁇ U/ml (FIG. 2B).
  • Insulin 100 D, 1 mg/ml
  • insulin/DCK 1:1, w/w
  • HEPES buffer 50 mmol/1; pH 7.4
  • ⁇ -chymotrypsin 10 D, 150 ⁇ g/ml
  • aliquots were acidified with 890 D of 0.1% trifluoroacetic acid.
  • a circular dichroism spectropolarimeter (Jasco J-715, Tokyo, Japan) was used to measure the effect of a delivery carrier on the aggregation state of insulin. Solutions containing 0.18 mM insulin and different concentration of MP-DCK (0.18-37 mM) were scanned from 300 to 250 nm at room temperature at a scanning speed of 50 nm/ min using a cuvette with a pathlength of 0.1 cm. The results of the test are illustrated in FIG. 5. These results show that increasing amounts of delivery agent decrease the aggregation state of the insulin.
  • An oral LMWH formulation was prepared by mixing of a LMWH solution and an illustrative delivery agent solution, N ⁇ -deoxychoyl-L-lysine-methylester.
  • Cen- taparinuxTM LMWH was dissolved in PBS (10 mM, pH 7.4) containing 2% Tween ® 80 to a final concentration 20 mg/ml as a stock solution.
  • the delivery agent was dissolved in PBS (20mg/ml).
  • LMWH complexes were prepared by addition of a predetermined dose of delivery agent solution to LMWH solution while vortexing. LMWH complexes were then orally administered to the animals in liquid form using a gavage needle.

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Abstract

L'invention concerne un agent de délivrance permettant de délivrer un agent biologiquement actif à un animal à sang chaud. Cet agent contient une fraction hydrophobe liée par covalence à une fraction hydrophile. La fraction hydrophobe peut contenir des acides biliaires, des stérols ou de petites molécules hydrophobes. La fraction hydrophile peut contenir des acides ?-aminés, des dipeptides ou tripeptides, ou de petites molécules hydrophiles. Un agent de délivrance, cité en exemple, est l'ester N?-déoxycholyl-L-lysine-méthylique. L'agent de délivrance et l'agent biologiquement actif sont mélangés pour former un complexe qui est alors administré à l'animal. Ces complexes sont notamment utiles pour l'administration par voie orale d'agents biologiquement actifs mais aussi d'autres modes d'administration.
PCT/KR2005/001359 2004-05-21 2005-05-10 Delivrance d'agents permettant d'ameliorer l'absorption mucosale d'agents therapeutiques Ceased WO2005113008A1 (fr)

Priority Applications (2)

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JP2007526975A JP4717071B2 (ja) 2004-05-21 2005-05-10 治療剤の粘膜吸収を増強するための伝達剤
EP05764770A EP1765406A4 (fr) 2004-05-21 2005-05-10 Delivrance d'agents permettant d'ameliorer l'absorption mucosale d'agents therapeutiques

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US10/851,477 US7906137B2 (en) 2004-05-21 2004-05-21 Delivery agents for enhancing mucosal absorption of therapeutic agents
KR10-2005-0008137 2005-01-28
KR1020050008137A KR100679677B1 (ko) 2004-05-21 2005-01-28 생물학적 활성제의 점막흡수 증강을 위한 전달제

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JP2011506587A (ja) * 2007-12-19 2011-03-03 ファリッド ベニス 消化酵素から保護される少なくとも１種のタンパク質活性成分を含む医薬組成物
WO2013082427A1 (fr) * 2011-11-30 2013-06-06 3M Innovative Properties Company Dispositif à micro-aiguilles comprenant un agent thérapeutique peptidique et un acide aminé et ses procédés de fabrication et d'utilisation
WO2014195950A1 (fr) 2013-06-06 2014-12-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Conjugués acides biliaires-acides aminés basiques et leurs utilisations
US10293052B2 (en) 2007-11-13 2019-05-21 Meritage Pharma, Inc. Compositions for the treatment of gastrointestinal inflammation
US10385008B2 (en) 2017-01-05 2019-08-20 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US11318191B2 (en) 2020-02-18 2022-05-03 Novo Nordisk A/S GLP-1 compositions and uses thereof
US11413296B2 (en) 2005-11-12 2022-08-16 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US11413258B2 (en) 2015-04-29 2022-08-16 Radius Pharmaceuticals, Inc. Methods for treating cancer
US11752198B2 (en) 2017-08-24 2023-09-12 Novo Nordisk A/S GLP-1 compositions and uses thereof

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11413296B2 (en) 2005-11-12 2022-08-16 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US10293052B2 (en) 2007-11-13 2019-05-21 Meritage Pharma, Inc. Compositions for the treatment of gastrointestinal inflammation
US11357859B2 (en) 2007-11-13 2022-06-14 Viropharma Biologics Llc Compositions for the treatment of gastrointestinal inflammation
JP2011506587A (ja) * 2007-12-19 2011-03-03 ファリッド ベニス 消化酵素から保護される少なくとも１種のタンパク質活性成分を含む医薬組成物
US9623087B2 (en) 2011-11-30 2017-04-18 3M Innovative Properties Company Microneedle device including a peptide therapeutic agent and an amino acid and methods of making and using the same
US9675675B2 (en) 2011-11-30 2017-06-13 3M Innovative Properties Company Microneedle device having a peptide therapeutic agent and an amino acid, methods of making and using the same
US10154957B2 (en) 2011-11-30 2018-12-18 3M Innovative Properties Company Microneedle device having a peptide therapeutic agent and an amino acid and methods of making and using the same
WO2013082427A1 (fr) * 2011-11-30 2013-06-06 3M Innovative Properties Company Dispositif à micro-aiguilles comprenant un agent thérapeutique peptidique et un acide aminé et ses procédés de fabrication et d'utilisation
US9884066B2 (en) 2013-06-06 2018-02-06 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Bile acid-basic amino acid conjugates and uses thereof
WO2014195950A1 (fr) 2013-06-06 2014-12-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Conjugués acides biliaires-acides aminés basiques et leurs utilisations
EP3004132A4 (fr) * 2013-06-06 2017-01-18 Yissum, Research Development Company of the Hebrew Conjugués acides biliaires-acides aminés basiques et leurs utilisations
US11413258B2 (en) 2015-04-29 2022-08-16 Radius Pharmaceuticals, Inc. Methods for treating cancer
US10385008B2 (en) 2017-01-05 2019-08-20 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US11752198B2 (en) 2017-08-24 2023-09-12 Novo Nordisk A/S GLP-1 compositions and uses thereof
US12214017B2 (en) 2017-08-24 2025-02-04 Novo Nordisk A/S GLP-1 compositions and uses thereof
US11318191B2 (en) 2020-02-18 2022-05-03 Novo Nordisk A/S GLP-1 compositions and uses thereof

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