JP2007535545A - Formulation for oral administration of poorly absorbable drugs - Google Patents

Abstract

  Disclosed are compositions for oral administration of poorly absorbable drugs. The composition of the present invention comprises a drug, a toughening agent that enhances the absorption of the drug through the intestinal mucosa, an enhancer that does not enhance the drug absorption through the intestinal mucosa alone, but further enhances the absorption of the drug in the presence of the toughening agent Contain a protective agent to protect the drug from physical or chemical degradation or inactivation in the gastrointestinal tract. Exemplary toughening agents include sucrose fatty acid esters, and exemplary accelerators include amino sugars and amino acid derivatives such as poly (amino acids). Exemplary protective agents include methylcellulose, poly (vinyl alcohol), and poly (vinyl pyrrolidone).

Description

Detailed Description of the Invention

The present invention relates to drug administration. More specifically, the present invention relates to compositions and methods for oral administration of poorly absorbable drugs.

  The gastrointestinal tract, especially the small intestine, is the primary site for absorption of nutrients and most bioactive agents. In order to facilitate the absorption process, the amount of surface area of the small intestine is increased due to the presence of villi and microvilli. However, before the bioactive compound is transferred from the intestinal lumen to the blood, it may be subject to degradation or deactivation by various components of the lumen. In addition, the compound is required to pass through several absorption barriers such as the mucus layer and the intestinal brush border membrane. Many compounds easily cross their barriers, but there are many nutrients and bioactive agents that make them a significant obstacle.

  There are many factors that affect the oral bioavailability of drugs in the gastrointestinal tract. These include factors relating to the drug itself such as active or passive transport, water solubility, molecular weight, chemical stability, ionization, pH, etc .; deamination, hydrolysis (or ionization), oxidation, racemization, β Factors related to chemical reactions such as desorption, disulfide exchange and the like; and factors related to physical processes such as aggregation, precipitation, denaturation, adsorption and the like.

  Although the prior art and methods used are known and generally suitable for limited purposes, they inherently impair the overall usefulness in delivering poorly absorbed drugs by oral administration. Have defects. That is, the prior art and methods cannot increase the intestinal absorption of the drug while preventing physical and / or chemical degradation or inactivation of the drug.

In view of these, providing a composition and method for the efficient oral administration of poorly absorbable drugs is expected to be a significant advance in the art.
SUMMARY OF THE INVENTION Provided are compositions that enhance intestinal absorption of drugs administered by the oral route and at the same time reduce or inhibit the degradation or inactivation of drugs by physical and / or chemical factors, and methods of use and preparation thereof This is a feature of exemplary embodiments of the invention.

They and other objects are compositions for oral administration of medicinal substances that are poorly absorbed through the intestinal mucosa, in an effective amount of the medicinal substance; a toughener to enhance absorption of the medicinal substance through the intestinal mucosa; An enhancer acting synergistically with the enhancer to further enhance the absorption of the drug substance through; and optionally a mixture of protectants to inhibit the degradation or inactivation of the drug substance, wherein said enhancer Is a member selected from the group consisting of fatty acid esters, phospholipids, phosphatidyl compounds, glycosylceramides, fatty acids, nonionic surfactants, vitamin E tocopheryl succinate polyethylene glycol, glycerides, derivatives thereof, and mixtures thereof;
The promoter is a member selected from the group consisting of amino acid derivatives, amino sugars, and mixtures thereof; and the protective agent is carbomer, carboxymethyl cellulose, polysaccharide, pectin, cellulose, dextrin, gelatin, polyethylene oxide, poly ( Vinyl alcohol), poly (vinyl propylene), poly (vinyl pyrrolidone), xanthan gum, sodium alginate, methacrylic acid copolymer, colloidal silica, synthetic silica, polysaccharides, water-soluble cellulose ether, hydroxypropyl methacrylate, tragacanth gum, water-soluble chitosan, poly A member selected from the group consisting of carbophil, derivatives thereof, and mixtures thereof;
This can be addressed by providing the composition.

  Another exemplary embodiment of the present invention is a composition for oral administration of a pharmaceutical substance that is poorly absorbed through the intestinal mucosa after oral administration, wherein the effective amount of the pharmaceutical substance increases the absorption of the pharmaceutical substance through the intestinal mucosa. An enhancer (where the enhancer comprises a sucrose fatty acid ester); an enhancer that acts synergistically with the enhancer (where the enhancer is glucosamine or polysulphide) to further enhance the absorption of the pharmaceutical substance through intestinal mucosa (Including L-lysine)); and optionally a composition comprising a mixture of protective agents (where the protective agent comprises methylcellulose or poly (vinyl alcohol)) for inhibiting the degradation or inactivation of the pharmaceutical substance It is.

A further exemplary embodiment of the present invention includes a composition for oral administration of a hydrophilic or amphipathic drug, comprising a mixture of said drug and a toughening agent to enhance absorption of the drug through the intestinal mucosa. The fortifying agent is selected from the group consisting of fatty acid esters, phospholipids, phosphatidyl compounds, glycosylceramides, fatty acids, nonionic surfactants, vitamin E tocopheryl succinate polyethylene glycol, glycerides, derivatives thereof, and mixtures thereof. And a synergistic accelerator that further enhances absorption of the drug through the intestinal mucosa, wherein the accelerator is a group consisting of poly (amino acids), amino sugars, and mixtures thereof A composition comprising a member selected from:

  Yet another exemplary embodiment of the present invention includes a dosage form for oral administration of a poorly absorbable drug in the intestine, wherein the effective amount of the drug; An enhancer that acts synergistically with the enhancer to further enhance the absorption of the drug through the intestinal mucosa; and optionally a protective agent to reduce or inhibit the degradation or inactivation of the drug in the gastrointestinal tract A dosage form is included.

  In a further exemplary embodiment of the present invention, there is provided a method for enhancing intestinal absorption of a poorly absorbable drug, comprising: an agent; a toughening agent for increasing absorption of the drug through the intestinal mucosa; and further absorption of the drug through the intestinal mucosa. Orally administering a composition comprising an enhancer, a synergistic enhancer; and optionally a protective agent to reduce or inhibit degradation or inactivation of the drug in the gastrointestinal tract A method of including is included.

DETAILED DESCRIPTION Before disclosing and describing the compositions and methods of the present invention, the present invention is directed to certain forms, process steps, and materials such as the somewhat modified forms, process steps, and materials disclosed herein. It should be understood that the invention is not limited to. Further, since the scope of the present invention is not limited to the appended claims and their equivalents, the terms used in this specification are used only for the purpose of describing particular embodiments, and It should also be understood that this is not the intention.

  The publications and other reference materials mentioned in this specification are hereby incorporated by reference to set forth the background of the invention and to provide additional details regarding its implementation. Reference materials mentioned herein are provided solely as their disclosure prior to the filing of this application. Nothing herein is to be construed as an admission that the inventors are not to be preceded by such disclosure prior to the prior art.

  As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include the plural unless the context clearly dictates otherwise. Must be careful. Thus, for example, for an oral drug-containing composition containing “a drug”, it includes a mixture of two or more such drugs, and for “an enhancer” It includes one or more of such tougheners, and for “a protector” includes a mixture of two or more such protectors.

In disclosing and claiming the present invention, the following terms are used in accordance with the definitions set forth below.
As used herein, “comprising”, “including”, “containing”, “characterized by”, and grammatical equivalents thereof are listed as additionals. An inclusive or open-ended term that does not exclude missing elements or method steps. “Comprising” is to be understood as including the more restrictive terms “consisting of” and “consisting essentially of”. As used herein, “consisting of” and its grammatical equivalents excludes elements, steps, or ingredients not specified in the claims. As used herein, “consisting essentially of” and its grammatical equivalent representations define the scope of the claim, the particular element or process, and the basic and novel nature of the claimed invention. Limit to those that do not inherently affect the features.

  As used herein, “protective agent” means a biopolymer that helps prevent the agent from degrading or inactivating due to conditions encountered in the small intestine. The protective agent does not form a complex with the drug and does not covalently bond with the drug. Exemplary protective agents of the present invention include methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), and mixtures thereof.

  “Enhancer” as used herein means a substance that enhances or increases the absorption of a drug or other drug substance that passes through the intestinal mucosa after administration of the drug or drug substance by the oral route. Exemplary toughening agents include surfactants such as sucrose esters.

  As used herein, an “accelerator” has little or no effect on enhancing or increasing the absorption of a drug or other drug substance that passes through the intestinal mucosa after administration of the drug or drug substance by the oral route. Although not meant, it means a substance that enhances the absorption enhancing effect of the enhancer when the drug or pharmaceutical substance is administered in combination or together with the enhancer and enhancer. Thus, for example, oral administration of a composition comprising a drug or other pharmaceutical substance, a enhancer, and a mixture of enhancers is more likely to occur through the intestinal mucosa than oral administration of similar compositions without an enhancer. Or result in a rather high absorption of the drug substance. Exemplary promoters include amino sugars and amino acid derivatives such as poly (amino acids).

  As used herein, “derivative” means an altered compound or molecule. For example, such variations include, but are not limited to, polymers or copolymers of compounds or molecules, esters, alkylated, arylated, aralkylated, and the like.

  As used herein, “surfactant” or “surfactant” refers to surface activity including, for example, wetting agents, cleaning agents, penetrating agents, spreading agents, dispersing agents and blowing agents, among others. A substance that changes the energy relationship at the interface, such as a synthetic organic compound. Illustrative examples of surfactants useful in the present invention are nonionic surfactants.

  As used herein, “HLB” means “hydrophilic-lipophilic balance”, which is an experimental value at any scale and is a measure of the polarity of a surfactant or mixture of surfactants. See P. Becher et al., “Nonionic Surfactant Physical Chemistry” 439-56 (Marcel Dekker, NY 1987). It is a widely used term. See US Pat. No. 5,707,648. .

  As used herein, an “effective amount” is an amount of a drug or pharmacologically active agent that is non-toxic but provides sufficient desirable local or systemic effects and performance at a reasonable benefit / risk ratio while producing medical treatment. Means.

  “Peptide” as used herein refers to peptides of any length and includes oligopeptides, polypeptides and proteins. The only limitation of peptide or protein formulations that can be used according to the present invention is function.

  As used herein, “refractory drug” and similar terms mean a drug or other pharmacologically active agent that is not immediately absorbed into the bloodstream through the intestinal mucosa after oral administration, such drug or drug substance being Usually not administered by oral route. In other words, “refractory drugs” usually include, as described above, for slight absorption into the bloodstream after oral administration, or for degradation or inactivation by physical and / or chemical factors. Includes drugs administered by injection, transdermal or transmucosal. Examples of poorly absorbable drugs are peptide or protein preparations, aminoglycoside antibiotics, and the like. Such poorly absorbable drugs can be hydrophilic, amphiphilic, or hydrophobic.

  The present invention provides compositions and methods for administering a wide variety of therapeutically and diagnostically effective molecules that are not rapidly absorbed through the intestinal membrane. In particular, the present invention relates to molecules that serve as drug carriers for large and highly water-soluble therapeutic molecules, and pharmaceutical ingredients comprising those carriers.

  The present invention serves to reduce or inhibit physical and / or chemical degradation or inactivation of an active agent and at the same time efficiently increases intestinal absorption and distribution to blood vessels, allowing the agent to enter cells and tissues. Works to increase migration. Thereby, the pharmaceutical ingredient of the present invention is particularly effective for oral administration. This enhanced system can be used in peptide and / or protein formulations (eg, insulin, calcitonin, and human growth hormone (HGH)), or because of high water solubility or because it is degraded or inactivated under conditions of the gastrointestinal tract. It is particularly effective for transporting other drugs that are difficult to absorb in the tube. In addition to peptide and / or protein formulations, other poorly absorbable drugs that are efficiently transported by the present invention include aminoglycoside antibiotics, glycopeptide antibiotics, carbapenems, catechins, and the like.

  Examples of poorly absorbable drugs that can be administered orally according to the present invention include various categories of drugs. Protein and peptide preparations include insulin, human growth hormone, calcitonin, high density lipoprotein (HDL), erythropoietin (EPO) and the like. Aminoglycoside antibiotics include netilmycin, isepamicin, amikacin, tobramycin, gentamicin and the like, and mixtures thereof. Glycopeptide antibiotics include teicoplanin, vancomycin, bleomycin and the like, and mixtures thereof. Various drugs include daptomycin, tigecycline, ramoplanin, catechin, aztreonam, imipenem, cilastatin, and the like, and mixtures thereof. Anti-cancer agents include paclitaxel and the like.

  Agents that can be administered according to the present invention include: Peptide formulations include adenosine deaminase, adrenocorticotropic hormone (ACTH) and fragments thereof, angiotensin and related peptides, antibody fragments, antigens and fragments thereof, atrial natriuretic factor, arginase, asparaginase, bioadhesive peptide (bioadhesive peptide ), Bradykinin and related peptides, calcitonin and related peptides, cell surface receptor protein fragments, chemotactic peptides, cyclosporine, chymotrypsin, cytokines, dynorphins and related peptides, endorphins and β-lidotropin fragments, enkephalins and species thereof Peptides, enzyme inhibitors, erythropoietin, fibronectin fragments and related peptides, gastrointestinal peptides ide), growth hormone releasing peptide, immunostimulatory peptide, interleukins, luteinizing hormone releasing hormone (LH-RH) and related peptides, melanocyte stimulating hormone and related peptides, monoclonal antibodies (eg, Remicade®) , Nuclear localization signal-related peptides, neurotensin and related peptides, neurotransmitter peptides, opioid peptides, oxytocin, papain, vasopressin and related peptides, parathyroid hormone and fragments thereof, prolactin, protein kinase related peptides, ribonucleases, somatostatin And related peptides, substance P and related peptides, superoxide dismutase, transforming growth factor (TGF) and related peptides, thyroid stimulating hormone, trypsin, tumor necrosis Factor fragments and toxins and / or modified toxins, functional peptides (angiostatin, anticancer peptides), antihypertensive peptides, anticoagulant peptides, antimicrobial peptides, etc., and mixtures thereof are included. Protein preparations include immunoglobulin, angiogenin, bone morphogenetic protein, chemokinesis, colony stimulating factor (CSF) and related peptides, cytokines, growth factors, interferons, interleukins, leptin, leukemia inhibitory factors, stem cell growth factors, trans Forming growth factors, tumor necrosis factors, etc., and mixtures thereof are included. Hydrophilic, amphiphilic, or hydrophobic drugs that can be used in accordance with the present invention include antiviral agents, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, antibiotics (especially aminoglycosides such as netilmycin, isepamicin, teicoplanin). ), Antibacterial agents, vitamins, hormones, prostaglandins, prostacyclins, anticancer agents (e.g., tamoxifen), antimetabolites, miotics, adrenergic antagonists, cholinergic agents, anticonvulsants, antidepressants, Antipsychotics, anesthetics, analgesics, steroids, estrogens, lipopeptide antibiotics (eg, daptomycin), progesterone, glycosaminoglycans, polynucleotides, immunosuppressants, immunopotentiators, and the like, and mixtures thereof.

  Strengthening agents that can be used in the present invention include sucrose stearate, sucrose palmitate, sucrose laurate, sucrose behenate, sucrose oleate, sucrose erucate, and the like, and mixtures thereof. Sucrose fatty acid ester; phospholipid derivative, phosphatidyl derivative, glycosylceramide derivative, fatty acid derivative, nonionic surfactant, vitamin E tocopheryl succinate polyethylene glycol (TPGS) derivative, Gelucire® series surfactant, glyceride derivative Etc., and mixtures thereof.

  Phospholipids include phosphoglycerides. Glycerides include mono-, di- and tri-esters of glycerol. Fatty acids are generally straight chain carboxylic acid compounds ranging from 3 to 18 carbons. Fatty acids include saturated fatty acids such as butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, and unsaturated acids containing one or more double bonds per molecule Is included. The most common of unsaturated fatty acids are oleic acid, linolenic acid, and linolenic acid. Ceramide is a fatty acid derivative of sphingosine, and thus glycosylceramide has a sugar group bonded to ceramide.

  GELUCIRE® series surfactants (Gattefosse S.A., Saint Priest, France) contain glycerol esters of fatty acids. For example, GELUCIRE® 33/01 contains glycerol esters of saturated C8-C18 fatty acids and is HLB1 with a melting point of 33-37 ° C. GELUCIRE® 39/01 contains glycerol esters of saturated C12-C18 fatty acids and has a melting point of 37.5-41.5 ° C. and HLB1. GELUCIRE® 43/01 contains glycerol esters of saturated C12-C18 fatty acids and has a melting point of 42-46 ° C. and HLB1. GELUCIRE® 44/14 comprises a well-defined mixture of mono- and di-fatty acid esters of mono-, di-, and tri-glycerides and polyethylene glycol. It is synthesized by an alcoholysis / esterification reaction using hydrogenated palm kernel oil and PEG 1500 as raw materials. The main fatty acid is lauric acid (C12). It has a melting point of 42-46 ° C. and HLB14. It is also known as lauroyl macrogol-32 glyceride. GELUCIRE® 50/13 is a well-defined mixture of mono-, di- and tri-glycerides and mono- and di-fatty acid esters of polyethylene glycol. It is synthesized by alcoholysis / esterification using hydrogenated palm oil and PEG 1500 as starting materials. The main fatty acid is palmitostearic acid (C16-C18). It has a melting point of 46-51 ° C and an HLB of 13. It is also known as stearoyl macrogol-32 glyceride.

  Exemplary phosphatides of the present invention include dioleyl phosphatidylcholine, dimyristoyl phosphatidylcholine, dipentadecanoyl phosphatidylcholine, dilauroyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), diarachidonyl phosphatidylcholine (DAPC). Phosphatidylcholine and saturated and unsaturated lipids; dioleyl phosphatidylethanolamine, dipalmitoylphosphatidylethanolamine (DPPE), and distearoylphosphatidylethanolamine (DSPE); phosphatidylethanolamines such as phosphatidylserine; distearoylphosphatidylglycerol (DSPG) Containing phosphatidylglycerol; phosphatidylinositol; dipalmit Phosphatidic acids containing Ruhosufachijin acid (DPPA) and distearoyl lysophosphatidic acid (DSPA); included and mixtures thereof; and the like.

  Exemplary fatty acids of the present invention include palmitic acid, stearic acid, oleic acid, arachidonic acid, and the like, and mixtures thereof. Exemplary nonionic surfactants of the present invention include polyoxyethylene-polyoxypropylene glycol block copolymers, sorbitan fatty acid esters, and fluorine-containing surfactants. An example of a polyoxyethylene-polyoxypropylene glycol block copolymer is an α-hydroxy-ω-hydroxy poly (oxyethylene) -poly (oxypropylene) -poly (oxyethylene) block copolymer. These latter block copolymers are commonly referred to as poloxamer copolymers. Examples of poloxamer copolymers particularly preferably used in the present invention include, for example, poloxamer F68, poloxamer L61, and poloxamer L64. These poloxamer copolymers are commercially available from Spectrum 1100 (Houston, Texas).

  Examples of sorbitan fatty acid esters are, for example, poly (oxy-1,2, -ethanediyl) derivatives of higher alkyl esters of sorbitan. Examples of such sorbitan esters include, for example, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, and sorbitan monostearate. These, as well as other derivatives, are typically referred to as polysorbates including, for example, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. Various polysorbates are commercially available from Spectrum 1100 (Houston, Texas).

  An example of a fluorine-containing surfactant is a surfactant containing one or more fluorine atoms. Examples of such surfactants are commercially available from DuPont Chemicals (Wilmington, Delaware) and sold under the trademark ZONYL ™, such as ZONYL ™ FSN-100 and ZONYL ™ FSO-100 Is included.

  Further nonionic surfactants in the present invention include octoxynol (eg TRITON-X® surfactant), polyoxyethylene sorbitan (eg TWEEN® surfactant), Polyoxyethylene ether (eg BRIJ® surfactant), polyethylene-polypropylene block copolymer (eg PLURONIC® surfactant), fluorosurfactant (eg ZONYL® surfactant) ), And FLUORAD® surfactant.

  Accelerators that can be used in the present invention include amino acid derivatives (such as poly (amino acids)), amino sugars, and the like, and mixtures thereof. Accelerators that can be used in the present invention include glucosamine, galactosamine, N-acetylglucosamine, muramic acid, N-acetylmuramic acid, N-acetylgalactosamine, sialic acid, poly (allylamine), poly (L-lysine). , Poly (L-arginine), poly (L-histidine), poly (ethyleneimine), poly (L / D-histidine), (poly) L-arginine, poly (allylamine), poly (ethylamine), glucagon, glycyridin (Glycirrizhin), glutamic acid derivatives (eg, L-glutamine, L-glutamic acid diethyl ester), bile acids, PEG derivatives, acylcarnitine, citric acid, and the like, and mixtures thereof. Exemplary accelerators that can be used in the present invention include poly-L-lysine, glucosamine, poly-L-arginine, galactosamine, N-acetylglucosamine, and the like, and mixtures thereof.

  Protective agents that can be used in the present invention include carbomer, carboxymethylcellulose, polysaccharides (kappa, iota, lambda), pectin, cellulose and derivatives thereof (methylcellulose and derivatives thereof, ethylcellulose and derivatives thereof, hydroxypropylcellulose and derivatives thereof) Such as dextrin, gelatin, polyethylene oxide, poly (vinyl alcohol), poly (vinyl propylene), poly (vinyl pyrrolidone) (PVP), xanthan gum, sodium alginate, Eudragit (R) Methacrylic acid copolymers, colloidal silica, and synthetic silica derivatives (eg, silicon dioxide, etc.), polysaccharides, water-soluble cellulose ethers, hydroxypropyl methacrylate (HPM) acetate succinate / phthalate Conductor, tragacanth, water-soluble chitosan, polycarbophil, and the like, and derivatives, and mixtures thereof. Exemplary protective agents according to the present invention include methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, and mixtures thereof.

  As used herein, “PEP” refers to the carrier composition of the present invention, which includes optional protective agents, reinforcing agents, and accelerators. The carrier is mixed with a drug to form a drug mixture composition.

  The formulation is prepared by mixing the drug, enhancer, accelerator, and optionally a protective agent to form a solution. The solution will usually be dried according to methods known to those skilled in the art, such as freeze drying, spray drying, etc., to give a dried product. This dried product is then processed into selected dosage forms such as tablets or capsules by methods known to those skilled in the art. The dosage forms are coated with an enteric coating so that the dosage form passes through the stomach in acidic conditions and reaches the intestines where it is easily absorbed through the intestinal mucosa and enters the bloodstream. Disintegrates to release components in the intestine.

  As used herein, a “tablet” is a solid pharmaceutical dosage form that contains a drug substance and a suitable diluent, or no diluent, either by compression or molding well known to those skilled in the art. Prepared. Tablets offer benefits to manufacturers (e.g. simplicity and economy of preparation, stability, convenience of packaging, transport and dispensing) and benefits given to patients (e.g. dosage accuracy, compactness). , Easy to carry, less irritating to taste, and easy to administer). Tablets are most commonly in the form of discs, but tablets may be spherical, oval, oblong, cylindrical, or triangular. They will vary greatly in size and weight depending on the amount of drug substance present and the intended method of administration. The tablets are divided into two general classes: (1) compressed tablets, and (2) molded tablets or tablet mills. In addition to single or multiple active or therapeutic ingredients, tablets contain a number of inert substances or additives. The first group of such additives includes substances that help to provide satisfactory compression properties for formulations including diluents, binders, and lubricants. A second group of such additives serves to impart further desirable physical properties to the final tablet, such as disintegrants, colorants, flavors, and sweeteners.

  As used herein, a “diluent” is an inert substance added to increase the bulk of the formulation in order to make the tablet a practical size for compression. Commonly used diluents include calcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar, silica and the like.

  As used herein, a “binder” is a substance used to impart tackiness to a powdered substance. Binders (or they are sometimes known as “granulates”) give the tablet formulation stickiness, which keeps the tablet active after compression, as well as the desired hardness and size of the granule formulation. Ensure improved free-flowing performance. Substances commonly used as binders include starch; gelatin; sugars such as sucrose, glucose, dextrose, molasses and lactose; extracts of acacia, sodium alginate, Irish moss, panwar gum, gati gum, isa Natural and synthetic gums such as isapol husks mucus, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, Veegum, microcrystalline cellulose, microcrystalline dextrose, amylose, and larch arabogalactan Etc. are included. “Lubricants” as used herein improve the flow rate of tablet granulation, reduce interparticle friction so that tablet material does not adsorb on the surface of the dies and punches, and die holes. It is a substance that performs many functions in tablet manufacture, such as to facilitate the removal of tablets from the tablet. Commonly used lubricants include talc, magnesium stearate, calcium stearate, stearic acid, and hydrogenated vegetable oils.

  As used herein, a “disintegrant” or “disintegrant” is a substance that facilitates breakage or disintegration of a tablet after administration. Substances that act as disintegrants are chemically classified as starch, clay, cellulose, algin, or gum. Other disintegrants include Veegum HV, methylcellulose, agar, bentonite, cellulose and wood products, natural sponges, cation-exchange resins, alginic acid, guar gum, citrus pulp, crosslinked polyvinylpyrrolidone, carboxymethylcellulose and the like.

  “Colorants” as used herein are substances that give the tablet a pleasant appearance and in addition help the manufacturer to control the product during its preparation and help the user identify the product . Approved water soluble FD & C colorants, mixtures thereof, or equivalent lakes thereof can be used to color tablets. Colored lakes combine by adsorbing water-soluble colorants to the hydrated oxides of heavy metals, resulting in insoluble forms of colorants.

  As used herein, "flavoring agents" vary greatly in their chemical structure, ranging from simple esters, alcohols, and aldehydes to carbohydrates and complex volatile oils. Almost any desired type of synthetic flavoring agent is currently available.

  Capsules are solid dosage forms in which the drug substance is enclosed in a hard or soft soluble container, or a suitable substance such as gelatin. The containment of a pharmaceutical agent is a common method of drug administration because the capsule is tasteless, easily administered and easily filled. Some patients prefer capsules to be easier to swallow than tablets and want to take them when possible. This preference helps to mark the formulation manufacturer as a capsule, even if the product is already manufactured as a tablet.

  An enteric coating is a film that does not allow a significant amount of drug release in the stomach, but releases the drug quickly and completely when the dosage form reaches the intestine. Many types of enteric coatings are known to those skilled in the art, as described in Remington's Pharmaceutical Sciences.

  In one exemplary embodiment of the invention, the drug (optionally with a protective agent) is contained in one tablet or capsule, and the toughening agent and accelerator are contained in another tablet or capsule. In this embodiment, the tablet or capsule containing the drug is administered with the enhancer / enhancer-containing tablet or capsule to effect oral administration of the drug.

The following examples are illustrative of certain aspects of the present invention and should not be considered as limiting the scope of the invention.
Example 1
Aggregation test A solution of recombinant human growth hormone (rhGH) (0.5 mg / mL) was prepared in 20 mM phosphate buffer. The phosphate buffer was prepared with triple-distilled, filtered water (0.22 μm filter) and the pH was adjusted to 7.4 with sodium hydroxide solution. RhGH solutions were prepared fresh before use and the concentration was determined by measuring the absorption at UV278 nm. Its absorption at UV278 nm correlated linearly with concentration in the range of 0.1 to 1 mg / mL.

  The rhGH (0.5 mg / mL) solution was shaken at high speed for 1 minute with a vortex mixer (Scientific Industries Inc.). After shaking, the sample was equilibrated at room temperature for 30 minutes. The absorbance of the resulting turbid solution was measured at 400 nm to check the amount of insoluble aggregation. This study was conducted with and without the addition of protective agents (eg, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), and methylcellulose (MC)).

  The mixture of 0.5 mg rhGH and 1 mg methylcellulose had an absorbance of 0.44 before shaking and 0.07 after shaking. The mixture of 0.5 mg rhGH and 20 mg PVA had an absorbance of 0.44 before shaking and 0.10 after shaking. The mixture of 0.5 mg rhGH and 25 mg PVP had an absorbance of 0.44 before shaking and 0.14 after shaking. Therefore, the protective agent can minimize aggregation by reducing the adsorption of the drug at the interface. Thus, the use of a protective agent can improve the physical stability of the drug.

Example 2
Decomposition test
A solution of rhGH (5 ng / mL) was prepared in 20 mM phosphate buffer. The phosphate buffer was prepared with triple-distilled filtered water (0.22 μm filter) and the pH was adjusted to pH 7.4 with sodium hydroxide solution. The RhGH solution was shaken at high speed for 1 minute with a vortex mixer (Scientific Industries Inc.). After shaking, the sample was equilibrated at specified time intervals at room temperature. The concentration of RhGH was determined by ELISA according to methods well known to those skilled in the art. The results are shown in Table 1.

^a グルコサミンとスクロースラウリン酸エステル16
^b Gelucire（登録商標）44/14
^c ポリビニルピロリドン
^d ポリビニルアルコール
^e メチルセルロース

それらの結果は、本発明は薬剤の分解を減少させることを示す。
実施例３
促進剤 (グルコサミンまたはポリ−Ｌ−リジン)、強化剤 (スクロースラウリン酸エステル16)、および保護剤(メチルセルロース)を含むRhGH溶液を、表２に示した割合に従って水中で調製した。

^a glucosamine and sucrose lauric acid ester 16
^b Gelucire® 44/14
^c polyvinylpyrrolidone
^d polyvinyl alcohol
^e methylcellulose

These results show that the present invention reduces drug degradation.
Example 3
A RhGH solution containing an accelerator (glucosamine or poly-L-lysine), a fortifier (sucrose laurate 16), and a protectant (methylcellulose) was prepared in water according to the proportions shown in Table 2.

  In order to measure absorption from the intestines, male SD rats (Sprague-Dawley rats) that were allowed to freely access water were fasted for about 12 hours. On the day of the experiment, the rats were anesthetized and the abdominal hair was shaved. A 2 cm midline incision was made through the muscle and the stomach was externalized with round forceps. A small incision was made at the cardia sinus site where the blood supply was sparse, a polyethylene tube was inserted into the middle duodenum, and the exposed end was closed with a cock to prevent drug outflow from the duodenum. The tube was guided through the stomach and pyloric sphincter to the duodenum, passed through the approximately 5 cm sphincter and fixed in the stomach. The abdominal muscles were sutured under the skin. Blood was collected from each rat at specific time intervals and centrifuged. Four rats were in each treatment group. Approximately 50 μg of serum was analyzed with an ELISA test kit and the concentration of rhGH was calculated. The results are shown in Table 3. When rhGH was administered without PEP solution, rhGH was not detected.

Example 4
To determine intestinal absorption, 250-300 g male SD rats (Sprague Dawley rats) with free access to water were fasted for approximately 18 hours prior to the experiment. The rats were anesthetized and maintained by intraperitoneal injection of ketamine / xylazine ((60 gm / kg) / (80 mg / kg)). The small intestine was exposed by a midline abdominal incision. Make a small incision in the stomach, insert a polyethylene tube (inner diameter 0.76 mm, outer diameter 1.22 mm, Clay Adams) into the middle of the duodenum, close the exposed end with a cock, and allow the drug to flow out of the duodenum. It was prevented. Blood samples were collected through the jugular vein catheter at predetermined time intervals with a heparinized syringe. After collection, the sample was allowed to solidify for about 90 minutes and then centrifuged at 6000 rpm for 10 minutes. The supernatant was removed and stored at -200 ° C. Samples were analyzed for hGH protein levels with a human growth hormone ELISA kit (coated plate, ICN Diagnostics) according to the manufacturer's protocol.

  As controls, either glucosamine 40 mg / kg, plus sucrose laurate 40 mg / kg (ie, 100 units of carrier) or 10 mg / kg rhGH (Advanced Protein Technologies Inc., Suwon, Korea) was administered intraduodenum. . Subcutaneous administration was 0.1 mg / kg rhGH, which showed a peak serum rhGH concentration of 73 ng / ML and a Tmax of 40 minutes. In order to evaluate the effect of changes in the amount of carrier administered, the amount of rhGH was kept at 3 mg / kg rhGH and Tmax was measured. Tmax was below 20 minutes for all doses and rhGH absorption was not proportional to the carrier dose. However, the data showed a relationship between rhGH dose and rhGH plasma concentration at 10 units of fixed carrier administration. In the case of subcutaneous administration (Figure 1), the serum plasma concentration profile was shown to be dose dependent. In the case of intraduodenal administration, the control was fixed on a 10 unit carrier. The amount of RhGH was varied to include 1, 3, and 10 mg / kg rhGH. In the study in the duodenum, the difference in concentration was dose-dependent (FIG. 2). For bioavailability, 3 mg / kg rhGH showed 7.1% (10 units dose carrier) and 10 mg / kg rhGH showed 6.1% (10 units dose carrier).

  This experiment showed that rhGH levels were dose dependent when the carrier amount was constant (FIG. 2). When RhGH is fixed at 3 mg / kg and the amount of carrier is changed to 100, 50, 20, 10, 5 units, the result is that a small amount of carrier (10-20 units) is compared to a high dose carrier. Increased rhGH absorption (FIG. 3). Finally, in order to evaluate the effect of the carrier itself, the type of carrier was changed with the rhGH level kept at 3 mg / kg). The carrier containing poly (L-lysine and sucrose laurate 16 showed a higher absorption compared to the carrier containing glucosamine and sucrose laurate 16 (21.3% as calculated availability respectively). (Fig. 4) Thus, the carrier system of the present invention markedly improved the duodenal absorption of rhGH without modification of the drug. Based on the above, it is effective for oral administration of rhGH.

Example 5
Insulin was dissolved in 0.01 N HCl and then mixed with a water protectant (methylcellulose), a fortifier (sucrose laurate 16), and an accelerator (glucosamine) prior to administration to rats. The insulin / PEP solution was mixed with a magnetic stirrer at room temperature. The composition of the insulin / PEP solution is 50 IU / kg of insulin, 400 mg / kg of sucrose laurate ester 16, glucosamine at a weight ratio of insulin to glucosamine of 1: 4, and methylcellulose to insulin. Formulation was made to contain 1: 0.5 by weight of methylcellulose. The insulin / PEP composition was administered to rats according to the procedure of Example 3. Blood was collected from each rat at specific time intervals and centrifuged. Plasma was measured with a glucose meter and radioimmunoassay test kit (ICN pharmaceuticals) to determine blood glucose and insulin concentrations. The results are shown in FIGS. 5-7.

  In diabetic rats, serum insulin was detected in the blood after insulin administration in the carrier of the present invention (FIG. 5) and a significant hypoglycemic effect was observed (FIG. 6). In non-diabetic rats, no significant hypoglycemic response was recorded with similar treatment (FIG. 7). Non-diabetic rats may offset the self-regulation of insulin secretion and the activity of exogenous insulin supplied with counter-regulatory hormones.

Thus, the carrier of the present invention markedly improved insulin absorption in the duodenum without modification of the drug.
Example 6
Calcitonin was dissolved in water and then mixed with water protective agent (methylcellulose), fortifier (sucrose laurate 16), and accelerator (glucosamine) prior to administration to rats. The insulin / PEP solution was mixed with a magnetic stirrer at room temperature. The composition of the calcitonin / PEP solution is 2 mg / kg calcitonin for individual administration, 40 mg / kg sucrose laurate 16, glucosamine in a weight ratio of calcitonin to glucosamine of 1: 4, and methylcellulose with calcitonin. The formulation was formulated so that the weight ratio of methylcellulose was 1: 0.5. The calcitonin / PEP composition was administered to rats according to the procedure of Example 3. Blood was collected from each rat at specific time intervals and centrifuged. Plasma was analyzed by ELISA according to methods well known to those skilled in the art. The results are shown in Table 4.

Example 7
The isepamicin solution was mixed with the methylcellulose solution, and the resulting mixture was mixed with a solution of glucosamine and sucrose stearate 16 in water prior to administration to rats. Isepamicin and PEP solution were mixed with a magnetic stirrer at room temperature to prepare isepamicin-PEP solution. The contents of isepamicin / PEP are 75 mg / kg isepamicin, 400 mg / kg sucrose stearate, glucosamine (1: 4 molar ratio of isepamicin and glucosamine), and methylcellulose (molar ratio of isepamicin to methylcellulose 1). : 0.5). The isepamicin / PEP composition was administered to rats according to the procedure of Example 3. At specific time intervals, blood was collected from each rat and centrifuged. Plasma was analyzed by HPLC and bioavailability was calculated. The results are shown in Table 5.

Example 8
The netilmicin solution was mixed with the methylcellulose solution and this mixture was added to a solution of glucosamine and sucrose stearate in water prior to administration to rats. The netilmycin and PEP solution were mixed with a magnetic stirrer at room temperature to prepare a netilmicin-PEP solution. The netilmycin / PEP content was 80 mg / kg netilmycin, 400 mg / kg sucrose stearate, glucosamine (methyl ratio of netilmicin and glucosamine 1: 4) and methylcellulose (molar ratio of netilmycin to methylcellulose 1: 0.5). The netilmicin / PEP composition was administered to rats according to the procedure of Example 3. Blood was collected from each rat at specific time intervals and centrifuged. Plasma was analyzed by HPLC and bioavailability was calculated. The results are shown in Table 6.

The results indicate that the percent bioavailability was 73.05%.
Example 9
Teicoplanin solution was mixed with methylcellulose solution and this mixture was added to a solution of glucosamine and sucrose stearate in water prior to administration to rats. The teicoplanin and the PEP solution were mixed with a magnetic stirrer at room temperature to prepare a teicoplanin / PEP solution. Teicoplanin / PEP content was 64 mg / kg teicoplanin, 400 mg / kg sucrose stearate, glucosamine (molar ratio of teicoplanin to glucosamine 1: 4) and methylcellulose (molar ratio of teicoplanin to methylcellulose 1: 0) for each administration. .5). The teicoplanin / PEP composition was administered to rats according to the procedure of Example 3. Blood was collected from each rat at specific time intervals and centrifuged. Plasma was analyzed by HPLC and bioavailability was calculated. The results are shown in Table 7.

The results indicate that the percent bioavailability was 35.07%.
Example 10
The catechin solution was mixed with the methylcellulose solution, and this mixture was added to a solution of glucosamine and sucrose palmitate in water prior to administration to rats. The catechin and PEP solution were mixed with a magnetic stirrer at room temperature to prepare a catechin / PEP solution. The content of catechin / PEP is 300 mg / kg catechin, 400 mg / kg sucrose palmitate, glucosamine (catechin to glucosamine molar ratio 1: 4), and methylcellulose (catechin to methylcellulose molar ratio 1: 0) for each administration. .5). The catechin / PEP composition was administered to rats according to the procedure of Example 3. Blood was collected from each rat at specific time intervals and centrifuged. Plasma was analyzed by HPLC and bioavailability was calculated. The results are shown in Table 8.

Example 10
Aztreonam solution (containing arginine as a pH adjuster) was mixed with methylcellulose solution and this mixture was added to a solution of glucosamine and sucrose palmitate in water prior to administration to rats. The aztreonam / PEP solution was mixed with a magnetic stirrer at room temperature to prepare an aztreonam / PEP solution. The content of aztreonam / PEP is 40 mg / kg aztreonam, 400 mg / kg sucrose palmitate, glucosamine (molar ratio of aztreonam to glucosamine 1: 4) and methylcellulose (molar ratio of aztreonam to methylcellulose 1: 0) for each administration. 5), and arginine (molar ratio of aztreonam to arginine 1: 0.6). The aztreonam / PEP composition was administered to rats according to the procedure of Example 3. Blood was collected from each rat at specific time intervals and centrifuged. Plasma was analyzed by HPLC and bioavailability was calculated. The results are shown in Table 9.

The results indicate that the percent bioavailability was 91.1 ± 14.6%.
Example 12
A paclitaxel solution was prepared by adding Solutol or TPGS (stabilizer) and mixed with a methylcellulose solution, and this mixture was added to a solution of glucosamine and sucrose palmitate in water prior to administration to rats. The paclitaxel and PEP solution were mixed with a magnetic stirrer at room temperature to prepare a paclitaxel / PEP solution. The paclitaxel / PEP content was set as shown in Table 10.

^ａパクリタキセル：メチルセルロースモル比＝１：０．５

そのパクリタキセル／PEP組成物を実施例３の手順に従ってラットに投与した。特定の時間間隔でそれぞれのラットから血液を採取し、遠心分離した。血漿をHPLCで解析し、そしてバイオアベイラビリティーを計算した。結果を表１１に示す。

^a paclitaxel: cellulose molar ratio = 1: 0.5

The paclitaxel / PEP composition was administered to rats according to the procedure of Example 3. Blood was collected from each rat at specific time intervals and centrifuged. Plasma was analyzed by HPLC and bioavailability was calculated. The results are shown in Table 11.

  The bioavailability of PEP10 and PEP11 was 20.7% and 21.3%, respectively.

FIG. 1 shows the serum recombinant human growth hormone (rhGH) concentration over time after subcutaneous injection with 0.1 mg / kg rhGH (▲) or 0.5 mg / kg rhGH (♦). Figure 2 shows the duodenum in 1 mg / kg rhGH (▲), 3 mg / kg rhGH (■), or 10 mg / kg rhGH (♦) and a fixed amount of carrier (10 units); n = 3-4 rats The serum rhGH concentration over time after internal administration is shown. Figure 3 shows the time course of 3 mg / kg rhGH after intraduodenal administration with 5 units (X), 10 units (●), 2 units (▲), 50 units (■), or 100 units (♦) carriers. Serum rhGH concentration is shown; n = 3-4 rats. Figure 4 shows the serum rhGH concentration over time after intraduodenal administration of 3 mg / kg rhGH with poly (L-lysine) / sucrose laurate 16 carrier (♦) or glucosamine / sucrose laurate 16 carrier (■). Show. FIG. 5 shows the serum insulin concentration over time after intraduodenal administration of insulin to diabetes-induced rats: insulin control, 2 IU / kg (●); insulin (50 IU / kg) / carrier (100 units) (■) N = 2. FIG. 6 shows serum glucose levels over time after intraduodenal administration of insulin (with zinc) to diabetes-induced rats: insulin control, 2 IU / kg (◆); insulin (50 IU / kg) / carrier (100 units) ) (■); n = 2. FIG. 7 shows serum glucose levels over time after intraduodenal administration of insulin to non-diabetic rats: insulin control, 2 IU / kg (subcutaneous, n = 3) (●); insulin (50 IU / kg) / Carrier (100 units) (ID, n = 5) (■).

Claims (44)

A composition for oral administration of a medicinal substance that is poorly absorbed through the intestinal mucosa, comprising an effective amount of the medicinal substance; a toughening agent to enhance the absorption of the medicinal substance through the intestinal mucosa; A composition comprising a promoter for synergistic action with a fortifier for further enhancement; and optionally a protective agent for inhibiting the degradation or inactivation of the pharmaceutical substance, wherein the fortifier is a fatty acid ester A member selected from the group consisting of phospholipids, phosphatidyl compounds, glycosylceramides, fatty acids, nonionic surfactants, vitamin E tocopheryl succinate polyethylene glycol, glycerides, derivatives thereof, and mixtures thereof;
The promoter is a member selected from the group consisting of amino acid derivatives, amino sugars, and mixtures thereof; and the protective agent is carbomer, carboxymethyl cellulose, polysaccharide, pectin, cellulose, dextrin, gelatin, polyethylene oxide, poly ( Vinyl alcohol), poly (vinyl propylene), poly (vinyl pyrrolidone), xanthan gum, sodium alginate, methacrylic acid copolymer, colloidal silica, synthetic silica, polysaccharides, water-soluble cellulose ether, hydroxypropyl methacrylate, tragacanth gum, water-soluble chitosan, poly The composition, wherein the composition is a member selected from the group consisting of carbophil, derivatives thereof, and mixtures thereof. 2. The composition of claim 1, wherein the protective agent is a member selected from the group consisting of methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, and mixtures thereof. 2. The composition of claim 1, wherein the toughener is from the group consisting of sucrose stearate, sucrose palmitate, sucrose laurate, sucrose behenate, sucrose oleate, sucrose erucate, and mixtures thereof. Said composition being a selected fatty acid ester. 2. The composition of claim 1, wherein the fortifying agent is a glycerol ester of a fatty acid. 2. The composition of claim 1, wherein the enhancer is a phospholipid derivative. 2. The composition of claim 1, wherein the toughening agent is a phosphatidyl derivative. 2. The composition of claim 1, wherein the toughening agent is a glycosylceramide derivative. The composition of claim 1, wherein the toughening agent is a fatty acid derivative. The composition of claim 1, wherein the reinforcing agent is a polyoxyethylene-polyoxypropylene glycol block copolymer, a sorbitan fatty acid ester, a fluorine-containing surfactant, octoxynol, polyoxyethylene sorbitan, polyoxyethylene ether, polyethylene- Said composition, which is a nonionic surfactant selected from the group consisting of polypropylene block copolymers, and mixtures thereof. 2. The composition of claim 1, wherein the toughening agent is a member selected from the group consisting of vitamin E tocopheryl succinate polyethylene glycol derivatives. 2. The composition of claim 1, wherein the toughening agent is a member selected from the group consisting of glyceride derivatives. The composition of claim 1, wherein the accelerator is glucosamine, galactosamine, N-acetylglucosamine, muramic acid, N-acetylmuramic acid, N-acetylgalactosamine, sialic acid, poly (allylamine), poly (L-lysine). ), Poly (L-arginine), poly (L-histidine), poly (ethyleneimine), poly (L / D-histidine), poly (L-arginine), poly (allylamine), poly (ethylamine), glucagon, The composition, wherein the composition is a member selected from the group consisting of glycirrizhin, glutamic acid derivatives, bile acids, poly (ethylene glycol), acylcarnitine, citric acid, and mixtures thereof. 13. The composition of claim 12, wherein the accelerator is a member selected from the group consisting of poly-L-lysine, glucosamine, poly-L-arginine, galactosamine, N-acetylglucosamine, and mixtures thereof. object. 2. The composition of claim 1, wherein the pharmaceutical substance comprises a peptide or protein. 2. The composition of claim 1, wherein the medicinal substance comprises an aminoglycoside antibiotic. 2. The composition of claim 1, wherein the pharmaceutical substance comprises a hydrophilic or amphiphilic agent. 2. The composition of claim 1, wherein the medicinal substance comprises insulin. 2. The composition of claim 1, wherein the medicinal substance comprises human growth hormone. 2. The composition of claim 1, wherein the pharmaceutical substance comprises calcitonin. 2. The composition of claim 1, wherein the pharmaceutical substance comprises isepamicin. 2. The composition of claim 1, wherein the pharmaceutical substance comprises netilmicin. 2. The composition of claim 1, wherein the medicinal substance comprises teicoplanin. 2. The composition of claim 1, wherein the medicinal substance comprises catechin. 2. The composition of claim 1, wherein the pharmaceutical substance comprises aztreonam. 2. The composition of claim 1, wherein the medicinal substance comprises paclitaxel. A composition for oral administration of a medicinal substance that is poorly absorbed through the intestinal mucosa after oral administration, said composition comprising an effective amount of the medicinal substance; a toughener for enhancing the absorption of the medicinal substance through the intestinal mucosa, wherein The enhancer comprises a sucrose fatty acid ester; an enhancer acting synergistically to enhance absorption of the pharmaceutical substance through the intestinal mucosa, wherein the enhancer comprises glucosamine or poly (L-lysine); And optionally a protective agent for inhibiting degradation or inactivation of the pharmaceutical substance, wherein the protective agent comprises methylcellulose or poly (vinyl alcohol),
Said composition. 27. The composition of claim 26, wherein the sucrose fatty acid ester comprises sucrose stearate. 27. The composition of claim 26, wherein the sucrose fatty acid ester comprises sucrose palmitate. 27. The composition of claim 26, wherein the accelerator comprises glucosamine. 27. The composition of claim 26, wherein the accelerator comprises poly (L-lysine). 27. The composition of claim 26, wherein the protective agent comprises methylcellulose. 27. The composition of claim 26, wherein the protective agent comprises poly (vinyl alcohol). A composition for oral administration of a hydrophilic or amphiphilic drug, said drug;
And enhancers to enhance drug absorption through the intestinal mucosa, where the enhancers are fatty acid esters, phospholipids, phosphatidyl compounds, glycosylceramides, fatty acids, nonionic surfactants, vitamin E tocopheryl succinate polyethylene glycol A facilitator acting synergistically with a toughener to further enhance absorption of the drug through the intestinal mucosa, wherein the facilitator is a member selected from the group consisting of: The agent is a member selected from the group consisting of poly (amino acids), amino sugars, and mixtures thereof;
A composition comprising 34. The composition of claim 33, further comprising a protective agent for protecting the drug from degradation or inactivation, wherein the protective agent is carbomer, carboxymethylcellulose, polysaccharide, pectin, cellulose, dextrin, gelatin, polyethylene. Oxide, poly (vinyl alcohol), poly (vinyl propylene), poly (vinyl pyrrolidone), xanthan gum, sodium alginate, methacrylic acid copolymer, colloidal silica, synthetic silica, water-soluble cellulose ether, hydropropyl methacrylate, tragacanth gum, water-soluble chitosan, The composition, wherein the composition is a member selected from the group consisting of polycarbophil, derivatives thereof, and mixtures thereof. 35. The composition of claim 34, wherein the protective agent is methylcellulose and the reinforcing agent is a sucrose fatty acid ester. 35. The composition of claim 34, wherein the protective agent is poly (vinyl alcohol) and the toughening agent is sucrose fatty acid ester. 35. The composition of claim 34, wherein the protective agent is polyvinyl pyrrolidone and the reinforcing agent is a sucrose fatty acid ester. 34. The composition of claim 33, wherein the promoter is glucosamine or poly (L-lysine). A dosage form for oral administration of a poorly absorbable drug in the intestine, in an effective amount of the drug; a toughening agent to enhance the absorption of the drug through the intestinal mucosa; to further enhance the absorption of the drug through the intestinal mucosa A dosage form comprising: a promoter acting synergistically with a toughener; and optionally a protective agent to reduce or inhibit degradation or inactivation of the drug in the gastrointestinal tract. 40. The dosage form of claim 39, wherein the dosage form comprises a tablet. 41. The dosage form of claim 40, wherein the tablet further comprises a member selected from the group consisting of diluents, binders, lubricants, disintegrants, colorants, flavoring agents, sweetening agents, and mixtures thereof. Dosage form. 41. The dosage form of claim 40, wherein the dosage form comprises a capsule. 40. The dosage form of claim 39, further comprising an enteric coating. A method for increasing intestinal absorption of a poorly absorbable drug,
An enhancer to enhance absorption of the drug through the intestinal mucosa; an enhancer that acts synergistically with the enhancer to further enhance absorption of the drug through the intestinal mucosa; and optionally of the drug in the gastrointestinal tract Protective agents to reduce or inhibit degradation or inactivation;
Orally administering a composition comprising a mixture of:

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