MXPA06012489A - Oral formulation for delivery of poorly absorbed drugs. - Google Patents

Abstract

A composition for oral delivery of a poorly absorbed drug is disclosed. The composition includes the drug, an enhancer for increasing absorption of the drug through the intestinal mucosa, a promoter, which alone does not increase absorption of the drug through the intestinal mucosa, but which further increases the absorption of the drug in the presence of the enhancer, and optionally a protector for protecting the drug from physical or chemical decomposition or inactivation in the gastrointestinal tract. Illustrative enhancers include sucrose fatty acid esters, and illustrative promoters include aminosugars and amino acid derivatives, such as poly(amino acids). Illustrative protectors include methylcellulose, poly(vinyl alcohol), and poly(vinyl pyrrolidone).

Description

ORAL FORMULATION FOR THE SUPPLY OF DEFICIENTLY ABSORBED DRUGS FIELD OF THE INVENTION This invention relates to the delivery of drugs. More particularly, this invention relates to compositions and methods for the oral delivery of poorly absorbed drugs.

BACKGROUND OF THE INVENTION The gastrointestinal tract, in particular the small intestine, is the primary site for the absorption of nutrients and the majority of bioactive agents. To adapt the absorption processes, the amount of surface area in the small intestine is long due to the presence of hairs and micro-hairs. However, before a bioactive compound is transferred from the intestinal lumen into the blood, the compound can be subject to degradation. or deactivation, through the various components of the lumen. However, the compound may be required to pass through various barriers to absorption, such as, for example, the mucosal layer and the intestinal brush border membrane. Many compounds pass these barriers easily, although there are many nutrients and bioactive agents for which you are barriers represent a serious obstruction. 'There are many factors that can affect the oral bioavailability of drugs in the gastrointestinal tract. They include, for example, factors that are related to the drug itself, such as, for example, active or passive transport, water solubility, molecular weight, chemical stability, ionization, pH, and the like; factors that are related to chemical processes, such as, for example, deamination, hydrolysis (or ionization), oxidation, racemization, beta elimination, disulfide exchange, and the like; and factors that relate to physical processes, such as, for example, aggregation, precipitation, denaturation, adsorption, and the like. While prior art products and methods of use thereof are known and are generally suitable for their limited purposes, they possess certain inherent deficiencies that detract from their total utility to deliver drugs that can be poorly absorbed by orally Namely, these prior art products and processes fail to increase the intestinal absorption of the drugs while preventing the decomposition or physical and / or chemical inactivation of the drugs. In view of the above, it will be appreciated that the Providing compositions and methods for an efficient oral delivery of poorly absorbed drugs could be a significant advance in the art.

SUMMARY OF THE INVENTION A feature of the illustrative embodiments of the present invention is to provide compositions and methods for use and elaboration thereof which improve the intestinal absorption of orally administered drugs and simultaneously reduce or inhibit the decomposition or inactivation of drugs due to to physical and / or chemical factors. These and other objects may be met by providing a composition for oral delivery of a pharmaceutical agent that is poorly absorbed through the intestinal mucosa, the composition comprising a mixture of an effective amount of the pharmaceutical agent; an enhancer to increase the absorption of the pharmaceutical agent through the intestinal mucosa; a promoter that works synergistically with the enhancer to further increase the absorption of the pharmaceutical agent through the intestinal mucosa; and optionally a protector to inhibit the decomposition or inactivation of the pharmaceutical agent; whereas the intensifier is a member selected from the group that consists of fatty acid esters, phospholipids, phosphatidyl compounds, glucosylceramides, fatty acids, non-ionic surfactants, vitamin E tocopheryl succinate polyethylene glycol, glycerides, derivatives thereof, and mixtures thereof; wherein the promoter is a member selected from the group consisting of amino acid derivatives, amino sugars, and mixtures thereof; and wherein the protector is a member selected from the group consisting of carbomers, carboxymethylcellulose, polysaccharides, pectin, cellulose, dextrin, gelatin, polyethylene oxide, polyvinyl alcohol, poly (vinylpropylene), poly (vinylpyrrolidone), xanthan, sodium alginate, sodium alginate, methacrylic acid copolymers, colloidal silica-, synthetic silica, polysaccharides, water-soluble cellulose ethers, hydroxypropylmethacrylates, tragacanth, water soluble chitosan, polycarbophil, derivatives thereof, and mixtures of the same. Another illustrative embodiment of the invention comprises a composition for the oral delivery of a pharmaceutical agent that is poorly absorbed through the intestinal mucosa after oral administration, the composition comprising a mixture of an effective amount of the pharmaceutical agent; an intensifier for increasing the absorption of the pharmaceutical agent through the intestinal mucosa wherein the enhancer comprises an ester of fatty acid and sucrose; a promoter that works synergistically with the enhancer to increase the absorption of the pharmaceutical agent through the intestinal mucosa when the promoter comprises glucosamine or poly (L-lysine); and optionally a protector for inhibiting the decomposition or inactivation of the pharmaceutical agent, wherein the protector comprises methylcellulose or polyvinyl alcohol. Yet another illustrative embodiment of the invention comprises a composition for the oral delivery of a hydrophilic or amphipathic drug, the. The composition comprises a mixture of the drug and an enhancer for increasing absorption of the drug through the intestinal mucosa, wherein the enhancer is a member selected from the group consisting of fatty acid esters, phospholipids, phosphatidyl compounds, glucosylceramides, fatty acids. , non-ionic surfactants, vitamin E polyethylene glycol tocopheryl succinate, glycerides, derivatives thereof, and mixtures thereof; and a promoter to work synergistically with the enhancer to further increase the absorption of the drug through the intestinal mucosa, wherein the Promoter is a member selected from the group consisting of poly (amino acid), amino sugars, and mixtures thereof. Yet another illustrative embodiment of the invention comprises a dosage form for the oral delivery of a drug that can be poorly absorbed in the intestine, the dosage form comprising: an effective amount of the drug; • an intensifier to increase the absorption of the drug through the intestinal mucosa; a promoter to work synergistically with the enhancer to further increase the absorption of the drug through the intestinal mucosa; and optionally, a protector to reduce or inhibit the decomposition or inactivation of the drug in the gastrointestinal tract. Yet another illustrative embodiment of the invention comprises a method for increasing the intestinal absorption of a drug that can be poorly absorbed, the method comprising orally administering a composition comprising a mixture of the drug; an intensifier to increase the absorption of the drug through the intestinal mucosa; a promoter that works synergistically with the intensifier to increase additionally the absorption of the drug through the intestinal mucosa; and optionally, a protector to reduce or inhibit the decomposition or inactivation of the drug in the gastrointestinal tract.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the concentration of the recombinant serum human growth hormone (rhGH) over time after subcutaneous injection with 0.1 mg / kg rhGH (A) or 0.5 mg / kg rhGH (). Figure 2 shows the concentration of serum rhGH over time after intraduodenal administration with 1 mg / kg rhGH (A), 3 mg / kg rhGH (I), or 10 mg / kg rhGH (i) and a fixed amount of the carrier (10 units); n = 3-4 rats. Figure 3 shows the concentration of serum rhGH over time after intraduodenal administration of 3 mg / kg of rhGH with 5 units (X) 10 units (•), 20 units (A), 50 units (I) or 100 units () of the carrier; n = 3-4 rats. Figure 4 shows the concentration of serum rhGH over time after intraduodenal administration of 3 mg / kg rhGH with a poly (L-) carrier. lysine) / sucrose laurate 16 () or a glucosamine / sucrose laurate carrier 16 (M). Figure 5 shows the serum insulin concentration over time after intraduodenal insulin administration for diabetes induced in rats; insulin control, 2 IU / kg (•); insulin (50 IU / kg) / carrier (100 units) '(B); n = 2. Figure 6 shows serum glucose levels over time after intraduodenal administration of insulin (with zinc) for diabetes induced in rats: insulin control, 2 IU / kg (•); insulin (50 IU / kg) / carrier (100 units) (B); n = 2. Figure 7 shows serum glucose levels over time after intraduodenal insulin administration for non-diabetic rats: insulin control, 2 IU / kg (subcutaneous, n = 3) (•); insulin (50 IU / kg) / carrier (100 units) (I.D. n = 5) (B).

DETAILED DESCRIPTION OF THE INVENTION In the foregoing the present compositions and methods were set forth and described, it should be understood that this invention is not limited to the particular configurations, process steps, • and materials set forth herein as such configurations, steps of process, and materials may vary to some extent. It must also understand that the terminology used herein is used for the purposes of describing only particular embodiments and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof. The publications and other reference materials referred to herein to describe the background of the invention and to provide additional details that relate to its practice are incorporated herein by reference. The references set forth herein are provided only by their disclosure prior to the filing date of the present application. Nothing herein shall be construed as an admission that the inventors are not entitled to precede this disclosure by virtue of the foregoing invention. It should be noted that, in the sense in which it is used in this specification and the appended claims, the singular forms "one," "an," and "the" include plural references unless the context clearly dictates otherwise. way. Thus, for example, reference to a composition containing an oral drug that includes "a drug" also includes a mixture of two or more of these drugs, reference to "an enhancer" includes reference to one or more of these intensifiers, and the reference to "a protector" includes "The reference to a mixture of two or more of these protectors. In order to describe and claim the present invention, the following terminology would be used according to the definitions set forth below. In the sense in which it is used in the present, "comprising", "including", "containing", "characterized by" and the grammatical equivalent thereof are inclusive and open terms that do not exclude additional elements, not mentioned or the steps of the method. "Understanding" should be interpreted to include the most restrictive terms "consisting of" and "consisting essentially of e". In the sense in which it is used in the present "consisting of" and the grammatical equivalents thereof exclude any element, step, or ingredient not specified in the claim. In the sense in which it is used herein, "consisting essentially of" and its grammatical equivalents limit the scope of a claim to specific materials or steps and those that do not materially affect the basic or novel characteristics or characteristics of the claimed invention. In 'the sense in which it is used in the present, "protector" means a biopolymer which serves to protect the drug from decomposition or inactivation due to conditions found in the small intestine. The protector does not form a complex with the drug and does not covalently bind to the drug. Exemplary protectors according to the present invention include methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and mixtures thereof. As used herein, "enhancer" means a substance that enhances or increases the absorption of a drug or other pharmaceutical agent through the intestinal mucosa after delivery of the drug or pharmaceutical agent by the oral route. . Illustrative intensifiers include surfactants, such as, for example, sucrose esters, and the like. As used herein, "promoter" means a substance that exhibits little or no effect to enhance or enhance the absorption of the drug or other pharmaceutical agent through the intestinal mucosa after delivery of the drug or agent pharmaceutical by the oral route, although it increases the intensifying effect of the absorption of an intensifier when the drug or the pharmaceutical agent is supplied in combination or together with an enhancer and a promoter. Thus, for example, oral administration of a composition comprising a mixture of a drug or other pharmaceutical agent, an enhancer, and a promoter results in greater absorption of the drug or pharmaceutical agent through the intestinal mucosa. of what the oral administration of a similar composition that lacks the promoter would do. Illustrative promoters include amino sugars and amino acid derivatives, such as, for example, poly (amino acids). In the sense in which it is used herein, "derivative" means a modified version of a compound or molecule. For example, this modified version may include, but is not limited to, a polymer, copolymer, ester, alkylated version, arylated version, aralkylated version, or the like of the compound or molecule. • "In the sense in which it is used herein," surfactant "or" surfactant "means a substance that alters the energy relationship to interfaces, such as, for example, synthetic organic compounds exhibiting surface activity, including , among others, wetting agents, detergents, penetrants, extenders, dispersing agents, and agents foaming. Illustrative examples of surfactants useful in the present invention are nonionic surfactants. In the sense in which it is used herein, "HLB" means "hydrophilic-lipophilic equilibrium" which is an empirical quantity, on an arbitrary scale, which is a measure of the polarity of a surfactant or 'mixture of su' rfactant P. Becher, et al, Nonionic, 'S'urfactant Physical Chemistry 439-56 (Marcel Dekker, NY, 1987). It is a widely known and used term. See, for example, U.S. Patent No. 5,707,648. As used herein, "effective amount" means an amount of a drug or a pharmacologically active agent that is not toxic but sufficient to provide the desired local and / or systemic effect and performance at a "reasonable" ratio. of benefit / risk attending to any medical treatment. In the sense in which it is used herein, "peptide" means peptides of any length and includes oligopeptides, polypeptides, and proteins. The only limitation to the protein and peptide drug that can be used according to the invention is functionality.

As used herein, "poorly absorbed drug" and similar terms mean drugs or other pharmacologically active agents that are not readily absorbed through the intestinal mucosa into the blood stream after oral administration, such as way that these drugs or pharmaceutical agents are not normally administered orally. In other words, "poorly absorbed drugs" include drugs that are normally administered by injection, or transdermal or transmucosal administration because of poor absorption in the bloodstream after oral administration or decomposition or inactivation due to physical and respiratory factors. / or chemicals, as described above. Illustrative of the poorly absorbed drugs are protein and peptide drugs, aminoglycoside antibiotics, and the like. These poorly absorbed drugs can be hydrophilic, amphiphilic or hydrophobic. The present invention provides compositions and methods for delivering a wide variety of therapeutic and diagnostically useful molecules that are not readily absorbed through intestinal membranes. In particular, this invention relates to compounds that act as carriers of the drug for large molecules therapeutic and quite soluble in water and the pharmaceutical ingredients comprising these carriers. The invention functions to reduce or inhibit the physical and / or chemical decomposition or inactivation of active drugs, and simultaneously increases the entry of the drug into cells and tissues, effectively increasing intestinal absorption and distribution to blood vessels. Therefore, the pharmaceutical ingredients of the invention are particularly useful for oral administration. This enhancer system is particularly useful for delivering protein and peptide drugs, for example, insulin, calcitonin, and human growth hormone (HGH) or other drugs that are poorly absorbed in the gastrointestinal tract due to the High solubility in water or because these drug undergo decomposition or inactivation under conditions found in the gastrointestinal tract. In addition to the protein and peptide drugs, other poorly absorbed drugs that can be effectively delivered in accordance with the present invention include aminoglycoside antibiotics, glycopeptide antibiotics, carbapenem, and catechin, and the like. • Examples of poorly absorbed drugs that can be given orally from according to the present invention include drugs from various categories. Protein and peptide drugs include insulin, human growth hormone, calcitonin, high-density lipoprotein (HDL), erythropoietin (EPO), and the like. Aminoglycoside antibiotics include netilmicin, isepamycin, amikacin, tobramycin, gentamicin, and the like, and mixtures thereof. Glycopeptide antibiotics include teicoplaniha, vancomycin, and bleomycin, and the like, and mixtures thereof. Various drugs include daptqmycin, tigecycline, ramoplanin, catechin, aztreonam, ipene, cilastatin, and the like, and mixtures thereof. Anti-cancer drugs include paclitaxel and the like. The drugs that can be delivered in accordance with the present invention include the following. Peptide drugs include adenosine, deaminase, adrenocorticotropic hormone (ACTH) and fragments thereof, angiotensin and related peptides, antibody fragments, antigens and fragments thereof, atrial natriuretic peptide, arginase, asparaginase, bioadhesive peptide, bradykinin and related peptides, calcitonin and related peptides, protein fragment of the cell surface receptor, chemotactic peptide, cyclosporins, chymotrypsin, cytokines, dynorphin and related peptides, endorphin and ß-lidotropin fragment, encephalitis and its peptide species, enzymatic inhibitors, erythropoietin, fibronectin fragment and related peptide, gastrointestinal peptide, peptide for hormone release growth, immuno-stimulating peptide, interleukins, leutinizing hormone-releasing hormone (LH-RH) and its related peptides, melanocyte-stimulating hormone and related peptides, monoclonal antibodies (eg, Remicade®), peptide related to nuclea localization signal, neurotensin and related peptides, neurotransmitter peptide, opioid peptides, oxytocin, papain, vasopressin and related peptides, parathyroid hormone and its fragments, prolactin, peptide related to cinsa protein, ribonuclease, somatostatin and related peptides , substance P and its pe related peptides, superoxide dismutase, transforming growth factor (TGF) and related peptides, thyroid stimulating hormones, trypsin, fragments of tumor necrosis factor and toxin and / or toxoid, functional peptide (angiostatin, peptide anti-cancer), anti-hypertension peptide, blood anti-coagulation peptide, anti-microbial peptide, and the like and mixtures thereof. Protein drugs include immunoglobulins, angiogenin, morphogenic bone protein, chemokines, colony stimulating factor (CSF) and related proteins, cytokines, growth factors, interferons, interleukins, leptin, leukemia inhibitory factor, I have ocitoblasts, transforming growth factor, tumor necrosis factor and the like and mixtures thereof. Hydrophilic, antipathic, or hydrophobic drugs that can be used in accordance with the present invention include anti-viral agents, anti-inflammatory steroidal drugs, non-steroidal anti-inflammatory drugs, antibiotics (in particular, aminoglycosides such as, for example, netilmicin, isepamycin, teicoplanin), antimicrobials, vitamins, hormones, prostaglandins, prostacyclines, anticancer drugs (for example, tamoxifen), antimetabolites, miotics, adrenaline antagonists, cholinomimetic drugs, anticonvulsants, antidepressants, antipsychotics, anesthetics, analgesic, steroids, estrogens , lipopeptide antibiotics (for example, dapto icine), progesterones, glycosaminoglycans, polynucleotides, immuno-suppressants, immuno-stimulant, and the like, and mixtures thereof.

Intensifiers that can be used in accordance with the present invention include fatty acid esters and sucrose, such as, for example, sucrose stearate, sucrose palmitate, sucrose laurate, sucrose behenate, sucrose oleate, sucrose erucate, and the like, and mixtures thereof; phospholipid derivatives, phosphatidyl derivatives, glucosylceramide derivatives, fatty acid derivatives, non-ionic surfactants, vitamin E derivatives polyethylene glycol (TPGS) tocopheryl succinate, derivatives of the Gelucire® series; derivatives of glyceride and the like and mixtures thereof. Phospholipids include phosphoglycerides. Glycerides include glycerol mono-, di-, and tri-esters. Fatty acids are generally straight-chain carboxylic acid compounds that vary from three to 18 carbons. Fatty acids include saturated compounds, such as, for example, butyric, caproic, caprylic, capric, lauric, myristic, palmitic and stearic acids; and unsaturated acids containing one or more double bonds per molecule. The most common of the unsaturated fatty acids are oleic acid, linoleic acid, and linolenic acid. Ceramides are derivatives of fatty acid and N-acyl of a sphingosine, in this way, glucosylceramides are ceramides linked to radicals saccharide. The GELUCIRE® series of surfactants (Gattefosse, S.A. San Priest, France) comprises glycerol esters of fatty acids. For example, GELUCIRE® 33/01 comprises glycerol esters of C8-C? 8 saturated fatty acids with a melting point of 33-37 ° C and a HLB of 1. GELUCIRE® 39/01 comprises glycerol esters of C? 2. -C? 8 saturated fatty acid esters with a melting point of 37.5-41.5 ° C and a HLB of 1. GELUCIRE® comprises glycerol esters of C? 2-C? 8 fatty acid esters saturated with a melting point of 42-46 ° C and a HLB of 1. GELUCIRE® 44/14 comprises a well-defined mixture of mono-, di-, and triglycerides and ono-and fatty acid diesters of polyethylene glycol. It is synthesized by an alcoholysis / esterification reaction using hydrogenated palm kernel oil and PEG1500 as starting materials. The predominant fatty acid is lauric acid (C? 2). It has a melting point of 42-4ß ° C and a HLB of 14. It is also known as 'lauroyl macrogol-3' glycerides. GELUCIRE® 50/13 is a well-defined mixture of mono-, di-, and triglycerides and mono- and diesters of polyethylene fatty acids. It is synthesized by an alcoholysis / esterification reaction using hydrogenated palm oil and PEG1500 as the starting materials. The acid predominant fatty acid is palmitoestearic acid (C16-C? 8). It has a melting point of 46-51 ° C and a HLB of 13. It is also known as stearoyl glycerides macrogol-32. Illustrative phosphatides according to the present invention include phosphatidylcholine with both saturated and unsaturated lipids, including dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), diarachidonylphosphatidylcholine. (DAPC, for its acronym in English); phosphatidylethanolamines, such as, for example, dioleoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine (DPPE), and distearoylphosphatidylethanolamine (DSPE); phosphatidyloserine; phosphatidylglycerols, including distearoylphosphatidyloglycerol (DSBG); phosphatidyloinositol; phosphatidic acids, including dipalmitoylphosphatidic acid (DPPA, for its acronym in English) and distearoylphosphatidic acid (DSPA, for its acronym in English); and the like; and mixtures thereof. Illustrative fatty acids according to the present invention include palmitic acid, acid stearic, oleinic acid, arachidonic acid, and the like, and mixtures thereof. Exemplary nonionic surfactants according to the present invention include polyoxyethylene-polyoxypropylene glycol block copolymers, fatty acid esters and sorbitan, and fluorine-containing surfactants. Illustrative of the polyoxyethylenepolyoxypropylene glycol block copolymers are block copolymers of α-hydroxy-α-hydroxypiol (oxyethylene) -poly (oxypropylene) -poly (oxyethylene). These latter block copolymers are generally referred to as poloxamer copolymers. Examples of poloxamer copolymers that are particularly suitable for use 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.). Illustrative of the sorbitan fatty acid esters are, for example, poly (oxy-1, 2, -etandiyl) derivatives of higher alkyl sorbitan esters. Examples of these sorbitan esters include, for example, sorbitan monolaurate, sorbitan mqnooleate, sorbitan monopalmitate, and sorbitan monostearate. These, as well as other sorbitan derivatives, are typically referred to as polysorbates, including, example, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. Several of the polysorbates are commercially available from Spectrum 1100 (Houston, Texas). Illustrative of fluorine-containing surfactants are surfactants that contain one or more fluorine atoms. Examples of these surfactants include those commercially available from DuPont Chemical (Wilmington, Delaware) and sold under the trademarks Z0NYLMR, including, for example, ZONYLMR FSN-100 and ZONYLMR FSO-100. Additional nonionic surfactants according to the present invention include 'octoxins (for example, TRITON-X® surfactants), polyoxyethylene sorbitans (for example, TWEEN® surfactants), polyoxyethylene ethers (for example, surf surfactants), BRIJ®), polyethylene-polypropylene block copolymers (for example, 'PLURONIC®' surfactants), fluorosurfactants (for example, ZONYLMR surfactants), and FLUORAD® surfactants. Promoters that can be used in accordance with the present invention include amino acid derivatives (such as, for example, poly (amino acids)), aminoazúcares, and the like, and mixtures thereof.

Promoters that can be used in accordance with 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 (ethylanimine), poly (L / D-histidine), (poly) L-arginine, poly (allylamine), poly (ethylamine), glucagon, glycyrrhizin, acid derivatives glutamic (eg, L-glutamine, diethyl ester of L-glutamic acid), bile salts, PEG derivatives, acylcarnitides, citric acids, and the like and mixtures thereof. Illustrative promoters that can be used in accordance with the present invention include poly-L-lysine, glucosamine, poly-L-arginine, galactosamine, N-acetylglucosamine, and the like, and mixtures thereof. Protectants that can be used in accordance with the present invention include carbomers, carboxymethylcellulose, polysaccharides (kappa, iota, lambda), pectin, celluloses and derivatives thereof (such as, for example, methylcellulose and derivatives thereof, ethylcellulose and derivatives thereof, hydroxypropyl cellulose and derivatives thereof), dextrin, gelatin, polyethylene oxide, polyvinyl alcohol, poly (vinylpropylene), poly (vinylpyrrolidone) xanthan gum, sodium alginate, methacrylic acid copolymers such for example, those sold under the trade name Eudragit®, colloidal silica, and synthetic silica derivatives (eg, silicon dioxide and the like), polysaccharides, water-soluble cellulose ethers, hydroxypropylmethacrylate (HPM) derivatives acetate succinate / phthalate, tragacanth, water soluble chitosan, polycarbophil, and the like and derivatives thereof, and mixtures thereof. Illustrative protectors according to the present invention include methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and mixtures thereof. As used herein, "PEP" means the carrier compositions according to the present invention, which includes an optional protector, an enhancer, and a promoter. The carrier is mixed with a drug to result in a composition containing the drug. The formulation is prepared by mixing. the drug, the enhancer, the promoter, and an optional protector to form a solution. The solution will usually be dried according to methods well known in the art, such as, for example, lyophilization, atomization and the like, to result in a dry product. This dry product is then manufactured in a form of selected dosage, such as for example, tablets or capsules, according to well-known methods. These dosage forms are coated with an enteric coating to allow the dosage forms to pass through the acid conditions of the stomach into the intestines., wherein the coating disintegrates to allow the release of the ingredients in the intestines to facilitate absorption through the intestinal mucosa and thereby into the bloodstream. As used herein, "tablets" are solid pharmaceutical dosage forms containing drug substances with or without suitable diluents and prepared either by compression or molding methods well known in the art. Tablets are still very popular as a dosage form due to the advantages produced both for the manufacturer (eg, simplicity and economy of preparation, stability, and convenience packaging, transport and distribution) and to the patient (eg, precision of dosage, compaction, portability, lack of flavor, and ease of administration). Although the tablets with the most frequency have discoidal shape, they can also be round, oval, oblong, cylindrical, or triangular They differ greatly in size and weight depending on the amount of the drug substance present and the intended method of administration. They are divided into two general classes, (1) compressed tablets, and (2) tablets molded or crushed tablet. In addition to the active or therapeutic ingredient or ingredients, the tablets contain various inert materials or additives. A first group of these additives includes those materials that help impart compression characteristics, satisfactory for the formulation, including diluents, binders, and lubricants.A second group of these additives helps to provide additional convenient physical characteristics to the finished tablet, such as for example, disintegrating agents, colorants, flavors, and sweeteners, in the sense in which "diluents" are used herein are added inert substances to increase the volume of the formulation to make the tablet a practical size The commonly used diluents include: calcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar, silica, and the like. used in the present, "binders" are agents used to impart cohesive qualities to the powdered material. Binders, or "granulators" as they are sometimes known, impart a cohesiveness to the tablet formulation, which ensures that the tablet remains intact after compression, as well as improving the free-flowing qualities by the formulation of granules or hardness and desired size. Materials commonly used as binders include starch; jelly; sugars, such as for example; sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as for example, acacia, sodium alginate, Irish moss extract, gum, panwar, ghatti gum, mucilage of isapol husks, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone, Veegum, microcrystalline cellulose, microcrystalline dextrose, amylase and arab'agalactano larch, and the like. In the sense in which is used in the present, "lubricants" are materials that perform various functions in the manufacture of tablets, such as, for example, improving the flow velocity of the granulation of the tablets, avoiding adhesion of the • material of the tablet to the surface of the dies and punches, reducing the friction between particles, and facilitating the execution of the tablets of the die cavity. The Lubricants used generally include talc, magnesium stearate, calcium stearate, stearic acid, and hydrogenated vegetable oils. In the sense in which it is used herein, "disintegrants" or "disintegrants" are substances that facilitate the decomposition or disintegration of the tablets after administration. The materials that serve as disintegrants have been chemically classified as starches, clays, celluloses, algines, or gums. Other disintegrators include Veegum HV, methylcellulose, 'agar,' bentonite, cellulose and wood products, natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp, cross-linked polyvinylpyrrolidone, carboxymethylcellulose, and the like. In the sense in which it is used in the present, "coloring agents" are agents that give the tablets a more pleasant appearance, and also help the manufacturer to control the product during its preparation and help the user to identify the product . Any of the FD &C water soluble, certified and approved dyes, mixtures thereof or their corresponding lacquers can be used to color the tablets. A coloring lacquer is. the combination by adsorbing a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of dye. In the sense in which it is used herein, "flavoring agents" vary considerably in their chemical structure, ranging from simple esters, alcohols and aldehydes to complex carbohydrates and volatile oils. Synthetic flavors of almost any type currently desired are available. Capsules are solid dosage forms in which the substance of the drug is enclosed in a container or soluble layer, whether hard or soft, of a suitable material, such as, for example, gelatin. Encapsulation of medicinal agents remains a popular method for drug administration, because the capsules are tasteless, easily administered, and easily filled. Some patients find it easier to swallow capsules than tablets, therefore, they prefer to use this form whenever possible. This preference has induced pharmaceutical manufacturers to label the products in the form of a capsule even though the product has already been provided in the form of a tablet. The enteric coatings are films that do not allow the release of a significant amount of the drug in the stomach, but that releases, quickly and completely the drug when the dosage form it goes inside the intestine. Many types of enteric coatings are known in the art, such as for example described in Remington's Pharmaceutical Sciences. In an illustrative embodiment of the invention, the drug is contained in a tablet or capsule, optionally together with a protector, and the enhancer and promoter are placed in another tablet or capsule. In this embodiment, the tablet or capsule containing the drug is taken together with the tablet or capsule containing the enhancer / promoter to effect oral administration of the drug. The following examples are illustrative of certain aspects of the invention and limitations of the scope of the invention should not be considered. ' Example 1 Aggregation test A solution of recombinant human growth hormone (rhGH) (0.5 mg / ml) in 20 mm phosphate buffer. The tampon of. Phosphate was prepared in filtered water, distilled three times (0.22 μm filter), and its pH adjusted to 7.4 with sodium hydroxide solution. The rhGH solutions were prepared just before use, and the concentrations were determined by measuring the UV absorbance at 278 nm. The UV absorbance at 278 nm was linearly related to the concentrations in the variation from 0.1 to 1 mg / ml. The solutions of rhGH (0.5 mg / ml) were stirred vigorously for 1 minute at high speed with a rotational mixer (Scientific Industries Inc.). After vigorous stirring, the samples were equilibrated for 30 minutes at room temperature. The optical density of the resulting turbid solutions was measured at 400 nm to verify the amount of insoluble aggregates.

This study was conducted with and without adding a protector (for example, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), and methylcellulose (MC)). A mixture of 0.5 mg of rhGH and 1 mg of methylcellulose gave an absorbance of 0.44 before vigorous agitation, and 0.07 after vigorous agitation. A mixture of 0.5 mg of rhGH and 20 mg of PVA gave an absorbance of 0.44 before vigorous agitation and 0.10 after vigorous agitation. A mixture of 0.5 mg of rhGH and 25 mg of PVP gave an absorbance of 0.44 before vigorous agitation and 0.14 after vigorous agitation. Therefore, protectors can minimize aggregation by reducing drug adsorption to interfaces. This In this way, the use of a protector can improve the physical stability of the drugs.

Example 2 Decomposition test A solution of rhGH (5 ng / ml) was prepared in 20 mm phosphate buffer. The phosphate buffer was prepared in filtered water, distilled three times (0.22 filter), and its pH adjusted to pH 7.4 with sodium hydroxide solution. The solutions of rhGH were stirred vigorously for 1 min at high speed with a rotational mixer (Scientific Industries Inc.) After vigorous agitation, the samples were equilibrated for specific time intervals at room temperature. The concentrations of rhGH were then determined by ELISA according to methods well known in the art. The results are presented in Table 1. a Glucosamine and sucrose laurate 16 b Gelucire® 44/14 c Polyvinylpyrrolidone d Polyvinyl alcohol Methylcellulose These results show that the present invention reduces the decomposition of a drug.

Example, 3 were prepared in water according to the proportions shown in Table 2, RhGH solutions containing a promoter (glucosamine or poly-L-lysis?), An enhancer (sucrose laur'ate 16), and a protector (methylcellulose).

To determine the absorption of the intestine, male Sprague-Dawley rats, with free access to water, were fasted for approximately 12 hours. On the day of the experiment, these rats were anesthetized and shaved in the abdomen. An incision was made in the 2-cm measured line through the muscle and the stomach was exposed with rounded forceps. A small incision was made of a region of the esophagus near the stomach, where the blood supply to insert a polyethylene tube into the middle duodenum was tight, which was closed at the opposite end by means of a stopcock to prevent drainage of the duodenum drug solution. This tube was guided through the stomach and the pyloric sphincter into the duodenum, approximately 5 cm after the > sphincter, and it was fixed in the stomach. The abdominal muscle was sutured under the skin. At specific time intervals, blood was drawn from each rat and subjected to centrifugation.

There were four rats in each treatment group. Approximately 50 μg of serum. they were analyzed by means of an ELISA test equipment and the concentration of rhGH was calculated. The results are shown in Table 3. In the case of rhGH administered without the PEP solution, rhGH was not detected.

Example 4 To determine the absorption of the intestine, male Sprague Dawley rats weighing 250-300 g with free access to water were fasted for approximately 18 hours before the experiments. These rats were anesthetized and maintained with ketamine / xylazine ((60 mg / kg) / (80 g / kg)) by intraperitoneal injection. The small intestine was exposed through an abdominal incision in the midline. A small incision was made in the stomach to insert a polyethylene tube (id 0.76 mm, o.dr- 1.22 mm, Clay Adams), into the middle duodenum, which was closed at the exposed end by a stopcock to prevent drainage of the drug solution of the duodenum. Blood samples were drawn with a heparinized syringe through a jugular vein catheter at predetermined time intervals. After harvesting, the samples were coagulated for approximately 90 min and then subjected to centrifugation for 10 min at 6000 rpm. The supernatant was removed and stored at -20 C. Samples were analyzed for hGH protein levels with an ELISA kit for human growth hormones (coated plate, ICN Diagnostics) according to the manufacturer's protocol. For the protocols, all controls were administered by intraduodene either glucosamine 40 mg / kg plus sucrose laurate 40 mg / kg (ie, 100 units of the carrier) or 10 mg / kg of rhGH (Advanced Protein Technologies Inc. , Suwon, Korea). The subcutaneous dosage was 0.1 mg / kg rhGH which showed a peak concentration of serum rhGH of 73 ng / ml with a Tmax of 40 min. To evaluate the effect of the variation of the amount of the administered carrier, the amount of rhGH was maintained at 3 mg / kg of rhGH and the Tmax was measured. The Tmax was less than 20 min for all doses, which showed that the absorption of rhGH was not proportional to the carrier dose. However, the data demonstrated a relationship between the dose of rhGH administered and the plasma concentration of rhGH at a fixed dose of the carrier of 10 units. In the case of subcutaneous administration (Figure 1), the serum plasma concentration profile was shown to depend on the dose. In the case of intraduodenal administration, the controls were fixed to. 10 units of the carrier. The amount of rhGH was varied to include 1, 3, and 10 mg / kg of rhGH. As with the intraduodenal study, the concentration differences depended on the. dose (Figure 2). As for bioavailability, 3 mg / kg of rhGH showed 7.1% (10 units of the dosage carrier) and 10. mg / kg of rhGH showed 6.1% (10 units of the dosage carrier). This experiment showed that the levels of rhGH depended on the dose when the amount of the 1 carrier was fixed (Figure 2). When, rhGH was set at -3 mg / kg and the amount of the carrier was varied to 100, 50, 20, 10, and 5 units, the results showed that small amounts of the carrier (10-20 units) exhibited an increased absorption of rhGH compared to higher dosages of the carrier (Figure 3). . Finally, to evaluate the effectiveness of the carrier itself, the carrier type was varied while the same level of rhGH was maintained (3 mg / kg). The carrier containing poly (L-lysine) and sucrose laurate 16 showed increased absorption compared to the carrier containing glucosamine and sucrose laurate 16 (Figure 4) based on the calculated availabilities of 21.3% and 6.6%, respectively . In this way, the carrier system of the present invention significantly improved the intraduodenal absorption of rhGH 'without the modification of the drug. The carrier system is effective -for the oral delivery of rhGH based on therapeutic levels of the drug.

Example 5 Insulin was dissolved in 0.01 N HCl and then mixed with a protector (methylcellulose), an intensifier (sucrose laurate 16), and a promoter (glucosamine) in water before administration to rats. The insulin / PEP solutions were mixed by a magnetic stirrer at room temperature. The composition of the insulin / PEP solution was formulated in such a way that an individual dosage contained 50 IU / kg of insulin, 400 mg / kg of sucrose laurate 16, glucosamine at a weight ratio of 1: 4 of insulin to glucosamine, and methylcellulose in a weight ratio of 1: 0.5 of insulin to methylcellulose. Insulin / PEP composition was administered to rats according to the procedure of Example 3. At specific time intervals, blood was drawn from each rat and subjected to centrifugation. Plasma was analyzed by a glucose meter and a radioimmunoassay test kit (ICN pharmaceutic.als) to determine blood glucose and insulin concentrations. The results are presented in Figures 5-7. In diabetic rats, serum insulin was detected in the blood (Figure 5) and significant hypoglycemic effects were observed (Figure 6) after administration of insulin in the carrier of the present invention. No -registered no significant hypoglycemic response in non-diabetic rats (Figure 7) after similar treatment. The self-regulation of insulin secretion and the secretion of counter-regulatory hormones may have compensated for the activity of insulin delivered exogenously in these non-diabetic rats. In this way, the carrier of the present invention significantly improved the intraduodenal absorption of insulin without the modification of the drug.

Example 6 Calcitonin was dissolved in water and then mixed with a protector (methylcellulose), an intensifier (sucrose laurate 16), and a promoter (glucosamine) in water before administration to rats. The insulin / PEP solutions were mixed by a magnetic stirrer at room temperature. The composition of the calcitonin / PEP solution was prepared in such a way that an individual dosage contained 2 mg / kg of calcitonin, 40 mg / kg of sucrose 16 laurate, glucosamine in a 1: 4 weight ratio of calcitonin to glucosamine , and methylcellulose in a 1: 0.5 weight ratio of calcitonin to methylcellulose. The calcitonin / PEP composition was administered to rats according to the procedure of Example 3.- A. Specific time intervals, blood was drawn from each rat and subjected to centrifugation. ' The plasma was analyzed by ELISA according to methods well known in the art. The results are presented in Table 4.

Example 7 A solution of isepamycin was mixed with a solution of methylcellulose, and the resulting mixture was mixed with solutions of glucosamine and saccharose stearate in water before administration to rats. The solutions of isepamycin and PEP were mixed by a magnetic stirrer at room temperature, forming a solution of isepamycin-PEP. The content. of isepamycin / PEP comprised an individual dosage of 75 mg / kg of isepamycin, '400 mg / kg of sucrose stearate, glucosamine in a 1: 4 molar ratio of isepamicin to glucosamine, and methylcellulose in a molar ratio of 1: 0.5 isepamycin to methylcellulose The composition of isepamycin / 'PEP was administered to rats according to the procedure of Example 3. At specific time intervals, blood was drawn from each rat and subjected to centrifugation. Plasma was analyzed by HPLC, and bioavailability was calculated. The results are shown in Table 5.

Example 8 A solution of netilmicin was mixed with a solution of methylcellulose, and this mixture was added to solutions of glucosamine and sucrose stearate in water prior to administration to rats. The solutions of netilmicin 'and PEP were mixed by means of a magnetic stirrer at room temperature, forming a solution of netilmicin-PEP. The content of netil icine / PEP comprised an individual dosage of 80 mg / kg of netilmicin, 400 mg / kg of sucrose stearate, glucosamine in a 1: 4 molar ratio of netilmicin to glucosamine, and methylcellulose in. a 1: 0.5 molar ratio of netilmicin to methylcellulose. The composition of netilmicin / PEP was administered to rats according to the procedure of Example 3. ' At specific time intervals, blood was drawn from each rat and subjected to centrifugation. Plasma was analyzed by HPLC, and bioavailability was calculated. The results are shown in Table 6.

These results show that the percentage bioavailability was 73.05%.

Example 9 A solution of teicoplanin was mixed with a solution of methylcellulose, and this mixture was added to solutions of glucosamine and sucrose stearate in water before administration to rats. The teicoplanin and PEP solutions were mixed by a magnetic stirrer at room temperature, forming a 'teicoplanin / PEP solution. The content of teicoplanin / PEP comprised an individual dosage of 64 mg / kg of teicoplanin, 400 mg / kg of sucrose stearate, glucosamine in a 1: 4 molar ratio of teicoplanin to glucosamine, and methylcellulose in a 1: 0.5 molar ratio teicoplanin to methylcellulose. The composition of teicoplanin / PEP- was administered to rats according to the procedure of Example 3. At specific time intervals, blood was drawn from each rat and subjected to centrifugation. Plasma was analyzed by HPLC, and bioavailability was calculated. The results are shown in Table 7.

These results show a percentage bioavailability of 35.07%.

Example 10 A catechin solution was mixed with a solution of methylcellulose, and this mixture was added to solutions of glucosamine and sucrose palmitate in water prior to administration to rats. The solutions of catechin and PEP were mixed by a magnetic stirrer at room temperature, forming a catechin / PEP solution. The catechin / PEP content comprised an individual dosage of 300 mg / kg of catechin, 400 mg / kg of sucrose palmitate, glucosamine in a 1: 4 molar ratio of catechin to glucosamine, and methylcellulose in a molar ratio of 1: 0.5 catechin to methylcellulose. The catechin / PEP composition was administered to rats according to the procedure of Example 3. At specific time intervals, blood was drawn from each bundle, and subjected to centrifugation. Plasma was analyzed by HPLC, and bioavailability was calculated. The results are shown in Table 8.

Example 11 A solution of aztreonam (which contained arginine as a pH adjuster) was mixed with a solution of methylcellulose, and this mixture was added to solutions of glucosamine and sucrose palmitate in water prior to administration to rats. The solutions of aztreonam and PEP were mixed by means of a magnetic stirrer at room temperature, forming a solution of aztreonam / PEP. The aztreonam / PEP content comprised an individual dosage of 40 mg / kg of aztreonam, 400 mg / kg of sucrose palmitate, glucosamine in a 1: 4 molar ratio of aztreonam to glucosamine, and methylcellulose in a molar ratio of 1: 0.5 aztreonam to methylcellulose and arginine in 1: 0.6 molar ratio of aztreonam to arginine. The aztreonam / PEP composition was administered to rats according to the procedure of Example 3. At specific time intervals, blood was drawn from each rat and subjected to centrifugation. Plasma was analyzed by HPLC, and bioavailability was calculated. The results are shown in Table 9.

These results show a percentage bioavailability of 91.1 ± -14.6%.

Example 12 A solution of paclitaxel was prepared by adding Solutol or TPGS (solubilizer) which was then mixed with a solution of methylcellulose and this mixture was added to the solutions of glucosamine and sucrose palmitate in water before administration in rats. The paclitaxel and PET solutions were mixed by a magnetic stirrer at room temperature, forming paclitaxel / PEP solutions. The content of the paclitaxel / PEP solutions is shown in Table 10. f Paclitaxel: Methylcellulose 'molar ratio = 1: 0.5 The paclitaxel / PEP compositions were administered to rats according to the procedure of Example 3. At specific time intervals, blood was drawn from each rat and subjected to centrifugation. Plasma was analyzed by HPLC, and bioavailability was calculated. The results are shown in Table 11.

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

Claims (44)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property: 1. A composition for the oral supply of a pharmaceutical agent that is absorbed. deficiently through the intestinal mucosa, the composition characterized in that it comprises a mixture of an effective amount of the pharmaceutical agent; an enhancer to increase the absorption of the pharmaceutical agent through the intestinal mucosa; a promoter that works synergistically with the enhancer to further increase the absorption of the pharmaceutical agent through the intestinal mucosa; and optionally a protector to inhibit the decomposition or inactivation of the pharmaceutical agent; wherein the enhancer is a member selected from the group consisting of fatty acid esters, phospholipids, phosphatidyl compounds, glucosylceramides, fatty acids, non-ionic surfactants, vitamin E tocopheryl succinate polyethylene glycol, glycerides, derivatives thereof, and mixtures thereof; wherein the promoter is a member selected from the group, consisting of amino acid derivatives,
2. amino sugars, and mixtures thereof; and while the protector is a member selected from the group consisting of carbomers, carboxymethylcellulose, polysaccharides, pectin, cellulose, dextrin, gelatin, polyethylene oxide, polyvinyl alcohol, poly (vinylpropylene), poly (vinylpyrrolidone), xanthan, • sodium alginate, methacrylic acid copolymers, colloidal silica, synthetic silica, polysaccharides, water-soluble cellulose esters, hydroxypropyl ethacrylates, tragacanth, water-soluble chitosan, polycarbophil, derivatives thereof, and mixtures thereof . The composition according to claim 1, characterized in that the protector is a member selected from the group consisting of methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and mixtures thereof.
3. 3. The composition according to claim 1, characterized in that the enhancer is a fatty acid ester selected from the group consisting of sucrose stearate, sucrose palmitate, sucrose laurate, sucrose behenate, sucrose oleate, erucate sucrose, and mixtures thereof.
4. 4. The composition according to claim 1, characterized in that the enhancer is an ester of

   glycerol of a fatty acid.
5. 5. The composition according to claim 1, characterized in that the enhancer is a phospholipid derivative.
6. 6. The composition according to claim 1, characterized in that the enhancer is a phosphatidyl derivative.
7. The composition according to claim 1, characterized in that the enhancer is a glucosylceramide derivative.
8. 8. The composition according to claim 1, characterized in that the enhancer is a fatty acid derivative.
9. 9. The composition according to claim 1, characterized in that the intensifier is a nonionic surfactant selected from the group consisting of block copolymers. polyoxyethylene-polyoxypropylene glycol, sorbitan fatty acid esters, fluorine-containing surfactants, octoxins, polyoxyethylene sorbitan, polyoxyethylene ethers, copolymers, polyethylene-polypropylene blocks, and mixtures thereof.
10. 10. The composition according to claim 1, characterized in that the. Intensifier is a selected member, of the group consisting of vitamin E derivatives p-polyethylene glycol tocopheryl succinate.
11. 11. The composition according to claim 1, characterized in that the enhancer is a member selected from the group consisting of glyceride derivatives.
12. The composition according to claim 1, characterized in that the promoter is a member selected from the group consisting of glucosaminase, 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,. glycyrrhizin, glutamic acid derivatives, bile salts, poly (ethylene glycol) derivatives, acylcarnitines, citric acids, and mixtures thereof.
13. The composition according to claim 12, characterized in that the promoter is a member selected from the group consisting of poly-L-lysine, glucosamine, poly-L-arginine, galactosamine, N-acetylglucosamine, and mixtures thereof.
14. The composition according to claim 1, characterized in that the pharmaceutical agent comprises a peptide or protein.
15. 15. The composition according to claim 1, characterized in that the pharmaceutical agent comprises a

    aminoglycoside antibiotic.
16. 16. The composition according to claim 1, characterized in that the pharmaceutical agent comprises a hydrifile or amphipathic drug.
17. 17. The composition according to claim 1, characterized in that the pharmaceutical agent comprises insulin.
18. 18. The composition according to claim 1, characterized in that the pharmaceutical agent • comprises human growth hormone.
19. 19. The composition according to claim 1, characterized in that the pharmaceutical agent comprises calcitonin.
20. The composition according to claim 1, characterized in that the pharmaceutical agent comprises isepamycin.
21. 21. The composition according to claim 1, characterized in that the pharmaceutical agent comprises netilmicin.
22. 22. The composition according to claim 1, characterized in that the pharmaceutical agent comprises teicoplanin.
23. 23. The composition according to claim 1, characterized in that the pharmaceutical agent comprises the catechin.
24. 24. The composition according to claim 1, characterized in that the pharmaceutical agent comprises aztreonam.
25. 25. The composition according to claim 1, characterized in that the pharmaceutical agent comprises paclitaxel.
26. 26. A composition for oral delivery of a pharmaceutical agent that is absorbed poorly through the intestinal mucosa afterwards. of oral administration, the composition characterized in that it comprises a mixture of an effective amount of the pharmaceutical agent; an intensifier to increase the. absorption of the pharmaceutical agent through the intestinal mucosa wherein the enhancer comprises an ester of fatty acid and sucrose; a promoter that works synergistically with the enhancer to increase the absorption of the pharmaceutical agent through the intestinal mucosa, wherein the promoter comprises glucosamine or poly (L-lysine); and optionally a protector for inhibiting the decomposition or inactivation of the pharmaceutical agent, wherein the protector comprises methylcellulose or poly (vinyl alcohol).
27. The composition according to claim 26, characterized in that the sucrose fatty acid ester comprises sucrose stearate ..
28. 28. The composition according to claim 26,

    characterized in that the sucrose fatty acid ester comprises sucrose palmitate.
29. 29. The composition according to claim 26, characterized in that the promoter comprises glucosamine.
30. 30. The composition according to claim 26, characterized in that the promoter comprises poly (L-lysine).
31. 31. The composition according to claim 26, characterized in that the protector comprises methylcellulose.
32. 32. The composition according to claim 26, characterized in that the protector comprises polyvinyl alcohol.
33. 33. A composition for oral-delivery of a hydrophilic or amphipathic drug, the composition characterized in that it comprises a mixture of the drug, and an enhancer for increasing the absorption of the drug through the intestinal mucosa, wherein the enhancer is a selected member of the drug. a group consisting of fatty acid esters, phospholipids, phosphatidyl compounds, glucosylceramides, fatty acids, non-ionic surfactants, vitamin E tocopheryl succinate polyethylene glycol, glycerides, derivatives thereof, and mixtures thereof; and a promoter to work synergistically with the enhancer to further increase the absorption of the drug through the intestinal mucosa, wherein the
34. promoter is a member selected from the group consisting of poly (amino acids), aminosugars, and mixtures thereof. The composition according to claim 33, further characterized in that it comprises a protector to protect the drug from decomposition or inactivation, wherein the protector is a member selected from the group consisting of carbomers, carboxymethylcellulose, polysaccharides, pectin, cellulose, dextrin, gelatin, polyethylene oxide, polyvinyl alcohol, poly (vinylpropylene), poly (vinylpyrrolidone), xanthan gums, sodium alginate, methacrylic acid copolymers, colloidal silica, synthetic silica ', water-soluble cellulose ethers, hydropropyl methacrylates, tragacanth, water-soluble chitosan, polycarbophil , derivatives thereof, and mixtures thereof.
35. 35. The composition according to. claim 34, characterized in that the protector is methylcellulose and the enhancer is an ester of fatty acid and sucrose.
36. 36. The composition according to claim 34, characterized in that the protector is poly (alcoholvinyl) and the enhancer is an ester of fatty acid and sucrose.
37. 37. The composition according to claim 34, characterized in that the protector is polyvinylpyrrolidone and the enhancer is an ester of fatty acid and sucrose.
38. 38. The composition according to claim 33, characterized in that the promoter is glucosamine or poly (L-lysine).
39. 39. A dosage form for oral delivery of a drug that can be poorly absorbed in the intestine, the dosage form characterized in that it comprises: f an effective amount of the drug; an intensifier to increase the absorption of the drug through the intestinal mucosa; a promoter to work synergistically with the enhancer to further increase the absorption of the drug through the intemal mucosa; , and, optionally, a protector to reduce or inhibit the decomposition or inactivation of the drug in the gastrointestinal tract.
40. 40. The dosage form according to claim 39, characterized in that the dosage form comprises a tablet.
41. 41. The dosage form - according to claim 40, characterized in that the tablet further comprises a member selected from the group consisting of diluents, binders, lubricants, disintegrants, colorants, flavors, sweeteners, and mixtures thereof.
42. 42. The dosage form according to claim 40, characterized in that the dosage form comprises a capsule.
43. 43. The dosage form according to claim 39, further characterized in that it comprises an enteric coating.
44. 44. A method to 'increase intestinal absorption. of a drug that can be poorly absorbed, the method characterized in that it comprises the oral administration of a composition comprising a mixture of: the drug; an intensifier to increase the absorption of the drug through the intestinal mucosa; a promoter that works synergistically with the enhancer to further increase the absorption of the drug through the intestinal mucosa; and optionally, a protector to reduce or inhibit the decomposition or inastivation of the drug in the gastrointestinal tract.