WO2007011171A1 - Formulation médicamenteuse contenant un agent solubilisant pour améliorer la solubilité, l’absorption et la perméabilité - Google Patents

Formulation médicamenteuse contenant un agent solubilisant pour améliorer la solubilité, l’absorption et la perméabilité Download PDF

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WO2007011171A1
WO2007011171A1 PCT/KR2006/002848 KR2006002848W WO2007011171A1 WO 2007011171 A1 WO2007011171 A1 WO 2007011171A1 KR 2006002848 W KR2006002848 W KR 2006002848W WO 2007011171 A1 WO2007011171 A1 WO 2007011171A1
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heparin
composition
drug
dmso
mixture
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PCT/KR2006/002848
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English (en)
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Youngro Byun
Sang Kyoon Kim
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Mediplex Corp.
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Priority claimed from US11/188,217 external-priority patent/US20070021325A1/en
Application filed by Mediplex Corp. filed Critical Mediplex Corp.
Priority to EP06783360A priority Critical patent/EP1926474A1/fr
Publication of WO2007011171A1 publication Critical patent/WO2007011171A1/fr

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    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/554—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof

Definitions

  • This invention relates to drug formulations containing solubilizers for increasing solubility, absorption, and permeability of the drug. More particularly, this invention relates to mixtures and complexes of a drug and a solubilizer, wherein the solubilizer increases the water solubility of the drug and the absorption and permeability of the drug through the intestinal mucosa into the bloodstream.
  • drugs are not available in oral formulations because of poor or insufficient solubility, absorption through the intestinal mucosa, and/or permeability of the drug.
  • Illustrative examples of such drugs include polysaccharides, proteins, polysaccharide conjugates, protein conjugates, and protein complexes, and mixtures thereof.
  • An illustrative example of a polysaccharide drug comprises heparin, and illustrative examples of protein drugs comprise insulin and calcitonin.
  • heparin is a polysaccharide composed of sulfated D-glucosamine and
  • heparin D-glucuronic acid residues. Due to its numerous ionizable sulfate groups, heparin possesses a strong electronegative charge. It is also a relatively strong acid that readily forms water-soluble salts, e.g. heparin sodium. It is found in mast cells and can be extracted from many body organs, particularly those with abundant mast cells. The liver and lungs are especially rich in heparin. The circulating blood contains no heparin except after profound disruption of mast cells. Heparin has many physiological roles, such as blood anticoagulation, inhibition of smooth muscle cell proliferation, and so forth. In particular, heparin is a potent anticoagulant agent that interacts strongly with antithrombin III to prevent the formation of fibrin clots.
  • heparin In vivo, however, applications of heparin are very limited. Because of its hydrophilicity and high negative charge, heparin is not absorbed efficiently from the GI tract, nasal or buccal mucosal layers, and the like. Therefore, the only routes of administration used clinically are intravenous and subcutaneous injections.
  • U.S. Patent No. 6,245,753 and U.S. Patent No. 6,656,922 disclose amphiphilic heparin derivatives, that is, hydrophobized heparin conjugates wherein bile acids, sterols, alkanoic acids, and the like are conjugated to heparin for increasing the hy- drophobicity of the very hydrophilic heparin molecule.
  • Increasing the hydrophobicity of heparin by bonding a hydrophobic agent thereto results in what may be termed an amphiphilic heparin derivative or a hydrophobic heparin derivative. Either term is proper because the heparin derivative has increased hydrophobicity as compared to native heparin, and the heparin derivative.
  • heparin-DOCA Since heparin cannot penetrate the intestinal bilayer because of its low partition coefficient and diffusivity in tissues, heparin-DOCA was synthesized by conjugation of heparin and deoxycholic acid for oral delivery. Heparin-DOCA was expected to interact readily with intestinal membranes, as well have a high partition coefficient in tissues. However, heparin-DOCA did not exhibit high absorption in the intestine due to its amphiphilicity. There was a problem that Amphiphilic heparin-DOCA made self- assembled particles due to hydrophobic interactions between the conjugated DOCA molecules under aqueous conditions, so that it decreased the absorption.
  • the inventors of the present invention conducting researches aimed at enhancing the absorption of the drugs, polysaccharides such as haparin, proteins such as insulin and calcitonin, etc. through the intestinal mucosa have found that the drugs can be used as oral formulations because solubility, absorption, and permeability of the drugs can be enhanced when the drugs contain a water-miscible solubilizer, and completed this invention.
  • the drug formulations according to the present invention contain a solubilizer for enhancing solubility, absorption, and permeability, they can be used as oral formulations.
  • FlG. 1 shows FT-IR analysis of DMSO bound to a heparin-DOCA conjugate: heparin (solid line); DMSO-bound heparin-DOCA (10%; dotted line); DMSO-bound heparin-DOCA (30%, dashed line).
  • FTG. 2 shows a TGA profile of DMSO-bound heparin-DOCA: heparin (solid line) ;
  • DMSO-bound heparin (long-dashed line); heparin-DOCA (short-dashed line); DMSO- bound heparin-DOCA (dotted line).
  • FTG. 3 shows a DSC profile of DMSO-bound heparin-DOCA: heparin (solid line);
  • DMSO-bound heparin (long-dashed line); heparin-DOCA (short-dashed line); DMSO- bound heparin-DOCA (dotted line).
  • FTG. 4 shows oral absorption of DMSO-bound heparin-DOCA in mice: heparin-
  • DOCA in 10% DMSO formulation (•); DMSO-bound heparin-DOCA ( ⁇ ); DMSO- bound heparin (A).
  • FTG. 5 shows absorption of DMSO-bound heparin-DOCA in capsule in monkeys when taken orally: 100 mg/kg heparin in buffer (•); 5 mg/kg DMSO-bound heparin- DOCA in capsule ( ⁇ ); 10 mg/kg DMSO-bound heparin-DOCA in capsule (A).
  • FTG. 6 shows an absorption profile of DMSO-bound heparin-DOCA in monkeys when taken orally: heparin in buffer (100 mg/kg; •); heparin-DOCA in buffer (10 mg/ kg; ⁇ ); DMSO-bound heparin in buffer (10 mg/kg; A); DMSO-bound heparin-DOCA in buffer (5 mg/kg; T); DMSO-bound heparin in buffer (5 mg/kg; ⁇ ).
  • An illustrative embodiment of the present invention comprises a composition comprising an aqueous mixture, complex, or combination of a mixture and a complex of a drug and a water-miscible organic solvent.
  • Illustrative examples of such drugs include polysaccharides, proteins, polysaccharide conjugates, protein conjugates, and protein complexes, and mixtures thereof.
  • An illustrative example of a polysaccharide drug comprises heparin
  • illustrative examples of protein drugs comprise insulin and calcitonin.
  • heparin-bile acid conjugates and insulin- or calcitonin-bile acid conjugates are illustrative examples of polysaccharide conjugates and protein conjugates, respectively.
  • water-miscible organic solvents include dimethyl sulfoxide, N-methylpyrrolidone, polyoxyl 35 castor oil, diethylene glycol monoethyl ether, benzoic acid, and mixtures thereof.
  • Another illustrative embodiment of the invention comprises a composition formed by a process comprising:
  • Still another illustrative embodiment of the present invention comprises a method of treating a condition in a warm-blooded animal in need of treatment therefor, the method comprising orally administered a composition comprising a mixture, a complex, or a combination of a mixture and a complex of a drug and a water-miscible organic solvent.
  • the composition can comprise an aqueous solution or a dried form.
  • Yet another illustrative embodiment of the invention comprises a composition comprising a mixture, a complex, or a combination of a mixture and a complex of heparin and dimethyl sulfoxide.
  • a still further illustrative example of the present invention comprises a method of treating a patient in need of anticoagulation therapy, the method comprising orally administering a safe and effective amount of a composition comprising a mixture, a complex, or a combination of a mixture and a complex of a heparin-bile acid conjugate and dimethyl sulfoxide.
  • Heparin-deoxycholic acid conjugate is an illustrative example of such a heparin-bile acid conjugate.
  • an illustrative embodiment of the present invention comprises a method of making an oral formulation for anticoagulation therapy, the method comprising:
  • This method can optionally further comprise evaporating the aqueous formulation to dryness and encapsulating or tableting the dried aqueous formulation.
  • the method can further comprise encapsulating the aqueous formulation.
  • DMSO dimethyl sulfoxide
  • NMP means ⁇ f-methyl pyrrolidone
  • polyoxyl 35 castor oil is a nonionic solubilizer and emulsifier produced by causing ethylene oxide to react with pharmaceutical grade castor oil in a molar ratio of 35:1.
  • the main component of polyoxyl 35 castor oil is glycerol- polyethylene glycol ricinoleate, which, together with fatty acid esters of polyethyleneglycol, represents the hydrophobic part of the product.
  • the smaller, hy- drophilic part comprises polyethylene glycols and ethoxylated glycerol.
  • Polyoxyl 35 castor oil has a hydrophilic-lipophilic balance (HLB) between 12 and 14.
  • DOCA deoxycholic acid
  • heparin-DOCA means a conjugate of heparin and deoxycholic acid
  • protein means peptides of any length and includes polypeptides and oligopeptides. In other words, “protein” is used herein without any particular intended size limitation, unless a particular size is otherwise stated.
  • Typical of proteins that can be used in the present invention are those selected from group consisting of oxytocin, vasopressin, adrenocorticotrophic hormone, epidermal growth factor, prolactin, luliberin or luteinising hormone releasing hormone, growth hormone, growth hormone releasing factor, insulin, somatostatin, glucagon, interferon, gastrin, tetragastrin, pentagastrin, urogastroine, secretin, calcitonin, enkephalins, endorphins, angiotensins, renin, bradykinin, bacitracins, polymixins, colistins, tyrocidin, gramicidines, and synthetic analogues, modifications
  • polysaccharide means a carbohydrate containing more than three monosaccharide units per molecule, the units being attached to each other by glycoside linkages.
  • Illustrative polysaccharides include heparin, heparin sodium, sulfonated polysaccharides, cellulose, hydroxymethylcellulose, and hydroxypropylcellulose.
  • Bile acids means natural and synthetic derivatives of the steroid, cholanic acid, including, without limitation, cholic acid, deoxycholic acid, chen- odeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isour- sodeoxycholic acid, lagodeoxycholic acid, glycocholic acid, taurocholic acid, gly- codeoxycholic acid, glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid, hyodeoxycholic acid, and mixtures thereof, and the like.
  • sterols means alcohols structurally related to the steroids including, without limitation, cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, ergocalciferol, and mixtures thereof, and the like.
  • alkanoic acids means saturated fatty acids of about 4 to 20 carbon atoms.
  • Illustrative alkanoic acids include, without limitation, butyric acid, valeric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, and mixtures thereof, and the like.
  • an effective amount means an amount of a 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.
  • an effective amount of a heparin-DOCA conjugate is an amount sufficient to provide a selected level of anticoagulation activity.
  • safe and effective amount refers to the quantity of a component which is sufficient to yield a desired response without undue adverse effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
  • the specific "safe and effective amount” will, obviously, vary with such factors as the particular condition that is being treated, the severity of the condition, the duration of the treatment, the physical condition of the patient, the nature of concurrent therapy (if any), and the specific formulation used in the present invention.
  • the instant technology relates to binding water-miscible solubilizers to drugs by secondary interactions, such as intermolecular or intramolecular hydrogen bonding, hydrophobic interaction, and the like to control the solubility of such drugs in aqueous environments.
  • heparin-DOCA chemical conjugate of heparin and deoxycholic acid
  • heparin-DOCA is not effectively absorbed in the intestine because it cannot be dissolved in the gastrointestinal (GI) tract.
  • the solubility of heparin-DOCA in aqueous solution is greatly increased, thereby significantly enhancing its absorption in the GI tract. Therefore, the present invention significantly increases drug solubility and absorption in the intestine because of the effects of the bound solubilizer molecules.
  • the present technology uses a very small amount of solubilizer, the final product can be prepared as in powder form, which can be formulated as tablet or capsule type. Also, the toxicity of the solubilizer is negligible du to the small amount necessary to achieve the effect.
  • heparin-DOCA Since heparin cannot penetrate the intestinal bilayer because of its low partition coefficient and diffusivity in tissues, heparin-DOCA was synthesized by conjugation of heparin and deoxycholic acid for oral delivery. Heparin-DOCA was expected to interact readily with intestinal membranes, as well have a high partition coefficient in tissues. However, heparin-DOCA did not exhibit high absorption in the intestine due to its amphiphilicity. Amphiphilic heparin-DOCA made self-assembled particles under aqueous conditions, because of hydrophobic interactions between the conjugated DOCA molecules.
  • Dimethyl sulfoxide (CAS No. 67-68-5, DMSO, (CH ) SO) is an important industrial solvent as well as being widely used in biology as a cryoprotector in the de- naturation of proteins and as a drug carrier across cell membranes. Merck Index, Monograph No. 3285, 573 (13 th ed. 2001); D. Martin & H.G. Hauthal, Dimethyl Suphoxide (Wiley, New York 1975). Its broad range of properties is closely related to its properties in water solutions. DMSO mixes with water at all proportions. The partial negative charge on the oxygen atom of the DMSO molecule favors the formation of hydrogen bonds with water molecules, giving rise to strongly nonideal behavior of the mixture.
  • NMP (CAS No. 872-50-4) is a dipolar aprotic solvent, which is commercially prepared by condensation of butryolactone with methylamine. It is an industrial solvent used primarily in the extraction of aromatics from lubrication oils, but also has use in other applications, such as recovery and purification of acetylenes, olefins and diolefins, gas purification, aromatics extraction from feedstocks, and a polymer solvent. NMP is miscible with water, as well as with alcohol, ether, acetone, ethyl acetate, chloroform, and benzene. Merck Index, Monograph no. 6140, 1090 (13 ed. 2001).
  • Diethylene glycol monoethyl ether (CAS No. 111-90-0), also known as l-(2-ethoxyethoxy)ethanol and carbitol is a water-miscible solvent, which is prepared from ethylene oxide and 2-ethoxy-ethanol in the presence of SO . It is also miscible with acetone, benzene, chloroform, ethanol, ether, pyridine, and the like. It is used as a solvent for cellulose esters and in lacquer and thinner formulations, in quick-drying varnishes and enamels, and for dye-stuffs and wood stains. Merck Index, Monograph No. 1809, 302 (13 th ed. 2001).
  • Benzoic acid (CAS No. 65-85-0) is readily soluble in water, as well as in a variety of other solvents, such as alcohol, carbon tetrachloride, chloroform, ether, acetone, benzene, carbon disulfide, and the like. Benzoic acid is used for preserving foods, fats, fruit juices, and alkaloidal solutions; in the manufacture of benzoates, benzoyl compounds, and dyes; as a mordant in calico printing; for curing tobacco; and as an antifungal. Merck Index, Monograph 1092, 187 (13 th ed. 2001).
  • heparin-DOCA heparin-deoxycholic acid conjugate
  • DOCA ⁇ f-hydroxylsuccinimide
  • DCC dicyclohexylcarbodiimide
  • Activated DOCA was then conjugated with heparin, and the resulting heparin-DOCA conjugate was purified by reverse phase and phenyl-Sepharose chromatography.
  • purified heparin-DOCA was freeze dried at -80 °C to result in a white powder.
  • heparin-DOCA conjugate was dissolved in 10%, 30%, 50%, 70% and 90% aqueous DMSO solution, respectively.
  • heparin-DOCA 100 mg was dissolved in five aliquots each of 500 D of distilled water. To each aliquot 1, 3, 5, 7, or 9 ml of DMSO was added. The resulting solutions were dispersed by sonication with a probe-type sonicator. Finally, distilled water was added to each solution to make a final volume of 10 D, and these solutions were well mixed before freeze drying at -80 °C for 3 days to obtain a white powder.
  • the resulting preparations contained DMSO molecules and DMSO/water complexes bonded to the hydroxyl groups of the heparin- DOCA conjugate, as well as simple mixtures of DMSO, DMSO/water complexes, and heparin.
  • Example 1 The procedure of Example 1 was repeated except that ⁇ f-methyl pyrrolidone (NMP) was substituted for DMSO.
  • NMP ⁇ f-methyl pyrrolidone
  • Example 1 The procedure of Example 1 was repeated except that diethylene glycol monoethyl ether was substituted for DMSO.
  • Example 1 The procedure of Example 1 was repeated except that benzoic acid was substituted for DMSO.
  • Protein-bile acid conjugates were chemically synthesized. Namely, insulin-de- oxycholic acid, insulin-lithocholic acid, insulin-cholic acid, calcitonin-deoxycholic acid, calcitonin-bis deoxycholic acid, and calcitonin-tris deoxycholic acid were synthesized according to methods well known in the art. These protein-bile acid conjugates were separately mixed with DMSO, polyoxyl 35 castor oil, N - methylpyrrolidone, diethyleneglycol monoethylether, and benzoic acid at 10%, 30%, 50%, 70%, and 90% organic solvent concentrations and then were freeze dried at -80 °C for 3 days.
  • TGA thermal gravimetry analysis
  • DSC differential scanning calorimetry
  • TGA determines the mass change of a sample as a function of temperature or time.
  • FIG. 2 shows the results of the TGA experiment, wherein the total weight of DMSO- bound heparin-DOCA was changed at increasing temperatures by the evaporation of DMSO.
  • DSC is a technique for measuring the energy necessary to establish a nearly zero temperature difference between a substance and an inert reference material, as the two substances are subjected to identical temperature regimes in an environment heated or cooled at a controlled rate.
  • FIG. 3 shows the results of the DSC experiment, wherein peaks present for heparin-DOCA disappeared when DMSO was present.
  • DMSO molecules may be bound or simply mixed with macromolecules.
  • the binding of DMSO molecules to macromolecules may change the conformation of the macromolecules from a more ordered form to an amorphous form.
  • DMSO molecules incorporated into the heparin-DOCA conjugates appears to affect the aggregate formation of amphiphilic heparin-DOCA and may reduce the crys- tallinity of heparin-DOCA.
  • DOCA can be changed by the evaporation of DMSO molecule.
  • DSC profile will be differed by the change of the heparin-DOCA structure intercalating of DMSO molecules. From the DSC and TGA results, we found that DMSO molecules are bound or mixed with macromolecules. Therefore, by the binding of DMSO molecules, the structure of heparin-DOCA might be changed to the amorphous form. From the below figures, we observed that specific peaks of heparin-DOCA gradually disappeared by the incorporation of DMSO molecules [95]
  • DMSO-bound heparin-DOCA was dissolved in distilled water, and it was determined that particles of DMSO-bound heparin-DOCA were not formed under these conditions. Accordingly, aqueous solutions of DMSO-bound heparin-DOCA were orally administered to mice (5 mg/kg) FlG. 4 shows that the absorption of DMSO-bound heparin-DOCA was significantly increased as compared to the absorption of DMSO-bound heparin. Further the bioavailability of DMSO-bound heparin-DOCA was not reduced as compared to heparin-DOCA in 10% aqueous DMSO.
  • DMSO-bound heparin-DOCA prepared according to the method of Example 1 was encapsulated and then administered orally to monkeys at either 5 mg/kg or 10 mg/kg dosages.
  • heparin in buffer was orally administered at 100 mg/kg.
  • FlG. 5 shows that absorption of heparin was negligible, however, absorption of DMSO-bound heparin-DOCA was substantial and increased according to dosage.
  • aqueous formulations of heparin, heparin-DOCA, DMSO-bound heparin, and DMSO-bound heparin-DOCA were orally administered to monkeys.
  • FlG. 6 shows that DMSO-bound heparin-DOCA at 5 mg/kg and 10 mg/kg dosages resulted in better absorption than any of the controls, namely, heparin (100 mg/kg), heparin-DOCA (10 mg/kg), and DMSO-bound heparin (10 mg/kg). Therefore, aqueous formulations of DMSO-bound heparin-DOCA are absorbed after oral administration, just as encapsulated powders are absorbed after oral administration (e.g., Example 11).
  • the drug formulations according to the present invention contain a solubilizer for enhancing solubility, absorption, and permeability, they can be used as oral formulations.

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Abstract

La présente invention concerne l’amélioration de la solubilité, de l’absorption et de la perméabilité de médicaments à administration orale lorsque lesdits médicaments sont mélangés et/ou associés à des solvants organiques miscibles dans l’eau. À titre d’illustration, l’absorption orale d’un conjugué d’acide désoxycholique et d’héparine est augmentée par le mélange et/ou l’association de ce conjugué avec du diméthyl-sulfoxide. À titre d’illustration, d’autres solvants organiques miscibles dans l’eau incluent la N-méthylpyrrolidone, l’huile de ricin polyoxyl 35, l’éther monoéthylique du diéthylène glycol, et l’acide benzoïque.
PCT/KR2006/002848 2005-07-21 2006-07-19 Formulation médicamenteuse contenant un agent solubilisant pour améliorer la solubilité, l’absorption et la perméabilité WO2007011171A1 (fr)

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EP06783360A EP1926474A1 (fr) 2005-07-21 2006-07-19 Formulation médicamenteuse contenant un agent solubilisant pour améliorer la solubilité, l absorption et la perméabilité

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US11/188,217 2005-07-21
US11/188,217 US20070021325A1 (en) 2005-07-21 2005-07-21 Drug formulation containing a solubilizer for enhancing solubility, absorption, and permeability
KR1020060067466A KR20070012219A (ko) 2005-07-21 2006-07-19 용해성, 흡수성 및 투과성을 향상시키기 위한 용제를함유하는 약물 제제
KR10-2006-0067466 2006-07-19

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Cited By (1)

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CN115462369A (zh) * 2022-09-29 2022-12-13 安徽省立医院(中国科学技术大学附属第一医院) 一种玻璃化冷冻外泌体保存方法

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US6458383B2 (en) * 1999-08-17 2002-10-01 Lipocine, Inc. Pharmaceutical dosage form for oral administration of hydrophilic drugs, particularly low molecular weight heparin
WO2004075877A1 (fr) * 2003-02-24 2004-09-10 Pharmaceutical Productions, Inc. Systeme d'administration de medicaments par voie transmuqueuse

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Publication number Priority date Publication date Assignee Title
US5352457A (en) * 1990-10-05 1994-10-04 Ethical Pharmaceuticals Limited Transdermal device
US6458383B2 (en) * 1999-08-17 2002-10-01 Lipocine, Inc. Pharmaceutical dosage form for oral administration of hydrophilic drugs, particularly low molecular weight heparin
WO2002064166A1 (fr) * 2001-02-13 2002-08-22 Korea Institute Of Science And Technology Preparation permettant d'ameliorer la biodisponibilite des matieres bioactives et procede de preparation correspondant
WO2004075877A1 (fr) * 2003-02-24 2004-09-10 Pharmaceutical Productions, Inc. Systeme d'administration de medicaments par voie transmuqueuse

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115462369A (zh) * 2022-09-29 2022-12-13 安徽省立医院(中国科学技术大学附属第一医院) 一种玻璃化冷冻外泌体保存方法
CN115462369B (zh) * 2022-09-29 2023-09-22 安徽省立医院(中国科学技术大学附属第一医院) 一种玻璃化冷冻外泌体保存方法

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