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WO2003026699A1 - Compositions medicinales favorisant l'absorption de medicaments - Google Patents

Compositions medicinales favorisant l'absorption de medicaments Download PDF

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Publication number
WO2003026699A1
WO2003026699A1 PCT/JP2002/009829 JP0209829W WO03026699A1 WO 2003026699 A1 WO2003026699 A1 WO 2003026699A1 JP 0209829 W JP0209829 W JP 0209829W WO 03026699 A1 WO03026699 A1 WO 03026699A1
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Prior art keywords
drug
absorption
pharmaceutical composition
solution
mucosa
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English (en)
Japanese (ja)
Inventor
Takeo Kitazawa
Mitsunori Harada
Yuji Horikiri
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Tanabe Pharma Corp
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Tanabe Seiyaku Co Ltd
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Publication of WO2003026699A1 publication Critical patent/WO2003026699A1/fr
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    • 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

Definitions

  • the present invention relates to a pharmaceutical composition that promotes the absorption of a drug, and more specifically, a drug such as a biologically active peptide, and a nonionic liquid containing one or more mucolytic agents selected from cysteine derivatives and alcohols containing an active SH group.
  • a pharmaceutical composition containing one or more surfactants, which promotes drug absorption in a mucous membrane.
  • the present invention also provides a composition for promoting absorption of a drug such as a bioactive peptide and a method for promoting the absorption of a drug, comprising a combination of at least one kind of the mucolytic agent and at least one kind of nonionic surfactant. Things. Background art
  • Bioactive peptides such as hormones and cytokins play important roles in vivo, and bioactive peptides themselves can be mass-produced and used as pharmaceuticals, and bioactive peptides can be produced by genetic engineering and protein synthesis. Structural changes and modifications are increasingly used as pharmaceuticals.
  • peptide drugs when administered orally, may be decomposed by digestive juices and enzymes in the gastrointestinal tract and the wall of the gastrointestinal tract. After passing through, there is a risk of being broken down in the liver because it circulates throughout the body (first-pass effect by the liver), and peptide drugs with high hydrophilicity are macromolecules and highly polar, so they pass through the gastrointestinal mucosa. Has the problem that it is usually hardly absorbed. For this reason, in order to obtain sufficient drug efficacy, peptide drugs are usually introduced into the blood circulation intradermally, intramuscularly or directly in the form of injection instead of oral administration. Administration with agents requires hospital visits and is painful, so forms that can be administered at home and painlessly are desired.
  • peptide drugs are usually mostly released from mucous membranes such as the nasal mucosa as well as the gastrointestinal mucosa.
  • Various methods have been studied to promote drug absorption from the mucous membranes such as the gastrointestinal mucosa and the nasal mucosa. For example, a method for improving nasal absorption using cyclodextrin (Japanese Patent Application Laid-Open —189-1118), a method for improving the nasal absorption of human parathyroid hormone (hPTH) and calcitonin using ionic and nonionic surfactants (Japanese Patent Application Laid-Open No. No.
  • a biologically active polypeptide was combined with polyoxyethylene alkylphenyl ether as an absorption enhancer and N-acylamino acids, cholic acids, pectins, taurine, saccharin, glycyrrhizic acid, aspartame, etc.
  • High-absorbing vaginal drugs are also known (Patent No. 2911 496).
  • N-acyl amino acids N_n-hexanoylglycine, N-n-octanoy Only non-sulfur-containing amino acids such as luglycine, N-n-decanoylglycine and Nn-dodecanoylglycine are used.
  • An object of the present invention is to provide a pharmaceutical composition in which absorption of a poorly absorbable hydrophilic drug such as a bioactive peptide from mucous membrane is promoted.
  • the present invention also provides a composition capable of promoting the absorption of such a hydrophilic poorly-absorbable drug from the mucous membrane and a method for promoting the absorption of the drug. The purpose is to do.
  • the present inventors have studied various additives in order to find a means for solving the above-mentioned problems, and as a result, have found that one or more mucolytic agents selected from cysteine derivatives and alcohols containing an active SH group, The present inventors have found that the absorption of a drug from mucous membrane is remarkably promoted by combining one or more nonionic surfactants, thereby completing the present invention.
  • Fig. 1 shows rat plasma in the jejunum administration using mucolytic agent (NAC) and nonionic surfactant (Triton X-100) alone or in combination.
  • NAC mucolytic agent
  • Triton X-100 nonionic surfactant
  • FIG. 5 is a graph showing the time course of F ITC-dextran (FD-4) concentration.
  • Figure 2 shows the time of FD_4 concentration in rat plasma during intrajejunal administration when applied in the form of a cap-type patch device using a combination of 5% Triton X-100 and various concentrations of NAC. It is a Darafu showing a dynamic transition.
  • Figure 3 shows the time course of FD_4 concentration in rat plasma during intrajejunal administration when applied in the form of a cap-type patch device using a combination of 5% NAC and various concentrations of Triton X-100.
  • Fig. 4 shows the time course of FD-4 concentration in rat plasma after intrajejunal administration when NAC and Triton X-100 were used at the same concentrations shown in the figure and applied in the form of a cap-type patch device. It is a graph.
  • FIG. 5 is a graph showing the time course of FD-4 concentration in rat plasma after intranasal administration when a combination of 5% NAC and 5% Triton X-100 was used.
  • FIG. 6 is a graph showing the time course of FD-4 concentration in rat plasma after pulmonary administration when a combination of 5% NAC and 5% Triton X-100 was used.
  • FIG. 7 is a graph showing the time course of the concentration of FD-4 in rat plasma after intrathecal administration when a combination of 5% NAC and 5% Triton X-100 was used.
  • FIG. 5 is a graph showing the time course of FD-4 concentration in rat plasma after intranasal administration when a combination of 5% NAC and 5% Triton X-100 was used.
  • FIG. 6 is a graph showing the time course of FD-4 concentration in rat plasma after pulmonary administration when a combination of 5% NAC and 5% Triton X-100 was used.
  • FIG. 7 is
  • FIG 8 is a graph showing the time course of FD-4 concentration in rat plasma after intrajejunal administration when a combination of Triton X-100 and various cysteine derivatives, 1,4-dithiothreitol was used.
  • Figure 9 shows the time course of FD_10 concentration in rat plasma after intrajejunal administration using a combination of 5% NAC and 5% Triton X-100 for a drug with a higher molecular weight. It is a graph.
  • Fig. 10 shows the time course of SCT concentration in rat plasma after intrajejunal administration when peptide drugs (SCT) were used as drugs and NAC and Triton X-100 were used alone or in combination. It is a graph.
  • SCT peptide drugs
  • FIG. 11 is a graph showing a comparison of intravenous administration of plasma desmopressin concentration in jejunal administration when a peptide drug (desmopletcin) was used as a drug and administered to beagle dogs in the form of a cap-type patch device.
  • a peptide drug desmopletcin
  • FIG. 12 is a graph showing the time course of FD_4 concentration in rat plasma when a combination of NAC and Triton X-100 was used in the jejunum in the form of a pellet.
  • FIG. 13 is a graph showing the time course of the concentration of FD-4 in rat plasma after intranasal administration when a combination of 5% NAC and 5% BL-25 was used.
  • Fig. 14 is a graph showing the temporal transition of SCT concentration in rat plasma during intranasal administration when a peptide drug (SCT) was used as the drug and a combination of 1 ⁇ 80 and 8-125 was used. It is.
  • SCT peptide drug
  • FIG. 15 shows the concentration of FD-4 in rat plasma after intrajejunal administration using the combination of NAC and Triton X_100 of the present invention, using the combination of NAC and a known absorption enhancer! / It is the graph which compared with the case where it did.
  • the present invention relates to a mucosa containing one or more mucolytic agents selected from a cysteine derivative and an alcohol containing an active SH group and one or more nonionic surfactants, together with a drug.
  • a pharmaceutical composition that promotes drug absorption.
  • the present invention also provides a composition for promoting absorption of a drug from mucous membranes containing one or more of the mucolytic agents and one or more of a nonionic surfactant.
  • the present invention further relates to the use of a combination of one or more of the mucolytic agents and one or more of the nonionic surfactants in combination with drug administration. A method of promoting absorption of a drug from mucosa by administering the combination.
  • the cysteine derivative used in the present invention for example, N- Asechirushisute like in the N- (C 2 ⁇ 5 Arukanoiru) cysteine, S- methyl cis Ting, S- E Chirushisutin etc. S- (C 4 alkyl) cysteine, S- carboxymethyl sheet Sutin etc. S - (C 2 ⁇ 5 carboxyalkyl) cysteine and the like.
  • Cysteine derivatives also include cysteine-containing peptides, and include, for example, one kind of daltathiones of triptides.
  • Examples of Darutachion such, in addition to glutathione, glutathione C WINCH 8 alkyl ester Honoré glutathione E Sutenore such as (see US Patent No. 4, 784, 685 issue) and the like.
  • cysteines in these cysteine derivatives include DL-form, L-form and D-form, but L-cysteine is particularly preferable.
  • the active SH group-containing alcohol, an active SH group-containing alcohol of C 3 ⁇ 6, the yo Ri specifically include 1, 4 one Jisureitoru.
  • nonionic surfactant a surfactant having a small protein denaturation and excellent membrane solubilizing ability is preferable.
  • non-ionic surfactants Poriokishe styrene one C 1C ⁇ 14 alkyl ethers, polyoxyethylene one (C 6. Alkyl one Hue) yl ether, ⁇ 6. Alkyl-glucose ether and N- (Ce ⁇ .alkyl) -rubumoyl-C ⁇ 4 alkyl-glucose ether.
  • alkyl-pheninole ether those having a polyoxyethylene portion in the range of 65 to 90% by weight of the whole are preferable, and specifically, polyoxyethylene monolauryl ether having an average molecular weight of 560 to 1300 (for example, BL-9: polyoxyethylene (9) lauryl ether; BL-25: polyoxyethylene (25) lauryl ether); polyoxyethylene octyl phenyl ether having an average molecular weight of 600 to 800, especially an average molecular weight of 600 to 800 Polyoxyethylene-tert-octylphenyl ether having a value of 800 (for example, Triton X-100: polyoxyethylene (9_10) p-tert-octylphenyl ether, triton X-102: polyoxyethylene (12-13 ) p-tert-octinole Polyoxyethylene-nonylphenyl ether having an average molecular weight of 600 to 700, particularly polyoxyethylene-n-no
  • —C alkyl monoglucose ether those having a glucose portion in the range of 50 to 65% by weight of the entirety are preferable, and specifically, 1-O-octyl-13_D—gunolecopyranoside, particularly 1—O—n—octyl-1] 3—D—Gnorecopyranoside; 6—O— (N—heptylcanolebamoyl) methyl-1-a—D—Gnorecopyranoside, especially 6—O— ( N_n-Heptinolecanolebamoinole) methinole a-D-gunolecoviranoside is exemplified.
  • mucolytic agent and non-ionic surfactants ⁇ - (C 2 ⁇ 5 alkanol I le) cysteine, S- ( ⁇ 4 alkyl) cysteine, S- (C 2 ⁇ 5 Karubokishiaru kills) cysteine, cysteine derivative selected from Darutachion acids, or C 3 ⁇ 1 or more mucolytic agent selected from the active SH group-containing alcohol 6 and, polyoxyethylene - C 1 (W4 alkyl ethers, polyoxyethylene one (C e ⁇ .
  • nonionic surfactants selected from alkyl-phenyl) ethers, alkyl-glucose ethers, and N- (Ce.alkyl) -powered alkyl-glucose ethers.
  • the preferred non-ionic surfactant in combination, poly O carboxymethyl ethylene unit content is in the range of overall 6 5-9 0 weight 0/0 Polyoxyethylene - C 1 () ⁇ 14 alkyl ethers or polyoxy Ethylene mono (C 6 ⁇ .alkyl monophenyl) ether, or alkyl glucose ether whose glucose portion is in the range of 50 to 65% by weight or (N-alkyl rubamoinoleanol) -glucose ether And more preferably polyoxyethylene-octyl ether having an average molecular weight of 600 to 800, polyoxyethylene mono-nonyl phenyl ether having an average molecular weight of 600 to 700, and an average molecular weight of 5 Polyoxyethylene monolauryl ether, 60-130, 1-O-octyl- ⁇ -D-gunolecopyranoside, or 6- ⁇ — ( - to Petit) -3,4-methyl- ⁇ - D- Darko Selected from
  • a mucolytic agent More preferred is a mucolytic agent and a nonionic surfactant.
  • Specific examples of the combination include N-acetyl-L-cystine, S-methyl-L-cystine, S-ethyl-L-cystine, and S-carboxymethyl.
  • One or more mucolytic agents selected from L-cysteine or 1,4-dithiothreitol, and polyoxyethylene (9) lauryl ether, polyoxyethylene (25) lauryl ether, polyoxyethylene (9-10) p-tert-octynolepheninoleatenole, polyoxyethylene (12-13) p-tert-octylphenyl ether, polyoxyethylene (10) p-n-noninolephenineoleatene, 1 — O— n—Otatinaci ⁇ -D—Gnoreco Pyranoside and 6-0_ ( ⁇ — ⁇ —Heptylcarbamoinole) methyl _a_D—Nonionic interface selected from dalcoviranoside Ru combination der with one or more sexual agents.
  • polyoxyethylene (9) lauryl ether polyoxyethylene (25) lauryl ether
  • the target drug is not particularly limited, and may be one that is absorbed through the mucous membrane by single administration, or one that is not easily absorbed. If the drug is hardly absorbed, the absorption promoting effect of the present invention is remarkable. appear. Therefore, it is preferable to use a hydrophilic poorly-absorbable drug because a desired absorption promoting effect can be achieved.
  • the term “hardly absorbed” means that if no absorption enhancer is present, it is not absorbed to the extent that a therapeutic effect is exhibited at a normal dose.
  • Such drugs include antibiotics, blood enhancers, treatments for infectious diseases, anti-dementia agents, anti-inoles agents, anti-tumor agents, antipyretics, analgesics, anti-inflammatory agents, anti-ulcer agents, anti-allergic agents, psychotropic agents Drugs used as drugs, inotropic agents, antiarrhythmic agents, vasodilators, antihypertensive agents such as antihypertensive diuretics, antidiabetic agents, anticoagulants, cholesterol lowering agents, osteoporosis agents, hormonal agents, vaccines, etc. Can be These drugs include peptidic drugs and non-peptidic drugs, but peptide drugs are preferred. Even among non-peptidic drugs, polysaccharide drugs such as low-molecular-weight heparin and heparin-like substances are preferable target drugs.
  • the mode of action of the peptidic drug also includes antagonists, agonists, or their soluble receptors and their derivatives.
  • those having a sugar chain include those having different structures.
  • polyethylene It may be modified with a synthetic polymer such as recall or a natural polymer such as hyaluronic acid, or may be modified with any sugar such as galactose or mannose, or a sugar chain or a non-peptidic compound.
  • bioactive peptides such as phospholipids and fatty acids or those which add fat solubility to proteins may be used.
  • These peptide drugs have a molecular weight of 200 to 200,000, preferably a molecular weight of 200 to 500.
  • 00 more preferably has a molecular weight of 200 to 25,000, most preferably has a molecular weight of 200 to: L0000.
  • Preferred peptide drugs include cytodynamics, peptide hormones, growth factors, factors acting on the cardiovascular system, factors acting on the central and peripheral nervous systems, and the like. Specific examples include the following. .
  • Cytokines include interferons (eg, interferon- ⁇ , — ⁇ , -y), interleukins (eg, interleukin-1 to 11), tumor necrosis factor (eg, TNF- ⁇ , ⁇ ⁇ ), Malignant leukemia inhibitory factor (LIF), hematopoietic factor [eg, erythropoietin, thrombopoetin, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), Mactophage colony stimulating factor (M—CSF)].
  • interferons eg, interferon- ⁇ , — ⁇ , -y
  • interleukins eg, interleukin-1 to 11
  • tumor necrosis factor eg, TNF- ⁇ , ⁇ ⁇
  • LIF Malignant leukemia inhibitory factor
  • hematopoietic factor eg, erythropoietin, thrombo
  • Peptide hormones include insulin, growth hormone, gonadotropin, melanocyte stimulating hormone, luteinizing hormone, luteinizing hormone, luteinizing hormone releasing hormone (LH-RH) and its derivatives (goserelin, buserelin, leuprorelin) , Adrenocorticotropic hormone (ACT H), parathyroid hormone (PT II), thyroid stimulating hormone (TSH), thyroid stimulating hormone releasing hormone (TRH) and its derivatives (taltirelin), calcitonin and the like.
  • ACT H Adrenocorticotropic hormone
  • PT II parathyroid hormone
  • TSH thyroid stimulating hormone
  • TRH thyroid stimulating hormone releasing hormone
  • Growth factors include nerve growth factors (eg, NGF, NGF-2 / NT-3), epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF) And transforming growth factor (TGF), platelet-derived cell growth factor (PDGF), hepatocyte growth factor (HGF) and the like.
  • nerve growth factors eg, NGF, NGF-2 / NT-3
  • EGF epidermal growth factor
  • FGF fibroblast growth factor
  • IGF insulin-like growth factor
  • TGF transforming growth factor
  • PDGF platelet-derived cell growth factor
  • HGF hepatocyte growth factor
  • Factors acting on the cardiovascular system include endothelin, endothelin inhibitor, endothelin antagonist, endothelin synthase inhibitor, desmopletsusin, renin, angiotensin I-III, atrial natriuretic peptide (A NP) and the like.
  • Factors acting on the central and peripheral nervous system include enkephalin, endorphin, dino norefine, neoendorphin and the like.
  • peptide drugs include the soluble receptor for polypeptides in their concept.
  • Each of these peptidic drugs may include synthetic polymers such as polyethylene glycol, natural polymers such as chondroitin and polysaccharides, or those chemically modified with non-peptide substances.
  • the non-peptide substance here may be a ligand for a receptor or an antigen for an antibody.
  • the above-mentioned peptide drug may include a plurality of peptides linked by a chemical method or a gene recombination technique.
  • the mixing ratio of the mucolytic agent to the nonionic surfactant in the pharmaceutical composition of the present invention is 1:10 to: I0: 1 (weight ratio, the same applies hereinafter), preferably 1: 5 to 5: 1. Range.
  • the compounding ratio between the drug and the (mucolytic agent + nonionic surfactant) is 1: 100 to 100: 1, preferably 1:50 to 5: 1, and more preferably 1:50 to 1 :. It is in the range of 1.
  • the (mucolytic agent + nonionic surfactant) is applied per 1 cm 2 of the mucosal surface of the application site (does not consider the increase in surface area due to fine irregularities on the mucosal surface) It is preferred that the total amount of both components is 0.1 to 50 mg, preferably 0.5 to 1 Omg.
  • the pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation generally used as a preparation for oral or parenteral administration.
  • solid preparations such as aqueous solution preparations, suppositories, tablets, powders, granules and the like, creams Preparations, ointments and the like.
  • Aqueous solution preparations are prepared by dissolving drugs, mucolytic agents, and nonionic surfactants in water, aqueous alcohol (for example, aqueous solutions of ethanol, glycerin, propylene glycol, and polyethylene glycol), etc., in a conventional manner. Is done.
  • This aqueous solution formulation is particularly preferably in the form of an aqueous solution.
  • the drug concentration in the aqueous solution is 0.001 to 200% (w / v), preferably in the range of 0.01-100% (w / V), more preferably in the range of 0.1 l SOO / w / v, most preferably in the range of 0.2-25% (wZv), the concentration of the mucolytic agent [amount of water ( The amount (g) of the mucolytic agent added to the Is 0.1 to 25% (wZv :), preferably 0.1 to 1 So / oiwZv;), more preferably 0.1 to 10% (w / v;), most preferably 0 to 10% (w / v;).
  • Nonionic surfactant concentration 0.01 to 25% (w / v), preferably 0.1 to 15% (WZV), more preferably 0.1 to 10% (wZv;), most preferably 0.2 to 5% ( ⁇ ⁇ ⁇ ) range.
  • the aqueous solution is adjusted to a pH of about 2-10, preferably 2-9, more preferably 2-8, most preferably 2-7.
  • the pH regulator used in this case include inorganic acids such as hydrochloric acid, boric acid, phosphoric acid, and carbonic acid; citric acid, malic acid, fumaric acid, succinic acid, tartaric acid, maleic acid, glutamic acid, polyglutamic acid, and aspartic acid.
  • Organic acids such as sodium hydroxide, alkali metal hydroxides such as sodium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal carbonates such as sodium hydrogen carbonate and sodium hydrogen carbonate
  • Organic bases such as arginine, polyarginine and lysine;
  • aqueous solution preparation may be, if desired, a water-soluble inorganic salt such as sodium chloride, sodium chloride, magnesium chloride, etc .; And the like.
  • compositions except for incorporating a mucolytic agent and a nonionic surfactant, pharmaceutical additives usually used for the drug used, such as dextran, pullulan, gelatin, serum albumin, polyethylene glycol It can be formulated using excipients such as
  • the combination of the mucolytic agent and the nonionic surfactant includes the coexistence of a drug such as a physiologically active peptide and the mucolytic agent and nonionic surfactant for promoting absorption.
  • a drug such as a physiologically active peptide
  • nonionic surfactant for promoting absorption.
  • aqueous solutions high concentrations of mucolytics and nonionic surfactants
  • a lyophilized preparation containing a mucolytic agent, a nonionic surfactant, and a drug uniformly used as a solid preparation can be prepared, for example, by preparing an aqueous solution preparation in advance and then preparing a ⁇ -shaped preparation having the required shape. And freeze-dried.
  • the pharmaceutical composition of the present invention may contain, if desired, a peptidase inhibitor (aprotinin, gabexate mesinoleate, al_antitrypsin, leupeptin, pepstatin, bestatin, bacitracin, egg white or soybean trypsin). Inhibitors).
  • a peptidase inhibitor aprotinin, gabexate mesinoleate, al_antitrypsin, leupeptin, pepstatin, bestatin, bacitracin, egg white or soybean trypsin.
  • a drug, a mucolytic agent and a nonionic surfactant are used together with an adhesive substance (a gastrointestinal mucoadhesive substance such as a carboxybutyl polymer).
  • the drug delivery layer (formed of a porous substance such as cellulose, gel, or the like) is included in the drug delivery layer, and the drug delivery layer is formed of an adhesion site control layer [methacrylic acid / methyl methacrylate copolymer (Eudragit L), hydroxypropyl cellulose] ⁇ Formed with enteric polymer such as phthalate etc.] and oral administration preparation in the form of being sandwiched between protective layers (formed with water-insoluble polymer such as ethylcellulose, box etc.) to protect the drug in the drug delivery layer ( Preparations described in WO 00/32172).
  • oral administration is preferred, since oral administration such as nasal administration, pulmonary administration, and eye dropping is easy for a user.
  • the drug is applied to the mucosa at the site of application, for example, gastrointestinal mucosa (small intestinal mucosa, ileal mucosa, jejunal mucosa, colon mucosa, rectal mucosa, etc.), nasal mucosa, oral mucosa Absorbed from lung mucosa, ocular mucosa, vaginal mucosa, etc.
  • gastrointestinal mucosa small intestinal mucosa, ileal mucosa, jejunal mucosa, colon mucosa, rectal mucosa, etc.
  • nasal mucosa for example, gastrointestinal mucosa (small intestinal mucosa, ileal mucosa, jejunal mucosa, colon mucosa, rectal mucosa, etc.), nasal mucosa, oral mucosa Absorbed from lung mucosa, ocular mucosa, vaginal mucosa, etc.
  • Preferred absorption sites are the
  • composition for promoting absorption of a drug from mucous membranes comprising a mucolytic agent and a nonionic surfactant. It is prepared in the same manner as the above pharmaceutical composition.
  • the present invention also relates to a method for administering the drug absorption-promoting composition and a drug simultaneously or sequentially or orally or parenterally, or a method wherein the mucolytic agent, the nonionic surfactant and the drug are simultaneously or separately in separate formulations.
  • a method is provided for enhancing absorption from a membrane.
  • the same mucolytic agent and nonionic surfactant as used in the above pharmaceutical composition are used, and the compounding ratio and drug ratio thereof are also the same. Selected from a range.
  • Fluorescein isothiocyanate (FITC)-dextran (average molecular weight 4,400, manufactured by Sigma-Aldrich Co., Ltd .; abbreviated as FD-4) 0. lg of saline for injection (Otsuka Pharmaceutical) 0. lmL (Hereinafter, abbreviated as dextran solution D1).
  • NAC N-acetyl-L-cysteine
  • NAC-Triton X-100 solution NT1 polyoxyethylene (9-10) p-tert-octynolepheninoleateyl
  • Dextran solution D1 and NAC-Triton X-100 solution NT1 were mixed in equal amounts to prepare a dosing solution.
  • NAC solution N1 0.1 g of NAC was dissolved in 1 mL of physiological saline for injection (hereinafter, abbreviated as NAC solution N1).
  • Triton X—100 O.lg was dissolved in 1 mL of physiological saline for injection (hereinafter abbreviated as Triton X—100 solution T1).
  • Equivalent amounts of dextran solution D1 and NAC solution N1 were mixed to obtain Comparative Solution 1
  • dextran solution D1 and Triton X-100 solution T1 were mixed in equal amounts to obtain Comparative Solution 2.
  • the dextran solution D 1 and physiological saline for injection were mixed in equal amounts to obtain Comparative Solution 3.
  • Wistar male rats (6 weeks old, Japan SLC) were acclimated for 1 week under the conditions of 12 hours illumination, room temperature, 23 soils, 2 ° C, free water and feeding. After that, about 20 hours before the experiment After fasting and anesthetizing with pentobarbital (5 Omg / kg, Nacalai), the administration solution prepared in (1) and the comparative solutions 1 to 3 were each injected into the rat jejunum using a micro syringe (manufactured by Ito Seisakusho). 20 L (FD-4 dose: 10 mg / rat).
  • FD-4 FITC-dextran
  • NAC NAC
  • Triton X-100 were dissolved in physiological saline for injection (Otsuka Pharmaceutical Co., Ltd.) to the concentrations shown in Table 1 below.
  • Wistar male rats (6-7 weeks old, Japan SLC) were illuminated for 12 hours at room temperature.
  • the animals were acclimated for 1 week under conditions of ⁇ 2 ° C, free water supply and feeding. Thereafter, they were fasted for about 20 hours before the experiment, anesthetized with pentobarbital (5 OmgZkg, manufactured by Nacalai), laparotomy was performed, and a bile duct was inserted into the bile duct to release bile outside the body.
  • pentobarbital 5 OmgZkg, manufactured by Nacalai
  • laparotomy was performed, and a bile duct was inserted into the bile duct to release bile outside the body.
  • jejunum The jejunal mucosa is lightly washed with about ImL of physiological saline, the water is wiped off, and the cap-type application device prepared in (1) is attached to the jejunal mucosa one per rat.
  • the cap-type application device prepared in (1) is attached to the jejunal mucosa one per rat.
  • Example 1 (1) To the rats that had undergone surgery, the administration solution of Example 1 (1) and the comparative solution 3 (control) were directly injected into the nasal cavity with a micropipette, 5 ⁇ L each (one type per rat). (FD-4 dose: 2.5 mg / rat).
  • the rat is fixed on its back, an incision is made in the neck on the abdominal side to expose the trachea, and a cut is made between the fourth and fifth C-shaped cartilage rings from the thyroid cartilage of the trachea and the cut is made.
  • a 25 mm polyethylene tube (1.5 mm, 2.5 mm in diameter) was inserted into the trachea as a tracheal force neuron by 6 mm and fixed with sutures.
  • Example 1 (1) and the comparative solution 3 (control jar) heated to 37 ° C. were each 5 ⁇ L from a microsyringe (one type per rat). It was administered in the lung (FD-4 dose: S. SmgZ rat).
  • the administration was performed for about 1 second.
  • the rat was left as it was for 15 seconds, the syringe was removed, and the rat was laid at an angle of about 10 ° (with the head high) from 45 seconds after the administration until the end of the experiment.
  • the angle of about 10 ° (with the head high) from 45 seconds after the administration until the end of the experiment.
  • FD-4 concentration in rat plasma was calculated in the same manner as in Example 1 (2) to calculate the FD-4 concentration in rat plasma.
  • Fig. 6 shows the time course of the concentration of FD-4 in the plasma. In the figure, points indicate the average value of three cases, and bars indicate the standard deviation.
  • Wistar male rats (7 weeks old, Japan SLC) were illuminated for 12 hours at room temperature 23 soil The animals were acclimated for 1 week at 2 ° C, free water and food. After that, they were fasted for about 20 hours before the experiment, anesthetized with pentobarbital (5 OmgZkg, Nacalai), and then opened. The colon is incised about 3 cm, the colonic mucosa is gently washed with about 1 mL of physiological saline, the water is wiped off, and the cap-type sticking device manufactured in Example 2 (1) is pasted one per rat. Was.
  • Example 1 (1) 5 / L each of the administration solution of Example 1 (1) and the comparative solution 3 (control) was applied to the cap-type application device attached to the large intestine of the rat (one type for each cap-type application device).
  • Injection was performed using a micropipet (manufactured by Labsystem) through the hole at the top of the device (FD-4 dose: 2.5 mg / rat).
  • Example 1 (1) In the preparation of the administration solution of Example 1 (1), in place of NAC, the same amount of S-methylol-L-cysteine, 3_ethyl ⁇ / -_ cysteine, and S-canolepoximethy ⁇ -cysteine (all Dosing solutions were prepared using either Sigma-Aldrich) or 1,4-dithiothreitol (DL-threo-1,4-dimercapto-1,2,3-butanediol; manufactured by Nacalai).
  • the cap-type patch device attached to the jejunal mucosa of the rat 5 / x1 (one type per cap-type sticking device) of the dosing solution prepared in Example 1 (1) and a micropipet (manufactured by Labsystem) through the hole at the top of the device. (FD-4 dose: 2.5 mg rat).
  • Fig. 8 shows the time course of the plasma FD-4 concentration. In the figure, points indicate the average values of three cases.
  • Example 1 In preparing the administration solution of (1), instead of Triton X-100, the same amount of polyoxyethylene (10) p-n-noenylphenyl ether (NP_10, manufactured by Nikkor), polyoxyethylene Ethylene (9) lauryl ether (BL-9, manufactured by Nikko Nole), 1-o- n -octyl-1] 3-D-darcoviranoside (OGP, manufactured by Nacalai), 6-O- (N-n-heptylcarbamoyl) ) Methyl- ⁇ -D-gunolecopyranoside (HECAMEG, manufactured by Nacalai) or polyoxyethylene (12-13) p-tert-octylphenyl ether (Triton X-102, manufactured by Nacalai) A solution was prepared.
  • polyoxyethylene (10) p-n-noenylphenyl ether NP_10, manufactured by Nikkor
  • Example 2 shows the results.
  • FITC-dextran (average molecular weight 9,400, manufactured by Sigma-Aldrich Co., Ltd .; hereinafter abbreviated as FD-10) 0.1 g was dissolved in 0.1 mL of physiological saline for injection (Otsuka Pharmaceutical Co., Ltd.) Dextran solution D2). An equal amount of the dextran solution D2 and the NAC-triton X-100 solution NT1 of Example 1 (1) were mixed to prepare an administration solution.
  • Dextran solution D2 and physiological saline for injection were mixed in equal amounts to prepare a comparative solution.
  • Wistar male rats (7 weeks old, Japan SLC) were illuminated for 12 hours at room temperature 23 soil The animals were acclimated for 1 week under the conditions of 2 ° C, free water supply and feeding. After that, they were fasted for about 20 hours before the experiment, anesthetized with pentobarbital (5 OmgZkg, Nacalai), and then opened.
  • pentobarbital (5 OmgZkg, Nacalai)
  • one cap-type application device was applied to the jejunal mucosa, one for each rat.
  • Example 2 Sampling was performed in the same manner as in Example 1 (2) to calculate the FD-10 concentration in rat plasma.
  • the time course of the plasma FD-10 concentration is shown in FIG. In the figure, the points indicate the average value of three cases, and the bars indicate the standard deviation.
  • SCT solution 2.5 mg of salmon calcitonin (molecular weight: 3431.9, manufactured by BACHEM, hereinafter abbreviated as SCT) was dissolved in 0.1 mL of physiological saline for injection (manufactured by Otsuka Pharmaceutical) (hereinafter, abbreviated as SCT solution). Equal amounts of the SCT solution and the NAC-Triton X-100 solution NT1 of Example 1 (1) were mixed to give a dosing solution.
  • Comparative Solution 1 Equal amounts of the SCT solution and the NAC solution N1 of Example 1 (1) were mixed to obtain Comparative Solution 1, and the SCT solution and the triton X-100 solution T1 of Example 1 (1) were mixed in equal amounts. Thus, Comparative Solution 2 was obtained. Furthermore, an equal amount of the SCT solution and physiological saline for injection were mixed to prepare Comparative Solution 3.
  • Wistar male rats (6 weeks old, Japan SLC) were illuminated for 12 hours at room temperature 23 soil The animals were acclimated for 1 week at 2 ° C under free water and feeding conditions. After that, the rats were fasted for about 20 hours before the experiment, anesthetized with pentobarbital (5 Omg / kg, Nacalai), and the administration solution prepared in (1) and the comparative solutions 1 to 3 were injected into the jejunum of the rat, respectively. 20 L was injected using (manufactured by Ito Seisakusho) (SCT dose: 0.25 mg Z rat).
  • FIG. 10 shows the time course of the SCT concentration in rat plasma. In the figure, points indicate the average value of two or three cases, and bars indicate the standard deviation.
  • NAC or Triton X-100 alone showed only a slight SCT absorption-enhancing effect compared to control (comparative solution 3 dissolved in physiological saline). By mixing, the absorption promotion effect is dramatically improved.
  • the AUC was calculated by the usual method, and the BA at the time of jejunal administration was calculated in comparison with the AUC when SCT was intravenously administered. Table 3 shows the results. Table 3
  • Desmopletsucin (molecular weight 1069.24, manufactured by AKZO N0BEL) Strength S 10 mg / mL, NAC and Triton X-100 dissolved in physiological saline for injection (Otsuka Pharmaceutical Co., Ltd.) to a concentration of 250 mg / mL. Was prepared.
  • a cap-type pasting device (fringe diameter: 15 mm) prepared according to the method of Example 2 (1) from No. 00 gelatin capsule (diameter: 9 mm, length: 24 mm; manufactured by Warner-Lambert) Five beagle dogs were attached to the jejunal mucosa.
  • the dosing solution prepared in (1) was added to the cap-type affixing device attached to the jejunal mucosa of the beagle dog by 15 / iL in a microsyringe from the top of the capsule.
  • syringe barrel (Terumo, 22 G) treated with heparin (Mochida Pharmaceutical) from the forelimb vein
  • the blood was sampled in 5 mL increments and centrifuged at 4 ° C (3000 rpm, 5 minutes) to obtain plasma.
  • the obtained plasma is stored at 80 ° C, and the concentration of desmopressin in plasma is measured by LC_MS (HPLC: Waters
  • the desmopleucine concentration in plasma was calculated from the prepared calibration curve.
  • Fig. 11 shows the time course of plasma desmopressin concentration when administered at a rate of 1 mL.
  • the graph in the figure shows the average soil standard deviation. Intravenous administration is the average of 6 cases, and jejunal administration is the average of 3 cases.
  • Triton X-100 To 2.5 mg of Triton X-100, a mixed solution of 150 ⁇ L of the dextran solution D of Example 1 (1) and 150 L of the NAC solution was added and dissolved.
  • Example 1 The dextran solution D1 of (1) and physiological saline for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.) were mixed in equal amounts to prepare a solution for comparison bellets.
  • An aluminum seal (manufactured by Costar) was attached to a support having 66 round holes of 4.5 mm ⁇ in the area of 6 cm x 10 cm, and a recess was made in the place of the round hole of the aluminum seal using an appropriate tool.
  • Wistar male rats (6-7 weeks old, Japan SLC) were illuminated for 12 hours at room temperature 23
  • the animals were acclimated for 1 week under conditions of ⁇ 2 ° C, free water supply and feeding. Thereafter, they were fasted for about 20 hours before the experiment, anesthetized with pentobarbital (5 Omg / kg, manufactured by Nacalai), laparotomy was performed, and a bile duct was inserted with a force neura to release bile outside the body.
  • pentobarbital 5 Omg / kg, manufactured by Nacalai
  • laparotomy was performed
  • a bile duct was inserted with a force neura to release bile outside the body.
  • the jejunum was incised about 3 cm
  • the jejunal mucosa was lightly washed with about ImL of physiological saline
  • the water was wiped off
  • the top of the cap-type application device prepared in Example 2 (1) was sheared.
  • the cut pieces were applied to the jejunal mucosa, one per rat.
  • the pellet prepared in (2) (one type per cap-type patching device) was administered from the top hole to the cap-type patching device attached to the rat jejunal mucosa (FD-4 dose: 2.5 mg) / Rat). Sampling was performed in the same manner as in Example 1 (2) to calculate the concentration of FD-4 in rat plasma.
  • Figure 12 shows the time course of the plasma FD-4 concentration. In the figure, points indicate the average value of three cases, and bars indicate the standard deviation. As shown in Fig. 12, the absorption promotion effect is dramatically improved by mixing NAC and Triton X-100 as compared to the control (comparison pellet).
  • NAC polyoxyethylene (25) lauryl ether
  • BL-25 polyoxyethylene (25) lauryl ether
  • An equal amount of the dextran solution D1 of Example 1 (1) and the NAC-BL-25 solution NB1 were mixed to prepare a dosing solution.
  • mice Male Wistar rats (7 weeks old, Japan SLC) were acclimated for 1 week under the conditions of illumination for 12 hours, room temperature of 23 ⁇ 2 ° C, free water and food. After that, they were fasted for about 20 hours before the experiment, anesthetized with pentobarbital (50 mg / kg, Nacalai), and subjected to surgery for nasal administration as in Example 3.
  • pentobarbital 50 mg / kg, Nacalai
  • the administration solution prepared in the above (1) and the comparison solution (control console) were administered directly into the nasal cavity by a micropip (one type per rat) to the rats that had undergone surgery.
  • FD-4 dose 2.5 mg / rat.
  • the blood was injected into a 0.15m1 syringe using a syringe (Termo, 25G) treated with heparin (Mochida Pharmaceutical) from the artery. Sampling was performed and centrifuged (12000 rpm, 3 minutes) to obtain plasma.
  • Fig. 13 shows the time course of plasma FD-4 concentration. In the figure, points indicate average values of 3-4 cases, and bars indicate standard deviations. As shown in Fig. 13, when NAC and BL-25 are mixed, they exhibit an excellent absorption-promoting effect in intranasal administration. Example 13
  • SCT 2 solution A solution obtained by dissolving 2 mg of SCT in 0.05 ml of physiological saline for injection (manufactured by Otsuka Pharmaceutical) (hereinafter abbreviated as SCT 2 solution). Equal amounts of the SCT 2 solution and the NAC-BL-25 solution NB 1 of Example 12 (1) were mixed to obtain a dosing solution.
  • Equal amounts of SCT 2 solution and physiological saline for injection were mixed to prepare a comparative solution.
  • mice Male Wistar rats (8-week-old, S-line SLC) were acclimated for 1 week under the conditions of illumination for 12 hours, room temperature of 23 ⁇ 23, free water intake and feeding. After that, they were fasted for about 20 hours before the experiment, anesthetized with pentobarbital (50 mg / kg, Nacalai), and subjected to surgery for nasal administration as in Example 3.
  • pentobarbital 50 mg / kg, Nacalai
  • the administration solution prepared in the above (1) and the comparative solution (control) were directly injected into the nasal cavity with a 5 microliter (1 rat / type) micropipette of the administration solution prepared in (1) above. (FD-4 dose: 2.5 mg / rat).
  • 0.1 ml of blood was sampled from the carotid artery using a syringe (Termo, 25G) treated with heparin (Mochida Pharmaceutical) Then, the mixture was centrifuged (12000 rpm, 3 minutes) at 4 ° C to obtain plasma.
  • FIG. 14 shows the time course of SCT concentration in rat plasma. In the figure, the points indicate the average of three cases, and the bar indicates the standard deviation.
  • Example 1 (1) of a well-known absorption enhancer, sodium caprate phosphate (manufactured by Tokyo Chemical Industry), sodium taurodeoxycholate (manufactured by Nacalai) or sodium lauryl sulfate (hereinafter, SDS, manufactured by Nacalai) was prepared in an amount of 5 mg.
  • NAC solution N 150 was dissolved in 50 / zL to prepare three kinds of solutions. These three types of solutions and the dextran solution D1 of Example 1 (1) were mixed in equal amounts to obtain three types of comparative solutions.
  • Example 1 (1) Male Wistar rats (5 weeks old, Japan SLC) were acclimated for 1 to 2 weeks under the conditions of illumination for 12 hours, room temperature, 23 soils, 2 ° C, free water supply and feeding. Fasted for about 20 hours before the experiment, anesthetized with pentobarbital (5 Omg / kg, manufactured by Nacalai), and 20 ⁇ L of each of the above three comparative solutions was injected into the jejunum of each rat using a microsyringe (Ito Seisakusho). Injected (FD-4 dose: l Omg / rat). In the same manner as in Example 1 (2), sampling was performed to calculate the FD-4 concentration in rat plasma.
  • Figure 15 shows the time course of the plasma FD-4 concentration. In the figure, points indicate the average values of 2 to 6 cases.
  • FIG. 15 also shows the results of the administration solution of Example 1 (1) (containing FD_4, NAC, and Triton X-100).
  • Triton X-100 showed an excellent absorption promoting effect as compared with known absorption enhancers.
  • the pharmaceutical composition of the present invention by using a combination of at least one kind of mucolytic agent and at least one kind of nonionic surfactant, sodium chlorophyllate, sodium taurodeoxycholate, sodium laurinole sulfate, etc. Can achieve a drug absorption promoting effect from the mucous membrane which is far superior to the known absorption enhancer, and is much more than when a mucolytic agent alone or a nonionic surfactant alone is used. Excellent drug absorption promoting effect can be obtained.

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Abstract

L'invention concerne des compositions médicinales renfermant un médicament hydrophile et difficilement absorbable (par exemple, de type peptidique), en combinaison avec au moins un agent de dissolution de mucus appartenant au groupe constitué par les dérivés de cystéine et les alcools à base de SH de type actif et au moins un tensioactif non ionique. Ces compositions favorisent l'absorption transmuqueuse du médicament.
PCT/JP2002/009829 2001-09-26 2002-09-25 Compositions medicinales favorisant l'absorption de medicaments Ceased WO2003026699A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078211A1 (fr) * 2003-03-04 2004-09-16 Tanabe Seiyaku Co., Ltd. Preparation en poudre pour l'administration nasale

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988009163A1 (fr) * 1987-05-22 1988-12-01 Danbiosyst U.K. Limited Systeme d'administration d'un medicament facilitant sa fixattion
JPH01203336A (ja) * 1988-02-09 1989-08-16 Teikoku Seiyaku Kk 経皮・口腔粘膜適用製剤
EP0369437A2 (fr) * 1988-11-16 1990-05-23 Kyowa Hakko Kogyo Co., Ltd. Composition à base de motiline
EP0845265A1 (fr) * 1995-08-15 1998-06-03 Asahi Kasei Kogyo Kabushiki Kaisha Preparation pour muqueuses a base de peptides a activite physiologique
WO2000032172A1 (fr) * 1998-11-27 2000-06-08 Kanji Takada Preparation orale servant a diffuser un medicament du tube digestif

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988009163A1 (fr) * 1987-05-22 1988-12-01 Danbiosyst U.K. Limited Systeme d'administration d'un medicament facilitant sa fixattion
JPH01203336A (ja) * 1988-02-09 1989-08-16 Teikoku Seiyaku Kk 経皮・口腔粘膜適用製剤
EP0369437A2 (fr) * 1988-11-16 1990-05-23 Kyowa Hakko Kogyo Co., Ltd. Composition à base de motiline
EP0845265A1 (fr) * 1995-08-15 1998-06-03 Asahi Kasei Kogyo Kabushiki Kaisha Preparation pour muqueuses a base de peptides a activite physiologique
WO2000032172A1 (fr) * 1998-11-27 2000-06-08 Kanji Takada Preparation orale servant a diffuser un medicament du tube digestif

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Title
BERNKOP-SCHNURCH ANDREAS ET AL.: "Perora polypeptide delivery", ARZNEIM.-FORSCH./DRUG RES., vol. 49, no. 9, 1999, pages 799 - 803, XP002960420 *
O'HAGEN DEREK T. ET AL.: "Nasal absorption enhancers for biosynthetic human growth hormone in rats", PHARMACEUTICAL RESEARCH, vol. 7, no. 7, 1990, pages 772 - 776, XP002960421 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078211A1 (fr) * 2003-03-04 2004-09-16 Tanabe Seiyaku Co., Ltd. Preparation en poudre pour l'administration nasale
US7591999B2 (en) 2003-03-04 2009-09-22 Mitsubishi Tanabe Pharma Corporation Powdery preparation for nasal administration

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