US20110301116A1 - Nsaids-induced gastrointestinal mucosal disorder alleviator and manufacturing method thereof - Google Patents

Nsaids-induced gastrointestinal mucosal disorder alleviator and manufacturing method thereof Download PDF

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US20110301116A1
US20110301116A1 US13/132,613 US200913132613A US2011301116A1 US 20110301116 A1 US20110301116 A1 US 20110301116A1 US 200913132613 A US200913132613 A US 200913132613A US 2011301116 A1 US2011301116 A1 US 2011301116A1
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nsaids
trehalose
peak
medical drugs
disaccharide
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Yuichi Tei
Nobuo Sasaki
Shigeki Suzuki
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Next21 KK
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Next21 KK
University of Tokyo NUC
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Assigned to NEXT21 K.K. reassignment NEXT21 K.K. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SUZUKI, SHIGEKI
Assigned to UNIVERSITY OF TOKYO, THE reassignment UNIVERSITY OF TOKYO, THE CORRECTIVE ASSIGNMENT TO CORRECT FIRST INVENTOR'S FIRST NAME TO YUICHI TEI, REEL/FRAME 026386/0636 Assignors: SASAKI, NOBUO, TEI, YUICHI
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/04—Disaccharides

Definitions

  • the present invention relates to a Medical Drugs which reduce damage of gastrointestinal mucosal induced by non-steroidal anti-inflammatory Drugs, NSAIDs, and the method for manufacturing thereof.
  • NSAIDs non-steroidal anti-inflammatory Drugs
  • NSAIDs are commonly used as a pain killer, antipyretic, and anti-inflammatory Drugs. Even though the NSAIDs have a suitable effect, it has a drawback to induce damage of gastrointestinal mucosal.
  • Japanese Patent Publication 2005-343886 disclose that damage of gastrointestinal mucosal induced by Ibuprofen, which is categorized in NSAIDs, is reduced by mixing sugars (Patent document 1). However the alleviative effect caused by the mixture of Ibuprofen and sugars at a dry sate is not sufficient.
  • Japanese Patent Publication 2005-139165 disclose that damage of gastrointestinal mucosal induced by NSAIDs including Loxoprofen is reduced by mixing sugars (Patent document 2). However the alleviative effect caused by the mixture of NSAIDs and sugars at a dry state is not sufficient.
  • the object of the present invention is to provide a Medical Drugs which reduce damage of gastrointestinal mucosal induced by NSAIDs.
  • the present invention is basically based on the new substance that is Intermolecular compounds with NSAIDs and a disaccharide. As shown in the following examples, the Intermolecular compounds, new compounds, have extremely high effect to alleviate damage of gastrointestinal mucosal induced by NSAIDs.
  • the present invention is also related to a method for manufacturing the drug medicine which includes a step of manufacturing the intermolecular compounds.
  • the first aspect of the invention relates to a Medical Drugs which reduce damage of gastrointestinal mucosal induced by non-steroidal anti-inflammatory Drugs, NSAIDs
  • the Medical Drugs comprises an intermolecular compound of NSAIDs and a disaccharide; thereby the Medical Drugs has anti-inflammatory effect of the NSAIDs and can reduce damage induced by the NSAIDs.
  • the Medical Drugs is manufactured by the method of the invention. The method comprises a step of mixing a disaccharide and the NSAIDs so as to obtain a liquid mixture of the disaccharide and the NSAIDs; and a step of drying the liquid mixture so as to obtain the Medical Drugs.
  • the Intermolecular compounds, new compounds have extremely high effect to alleviate damage of gastrointestinal mucosal induced by NSAIDs
  • the example of a Medical Drugs which reduce damage of gastrointestinal mucosal induced by NSAIDs is a Medical Drugs which reduce damage of gastric mucosal induced by NSAIDs.
  • the drug medicine of the present invention which is manufactured by the above method interacts with molecular.
  • the drug medicine lyophilized agent
  • the drug medicine of the present invention has reduce damage of gastrointestinal mucosal induced by NSAID better than the mixture of NSAIDs and a disaccharide (mixture of powders).
  • the drug medicine of the present invention which is manufactured by the above method, has intermolecular compound between NSAIDs and a disaccharide, thereby the intermolecular compound effectively reduce damage of gastrointestinal mucosal induced by NSAIDs.
  • NSAIDs are acidic NSAIDs.
  • the example of the NSAIDs is one or more selected from the group of “aspirin, sodium salicylate, salicylamide, sazapirin, diflunisal, ethenzamide, aluminum aspirin, 5-amino salicylic acidic, indomethacin, etodolac, sodium diclofenac, sulindac, sodium anfenac, proglumetacin maleate, acemetacin, nabumeton, mofezolac, ibuprofen, naproxen, loxoprofen, flurbiprofen, flurbiprofen axetil, oxaprozin, tiaprofenic acidic, pranoprofen, aluminoprophen, zaltoprofen, Mefenamic acidic, tolFenamic acidic, aluminum flufenamate, ketophenylbuta
  • the preferred NSAIDs are one or more of aspirin, indomethacin, sodium diclofenac, ibuprofen, piroxicam, loxoprofen and Mefenamic acidic.
  • the drug medicine can effectively reduce damage of gastrointestinal mucosal induced by NSAIDs by using the above NSAIDs.
  • the drug medicine comprises, as the disaccharide, one or more selected from trehalose, maltose, lactose and sucrose.
  • Trehalose is more preferred as the disaccharide.
  • a preferred working example of the first aspect of the invention is that the form of the Medical Drugs is tablets, granules, or capsules.
  • the disaccharides and NSAIDs are attached by means of molecular interactions by dissolving disaccharides and NSAIDs jointly, drying the dissolved disaccharides and NSAIDs and forming them into tablets, granules or capsules.
  • forms of Medical Drugs bring high reduction effect for damage of gastrointestinal mucosal induced NSAIDs.
  • a preferred working example of the first aspect of the invention is that the NSAIDs is Indomethacin and the disaccharide is trehalose.
  • the DSC curve of the intermolecular compound obtained by the method of differential scanning calorimetry, DSC has a first peak and a second peak at 80 to 95 degrees Celsius and 260 to 270 degrees Celsius, respectively.
  • a preferred working example of the first aspect of the invention is that the NSAIDs is ibuprofen and the disaccharide is trehalose.
  • the DSC curve of the intermolecular compound obtained by the method of differential scanning calorimetry, DSC has a third peak and a fourth peak at 175 to 190 degrees Celsius and 130 to 145 degrees Celsius, respectively.
  • a preferred working example of the first aspect of the invention is that the NSAIDs is aspirin and the disaccharide is trehalose.
  • the DSC curve of the intermolecular compound obtained by the method of differential scanning calorimetry, DSC has a first peak and a second peak at 110 to 120 degrees Celsius and 135 to 145 degrees Celsius, respectively.
  • a preferred working example of the first aspect of the invention is that the NSAIDs is sodium diclofenac and the disaccharide is trehalose.
  • the DSC curve of the intermolecular compound obtained by the method of differential scanning calorimetry, DSC has a first peak and a second peak at 90 to 100 degrees Celsius and 130 to 145 degrees Celsius, respectively.
  • a preferred working example of the first aspect of the invention is that the NSAIDs is Mefenamic acidic and the disaccharide is trehalose.
  • the DSC curve of the intermolecular compound obtained by the method of differential scanning calorimetry, DSC has a first peak and a second peak at 225 to 235 degrees Celsius and 90 to 110 degrees Celsius, respectively.
  • the absolute values of the first peak and the second peak are larger than absolute values of a peak at 225 to 235 degrees Celsius and a peak at 90 to 110 degrees Celsius in a DSC curve of Mefenamic acidic obtained by the method of DSC, respectively.
  • a preferred working example of the first aspect of the invention is that the NSAIDs is piroxicam and the disaccharide is trehalose.
  • the DSC curve of the intermolecular compound obtained by the method of differential scanning calorimetry, DSC has a first peak and a second peak at 90 to 105 degrees Celsius and 195 to 205 degrees Celsius, respectively.
  • the absolute values of the first peak and the second peak are smaller than absolute values of a peak at 90 to 105 degrees Celsius and a peak at 195 to 205 degrees Celsius in a DSC curve of Mefenamic acidic obtained by the method of DSC, respectively.
  • the second aspect of the invention relates to above described Medical Drugs in which the Medical Drugs is a Medical Drugs of alleviating damage of gastric mucosal.
  • the Medical Drugs is manufactured by the method of the invention.
  • the method comprises a step of mixing a disaccharide and the NSAIDs so as to obtain a liquid mixture of the disaccharide and the NSAIDs; and a step of drying the liquid mixture so as to obtain the Medical Drugs.
  • a drug medicine by making a drug medicine through the above method, it is possible to manufacture a drug medicine which can effectively strengthen the technical effect of the disaccharide that reduce damage of gastrointestinal mucosal induced by NSAIDs.
  • NSAIDs are acidic NSAIDs.
  • the example of the NSAIDs is one or more selected from the group of “aspirin, sodium salicylate, salicylamide, sazapirin, diflunisal, ethenzamide, aluminum aspirin, 5-amino salicylic acidic, indomethacin, etodolac, sodium diclofenac, sulindac, sodium anfenac, proglumetacin maleate, acemetacin, nabumeton, mofezolac, ibuprofen, naproxen, loxoprofen, flurbiprofen, flurbiprofen axetil, oxaprozin, tiaprofenic acidic, pranoprofen, aluminoprophen, zaltoprofen, Mefenamic acidic, tolFenamic acidic, aluminum flufenamate, ketophenylbuta
  • the preferred NSAIDs are one or more of aspirin, indomethacin, sodium diclofenac, ibuprofen, piroxicam, loxoprofen and Mefenamic acidic.
  • the drug medicine can effectively reduce damage of gastrointestinal mucosal induced by NSAIDs by using the above NSAIDs.
  • the present invention can provide a Medical Drugs which reduce damage of gastrointestinal mucosal induced by NSAIDs without decreasing the technical effect caused by NSAIDs.
  • FIG. 1 is a graph, which is a substitute of a drawing, which shows ulcer index (mm 2 ) when test substances are administered.
  • FIG. 2 is a graph, which is a substitute of a drawing, which shows a rat ulcer index (mm 2 ) when indomethacin alone, a mixture of indomethacin and trehalose and lyophilized indomethacin and trehalose are administered.
  • FIG. 3 is a graph, which is a substitute of a drawing, which shows a rat ulcer index (mm 2 ) when aspirin alone, a mixture of aspirin and trehalose and lyophilized aspirin and trehalose are administered.
  • FIG. 4 is a graph, which is a substitute of a drawing, which shows a rat ulcer index (mm 2 ) when diclofenac alone, a mixture of diclofenac and trehalose and lyophilized diclofenac and trehalose are administered.
  • FIG. 5 is a graph, which is a substitute of a drawing, which shows an effect for gastric mucosal damages with lyophilized state and mixed state.
  • FIG. 5A is a graph, which is a substitute of a drawing, which shows cell viability rate.
  • FIG. 5B is a graph, which is a substitute of a drawing, which shows cell lethality rate.
  • FIG. 6 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone, indomethacin alone, a mixture of indomethacin and trehalose and lyophilized indomethacin and torehalose.
  • FIG. 7 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone, ibuprofen alone, a mixture of ibuprofen and trehalose and lyophilized ibuprofen and torehalose.
  • FIG. 8 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone, aspirin alone, a mixture of aspirin and trehalose and lyophilized aspirin and torehalose.
  • FIG. 9 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone, diclofenac alone, a mixture of diclofenac and trehalose and lyophilized diclofenac and torehalose.
  • FIG. 10 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone, piroxicam alone, a mixture of piroxicam and trehalose and lyophilized piroxicam and torehalose.
  • FIG. 11 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone, Mefenamic acidic alone, a mixture of Mefenamic acidic and trehalose and lyophilized Mefenamic acidic and torehalose.
  • FIG. 12 is a graph, which is a substitute of a drawing, which shows the result of measurement of ulcer area when each of maltose, sucrose, and lactose were lyophilized with aspirin to conform a molecular compound.
  • FIG. 13 is a graph, which is a substitute of a drawing, which shows the result of measurement of ulcer area when each of maltose and lactose were lyophilized with diclofenac to conform a molecular compound.
  • the first aspect of the invention relates to a Medical Drugs which reduce damage of gastrointestinal mucosal induced by non-steroidal anti-inflammatory Drugs, NSAIDs
  • the Medical Drugs comprises an intermolecular compound of NSAIDs and a disaccharide; thereby the Medical Drugs has anti-inflammatory effect of the NSAIDs and can alleviate damage induced by the NSAIDs.
  • the Medical Drugs is manufactured by the method of the invention.
  • the method comprises a step of mixing a disaccharide and NSAIDs so as to obtain a liquid mixture of the disaccharide and the NSAIDs; and a step of drying the liquid mixture so as to obtain the Medical Drugs.
  • the liquid mixture comprises dissolved disaccharide and dissolved NSAIDs.
  • a Medical Drugs which reduce damage of gastrointestinal mucosal induced by NSAIDs is a drug medicine that can alleviate damage of gastrointestinal mucosal induced by NSAIDs, which keeps the anti-inflammatory effect caused by NSAIDs. It is preferred for the Medical Drugs of the invention to comprise disaccharide and NSAIDs that have molecular interactions between them. It is preferred for the Medical Drugs of the invention to comprise an effective amount of disaccharide to alleviate damage of gastrointestinal mucosal induced by NSAIDs. Namely, disaccharide and NSAIDs that have molecular interactions between them are main ingredients for alleviating damage of gastrointestinal mucosal induced by NSAIDs.
  • the term damage of gastrointestinal mucosal induced by NSAIDs includes not only pathological changes of gastric mucosa (e.g. erosion, ulcer, and edema) induced by NSAIDs but also disorders of duodenum which is close part of stomach and disorders of small intestine and large intestine.
  • the term Gastrointestinal Tract includes stomach, duodenum, small intestine and large intestine.
  • NSAIDs may bring intestinal perforation at small intestine.
  • the Medical Drugs which reduce damage of gastrointestinal mucosal induced by NSAIDs is effective for an intestinal perforation at small intestine caused by NSAIDs.
  • the present invention is most effective for Gastric mucosal disorders. Namely, the most effective working example of the Medical Drugs which reduce damage of gastrointestinal mucosal induced by NSAIDs of the present invention is the Medical Drugs which reduce damage of gastric mucosal induced by NSAIDs.
  • disaccharide examples include maltose, sucrose, cellobiose, lactose, and trehalose.
  • disaccharides the preferred disaccharides are maltose, sucrose, lactose, and trehalose, and most preferable disaccharide is trehalose.
  • Trehalose is one of disaccharides in which two D-glucoses are connected. Trehalose has three isomers, which are different in their connecting style, ⁇ , ⁇ body ( ⁇ -D-glucopyranosyl ⁇ -D-glucopyranoside), ⁇ , ⁇ body ( ⁇ -D-glucopyranosyl ⁇ -D-glucopyranoside)) and ⁇ , ⁇ body ( ⁇ -D-glucopyranoyl ⁇ -D-glucopyranoside)).
  • the Medical Drugs comprises effective amount of one or more of these isomers in total, it is possible to use any isomers produced by any production method, with any purity and with any states.
  • NSAIDs non-steroidal anti-inflammatory Drugs
  • the drug medicine of the present invention may comprise each of acidic NSAIDs and base NSAIDs.
  • Preferred NSAIDs of the invention is acidic NSAIDs.
  • Further preferred NSAIDs of the invention is Carboxylic acidic NSAIDs.
  • the drug medicine of the invention may comprise one or more kinds of NSAIDs.
  • the drug medicine may comprise NSAIDs in the same category (for example, two kinds of salicylic acidic NSAIDs) or NSAIDs in the different categories (for example, salicylic acidic NSAID and Aryl acetic acidic NSAID).
  • These NSAIDs may be manufactured using well known methods or it is possible to use commercially obtainable NSAIDs.
  • NSAIDs are categorized in salicylic acidic NSAIDs, aryl acetic acidic NSAIDs, propionic acidic NSAIDs, Fenamic acidic NSAIDs, enol acidic NSAIDs, and basic NSAIDs.
  • the examples of salicylic acidic NSAIDs are aspirin, sodium salicylate, salicylamide, sazapirin, diflunisal, ethenzamide, aluminum aspirin, and 5-amino salicylic acidic.
  • aryl acetic acidic NSAIDs are indomethacin, etodolac, sodium diclofenac, sulindac, sodium anfenac, proglumetacin maleate, acemetacin, nabumeton, and mofezolac.
  • propionic acidic NSAIDs are ibuprofen, naproxen, loxoprofen, flurbiprofen, flurbiprofen axetil, oxaprozin, tiaprofenic acidic, pranoprofen, aluminoprophen and zaltoprofen.
  • Fenamic acid examples are Mefenamic acidic, tolfenamic acidic, and aluminum flufenamate.
  • enol acidic NSAIDs are Pyrazolone NSAIDs, Pyrimidine NSAIDs and oxycum NSAIDs.
  • the examples of Pyrazolone NSAIDs are ketophenylbutazone and clofezone.
  • the example of Pyrimidine NSAIDs is bucolome.
  • the examples of oxycum NSAIDs are piroxicam, lornoxicam, tenoxicam, meloxicam, and ampiroxicam.
  • NSAIDs are epirizole, tiaramide and elmofazon.
  • intermolecular bonding means that two or more molecules connect each other.
  • the examples of such intermolecular bonding are ionic bonding, complex bonding, hydrophobic bonding, hydrogen bonding, and van der Waals bonding.
  • the drug medicine of the invention which has such a bonding, can be manufactured by means of the method explained below. It is possible to investigate that the molecular interaction of NSAIDs and disaccharide that are included in the manufactured drug medicine by means of conventional analysis methods.
  • the examples of the analysis methods are DSC (Differential Scanning Calorimetry), FTIR (Fourier Transform Infrared Spectroscopy), XPS (X-ray photoelectron spectroscopy) and NMR (nuclear magnetic resonance).
  • DSC Different Scanning Calorimetry
  • FTIR Fastier Transform Infrared Spectroscopy
  • XPS X-ray photoelectron spectroscopy
  • NMR nuclear magnetic resonance
  • the drug medicine of the invention may comprise a pharmaceutically acceptable carrier or a pharmaceutically acceptable medium.
  • the examples of the pharmaceutically acceptable carrier and a pharmaceutically acceptable medium are the pharmaceutically acceptable substances including an anti oxidant and a retainer. It is possible to use polymers like Polyethylene glycol (PEG), and Conjugated compounds such as cyclodextrin. The followings are the examples but the present invention is not limited to such examples.
  • the examples of the stabilizer are albumin, gelatin, sorbitol, mannitol, lactose, sucrose, maltose, and glucose.
  • the examples of the anti-oxidant are sodium sulfite, ascorbic acidic, tocopherol, cysteine hydrochloride, thioglycolic acidic, and catechol.
  • the examples of the retainer are phenol, thimerosal, and benzalkonium chloride.
  • the Medical Drugs of the invention is manufactured by the method of the invention.
  • the method comprises a step of mixing a disaccharide and NSAIDs so as to obtain a liquid mixture of the disaccharide and the NSAIDs; and a step of drying the liquid mixture so as to obtain the Medical Drugs.
  • the liquid mixture comprises dissolved disaccharide and dissolved NSAIDs.
  • the examples of the step of drying are a step of lyophilize, a step of Granulating and Spray Drying, a step of spray drying and a step of Crushing after drying for granulation. Conventionally, the skilled person would mix powdered NSAIDs and powdered disaccharides to manufacture powdered drug medicine.
  • the skilled person would mix NSAIDs solution and disaccharide solution, would pour powdered NSAIDs and powdered disaccharides separately into a liquid and would stir the solution so as to dissolve the powders, or would pour the mixture of powders that includes powdered NSAIDs and powdered disaccharides into a liquid and would stir the solution so as to dissolve the powders.
  • the mixed solution of NSAIDs solution and disaccharide solution has not sufficient effect to alleviate damage of gastrointestinal mucosal induced by NSAID. The reason of the fact is thought that the disaccharide and NSAIDs in liquid drug medicine do not form intermolecular connections enough.
  • the present invention intentionally makes NSAIDs and disaccharide to be dissolved to obtain a liquid mixture so as to bring interactions and then the present invention makes the liquid mixture to be dried so as to obtain a Medical Drugs that has enough activity to reduce damage of gastrointestinal mucosal induced by NSAID.
  • the drug medicine manufactured by the method has molecular interactions as explained below. Namely, the drug medicine manufactured by the method comprises molecular interactions between disaccharide and NSAIDs.
  • the drug medicine of the invention therefore has NSAIDs molecular dispersed into disaccharide molecules with keeping molecular interactions of NSAIDs and thus it can alleviate damage of gastrointestinal mucosal induced by NSAID effectively.
  • the step of mixing is a step for mixing a disaccharide and NSAIDs so as to obtain a liquid mixture of the disaccharide and the NSAIDs.
  • the liquid mixture comprises dissolved disaccharide and dissolved NSAIDs.
  • the examples of solvates for dissolving disaccharide and NSAIDs jointly are already known solutions that are used for manufacturing drug medicine that includes water, distilled water, de-ionized water, Milli Q water, and saline. It is possible to obtain a liquid mixture by mixing NSAIDs solution and disaccharide solution.
  • a liquid mixture by the method that includes dissolving one of powdered NSAIDs and powdered disaccharides to obtain a liquid solution of one ingredient and then dissolving other ingredient into the solution. Further it is possible to obtain a liquid mixture by mixing and dissolving powdered NSAIDs and powdered disaccharides into a liquid. Further it is possible to dissolve NSAIDs into a solvate such as ethanol because NSAIDs has less solubility and make such NSAIDs to be dissolved and then disaccharides are dissolved into the solution to obtain the mixed solution.
  • the example of the weight rate of NSAIDs and disaccharides in the mixed solution is 1 ⁇ 10 2 :1 ⁇ 1:1 ⁇ 10 2 , preferably is 1 ⁇ 10:1 ⁇ 1:5 ⁇ 10 and more preferably is 1:1 ⁇ 1:1 ⁇ 30.
  • the example of the concentration of disaccharide in the mixed solution in manufacturing the Medical Drugs of the invention is 1 ⁇ 10 ⁇ 2 ⁇ 5 ⁇ 10 wt %, preferably is 1 ⁇ 10 0 ⁇ 4.5 ⁇ 10 wt % and more preferably is 1 ⁇ 10 ⁇ 4 ⁇ 10 wt %.
  • the step of lyophilization is a step of sublimating water from the freeze sample under decompression circumstance.
  • the step of lyophilization may have following steps.
  • the method of lyophilization of the above freezes the sample at low temperature and sublimates water (ice) under high vacuum.
  • the lyophilized compound of the invention may be manufactured in accordance with the above described protocol. However, the method of lyophilization is not limited to the above protocol and the skilled person may alter the parameters that include temperatures, pressures, and duration times of each of steps.
  • the method of Granulating and Spray Drying is a method for obtain dried granules by contacting hot wind to the samples that include moiety with moving the samples.
  • the step of Granulating and Spray Drying is attained by means of already known Granulating and Spray Drying apparatus.
  • the drug medicine of the invention may be manufactured in accordance with the following steps.
  • pre drying step (1) pre drying the sample by attaching hot wind of 50 to 100 degrees C. with 1 to 2 m/s speed for 10 to 30 minutes to the sample with stirring the sample (mixed solution) (pre drying step); (2) granulating the sample by attaching hot wind of 20 to 50 degrees C. with 2 to 3 m/s speed for 30 minutes to 1 hour to the sample (granulating step); (3) drying the sample by attaching hot wind of 50 to 100 degrees C. with 1 to 2 m/s speed for 30 minutes to 2 hours to the sample (drying step); and (4) cooling the sample by attaching cool wind of 5 to 20 degrees C. with 1 to 2 m/s speed for 10 minutes to 60 minutes to the sample (cooling step).
  • the method of Granulating and Spray Drying obtain granules by attaching hot wind to the sample so as to dry the sample with the sample floating in the air.
  • the drug medicine of the invention may be manufactured in accordance with the above described protocol.
  • the method of Granulating and Spray Drying is not limited to the above protocol and the skilled person may alter the parameters that include temperatures, pressures, and duration times of each of steps.
  • the examples of the form of the Medical Drugs of the invention when the Medical Drugs is manufactured by means of the method of Granulating and Spray Drying are tablets, granules, or capsules. It is possible to manufacture tablets, granules, or capsules by compacting Medical Drugs using conventional compacting method, in which the Medical Drugs are manufactured by wet granulating method. It is possible to obtain capsule drug medicine by filling tablets or granules into the capsule.
  • the volume of the each of the drug medicine is not limited but it is possible to adjust the volume based on the amount of disaccharides and NSAIDs.
  • the disaccharides and NSAIDs are attached by means of molecular interactions by dissolving disaccharides and NSAIDs jointly, drying the dissolved disaccharides and NSAIDs and forming them into tablets, granules or capsules.
  • Such forms of Medical Drugs bring high alleviative effect for damage of gastrointestinal mucosal induced NSAIDs. Thus the above described forms of the Medical Drugs are preferred.
  • the step of spray drying is a step of drying object quickly by spraying liquid samples with heated wind though narrow nozzle such that the samples become minute drops in the chamber. It is possible to manufacture the spray dried object by means of a conventional spray dryer. It is possible to manufacture the Medical Drugs of the invention using the following steps.
  • the method of spray drying is the method for drying and granulating samples by contacting heated wind to the minute drops that are made by spraying the sample into high temperature chamber. It is possible to manufacture the Medical Drugs of the invention by means of the above method. However the invention is not limited to the Medical Drugs manufactured the above method. It is possible for the skilled person to adjust the parameters that include temperature and duration time for each step.
  • the step of crushing after drying for granulation is a step for manufacturing granules by crushing dried samples that contained moiety. It is possible to manufacture the Medical Drugs of the invention is based on the following steps.
  • the method of Crushing after drying for granulation is a method for manufacturing a powders with predetermined size by crashing lump of samples. It is possible to manufacture the Medical Drugs of the invention by means of the above method. However the invention is not limited to the Medical Drugs manufactured the above method. It is possible for the skilled person to adjust the parameters that include temperature and duration time for each step.
  • the apparatus for dissolving and mixing is already known. It is possible to use such conventional apparatus to execute the dissolving and mixing step.
  • the example of apparatus for executing the dissolving and mixing step is a satirizing apparatus. It is possible to obtain crystal of molecular compound by stirring mixed solution of disaccharide and NSAIDs at the temperature that is higher than the melting point of disaccharide and NSAIDs and by executing static crystallization after the stirring for predetermined time. It is possible to obtain molecular compound with high purity by repeating the processes of melting, stirring and executing static crystallization.
  • the melting and mixing step is executed under an anaerobic condition. More specifically, the melting and mixing step is executed under the existence of nitrogen gas or inert gas.
  • the examples of the inert gas are noble gases and the examples of the novel gases are helium, neon, argon, and krypton. Within the noble gasses, argon is most preferred.
  • the melting and mixing step is executed under atmospheric pressure, reduced pressure and high pressure. It is possible to use conventional catalyst at the melting and mixing step.
  • the bicrystal furnace is an apparatus that can control the boundary at which seed crystals contact (grain boundary) and grow the seed crystals by melting contacted part of ingredients crystals and moving the cast.
  • the method of contact melting is the method that comprises crashing crystals of disaccharide and NSAIDs continuously for a long period, locally dissolving contacted points of crystals and growing the molecular compound of disaccharide and NSAIDs.
  • the Medical Drugs of the invention manufactured as described the above has effects of anti-inflammatory, analgesic, and antipyretic of NSAIDs.
  • the Medical Drugs of the invention which comprises disaccharide and NSAIDs can alleviate damage of gastrointestinal mucosal induced by NSAID and thus it is possible to be used for the patients whom NSAIDs are effective to cure or prevent diseases to take an effective amount of the Medical Drugs of the invention.
  • the present invention provides a method for treatment or prevent method which include a step of giving a Medical Drugs which reduce damage of gastrointestinal mucosal induced by NSAIDs to an object.
  • the object may be a human.
  • the preferred example of the Medical Drugs which reduce damage of gastrointestinal mucosal induced by NSAIDs that comprises disaccharide and NSAIDs with molecular interactions are the Medical Drugs which is manufactured by a step of lyophilization or a step of wet granulating.
  • NSAIDs usually have stimulated taste such as sour taste and bitter taste and thus the taste of NSAIDs is not suitable for oral doses.
  • the Medical Drugs of the invention comprises disaccharide as well as NSAIDs in which disaccharide and NSAIDs have molecular interactions.
  • the disaccharide softens the taste of NSAIDs.
  • the Medical Drugs of tablet form, especially of granules, is easy to take. Further anti-oxidant effect of disaccharide strengthens the chemical stability of NSAIDs.
  • the Medical Drugs manufactured by the above method is mainly used for oral doses. However it is possible to use the Medical Drugs of the invention to non oral doses.
  • the Medical Drugs of the invention When the Medical Drugs of the invention is used as an oral dose, the patient shall take the Medical Drugs together with a pharmaceutically acceptable solution such as water.
  • a pharmaceutically acceptable solution such as water.
  • the example of non oral dose is syringe.
  • the Medical Drugs of the invention is given by means of syringe, the Medical Drugs should be dissolve into a predetermined pharmaceutically acceptable solvent such that the solution contains predetermined concentrate.
  • the examples of the pharmaceutically acceptable solvent are water for injection, saline solution, and glucose solution.
  • the amount of dose varies in accordance with the kind of patient, the age of patient and symptoms.
  • the daily dose is from 10 mg to 1000 mg, preferably from 100 mg to 500 mg, of NSAIDs as a part of an active ingredient. It is possible to give the Medical Drugs of the invention twice to five times a day. By giving the medical Drug separately to several times it is possible to escape drastic change of concentrate of the Medical Drugs in blood and it is possible to prevent side effect and reduce load to the patient.
  • a preferred working example of the invention is to provide a use of disaccharide and NSAIDs in manufacturing a Medical Drugs which reduce damage of gastrointestinal mucosal induced by NSAIDs. Further the present invention provide a use of disaccharide and NSAIDs that have intermolecular bonding for manufacturing a Medical Drugs which reduce damage of gastrointestinal mucosal induced by NSAID.
  • a preferred example of the disaccharide and NSAIDs that have intermolecular bonding are those manufactured by the methods of lyophilization or wet granules. It is possible to use the above explained one or more kinds of NSAIDs.
  • aspirin, indomethacin, ibuprofen, and sodium diclofenac were used as NSAIDs.
  • Trehalose was dissolved in milli Q water so as to obtain 30% (w/v) trehalose solution
  • 1.0 g of each of NSAIDs was dissolved in 2.0 mL ethyl alcohol.
  • (3) Suitable amount of trehalose solutions were added to the ethyl alcohol solutions in which each of NSAIDs was dissolved.
  • indomethacin and ibuprofen solution brings precipitation if all of the trehalose solution required were to be added.
  • maximum amount of trehalose solutions which were not bring precipitation were added and then the mixed solutions were stirred for about 10 to 20 minutes.
  • Milli Q water was added so that the final concentrate of ethyl alcohol to be less than 10%, preferably less than 5%.
  • aspirin and sodium diclofenac it was not found precipitation.
  • each of the solutions of and sodium diclofenac was stirred for about 10 to 20 minutes.
  • the mixed solutions were dried for more than 48 hours by means of a lyophilizing apparatus (Tokyo Rika Co., EYELA, lyophilizing apparatus, FDU-1100).
  • test substances were adjusted by suspending or dissolving them into 0.5% CMC.Na solution.
  • Each of 9 mL of Liquid doses was given per 1 kg weight by oral dose. 0.5% CMC.Na solutions were given to control group.
  • the rats were kept fasting and test substances were fed though mouse. After 5 hours passed, these rats were killed by carbon dioxide gas and stomachs were picked up. The duodenums were tagged. 6 mL of neutral formalin was poured from the esophagi so as to fix the stomachs for 30 minutes. The stomachs were cut along with the greater curvature. The cut stomachs were gently washed by saline, the presence of blood spot were observed by a stereoscopic microscope. The area of blood spots was measured by 0.5 mm ⁇ 0.5 mm unit as an index of ulcer and the sum of each animal was calculated. The rate of suppressed ulcer was calculated, using the ulcer index for the group in which each of test sample was given and the group in which trehalose was also given, in accordance with the following equation.
  • Rate of suppressed ulcer(%) [1 ⁇ A/B ] ⁇ 100
  • FIG. 1 is a graph, which is a substitute of a drawing, which shows ulcer index (mm2) when test substances are administered.
  • the horizontal axis of FIG. 1 indicates that the tested substances that were administered.
  • the vertical axis of FIG. 1 indicates the area of ulcer. The result shows that, for all of NSAIDs, when lyophilized NSAIDs as well as trehalose were administered have a tendency to suppress the generation of ulcer compared to NSAIDs alone were administered.
  • the stomach ulcer model induced by indomethacin was examined.
  • indomethacin alone (30 mg/kg) was administered ulcer of 4.83 ⁇ 0.90 (average of 10 cases ⁇ standard deviation) mm 2 was observed.
  • lyophilized indomethacin and trehalose (30 mg/kg of indomethacin and 800 mg/kg of trehalose) was administered 2.98 ⁇ 0.90 (average of 10 cases ⁇ standard deviation) mm 2 was observed.
  • the rate of suppressed ulcer caused by lyophilizing was 38.8%.
  • the stomach ulcer model induced by ibuprofen was examined.
  • ibuprofen alone 400 mg/kg
  • trehalose 400 mg/kg of ibuprofen and 800 mg/kg of trehalose
  • 1.90 ⁇ 0.69 average of 5 cases ⁇ standard deviation
  • the stomach ulcer model induced by aspirin was examined.
  • aspirin alone 200 mg/kg
  • trehalose 200 mg/kg of aspirin and 800 mg/kg of trehalose
  • 3.00 ⁇ 1.20 average of 5 cases ⁇ standard deviation
  • the stomach ulcer model induced by diclofenac was examined.
  • diclofenac alone 40 mg/kg
  • trehalose 40 mg/kg of diclofenac and 800 mg/kg of trehalose
  • 1.65 ⁇ 0.43 average of 10 cases ⁇ standard deviation
  • the working example 1 shows that by using lyophilized NSAIDs and trehalose, it is possible to suppress ulcer.
  • indomethacin, aspirin and sodium diclofenac were used as NSAIDs.
  • indomethacin from Wako Pure Chemical Industries and bought sodium diclofenac from Cayman Inc.
  • trehalose manufactured by Hayashibara and used Sodium carboxy methyl cellulose manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd.
  • the liquid doses were prepared on the date when the examination was executed. Weighted NSAIDs were suspended or dissolved into 0.5% CMC.Na solution to prepare doses of administrating NSAIDs only. Suspension of NSAIDs and solution of trehalose were prepared. Then the same amount of the suspension and solution were mixed to prepare the dosed of mixture of trehalose and NSAIDs just before administrating them. Predetermined amount of lyophilized compounds that contains lyophilized trehalose and NSAIDs with predetermined rate were weighted and each of them was mixed with 0.5% CMC.Na solution to prepare doses of lyophilized trehalose and NSAIDs. For each groups the amount of dose was 8 mL per kg or rat.
  • the rats were kept fasting and test substances were fed though mouse. After 5 hours passed, these rats were killed by carbon dioxide gas and stomachs were picked up. The duodenums were tagged. 6 mL of neutral formalin were poured from the esophagi so as to fix the stomachs for 30 minutes. The stomachs were cut along with the greater curvature. The cut stomachs were gently washed by saline, the presence of blood spot were observed by a stereoscopic microscope.
  • Rate of suppressed ulcer(%) [1 ⁇ A/B] ⁇ 100
  • ulcer index mm 2
  • indomethacin, aspirin, or diclofenac was administered are shown in FIG. 2 , FIG. 3 and FIG. 4 .
  • FIG. 2 is a graph, which is a substitute of a drawing, which shows a rat ulcer index (mm 2 ) when indomethacin alone, a mixture of indomethacin and trehalose and lyophilized indomethacin and trehalose are administered.
  • the horizontal axis of the FIG. 2 indicates tested substances.
  • the vertical axis of the FIG. 2 indicates ulcer area.
  • FIG. 3 is a graph, which is a substitute of a drawing, which shows a rat ulcer index (mm 2 ) when aspirin alone, a mixture of aspirin and trehalose and lyophilized aspirin and trehalose are administered.
  • the horizontal axis of the FIG. 3 indicates tested substances.
  • the vertical axis of the FIG. 3 indicates ulcer area.
  • the mark * indicates that there is effective difference.
  • FIG. 4 is a graph, which is a substitute of a drawing, which shows a rat ulcer index (mm 2 ) when diclofenac alone, a mixture of diclofenac and trehalose and lyophilized diclofenac and trehalose are administered.
  • the horizontal axis of the FIG. 4 indicates tested substances.
  • the vertical axis of the FIG. 4 indicates ulcer area.
  • p indicates a rejection rate.
  • the working example 2 shows that lyophilized NSAIDs and trehalose can effectively suppress ulcer.
  • the medium that comprised 1 mM diclofenac or the medium that comprised 1 mM diclofenac and 5% trehalose were added separately to the medium; in FIG. 5 , the which is described as “Mix”) were added to the 9 to 22 cells of Ca, which are different from those described above. All of the cells were incubated for 16 hours and cell viability and cell lethality were measured by means of LIVE/DEAD Assay (Molecular Probes). We also analyzed for the cells incubated by the usual medium as a control.
  • the number of samples, N were 4 to 6.
  • the result is shown in the FIG. 5 .
  • FIG. 5 is a graph, which is a substitute of a drawing, which shows an effect for gastric mucosal damages with lyophilized state and mixed state.
  • FIG. 5A is a graph, which is a substitute of a drawing, which shows cell viability rate. The vertical axis of the FIG. 5A indicates cell viability [%] and higher value means more cells are alive.
  • FIG. 5B is a graph, which is a substitute of a drawing, which shows cell lethality rate. The vertical axis of the FIG. 5B indicates cell lethality [%] and higher value means more cells have been dead. Thus high cell viability and low cell lethality indicate that cell disorder induced by diclofenac is suppressed.
  • FIG. 5 shows that the mixed sample that was merely mixed with solutions (“Mix” in FIG. 5 ) had the effect of trehalose to suppress cell disorder induced by the diclofenac. However, lyophilized sample (“Lyo” in FIG. 5 ) shows more effect of suppressing cell disorder induced by the diclofenac.
  • DSC Differential Scanning Calorimetry
  • FIGS. 6 to 11 indicates the result of DSC measurement.
  • FIG. 6 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone, indomethacin alone, a mixture of indomethacin and trehalose and lyophilized indomethacin.
  • FIG. 7 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone, ibuprofen alone, a mixture of ibuprofen and trehalose and lyophilized ibuprofen.
  • FIG. 6 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone, indomethacin alone, a mixture of indomethacin and trehalose and lyophilized indomethacin.
  • FIG. 6 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone
  • FIG. 8 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone, aspirin alone, a mixture of aspirin and trehalose and lyophilized aspirin.
  • FIG. 9 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone, diclofenac alone, a mixture of diclofenac and trehalose and lyophilized diclofenac.
  • FIG. 10 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone, piroxicam alone, a mixture of piroxicam and trehalose and lyophilized piroxicam.
  • FIG. 11 is a graph, which is a substitute of a drawing, which shows the result of DSC of torehalose alone, Mefenamic acidic alone, a mixture of Mefenamic acidic and trehalose and lyophilized Mefenamic acidic.
  • the term “Mixture” means DSC curve for the mixture of trehalose and NSAIDs.
  • the term “lyophilize” means DSC curve for the lyophilized trehalose and NSAIDs.
  • the vertical axis indicates heat flow per mole [W/mol] for trehalose alone or NSAIDs alone.
  • the vertical axis indicates heat flow per one mole of trehalose [W/mol] for the mixture and the lyophilized compound.
  • the horizontal axis indicates temperature (degrees C.).
  • the peaks of the mixture of NSAIDs and trehalose are similar to the sum of the peaks of NSAIDs alone and the peaks of trehalose alone.
  • the peak which is around 120 degrees C. and derives from trehalose is extinguished or is shifted to low temperature direction or high temperature direction.
  • the result shown in FIG. 6 indicates that the mixture of indomethacin and trehalose had the first peak at the region of 98 to 102 degrees C., the second peak at the region of 190 to 210 degrees C. and the third peak at the region of 115 to 125 degrees C.
  • the first peak means the highest peak (the largest peak of absolute value of DSC measured value) in a DSC curve.
  • the result of the mixture almost coincides with the peaks of DSC curve of trehalose alone.
  • the DSC curve of the lyophilized indomethacin and trehalose had the first peak at the region of 80 to 95 degrees C. and the second peak at the region of 260 to 270 degrees C.
  • the DSC curve of the lyophilized indomethacin and trehalose further had the third peak at the range of 270 to 280 degrees C.
  • the result shown in FIG. 7 indicates that the mixture of ibuprofen and trehalose had the first peak at the region of 98 to 102 degrees C., the second peak at the region of 70 to 80 degrees C., the third peak at the region of 190 to 210 degrees C. and the fourth peak at the region of 115 to 125 degrees C.
  • the result of the mixture almost coincides with the peaks of DSC curves of trehalose alone and ibuprofen alone.
  • the DSC curve of the lyophilized ibuprofen and trehalose had the first peak at the region of 98 to 102 degrees C. and the second peak at the region of 70 to 80 degrees C., the third peak at the range of 175 to 190 degrees C. and the fourth peak at the region of 130 to 145 degrees C.
  • the peaks of at the range of 175 to 190 degrees C. and at the region of 130 to 145 degrees C. were not found in the DSC curve of the mixture.
  • the intermolecular compound of ibuprofen and trehalose was generated by lyophilizing the mixed solution after ibuprofen and trehalose were dissolved jointly.
  • the result shown in FIG. 8 indicates that the mixture of aspirin and trehalose had the first peak at the region of 145 to 150 degrees C. and the second peak at the region of 98 to 102 degrees C.
  • the DSC curve of the lyophilized aspirin and trehalose had the first peak at the region of 110 to 120 degrees C. and the second peak at the region of 135 to 145 degrees C.
  • the differences of the positions of peaks between the mixture and the lyophilized compound indicate that the intermolecular compound of aspirin and trehalose was generated by lyophilizing the mixed solution after aspirin and trehalose were dissolved jointly.
  • the result shown in FIG. 9 indicates that the mixture of sodium diclofenac and trehalose had the first peak at the region of 95 to 110 degrees C. and the second peak at the region of 190 to 220 degrees C.
  • the DSC curve of the lyophilized sodium diclofenac and trehalose had the first peak at the region of 90 to 100 degrees C. and the second peak at the region of 135 to 145 degrees C.
  • the differences of the positions of peaks between the mixture and the lyophilized compound indicate that the intermolecular compound of sodium diclofenac and trehalose was generated by lyophilizing the mixed solution after sodium diclofenac and trehalose were dissolved jointly.
  • the result shown in FIG. 10 indicates that the mixture of Mefenamic acidic and trehalose had the first peak at the region of 98 to 102 degrees C., the second peak at the region of 225 to 235 degrees C. and the third peak at the region of 190 to 210 degrees C.
  • the DSC curve of the lyophilized Mefenamic acidic and trehalose had the first peak at the region of 225 to 235 degrees C. and the second peak at the region of 90 to 110 degrees C.
  • the absolute values of peak top of the first peak and the second peak of the lyophilized compound are larger than the peaks at the regions of 225 to 235 and 90 to 110 degrees C. for Mefenamic acidic alone.
  • the result shown in FIG. 11 indicates that the mixture of piroxicam and trehalose had the first peak at the region of 98 to 102 degrees C., the second peak at the region of 225 to 235 degrees C. and the third peak at the region of 190 to 210 degrees C.
  • the DSC curve of the lyophilized piroxicam and trehalose had the first peak at the region of 90 to 105 degrees C. and the second peak at the region of 195 to 205 degrees C.
  • the absolute values of peak top of the first peak and the second peak of the lyophilized compound are larger than the peaks at the regions of 90 to 105 degrees C. and 195 to 205 degrees C.
  • the peaks of the mixture of NSAIDs and trehalose are similar to the sum of the peaks of NSAIDs alone and the peaks of trehalose alone.
  • the peak which is around 120 degrees C. and derives from trehalose is extinguished or is shifted to low temperature direction or high temperature direction.
  • the Medical Drugs that comprises trehalose and NSAIDs that have molecular interactions between them, thereby it can alleviate damage of gastrointestinal mucosal induced by NSAIDs, such as disorder of gastric mucosa induced by NSAIDs.
  • the Medical Drugs of the invention reduce damage of gastrointestinal mucosal induced by NSAIDs.
  • Ulcer area was measured by the same conditions in working example 2 except for replacing trehalose with maltose, sucrose, or lactose.
  • the obtained ulcer area is shown in FIG. 12 .
  • Aspirin effectively suppress ulcer by forming molecular compound of aspirin with disaccharide.
  • Ulcer area was measured by the same conditions in working example 2 except for replacing trehalose with maltose, or lactose.
  • the obtained ulcer area is shown in FIG. 13 .
  • diclofenac effectively suppress ulcer by forming molecular compound of diclofenac with disaccharide.
  • the present invention may be used in medical industry.

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