MXPA06004957A - Compositions and dosage forms for enhanced absorption - Google Patents

Abstract

Disclosed is controlled delivery of pharmaceutical agents and methods, dosage forms and devices therefore. In particular, formulation, dosage forms, methods and devices for enhanced absorption and controlled delivery drug compounds are disclosed.

Description

COMPOSITIONS AND DOSAGE FORMS FOR INTENSIFIED ABSORPTION FIELD OF THE INVENTION This invention relates to the controlled delivery of pharmaceutical agents, and methods, dosage forms and devices for the same. In particular, the invention is directed to formulations, dosage forms, methods and devices for intensified absorption and controlled delivery of pharmaceutical compounds.

BACKGROUND OF THE INVENTION In conventional pharmaceutical development, the choice of dosage forms such as a base or salt is based on obtaining, on the one hand, the more stable dosage form, and on the other hand, providing maximum absorption in the upper gastrointestinal (Gl) tract . Since most drug dosage forms are designed for immediate release of the drug dosage, the dosage form is made to be well dissolved in the gastrointestinal tract G.l. superior, and usually highly dissociated, that is, highly charged, in the environment G.l. of the small and large intestines (pH = approximately 5-7). The pharmaceutical development typically also directs the drug forms for absorption in the G.l. superior, more than the G.l. lower, due to the much larger surface area for drug absorption in the G.l. higher. The tract G.l. inferior lacks the microvilli that are present in the G.l. higher. The presence of microvilli greatly increases the surface area for the absorption of the drug, and the G.l. superior has 480 times the surface area that has the tract G.l. lower. The differences in the cellular characteristics of the tracts G.l. superior and inferior, also contribute to the malabsorption of molecules in the G.l. lower. Figure 1 illustrates two common routes for the transport of compounds through the epithelium of the G.l. tract. Individual epithelial cells, represented by 10a, 10b, 10c, form a cellular barrier along the small and large intestine. The individual cells are separated by water channels or tight junctions, such as the junctions 12a, 12b. Transport through the epithelium occurs through a transcellular pathway and a paracellular pathway, or any of them. The transcellular route for transport, indicated in Figure 1 by arrow 14, includes movement of the compound through the wall and body of the epithelial cell by passive diffusion, or by vehicle-mediated transport. The paracellular transport pathway includes movement of the molecules through the tight junctions between the individual cells, as indicated by arrow 16. Paracellular transport is less specific, but has a much larger overall capacity, in part because it occurs along the length of the Gl tract However, tight joints vary along the length of the G.I. tract, with a proximal to distal gradient increasing in effective "tightness" of the tight junction. In this way, the duodenum in the G.l. superior is more "permeable" than the ileum in the G.l. superior, which is more "permeable" than the colon in the G.l. Bottom (Knauf, H. et al., Klin. Wochenschr., 60 (19): 1191-1200 (1982)). Since the typical residence time of a drug in the G.l. higher is approximately four to six hours, drugs that have malabsorption in the G.l. Lower are absorbed by the body through a period of only four to six hours after oral ingestion. Frequently, it is medically desirable that the drug administered be present in the patient's bloodstream at a relatively constant concentration throughout the day. To achieve this with traditional drug formulations that exhibit minimal absorption in the G.l. Bottom-up, patients would need to ingest the drugs three to four times a day. Practical experience with this inconvenience for patients, suggests that this is not an optimal treatment protocol. Accordingly, it is desired to achieve administration of said drugs once a day, with long-term absorption throughout the day. To provide constant dosing treatments, conventional pharmaceutical development has suggested several systems for controlled release of the drug. Such systems function by releasing their drug payload for an extended period after administration. However, these conventional forms of controlled release systems are not effective in the case of drugs exhibiting minimal colonic absorption. Since the drugs are only absorbed in the G.l. superior, and since the residence time of the drug in the G.l. higher is only four to six hours, the fact that a proposed controlled release dosage form can release its payload after the residence period of the dosage form in the G.l. superior, does not mean that the body will continue to absorb the controlled release drug beyond four to six hours of residence in the G.l. higher. Rather, the drug released by the controlled release dosage form after the dosage form has entered the G.l. The lower part is usually not absorbed and, rather, is expelled from the body. In response to this and in recognition of the same, attempts have been made to provide a remedy. These attempts have not typically provided satisfactory results. Thus, there is a need to develop compounds, methods and products that achieve improved absorption of drugs previously not known to have high absorption throughout the gastrointestinal tract.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, the invention relates to a substance comprising: a complex comprising a drug portion and a transport portion. In another aspect, the invention relates to a method for obtaining a composition, comprising: providing a portion of drug in an ionic form; provide a transport portion in an ionic form; combining the drug portion and the transport portion, in the presence of a solvent having a dielectric constant less than that of water, to form a complex; and separate the solvent complex. In one aspect, the invention relates to a method of treatment, comprising: providing a portion of drug in an ionic form; provide a transport portion in an ionic form; combining the drug portion and the transport portion, in the presence of a solvent having a dielectric constant less than that of water, to form a complex; separate the solvent complex; and administer the separate complex to a patient who needs it. In another aspect, the invention relates to a method for improving the absorption of a drug portion, comprising: providing a complex of the drug portion and a transport portion; and administer the complex to a patient who needs to! same.

BRIEF DESCRIPTION OF THE FIGURES The following figures are not drawn to scale, and are shown to illustrate various embodiments of the invention. Figure 1 is a diagram of epithelial cells of the gastrointestinal tract, illustrating two routes of drug transport through the epithelium of the G.l. tract. Figure 2 shows a diagram of a dosage form of elemental osmotic pump. Figure 3 shows a diagram of an osmotic dosage form. Figure 4 shows a diagram of a three layer osmotic dosage form. Figures 5A-5C show diagrams of a controlled release dosage form. Figure 6 is a plot of the logarithm of the octanol / water partition coefficient as a function of pH for metformin hydrochloride; Figures 7A-7D are traces of CLAR of metformin hydrochloride (Figure 7A), sodium laurate (Figure 7B), and a physical mixture of metformin hydrochloride, sodium laurate (Figure 7C) and metformin-laurate complex (Figure 7D); Figures 8A-8B are conductivity graphs, in microsiemens / centimeter (μS / cm, Figure 8A), and percent non-ionized drug (Figure 8B), as a function of metformin concentration for metformin hydrochloride (circles) , metformin combined with succinate (inverted triangles), caprate (squares), laurate (diamonds), palmitate (triangles) and oleate (octagons); Figure 9 shows the concentration of metformin in plasma, in ng / mL, in rats, as a function of time, in hours, for metformin hydrochloride (circles) and a complex of metformin-laurate (diamonds), after oral fattening from the compounds to rats; Figure 10 shows the concentration of metformin in plasma, in ng / mL, in rats, as a function of time, in hours, for metformin hydrochloride (circles), metformin combined with succinate (diamonds), palmitate (triangles), oleate (inverted triangles), caprate (squares) and laurate (octagons), using a ligated-washed colon model; Figure 11 shows the percent bioavailability as a function of metformin dose, in mg of base / kg, of a physical mixture of metformin hydrochloride and sodium laurate (circles) and a metformin-laurate complex (squares ), in rat plasma using a ligated-washed colon model; Figure 12 is a graph of the concentration of metformin base in plasma, in ng / mL, in rats, as a function of time, in hours, after intravenous administration of 2 mg / kg of metformin hydrochloride (triangles) and after administration of a 10 mg / rat dose of metformin hydrochloride (circles) or metformin-laurate complex (diamonds), using a ligated-washed colon model; Figure 13 shows the average release rate of metformin, in mg / hour, as a function of time, in hours for dosage forms according to the invention. Figures 14A-14D are FTIR scans of gabapentin (Figure 14A), sodium lauryl sulfate (Figure 14B), a physical mixture (loose ion pair) of gabapentin and sodium lauryl sulfate (Figure 14C) and gabapentin-lauryl complex sulfate (Figure 14D). Figure 15 shows the concentration of gabapentin in plasma, in ng / mL, in rats, as a function of time, in hours, for gabapentin administered intravenously (triangles) and by intubation in a ligated colon (circles), and for a complex of gabapentin-lauryl sulfate (diamonds) administered by intubation in a ligated colon. Figure 16A shows the concentration of gabapentin in plasma, in ng / mL, in rats, as a function of time, in hours, for gabapentin administered intravenously (triangles), and to the duodenum at dosages of 5 mg (circles), 10 mg (squares) and 20 mg (diamonds). Figure 16B shows the concentration of gabapentin in plasma, in ng / mL, in rats, as a function of time, in hours, after the administration of gabapentin-lauryl sulfate complex intravenously (triangles) and to the duodenum at dosages of 5 hours. mg (circles), 10 mg (squared) and 20 mg (diamonds).

Figure 16C is a graph of the bioavailability of gabapentin, in percent, as a function of dose after administration of gabapentin (inverted triangles) or gabapentin-lauryl sulfate complex (circles) to the duodenum of rats.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions The present invention is best understood by reference to the following definitions, drawings and descriptive examples that are provided herein. By "composition" is meant one or more of the complexes of the invention, optionally in combination with additional active pharmaceutical ingredients, and optionally in combination with inactive ingredients, such as vehicles, excipients, suspending agents, surfactants, disintegrators, binders, pharmaceutically acceptable diluents, lubricants, stabilizers, antioxidants, osmotic agents, colorants, plasticizers, and the like. By "complex" is meant a substance comprising a portion of drug and a portion of transport associated by a tight ion-pair bond. A drug portion-transport portion complex can be distinguished from a loose ion pair of the drug portion and the transport portion, by a difference in the octanol / water partition behavior, characterized by the following ratio:? LogD = Log D (complex) - Log D (loose ion pair) > 0.15 (equation 1) where: D, the distribution coefficient (apparent distribution coefficient), is the ratio of the equilibrium concentrations of all the species of the drug portion and the transport portion in octanol to the same species in water (deionized water) at a pH value (typically from about pH = 5.0 to about pH = 7.0) and at 25 degrees Celsius. The Log D (complex) is determined for a complex of the drug portion and the transport portion prepared according to the teachings herein. Log D (loose ion pair) is determined for a physical mixture of the drug portion and the transport portion in deionized water. Log D can be determined experimentally, or can be predicted for loose pairs, using commercially available software packages (eg, ChemSilico, Inc., Advanced Chemistry Development Inc.). For example, the apparent octanol / water partition coefficient (D = C0ctanoi / Cagua) of a putative complex (in deionized water at 25 degrees Celsius), can be determined and compared with a physical mixture of 1: 1 (mol / mol) of the transport portion and the drug portion in deionized water at 25 degrees Celsius. If it is determined that the difference between Log D for the putative complex (D + T-) and Log D for the physical mixture of 1: 1 (mol / mol), D + || T "is greater than or equal to 0.15, it is confirmed that the putative complex is a complex according to the invention.

In preferable modalities,? Log D > 0.20, and more preferably? Log D > 0.25, more preferably still? Log D > 0.35. It is intended that the term "DPP IV", as used herein, means dipeptidyl peptidase IV (EC 3.4.14.5), also known as CD26. An "DPP IV inhibitor" is intended to indicate a molecule that exhibits inhibition of DPP-IV enzymatic activity; however, the molecule may also have inhibitory activity on other DPP enzymes.

An inhibitor of DPP IV preserves the action of substrate molecules including, but not limited to, GLP-1, GIP, histidine methionine peptide, substance P, neuropeptide Y, and other molecules typically containing alanine or proline residues in the second amino-terminal position. In the present context, it is also intended that a "DPP IV inhibitor" encompass active metabolites, and prodrugs thereof. Examples of inhibitors DPP IV, include 1 - [[(3-hydroxy-1-adamantyl) amino] acetyl] -2-cyano (S) -pyrrolidine; 1- hydrochloride. { N- (5,6-dichloronicotinoyl) -L-orn.t.n.l.l] -3,3-d.fluoropyrrolidine; and compounds described in WO2004032836; WO2004 / 024184; and WO03 / 000250, which are incorporated herein by reference; and are described, for example, in documents W098 / 19998, DE19616 486 A1, WO00 / 34241, WO95 / 15309, WO01 / 72290, WO01 / 52825, WO93 / 10127, W099 / 25719, WO99 / 38501, WO99 / 46272, W099 / 67278 and W099 / 67279. By "dosage form" is meant a pharmaceutical composition in a medium, carrier, vehicle or device suitable for administration to a patient in need thereof.

By "drug" or "drug portion" is meant a drug, compound or agent, or a residue of said drug, compound or agent, which provides some pharmacological effect when administered to a subject. For use in the formation of a complex, the drug comprises an acid, basic or zwitterionic structural element, or an acid, basic or zwitterionic residual structural element. In embodiments according to the invention, portions of drug comprising acid structural elements or acidic residual structural elements are combined with transport portions comprising basic structural elements or basic residual structural elements. In embodiments according to the invention, portions of drug comprising basic structural elements or basic residual structural elements are combined with transport portions comprising acidic structural elements or acidic residual structural elements. In embodiments according to the invention, drug portions comprising zwitterionic structural elements or residual zwitterionic structural elements are combined with transport portions comprising acidic or basic structural elements, or acidic or basic residual structural elements. In one embodiment, the pKa of an acid structural element or acidic residual structural element is less than about 7.0, preferably less than about 6.0. In one embodiment, the pKa of a basic structural element or basic residual structural element is greater than about 7.0, preferably greater than about 8.0. The zwitterionic structural elements or residual zwitterionic structural elements are analyzed in terms of their individual basic structural element or basic residual structural element, or their acid structural element or residual acid structural element, depending on how the complex will be formed with the transport portion. By "fatty acid" is meant any of the group of organic acids of the general formula CH3 (CnHx) COOH, wherein the hydrocarbon chain is saturated (x = 2n, for example, palmitic acid, C? SH31COOH) or unsaturated ( for monounsaturated, x = 2n-2, for example, oleic acid, CH3C16H3oCOOH). The term "gabapentin" refers to 1- (aminomethyl) cyclohexaneacetic acid, with a molecular formula of C9H17NO2 and a molecular weight of 171.24. It is commercially available under the trade name Neurontin®. Its structure is shown in formula 2 below.

By "intestine" or "gastrointestinal tract (Gl)" is meant the portion of the digestive tract that extends from the inferior opening of the stomach to the anus, formed of the small intestine (duodenum, jejunum and ileum) and the large intestine (colon). ascending, transverse colon, descending colon, sigmoid colon and rectum). By "loose ion pair" is meant a pair of ions which are, at physiological pH and in an aqueous environment, easily interchangeable with other freely-paired ions or free ions which may be present in the environment of the loose ion pair. Loose ion pairs can be found experimentally by noting the exchange of one member of a loose ion pair with another ion, at physiological pH and in an aqueous environment, using isotopic labeling and NMR or mass spectroscopy. Loose ion pairs can also be found experimentally by noting the ion pair spacing, at physiological pH and in an aqueous environment, using inverted phase HPLC. Loose ion pairs can also be referred to as "physical mixtures", and are formed by physically mixing the ion pair in a medium. By "lower gastrointestinal tract" or G.l. tract lower", it means the large intestine. By "patient" is meant an animal, preferably a mammal, more preferably a human, that needs therapeutic intervention. By "pharmaceutical composition" is meant a composition suitable for administration to a patient in need thereof. The term "pregabalin" refers to (S) - (+) - 3- (aminomethyl) -5-methylhexanoic acid. Pregabalin is also referred to in the literature as (S) -3-isobutyl GABA or CI-1008. The structure of pregabalin is shown in formula 3 below.

By "residual structural element" is meant a structural element that undergoes modification by interaction or reaction with another compound, chemical group, ion, atom, or the like. For example, a carboxyl structural element (COOH) interacts with sodium to form a sodium carboxylate salt, the COO- being a residual structural element. By "solvent (s)" is meant one or more substances in which several other substances can be completely or partially dissolved. In the present invention, preferred solvents include aqueous solvents, and solvents having a dielectric constant lower than that of water. The dielectric constant is a measure of the polarity of a solvent, and dielectric constants for solvent examples are shown in Table 1.

TABLE 1 Characteristics of solvent examples The solvents water, methanol, ethanol, 1-propanol, 1-butanol and acetic acid, are polar protic solvents having a hydrogen atom attached to an electronegative atom, typically oxygen. The solvents acetone, ethyl acetate, methyl ethyl ketone and acetonitrile are dipolar aprotic solvents and, in one embodiment, are preferred for use in the formation of the invention complexes. Dipolar aprotic solvents do not contain an OH bond, but typically have a large bond dipole by virtue of a multiple bond between carbon and oxygen or nitrogen. Most dipolar aprotic solvents contain a C-O double bond. Solvents having a dielectric constant less than that of water are particularly useful in the formation of the complexes of the invention. The dipolar aprotic solvents included in Table 1 have a dielectric constant at least twice less than that of water, and a dipole moment close to or greater than water. By "structural element" is meant a chemical group that (i) forms part of a larger molecule, and (ii) has distinguishable chemical functionality. For example, an acidic group or a basic group in a compound is a structural element. "Substance" means a chemical entity that has specific characteristics. By "tight ion pair" is meant a pair of ions which, at physiological pH and in an aqueous environment, are not readily interchangeable with other freely-matched ions or free ions that may be present in the tight ion pair environment. A tight ion pair can be experimentally detected, noting the absence of exchange of one member of a tight ion pair with another ion, at physiological pH and in an aqueous environment, using isotopic labeling and NMR or mass spectroscopy. Tight ion pairs can also be found experimentally by noting the lack of ion pair separation, at physiological pH and in an aqueous environment, using inverted phase HPLC. By "transport portion" is meant a compound that is capable of forming, or a residue of that compound which has formed, a complex with a portion of drug, wherein the transport portion serves to improve the transport of the drug through of the epithelial tissue, compared to that of the non-combined drug. The transport portion comprises a hydrophobic portion and an acid, basic or zwitterionic structural element, or an acid, basic or zwitterionic residual structural element. In a preferred embodiment, the hydrophobic portion comprises a hydrocarbon chain. In one embodiment, the pKa of the basic structural element or the basic residual structural element is greater than about 7.0, preferably greater than about 8.0. The zwitterionic structural elements or residual zwitterionic structural elements are analyzed in terms of their individual basic structural element or basic residual structural element or its acid structural element or residual acid structural element, depending on how the complex will be formed with the drug portion.

In a more preferred embodiment, the transport moieties comprise pharmaceutically acceptable acids including, but not limited to, carboxylic acids, and salts thereof. In other embodiments, the transport moieties comprise fatty acids or their salts, benzenesulfonic acid or its salts, benzoic acid or its salts, fumaric acid or its salts, or salicylic acid or its salts. In preferred embodiments, the fatty acids or their salts comprise from 6 to 18 carbon atoms (C6-C18), more preferably from 8 to 16 carbon atoms (C8-C16), even more preferably from 10 to 14 carbon atoms ( C10-C14), and most preferably 12 carbon atoms (C12). In more preferred embodiments, the transport moieties comprise alkyl sulfates (saturated or unsaturated) and their salts, such as potassium, magnesium and sodium salts, including particularly sodium octyl sulfate, sodium decyl sulfate, sodium lauryl sulfate and sodium tetradecyl sulfate. In preferred embodiments, the alkyl sulfate or its salt comprises from 6 to 18 carbon atoms (C6-C16), more preferably from 8 to 16 carbon atoms (C8-C16), even more preferably from 10 to 14 carbon atoms ( C10-C14), and most preferably 12 carbon atoms (C12). Also suitable are other anionic surfactants. In another more preferred embodiment, the transport moieties comprise pharmaceutically acceptable primary amines, or salts thereof, in particular primary aliphatic amines (saturated and unsaturated), or salts thereof, diethanolamine, ethylenediamine, procaine, choline, tromethamine, meglumine. , magnesium, aluminum, calcium, zinc, alkyltrimethylammonium hydroxides, alkyltrimethylammonium bromides, benzalkonium chloride and benzethonium chloride. Also useful are other pharmaceutically acceptable compounds comprising secondary or tertiary amines, and their salts, and cationic surfactants. By "upper gastrointestinal tract" or "upper tract G.l." is meant that portion of the gastrointestinal tract that includes the stomach and small intestine.

Formation and characterization of the complex It has surprisingly been found that many common drug portions with poor absorption characteristics, once combined with certain transport portions, exhibit significantly enhanced absorption, particularly absorption in the G.l. lower, although absorption in the upper gastrointestinal tract can also be intensified. It is further surprising that the complexes according to the invention show improved absorption compared to the loose ion pairs (ie, a non-combined form) comprising the same ions as the complexes of the invention. It has been found that these unexpected results apply to many categories of drug portions, including portions of drug comprising a basic structural element or a basic residual structural element. Examples of said drug portions to which the present invention is applied include metformin, iron, ranitidine hydrochloride, cetirizine hydrochloride, sumatriptan succinate, oxycodone hydrochloride, tramadol hydrochloride, ciprofloxacin hydrochloride, dipeptidyl peptidase IV inhibitors. (DPP IV) and cimetidine hydrochloride. The unexpected results of the present invention also apply to drug portions comprising a zwitterionic structural element or a residual zwitterionic structural element. Examples of said drug portions to which the present invention applies are gabapentin and levodopa. Unexpected results of the present invention also apply to drug portions comprising an acidic structural element or an acidic residual structural element. An example of said drug portion to which the present invention is applied is rabeprazole sodium. Examples of preferred embodiments of the present invention, are presented later. Preferred modalities are presented, where complexes are formed with metformin, iron and gabapentin. Although not wishing to be limited by the specific understanding of mechanisms, the inventors reason as follows: When the loose ion pairs are placed in a polar solvent environment, it is assumed that polar solvent molecules will insert themselves into the polar solvent. space occupied by the ionic bond, thus moving the united ions away. A solvation shell, comprising polar solvent molecules electrostatically attached to a free ion, can be formed around the free ion. This cover of solvation then prevents the free ion from forming anything, but an ionic bond of the loose ion pair with another free ion. In a situation where there are multiple types of counterions present in the polar solvent, any given loose ion pair may be relatively susceptible to competition with counterions. This effect is more pronounced as the polarity increases, expressed as the dielectric constant of the solvent. Based on the law of Coulomb, the force between two ions with charges (q1) and (q2), and separated by a distance (r) in a medium of dielectric constant (e), is given by the equation: F - _. - ?? al - (equation 2) where eo is the space permitivity constant. The equation shows the importance of the dielectric constant (e) on the stability of a dissolved ion pair in solution. In aqueous solution having a high dielectric constant (e = 80), the electrostatic attraction force is significantly reduced if the water molecules attack the ionic bond and separate the ions with opposite charge. Therefore, solvent molecules with high dielectric constant, once present in the vicinity of the ionic bond, will attack the bond, and eventually break it. The unbound ones are then free to move around in the solvent. These properties define a loose ion pair.

The tight ion pairs are formed differently from the loose ion pairs, and consequently have different properties to those of a loose ion pair. The tight ion pairs are formed by reducing the number of polar solvent molecules in the bond space between two ions. This allows the ions to move tightly together, and results in a bond that is significantly stronger than a loose pair bond, but is still considered as an ionic bond. As more fully described herein, tight pairs are obtained using less polar solvents than water to reduce the entrapment of polar solvents between the ions. For an additional discussion of loose and tight ion pairs, see D. Quintanar-Guerrero et al., Applications of the Ion Pair Concept to Hydrophilic Substances with Special Emphasis on Peptides, Pharm. Res., 14 (2): 119-127 (1997). The difference between loose and tight ion pairs can also be observed using chromatographic methods. By using inverted phase chromatography, loose ion pairs can be easily separated under conditions that will not separate the tight ion pairs. The bonds according to this invention can also be made stronger, by selecting the concentration of the cation and anion with respect to some other. For example, in the case where the solvent is water, the cation (base) and the anion (acid) can be selected to attract someone else more strongly. If a weaker link is desired, then a weaker attraction can be selected. Pieces of biological membranes can be molded to a first-order approximation, such as lipid bilayers, for the purpose of understanding molecular transport through said membranes. The transport through the portions of the lipid bilayer (as opposed to the active transporters, etc.) is unfavorable for the ions, due to the unfavorable distribution. Several researchers have proposed that the neutralization of charges of these, can intensify the transport through the membrane. In the theory of "ion pair", ionic drug moieties pair with counterions of the transport portion to "bury" the charge, and make the resulting ion pair more subject to move through a lipid bilayer. This procedure has generated a great deal of attention and research, especially with regard to intensifying the absorption of drugs administered orally through the intestinal epithelium. Although mating has generated a lot of attention and research, it has not always generated much success. For example, it was found that the ion pairs of two antiviral compounds do not result in increased absorption due to the effects of the ion pair on transcellular transport, but rather to an effect on the integrity of the monolayer. The authors concluded that ion pair formation may not be very efficient as a strategy to enhance the trans-epithelial transport of hydrophilic compounds under load, since the competition for other ions present in in vivo systems can suppress the beneficial effect of the counterions. See, J. Van Gelder et al., "Evaluation of the Potential of Ion Pair Formation to Improve the Oral Absorption of Two Potent Antiviral Compounds, AMD3100 and PMPA", Int. J. of Pharmaceutics 186: 127-136 (1999). Other authors have observed that absorption experiments with ion pairs have not always pointed towards well-defined mechanisms (D. Quintanar-Guerrero et al., Applications of the Ion Pair Concept to Hydrophilic Substances with Special Emphasis on Peptides, Pharm. Res., 14 (2): 119-127 (1997) The inventors have unexpectedly discovered that a problem with these ion pairs absorption experiments is that they were performed using loose ion pairs, rather than tight ion pairs, of course, many experiments of absorption with ion pairs described in the art do not yet expressly differentiate between loose ion pairs and tight ion pairs The person skilled in the art has to distinguish which loose ion pairs are described, actually reviewing the methods described to obtain the ion pairs, and noting which described manufacturing methods are directed towards loose ion pairs and not towards tight ion pairs. Singletons are relatively susceptible to competition with counterions, and to solvent-mediated breakdown (eg, mediated by water) of the ionic bonds that bind loose ion pairs. Accordingly, when the drug portion of the ion pair reaches the membrane wall of an intestinal epithelial cell, it may or may not be associated in a loose ion pair with a transport portion. The probability that the ion pair exists near the membrane wall may depend more on the local concentration of the two individual ions than on the ionic bond that holds the ions together. With the two portions that are attached missing when approaching the membrane wall of an intestinal epithelial cell, the absorption regimen of the non-combined drug portion may not be affected by the non-combined transport portion. Therefore, loose ion pairs could have only a limited impact on absorption compared to the administration of the drug portion alone. In contrast, the complexes of the invention possess bonds that are more stable in the presence of polar solvents such as water. Accordingly, the inventors reasoned that, by forming a complex, it would be more likely that the drug portion and the transport portion are associated as ion pairs at the time the portions are close to the membrane wall. This association would increase the likelihood that the charges of the portions will be buried, and would cause the resulting ion pair to be more subject to moving through the cell membrane. In one embodiment, the complex comprises a tight ion pair bond between the drug portion and the transport portion. As discussed herein, the tight ion pair bonds are more stable than the loose ion pair bonds, thus increasing the likelihood that the drug portion and the transport portion are associated as ion pairs at the time in that the portions are close to the wall of the membrane. This association would increase the likelihood that the charges of the portions will be buried, and would cause the tight complex of the tight ion pair to be more subject to moving through the cell membrane. It should be noted that the complexes of the invention can improve absorption with respect to the non-combined drug portion through the G.I. tract, not only the G.I. tract. Lower, since it is intended that the complex generally improves transcellular transport, not only in the G.l. Lower. For example, if the drug portion is a substrate for an active transporter present mainly in the G.l. higher, the complex formed from the drug portion may still be a substrate for that carrier. Accordingly, the total transport may be a sum of the transport flux effected by the transporter plus the improved transcellular transport provided by the present invention. In one embodiment, the complex of the invention provides improved absorption in the G.l. superior, the G.l. lower, and in the G.l. superior and the tract G.l. Lower. Complexes in accordance with the invention can be formed from a variety of drug and transport portions. Generally speaking, the drug portion is selected first, and then the appropriate transport portion is selected to form the complex of the invention. The person skilled in the art could consider many factors in the selection of the transport portions including, but not limited to, the toxicity and tolerability of the transport portion, the polarity of the structural element or structural element residue of the portion of transport. drug, the concentration of the structural element or structural element residue of the drug portion, the concentration of the structural element or structural element residue of the transport portion, possible therapeutic advantages of the transport portion. In certain preferred embodiments, the hydrophobic portions of the transport portion comprise a hydrophobic chain, more preferably an alkyl chain. This alkyl chain can help promote the stability of the complex, sterically protecting the ionic bond from attack by polar solvent molecules. In preferred embodiments, the transport moieties comprise alkyl sulfates, or their salts, having from 6 to 18 carbon atoms (C6-C18), more preferably from 8 to 16 carbon atoms (C8-C16), even more preferably from 10 to 10 carbon atoms. to 14 carbon atoms (C10-C14), and most preferably 12 carbon atoms (C12). In other preferred embodiments, the transport moieties comprise fatty acids, or their salts, having from 6 to 18 carbon atoms (C6-C18), more preferably from 8 to 16 carbon atoms (C8-C16), even more preferably from 10 to 14 carbon atoms (C10-C14), and most preferably 12 carbon atoms (C12). The complexes of the invention can be incorporated in a variety of compositions, especially pharmaceutical compositions. In one embodiment, the invention comprises a composition comprising a complex according to the invention and a pharmaceutically acceptable carrier. In another embodiment, the invention comprises a pharmaceutical composition comprising a complex according to the invention and a pharmaceutically acceptable carrier. The person skilled in the art can determine amounts of the complex and other ingredients in the compositions, pharmaceutical compositions and dosage forms of the invention, based on pharmacological requirements and the like. The formulation of said compositions can be carried out according to conventional pharmaceutical practices, including milling, mixing, extrusion, compression, coating, and the like. Complexes can be obtained according to the invention, according to the following general principles. Additional strategies may be used, such as that exemplified strategy for iron complexes as described in the examples set forth below. First, the drug portion needs to be evaluated as to whether it comprises an acid structural element or an acidic residual structural element that will form part of the complex (tight ion-pair bond). If so, the next evaluation is whether the structural element is acidic or an acidic residue. If an acid residue is present, the next step is to determine if it is a residue of a strong acid or a weak acid. A "weak acid" is a compound that has an acid dissociation constant less than about 10"4., and as used herein, weak acids are compounds that, when dissolved in water, form moderately acid solutions, ie, solutions with pH values between about 3 to 6. Examples of weak acids include formic acid, acetic, propanoic acid, butanoic acid, pentanoic acid, and substituted forms thereof. A "strong acid" typically refers to a compound having an acid dissociation constant greater than 1. If the residue is characteristic of a strong acid, the drug portion can be processed using an ion exchange to arrive at the form of acid of the drug portion, which is then isolated using conventional chemical techniques. In one embodiment, the solvent used during the ion exchange comprises a mixture of water and organic solvent. If the residue is that of a weak acid, the drug portion can be processed using pH titration to reduce the pH of the environment, and arrive at the acid form of the drug portion, which is then isolated from the aqueous medium using techniques conventional chemistries. The acid form of the drug moiety, either originally present as an acid structural element or a processed acidic backbone structural element as set forth herein to arrive at the acid form of the drug moiety, is then reacted with the transport portion (which may be present in its basic form) in the presence of a solvent having a dielectric constant less than that of water. Suitable transport portions comprise those described herein, and preferably comprise cationic surfactants or amines, and salts thereof. The complex is then separated from the solvent. If the structural element is basic or a basic waste, the next step is to determine if it is a residue of a strong base or a weak base. Typically, and as used herein, weak bases are compounds that, when dissolved in water, form moderately basic solutions, ie, solutions with pH values between about 8 to 11. A "strong base" refers to typically to a basic compound that is highly dissociated in an aqueous solution. If the residue is that of a strong base, the drug portion can be processed using an ion exchange to arrive at the base form of the drug portion, which is then isolated using conventional chemical techniques. In one embodiment, the solvent used during the ion exchange comprises a mixture of water and organic solvent. If the residue is that of a weak base, the drug portion can be processed using pH titration to raise the pH of the environment, and arrive at the base form of the drug portion, which is then isolated from the aqueous medium using techniques conventional chemistries. The base form of the drug portion, either originally present as a basic structural element or a basic residual structural element processed as set forth herein to arrive at the base form of the drug portion, is then reacted with the transport portion (which may be present in its acid form) in the presence of a solvent having a dielectric constant less than that of water. Suitable transport portions comprise those described herein, and preferably comprise fatty acids and their salts, anionic surfactants or other pharmaceutical excipients containing carboxyl groups. The complex is then separated from the solvent. If the structural element is a zwitterion, or a zwitterionic residue, the next step is to determine whether the acidic or basic group will be the group that forms the complex with the complementary ion in the transport portion. The group that is not forming the complex by joining with the transport portion, can be blocked. A preferred method for blocking the structural element or residual structural element that does not bind, is to adjust the pH of the environment, so that the structural element that does not join is not ionized. For example, to block an acid structural element, the pH of the environment is reduced, so that the acid structural element is not ionized, but the basic structural element. To block the basic structural elements, the pH is raised so that the basic structural element is not ionized, but the acid structural element. Once the desired structural element has been blocked, the drug portion is isolated, and then reacted with the transport portion in the presence of a solvent having a dielectric constant less than that of water. The complex is then separated from the solvent. In an alternative scheme for zwitterionic structural elements or residual zwitterionic structural elements, the transport portion can be processed using ion exchange to arrive at the acid or base form of the transport portion, depending on whether the acidic or basic group will be the group that forms the complex with the complementary ion in the transport portion. The group that is not forming the complex by joining with the transport portion, can be blocked. The acid or base form of the transport portion can then be reacted with the ionized form of the drug portion in aqueous media, or a mixture of aqueous media and a solvent having a dielectric constant lower than that of water, to form the complex. The complex is then separated from the mixture or aqueous medium using conventional chemistry techniques. In an alternative scheme, use can be made of the different solubility of the counterions of the drug portion and the transport portion. For example, if a loose ion pair formed from the counterions is insoluble in water, it will then precipitate, leaving the drug portion and the transport portion in solution. The complex can then be formed, or it can be extracted using a solvent having a dielectric constant less than that of water. An example of this strategy is provided as part of the iron examples below. Various solvents can be selected for use in the present invention. Solvents may be selected in part based on the physical properties of the drug portion and / or the transport portion that will dissolve therein. Methanol is an example of a solvent; other solvents are also suitable. For example, fatty acids are soluble in chloroform, benzene, cyclohexane, ethanol (95%), acetic acid and acetone. The solubility (in g / L) of capric acid, lauric acid, myristic acid, palmitic acid and stearic acid in these solvents is indicated in Table 2.

TABLE 2 Solubility (g / L) of fatty acids at 20 ° C In one embodiment, the solvent used for complex formation is a solvent having a dielectric constant less than that of water, and preferably at least twice less than the dielectric constant of water, more preferably at least three times less than the dielectric constant of water. Solvents, in particular in embodiments wherein a solvent phase with lower dielectric constant and an aqueous phase are present in a mixture, can be selected based, in part, on solvent / molecule interactions. Preferred solvents do not react with the drug portion or transport portion, and are relatively easy to separate from the complex once the complex is formed. The relative hydrophilic character of the solvent, in comparison with the hydrophobic character of the complex, may also be important. If the solvent is too hydrophilic, in comparison with the hydrophobic character of the complex, then the complex can not leave the aqueous phase and enters the solvent phase. The complex, as formed, needs to be able to enter the lower dielectric constant solvent phase (if present), but preferably free ions (with definitely high polarity) of the solvent phase with lower dielectric constant should be excluded (if is present). If the complex is a precipitate, then the complex is isolated by filtration, washing and drying. If the complex dissolves, then one or more methods may be used: (1) evaporation of the solvent under vacuum conditions, (2) crystallization, or (3) solvent extraction followed by evaporation. The conditions under which these operations are carried out can be optimized by those skilled in the art.

Examples of dosage forms, and methods of use thereof The complexes according to the invention can be administered to patients who need them. In certain embodiments, the complexes of the invention are formulated in dosage forms administrable to patients in need thereof. In preferred embodiments, the complexes are formulated into compositions, more preferably pharmaceutical compositions, of which dosage forms are formed. The complexes described herein provide an intensified absorption regime in the G.I. tract, and in particular in the G.I. tract. lower. Dosage forms and methods of treatment will now be described using the complex and its increased colonic absorption. It will be appreciated that the dosage forms described below serve only as an example. A variety of dosage forms is suitable for use with the complexes of the invention. A dosage form is provided that allows dosing once a day to achieve therapeutic efficacy for at least about 12 hours, preferably at least about 15 hours, more preferably at least 18 hours, and even more preferably at least approximately 20 hours, due to the intensified absorption in the Gl tract lower achieved by the complex. The dosage form can be configured and formulated according to any design that delivers a desired dose of the drug portion. Typically, the dosage form is orally administrabie, and is sized and configured as a conventional capsule or tablet. Orally administrable dosage forms can be manufactured according to one of several different methods. For example, the dosage form can be manufactured as a diffusion system, such as a reservoir device or matrix device, a dissolution system, such as encapsulated dissolution systems (including, for example, "minute temporary pills", and pearls) and matrix dissolution systems, and diffusion / dissolution combination systems and ion exchange resin systems, as described in Remington's Pharmaceutical Sciences, eighteenth edition, pp. 1682-1685 (1990). An important consideration in the practice of this invention is the physical state of the complex to be delivered by the dosage form. In certain embodiments, the complexes of the invention may be in a paste or liquid state, in which case the solid dosage forms may not be suitable for use in the practice of this invention. In such cases, dosage forms capable of delivering substances in a paste or liquid state must be used. Alternatively, in certain embodiments, a different transport portion can be used that raises the melting point of the substances, thereby making it more likely that the complexes of the invention are present in a solid form. A specific example of a dosage form suitable for use with the present invention is an osmotic dosage form. Osmotic dosage forms, in general, use osmotic pressure that generates a driving force to include fluid in a compartment formed, at least in part, by a semipermeable wall that allows fluid-free diffusion but no drug or osmotic agents, if they are present An advantage for osmotic systems is that their operation is independent of pH, and thus continues to the osmotically determined regimen over an extended period, even as the dosage form transits the gastrointestinal tract and encounters different microenvironments that have values of pH significantly different. A review of such dosage forms is found in Santus and Baker, Osmotic drug delivery: a review of the patent literature, "Journal of Controlled Relay, 35: 1- 21 (1995). Osmotic dosage forms are also described in detail in the following US patents, each of which is hereby incorporated by reference in its entirety: Nos. 3,845,770; 3,916,899; 3,995,631; 4,008,719; 4,111, 202; 4,160,020; 4,327,725; 4,519,801; 4,578,075; 4,681, 583; 5,019,397; and 5, 156,850. An example dosage form, referred to in the art as a dosage form of elemental osmotic pump, is shown in Figure 2. Dosage form 20, shown in a cropped view, is also referred to as an elemental osmotic pump, and comprises a semipermeable wall 22 surrounding and enclosing an internal compartment 24. The internal compartment contains a single component layer referred to herein as a drug layer 26, which comprises a complex 28 in a mixture with selected excipients. The excipients are adapted to provide a gradient of osmotic activity to attract fluid from an external environment through the wall 22, and to form a complex formulation available after the inclusion of fluid. The excipients may include a suitable suspending agent, also referred to herein as a drug carrier 30, a binder 32, a lubricant 34, and an osmotically active agent referred to as an osmagent 36. Examples of materials are provided below for each one of these components. The semipermeable wall 22 of the osmotic dosage form is permeable to the passage of an external fluid, such as water and biological fluids, but is substantially impermeable to the passage of components in the internal compartment. The materials useful for forming the wall are essentially non-erodible, and are substantially insoluble in biological fluids during the life of the dosage form. Representative polymers forming the semipermeable wall include homopolymers and copolymers such as cellulose esters, cellulose ethers and cellulose ester-ethers. Flow regulating agents can be mixed with the material forming the wall to modulate the permeability of the wall to fluids. For example, agents that produce a remarkable increase in permeability to fluids such as water are often essentially hydrophilic, while those that produce a noticeable decrease in water permeability are essentially hydrophobic. Examples of flow regulating agents include polyhydric alcohols, polyalkylene glycols, polyalkylene diols, alkylene glycol polyesters, and the like. In operation, the osmotic gradient across the wall 22 due to the presence of osmotically active agents, causes the gastric fluid to be included through the wall, and causes swelling of the drug layer and formation of a complex formulation available (for example, a solution, suspension, slurry or other fluid composition) within the internal compartment. The supply complex formulation is released through an outlet 38 as the fluid continues to enter the internal compartment. Even when the drug formulation is released from the dosage form, the fluid continues to be extracted into the internal compartment, thereby directing continuous release. In this way, the complex of the invention is released in a sustained and continuous manner over an extended period. Figure 3 is a schematic illustration of another example of osmotic dosage form. Dosage forms of this type are described in detail in the US patents. Nos. 4,612,008; 5,082,668; and 5,091, 190, which are incorporated herein by reference. In summary, the dosage form 40, shown in cross section, has a semipermeable wall 42 defining an internal compartment 44. The inner compartment 44 contains a compressed two-layer core having a drug layer 46 and a push layer 48. As will be described below, the push layer 48 is a displacement composition that is positioned within the dosage form, so that as the push layer expands during use, the materials forming the drug layer are expelled from the dosage form by one or more exit orifices, as is the case with the outlet orifice 50. The push layer can be positioned in a stratified contact arrangement with the drug layer, as illustrated in Figure 3, or it can have one or more intermediate layers separating the layer push and layer of drug. The drug layer 46 comprises a complex in a mixture with selected excipients, such as those discussed above in relation to Figure 2. An exemplary dosage form can have a drug layer formed of a poly ( ethylene) as a carrier, sodium chloride as an osmagent, hydroxypropylmethylcellulose as a binder, and magnesium stearate as a lubricant. The push layer 48 comprises osmotically active components, such as one or more polymers that include an aqueous or biological fluid and which swells, referred to in the art as an osmopolymer. Osmopolymers are swellable hydrophilic polymers that interact with water and aqueous biological fluids, and swell or expand to a high degree, typically exhibiting an increase in volume from 2 to 50 times. The osmopolymer may be non-interlaced or interlaced, and in a preferred embodiment, the osmopolymer is at least slightly interlaced to create a polymer network that is too large and entangled to easily exit the dosage form during use. Examples of polymers that can be used as osmopolymers are provided in the references cited above, which describe osmotic dosage forms in detail. A typical osmopolymer is a poly (alkylene) oxide, such as poly (ethylene) oxide, and a poly (carboxymethylcellulose) alkaline, wherein the alkali is sodium, potassium or lithium. Other excipients such as a binder, a lubricant, an antioxidant and a dye can also be included in the push layer. In use, as the fluid is included through the semipermeable wall, the osmopolymers swell and push against the drug layer to cause release of the drug from the dosage form through the exit orifices. The push layer may also include a component referred to as a binder, which is typically a cellulose or vinyl polymer, such as poly-n-vinylamide, poly-n-vinylacetamide, poly (vinylpyrrolidone), poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, and the like. The push layer may also include a lubricant, such as sodium stearate or magnesium stearate, and an antioxidant to inhibit the oxidation of the ingredients. Representative antioxidants include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3 t-butyl-4-hydroxyanisole and butylated hydroxytoluene. An osmagent can also be incorporated into the drug layer and / or the push layer of the osmotic dosage form. The presence of the osmoagent establishes a gradient of osmotic activity through the semipermeable wall. Examples of osmagents include salts, such as sodium chloride, potassium chloride, lithium chloride, etc., and sugars such as raffinose, sucrose, glucose, lactose and carbohydrates.

With continued reference to FIGS. 2 or 3, the dosage form may optionally include a top coat (not shown) to color code the dosage forms according to the dose, or to provide an immediate release of the complex of the invention or another drug. In use, water flows through the wall and into the push layer and the drug layer. The thrust layer absorbs fluid and begins to swell and, consequently, pushes the drug layer 44, causing the material in the layer to be expelled through the exit orifice and into the gastrointestinal tract. The push layer 48 is designed to absorb fluid and continue to swell, thereby continually ejecting the complex of the invention from the drug layer throughout the period during which the dosage form is in the gastrointestinal tract. In this way, the dosage form provides a continuous supply of complex to the gastrointestinal tract for a period of 12 to 20 hours, or through substantially the entire period of the passage of the dosage form through the G.l. tract. Since the complex can be easily absorbed in tracts G.l. upper and lower, administration of the dosage form provides delivery of the drug portion into the blood stream during the period of 12 to 20 hours of transit of the dosage form in the G.l. In one embodiment, the dosage forms of the present invention comprise novel complexes and second forms of the drug moiety (such as a loose ion pair salt), so that the second form of the drug is available for absorption in the G.l. tract. superior, and the complex is present for absorption in the G.l. Lower. This can facilitate optimal absorption in circumstances where different characteristics are needed to optimize absorption through the G.l. tract. An example of a specific dosage form comprising the complexes of the invention and second forms of the drug portion (such as a loose ion pair salt) is shown in Figure 4. Dosage forms of three layers of this type are describe in detail in the US patents Nos. 5,545,413; 5,858,407; 6,368,626 and 5,236,689, which are incorporated herein by reference. The osmotic dosage form 60 has a three layer core 62 formed of a first layer 64 of a salt of the drug portion, present as a loose ion pair, a second layer 66 comprising the drug portion present in the form of a complex of the invention, and a third layer 68 referred to as a push layer. A three-layered dosage form having a first layer of 85.0 wt.% Of salt of the drug moiety present as a loose-ion salt, 10.0 wt.% Polyethylene oxide with a molecular weight of 100,000 is prepared. , 4.5% by weight of polyvinylpyrrolidone with a molecular weight of about 35,000 to 40,000, and 0.5% by weight of magnesium stearate. The second layer comprises 93.0% by weight of complex, 5.0% by weight of polyethylene oxide with a molecular weight of 5,000,000, 1.0% by weight of polyvinylpyrrolidone with a molecular weight of about 35,000 to 40,000, and 1.0% by weight of stearate of magnesium. The push layer consists of 63.67% by weight of polyethylene oxide, 30.00% by weight of sodium chloride, 1.00% by weight of ferric oxide, 5.00% by weight of hydroxypropylmethylcellulose, 0.08% by weight of butylated hydroxythiuene, and 0.25% by weight of magnesium stearate. The semipermeable wall comprises 80.0% by weight of cellulose acetate with an acetyl content of 39.8%, and 20.0% by weight of polyoxyethylene-polyoxypropylene copolymer. Dissolution regimes of the dosage forms, such as those shown in Figures 2 to 4, can be determined according to the procedure set forth in Example 6. In general, the release of the drug formulation from the dosage form begins after contact with a watery environment. In the dosage form illustrated in figure 2, the release of the drug portion-transport portion complex, present in the layer adjacent to the exit orifice, occurs after contact with an aqueous environment, and continues during the lifetime of the device. The dosage form illustrated in Figure 4 provides an initial release of salt from the drug portion, present in the drug layer adjacent to the exit orifice, with subsequent release of the drug portion-transport portion complex. It will be appreciated that this dosage form is designed to release salt from the drug portion, while transiting in the G.l. superior, which corresponds approximately to the first 8 hours of transit. The complex is released as the dosage form travels through the G.l. tract. lower, corresponding approximately to times greater than approximately 8 hours after ingestion. This design takes advantage of the increased absorption in the G.l. lower provided by the complex. Figures 5A-5C illustrate another example of dosage form, known in the art and described in the U.S. Patents. Nos. 5,534,263; 5,667,804; and 6,020,000, which are specifically incorporated herein by reference. In summary, a cross-sectional view of a dosage form 80 is shown before ingestion in the gastrointestinal tract in Figure 5A. The dosage form comprises a cylindrical shaped matrix 82 comprising a complex. The ends 84, 86 of the matrix 82 are preferably rounded, and are convex to ensure ease of ingestion. Bands 88, 90 and 92 concentrically surround the cylindrical matrix, and are formed of a material that is relatively insoluble in an aqueous environment. Suitable materials are set forth in the patents set forth above and in example 6 below. After ingestion of the dosage form 80, the regions of the matrix 82 between the bands 88, 90, 92 begin to erode, as illustrated in Figure 5B. Erosion of the matrix initiates the release of the complex in the fluidic environment of the G.l. As the dosage form continues to transit through the tract G.I., the matrix continues to erode, as illustrated in Figure 5C. There, the erosion of the matrix has progressed to such a degree that the dosage form is broken into three pieces, 94, 96, 98. The erosion will continue until the portions of the matrix of each of the pieces have been eroded completely . Bands 94, 96, 98 will be expelled after the G.l. It will be appreciated that the dosage forms described in Figures 2 through 5C are only one example of a variety of dosage forms designed for, and capable of achieving, the delivery of the complex of the portion of the invention to the G.l. tract. Those skilled in the pharmaceutical arts can identify other dosage forms that would be suitable. The complexes, compositions and dosage forms of the invention are useful in the treatment of a variety of indications. In general, the number of treatable indications using the complexes, compositions and dosage forms of the invention, is the same as the number of drug portions useful in the practice of the invention. In one aspect, the invention provides a method for the treatment of an indication, such as a disease or disorder, in a patient, by administering a composition or a dosage form comprising a complex of the invention, the complex characterized by a hybrid link. or a tight ion-pair bond between the drug portion and the transport portion. In one embodiment, a composition comprising the complex and a pharmaceutically acceptable carrier is administered to the patient by oral administration. The dose administered is generally adjusted according to the age, weight and condition of the patient, taking into account the dosage form and the desired result. In general, the dosage forms and compositions comprising the complex of the invention can be administered in amounts that provide an amount of the drug portion within an order of magnitude of the immediate release form typical of the non-drug portion. combined Due to the enhanced absorption provided by the complex, the dose of the complex may often be lower than that which is typically recommended for conventional therapies with the non-combined drug portion. Typical doses may comprise drug moiety in an amount ranging from about 0.01 micrograms of drug moiety to about 5000 mg of drug moiety, preferably ranging from about 1 microgram of drug moiety to about 2500 mg of drug moiety, plus preferably ranging from about 10 micrograms of drug serving to about 2000 mg of drug serving, even more preferably ranging from about 100 micrograms of drug serving to about 1500 mg of drug serving, and even more preferably varying from about 500 micrograms of drug serving. drug portion to approximately 1000 mg of drug moiety. Typical doses may comprise the complex of the invention in an amount ranging from about 0.01 microgram of the complex of the invention to about 5000 mg of the complex of the invention, preferably varying from about 1 microgram of the complex of the invention to about 2500 mg of the complex of the invention, more preferably ranging from about 10 micrograms of the complex of the invention to about 2000 mg of the complex of the invention, even more preferably varying from about 100 micrograms of the complex of the invention to about 1500 mg of the complex of the invention, and even more preferably varying from about 500 micrograms of the complex of the invention to about 1000 mg of the complex of the invention. From the above, it can be seen how various objectives and characteristics of the invention are satisfied. A complex comprising a drug moiety and a transport moiety linked by a hybrid bond or a tight pair bond can provide enhanced colonic absorption of the drug moiety, relative to that observed for the non-pooled drug moiety. . The complex is prepared from a novel process, wherein the drug portion is reacted with a transport portion, such as a fatty acid, solubilized in a solvent, the solvent being less polar than water, the lower polarity evidenced , for example, by a lower dielectric constant. This reaction results in the formation of a complex between the drug portion and the transport portion, where the two species are associated by a bond that is not an ionic bond or a covalent bond, but is a tight ion-pair bond. The invention relates to a substance comprising: a complex comprising a drug portion and a transport portion. In preferable embodiments, the transport portion comprises an acid, basic or zwitterionic structural element.; or an acid, basic or zwitterionic residual structural element, paired with an ion in the transport portion. In preferred embodiments, the transport portion comprises fatty acids or their salts, benzenesulfonic acid or its salts, benzoic acid or its salts, fumaric acid or its salts, or salicylic acid or its salts. In other preferred embodiments, the fatty acid or its salt comprises a C6-C18 fatty acid or its salt, more preferably the C6-C18 fatty acid or its salt comprises a C12 fatty acid or its salt. In preferable embodiments, the transport portion comprises an alkyl sulfate or its salt, more preferably the alkyl sulfate or its salt comprises a C 6 -C 18 alkyl sulfate or its salt, more preferably still the C 6 -C 18 alkyl sulfate or its salt, It is sodium lauryl sulfate. In preferable embodiments, the transport portion comprises a pharmaceutically acceptable primary, secondary or tertiary amine, or salts thereof. In more preferable embodiments, the drug portion comprises an acid, basic or zwitterionic structural element; or an acid, basic or zwitterionic residual structural element paired with an ion to form a salt. The invention further relates to a composition comprising the substance and an inactive ingredient, and to a dosage form comprising the composition. The invention relates to a method of treating a disease or condition, comprising: administering the substance to a patient in need thereof. In preferred embodiments, the substance is administered by an oral, intravenous, subcutaneous, intramuscular, transdermal, intraarterial, intraarticular or intradermal route. The invention relates to a method for obtaining a composition, comprising: providing a portion of drug in an ionic form; provide a transport portion in an ionic form; combining the drug portion and the transport portion, in the presence of a solvent having a dielectric constant less than that of water, to form a complex; and separate the solvent complex. In preferred embodiments, the transport portion comprises an acid, basic or zwitterionic structural element; or an acid, basic or zwitterionic residual structural element, paired with an ion in the transport portion. In preferred embodiments, the drug moiety comprises an acid, basic or zwitterionic structural element; or an acid, basic or zwitterionic residual structural element, paired with an ion in the transport portion. In preferred embodiments, the drug portion comprises an acidic structural element or an acidic residual structural element; and the drug portion is processed to obtain the acid form of the drug portion. In preferred embodiments, the drug portion comprises a basic structural element or a basic residual structural element; and the drug portion is processed to obtain the basic form of the drug portion. In preferred embodiments, the drug portion comprises a zwitterionic structural element or residual zwitterionic structural element; and a structural element or residual structural element that does not bind, the zwitterionic structural element or residual zwitterionic structural element, is blocked before the drug portion and the transport portion react. The invention relates to a method of treatment, comprising: providing a portion of drug in an ionic form; provide a transport portion in an ionic form; combining the drug portion and the transport portion, in the presence of a solvent having a dielectric constant less than that of water, to form a complex; separate the solvent complex; and administer the separate complex to a patient who needs it. In preferred embodiments, the transport portion comprises an acid, basic or zwitterionic structural element; or an acid structural element, basic or zwitterionic, paired with an ion to form a salt. In preferred embodiments, the drug portion comprises an acid, basic or zwitterionic structural element.; or an acid structural element, basic or zwitterionic, paired with an ion to form a salt. In preferred embodiments, the drug portion comprises an acidic structural element or an acidic residual structural element; and the drug portion is processed to obtain the acid form of the drug portion. In preferred embodiments, the drug portion comprises a basic structural element or a basic residual structural element; and the drug portion is processed to obtain the basic form of the drug portion. In preferred embodiments, the drug portion comprises a zwitterionic structural element or residual zwitterionic structural element; and a structural element or residual structural element that does not bind, the zwitterionic structural element or residual zwitterionic structural element, is blocked before the drug portion and the transport portion react. In preferred embodiments, the complex is administered by an oral, intravenous, subcutaneous, intramuscular, transdermal, intraarterial, intraarticular or intradermal route. The invention also relates to a method for improving the absorption of a drug portion, comprising: providing a complex of the drug portion and a transport portion; and administer the complex to a patient who needs it. In preferred embodiments, the complex is administered orally, and the improved absorption comprises improved oral absorption. In preferred embodiments, improved oral absorption comprises improved absorption in the lower gastrointestinal tract. In preferred embodiments, improved oral absorption comprises improved absorption in the upper gastrointestinal tract. In preferred embodiments, the complex is administered transdermally, and the improved absorption is improved transdermal absorption. In preferred embodiments, the complex is administered subcutaneously, and the improved absorption is improved subcutaneous absorption. Although features and advantages of the invention applied to the present embodiments have been described and pointed out, those skilled in the medical art will appreciate that various changes, modifications, additions and omissions can be made in the method described in the specification, without departing from the spirit. of the invention.

EXAMPLES The following examples are illustrative of the claimed claim, and are not in any way limiting thereof.

Metformin Metformin refers to N, N-dimethylimidodicarbonimide d-amide, with molecular formula of C HnN5 and molecular weight of 129.17. The compound is commercially available as metformin hydrochloride. Formula 1, below, shows the chemical structure of metformin.

EXAMPLE 1 Preparation of the metformin complex-transport portion Materials: Metformin hydrochloride 13.0 g Lauric acid 16.0 g Methane! 675 mL Acetone 300 mL Demineralized water 14 mL Anionic resin (Amberlyst A-26 (OH)) 108 g Preparation of metformin base The ion exchange column was packed with the anionic resin, Amberlyst A-26 (OH), and a net weight was obtained. The column was rinsed first with deionized water (backwash), and then rinsed with methanol containing deionized water at 2% v / v, taking care not to allow the column to dry. Metformin hydrochloride was dissolved in an eluent comprising 365 ml of methanol containing deionized water at 2% by volume. The solution from step 3 was passed dropwise through the column using a separatory funnel, and the eluate was collected. It was calculated that the total metformin hydrochloride that was passed through is less than the equilibrium point (capacity) of the ion exchange resin. The column was rinsed with an almost equal volume of eluent. A total of 690 mL of metformin base eluate was collected. The combined eluates were evaporated to dryness under vacuum at an external temperature of 40 ° C, which was raised to 65 ° C at the end of the concentration step to remove all remaining water. This step of concentration was carried out in the most expeditious manner, due to the instability of metformin base.

Complex formation A solution of lauric acid-acetone, 16.0 g of lauric acid dissolved in 300 mL of acetone was prepared. The concentrated metformin from the previous step was dissolved using several acetone washes, and these washes were immediately filtered in the presence of a filter aid, to remove any unconverted metformin hydrochloride. The filtrate was collected in an Erlenmeyer flask and, with stirring, the lauric acid-acetone solution was added dropwise, using a separatory funnel. Metformin-laurate was precipitated. Stirring was continued overnight at room temperature (20-25 ° C). The mixture of solvent and precipitated metformin-laurate was filtered through a Buchner funnel. The filter cake was rinsed with 4 x 200 mL of acetone, and then dried under suction in vacuo for one hour. The filter cake was scraped off the paper filtered, and weighed. The melting point was determined in a capillary tube. The final drying was carried out in a vacuum oven for 3 hours at room temperature.

The above procedure resulted in the formation of a metformin-laurate complex with a melting point of 150 ° -153 ° C. The melting point of metformin hydrochloride is reported as 225 ° C. Total performance = 75% with respect to the theoretical amount calculated from the stoichiometric amounts of metformin hydrochloride and lauric acid used. Reaction scheme 1 shows a generalized synthesis reaction scheme for the preparation of a metformin-transport portion complex. Reaction scheme 2 shows a generalized synthesis reaction scheme for the preparation of a metformin-transport portion complex, wherein the transport portion includes a carboxyl group. The reaction scheme 3 shows a synthesis reaction scheme for the preparation of a metformin-fatty acid complex, as illustrated in this example.

REACTION SCHEME 1 Metforrnma - T, ^, Ifr Metformin + T. solvent * REACTION SCHEME 2 etf ormma + T • COOH -7 I - l Me? formí] + [HOOC • T] - solvent REACTION SCHEME 3 Etform hydrochloride to meErormirta Mßtfor ina - lauraio (»= 11) EXAMPLE 2 Characterization of the metformin complex-transport portion Characterization by means of HPLC High pressure liquid phase chromatography was used inverted (RP-CLAR), to analyze the complex of metformin-laurate formed as described in example 1. For comparison, also generated HPLC traces of metformin hydrochloride, sodium laurate, and a physical mixture of hydrochloride of metformin and sodium laurate. Inverted phase HPLC was carried out in a Hewlett Packard 1100 liquid chromatograph with an evaporative light scattering detector, and using a C3 column (Agilest Zorbas SB C3, 5 μm, 3.0 x 75 mm). A mobile phase of water was used: acetonitrile 50:50 in v: v. The temperature of the column was 40 ° C, and the flow rate was 0.5 mL / min. The results are shown in Figures 7A-7D. The trace for metformin hydrochloride is shown in Figure 7A, and a single maximum value is observed at 1.1 minutes. The salt form of lauric acid, sodium laurate, elutes as a single broad maximum value between about 3-4 minutes (Figure 7B). A 1: 1 molar physical mixture of metformin hydrochloride and sodium laurate in water elutes as two maximum values, a maximum value at 1.1 minutes corresponding to metformin hydrochloride, and a second maximum value between approximately 2.7-4 minutes of laurate sodium (figure 7C). Figure 7D shows the HPLC trace for the complex formed by the procedure of Example 1, where a single maximum value eluting between 3.9-4.5 minutes is observed. The CLAR traces show that the complex formed of metformin base and lauric acid, is different from the physical mixture of the two components in water. The trace also shows that the complex does not dissociate when it is subjected to the solvent system (water: acetonitrile 50:50 in v: v), for the analysis by means of HPLC.

Octanol / water partition coefficient In another study to characterize the metformin-laurate complex, the apparent octanol / water partition coefficient (D = Coctanoi / Cagua) of the complex was measured and compared with metformin hydrochloride, a mixture 1: 1 (mol / mol) of metformin hydrochloride: sodium lauryl sulfate and a 1: 1 mixture (mol / mol) of metformin hydrochloride: sodium laurate. The results are shown in table 3.

TABLE 3 Octanol / water distribution coefficients L? G [Coctanol'CaguaJ The complex had a logD of 0.44, a significant increase compared to metformin hydrochloride, indicating that the complex distributes more favorably towards octanol than the metformin salt form. The complex also had a higher logD compared to the physical mixtures of metformin hydrochloride in the fatty acid salts. This difference in logD further confirms that the metformin-fatty acid complex is not a physical mixture of the two species, that is, a simple ion pair, but is otherwise. Figure 6 is a graph of the logarithm of the octanol / water partition coefficient as a function of pH for metformin hydrochloride.

Dissociation properties Metformin-fatty acid complexes were prepared according to the procedure described in Example 1, using the fatty acids capric acid, lauric acid, palmitic acid and oleic acid. A complex of metformin and ethylene succinic acid was also prepared. The complexes were characterized by melting points and solubility, and the data are summarized in Table 4A. In addition, the conductivity of the various complexes in aqueous solutions (pH = 5.8) was measured with a CDM 83 conductivity meter (Radiometer Copenhagen) at 23 ° C. The values are summarized in Table 4B, and are presented graphically in Figure 8A.

TABLE 4A TABLE 4B Figure 8A shows the conductivity, in microsiemens / centimeter (μS / cm), as a function of the concentration of metformin for metformin hydrochloride (circles), metformin combined with succinate (inverted triangles), caprate (squares), laurate (rhombuses), palmitate (triangles) and oleate (octagons). Metformin hydrochloride had the highest conductivity at all concentrations. The complexes had a lower conductivity than metformin hydrochloride, with a decreasing conductivity when increasing the apparent number of carbons of the fatty acid. Figure 8B shows the percent of non-ionized drug for each of the complexes as a function of the concentration of metformin, determined from equation 3. Metformin hydrochloride (circles) is completely ionized, while the complex of Metformin-succinate (inverted triangles) is approximately 80% ionized. The complexes of metformin-caprate (squares) and metformin-laurate (diamonds) are approximately 50% ionized, and metformin-palmitate (triangles) and metformin-oleate (octagons) are approximately 30% ionized. Again, these data establish a difference between metformin hydrochloride of the ion pair, and the metformin-fatty acid complexes.

EXAMPLE 3 Absorption in vivo in the GJ tract. lower using the oral fattening model in rats Eight rats were randomized into two treatment groups. After being fasted for 12 to 24 hours, the first group received, by oral priming, 40 mg / kg of free base equivalent of metformin hydrochloride. The second group received, by oral priming, 40 mg / kg of free base equivalent of metformin laurate complex, prepared as described in example 1. Blood samples were taken from the tail vein 15 minutes, 30 minutes , 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours after oral priming. The concentration of metformin in plasma was analyzed by LC / MS / MS. The results are shown in Figure 9. The plasma concentration in rats given metformin hydrochloride (circles) by oral priming reached a maximum concentration in plasma approximately 1 hour after treatment, with a Cmax of approximately 4080 ng / mL. Rats treated by oral priming with the metformin-laurate complex (diamonds) had a maximum plasma concentration approximately 1 hour after treatment, with a Cmax of approximately 5090 ng / mL. The plasma concentration for rats treated with the complex was higher at all test points in the period of 1 to 8 hours after treatment. Analysis of the data showed that the relative bioavailability of metformin when administered in the complex form was 151%, relative to the bioavailability of metformin when administered intravenously as metformin hydrochloride (100% bioavailability). At the end of the study, the rats were subjected to euthanasia, and a gross evaluation of the G.l. tract was made. of the test animals to look for signs of irritation. No irritation was observed in the rats treated with the complex or with metformin hydrochloride.

EXAMPLE 4 Absorption in vivo using the ligated-washed colon model in rats An animal model commonly known as the "ligated-washed colon model" was used to test the formulations. The surgical preparation of male Sprague-Dawley rats of 0.3-0.5 kg anesthetized fasting proceeded as follows. A segment of proximal colon was isolated, and the colon was washed to remove fecal material. The segment was ligated at both ends, while a catheter was placed in the lumen and externalized on the skin for delivery of the test formulation. The colonic contents were washed away, and the colon was returned to the abdomen of the animal. Depending on the experimental arrangement, the test formulation was added after the segment was filled with 1 mL / kg of pH buffer of 20 mM sodium phosphate, pH 7.4, to more accurately simulate the actual colon environment in a clinical situation. The rats were allowed to reach equilibrium for approximately 1 hour after the surgical preparation, and prior to exposure to each test formulation. Metformin hydrochloride or a metformin-fatty acid complex was administered as an intracolonic bolus at dosages of 10 mg of metformin hydrochloride / rat or 10 mg of metformin / rat complex. The rats were treated with metformin-fatty acid complexes prepared as described in Example 1, with the fatty acids capric acid, lauric acid, palmitic acid and oleic acid, and with a succinic acid dimer. Blood samples were obtained from the jugular catheter at 0, 15, 30, 60, 90, 120, 180 and 240 minutes after administration of the test formulation, and analyzed for metformin concentration in blood. Tables 5 to 10 below show for each complex and for each rat, the metformin base concentration detected in the blood plasma measured in nanograms per milliliter at each time point.

TABLE 5 TABLE 6 TABLE 7 TABLE 8 TABLE 9 TABLE 10 For comparison, metformin hydrochloride was injected intravenously, at a dosage of 2 mg / kg body weight of the rat, directly into the bloodstream of three test rats. Blood samples were taken periodically for a period of four hours for the analysis of metformin base. The results are shown in table 11.

TABLE 11 The results of Tables 5 to 10 are shown graphically in Figure 10. Figure 10 shows the concentration of metformin in plasma, in ng / mL, in rats, as a function of time, in hours, for metformin hydrochloride (circles ), metformin combined with succinate (diamonds), palmitate (triangles), oleate (inverted triangles), caprate (squares) and laurate (octagons). The highest concentrations in the blood plasma were obtained from the complexes prepared from lauric acid (circles) and with capric acid (squares). The complexes with palmitic acid (triangles) and oleic acid (inverted triangles), reached lower concentrations of metformin in plasma than those obtained from the complexes with lauric acid and capric acid, but higher than the concentration in plasma provided by the hydrochloride of metformin or metformin succinate. Table 12 shows the relative Cmax (maximum plasma concentration of metformin base for each complex relative to the concentration of metformin hydrochloride in plasma), and the relative bioavailability of each complex normalized to the bioavailability of metformin hydrochloride administered by intubation to a ligated colon (fourth column) and regarding the bioavailability of metformin hydrochloride administered intravenously (third column).

TABLE 12 1AUC achieved for each complex normalized to AUC metformin hydrochloride administered intravenously; (ng-h / mL-mg). 2AUC achieved by each complex normalized to AUC metformin hydrochloride administered by intubation to the bound colon.

Metformin, when provided for absorption to the G.l. lower in the form of a metformin-transport portion complex is significantly enhanced, as observed by the increase in bioavailability of almost 5 times achieved with a metformin-palmitate complex, relative to that of the hydrochloride salt. The oleate complex gave an improvement in bioavailability of 14 times compared to that of the hydrochloride salt. The metformin-caprate complex, provided an improvement in bioavailability of almost 18 times compared to that of the hydrochloride salt. The metformin-laurate complex gave an improvement in bodisponibility greater than 20 times compared to that of the hydrochloride salt. Accordingly, the invention contemplates a compound comprising a complex formed of metformin and a transport portion, wherein the complex provides an increase of at least 5 times, more preferably an increase of at least 15 times, and more preferably a increase of at least 20 times in absorption in the Gl tract lower compared to the absorption of metformin hydrochloride in the G.l. Lower, as evidenced by the bioavailability of metformin determined from the concentration of metformin in plasma. Thus, metformin when administered in the form of a metformin-transport portion complex, provides a significantly enhanced absorption of metformin in blood in the G.l. lower.

EXAMPLE 5 Absorption in vivo using the ligated-washed colon model in rats Another study was carried out using the ligated-washed colon model described in Example 4, to compare the bioavailability of metformin when provided in the form of a complex, with the bioavailability of metformin when provided as a physical mixture of hydrochloride of metformin and sodium laurate (molar ratio 1: 1). Several doses of the two test formulations (metformin-laurate complex and 1: 1 molar ratio of metformin hydrochloride: sodium Iaurate) or metformin hydrochloride were intubated., in the bound colon. Plasma samples were analyzed for metformin concentration, and bioavailability was determined, regarding the bioavailability of metformin administered intravenously. The results are shown in Figure 11. Figure 11 shows the percent bioavailability as a function of the dose of metformin, in mg of base / kg, of the physical mixture of metformin hydrochloride and sodium laurate (circles) and of the metformin-laurate complex (squares). The complex had a higher bioavailability with less variability, than the physical mixture. Figure 12 shows the data in Tables 5, 11 and 12 of Example 3, illustrating the complex pharmacokinetics (diamonds) compared to metformin hydrochloride administered by intubation to the bound colon (circles), or intravenously (triangles). The complex provides greater colonic absorption than the salt form of the drug, and has a longer lasting blood concentration than intravenous administration.

EXAMPLE 6 Preparation of a dosage form comprising a complex of metformin-transport portion A dosage form comprising a layer of metformin hydrochloride and a complex layer of metformin-laurate, was prepared as follows: 10 g of metformin hydrochloride, 1.18 g of polyethylene oxide with a molecular weight of 100,000, and 0.53 g of polyvinyl pyrrolidone with a molecular weight of about 38,000 was mixed dry in a conventional mixer for 20 minutes to give a homogeneous mixture. Then, 4 mL of denatured anhydrous alcohol was slowly added, with the mixer continuously mixing, to the dry three-component mixture. The mixing was continued for another 5 to 8 minutes. The mixed wet composition was passed through a 16 mesh screen, and dried overnight at room temperature. Then, the dried granules were passed through a 16 mesh screen and 0.06 g of magnesium stearate was added, and all the ingredients were dry mixed for 5 minutes. The fresh granules were ready for formulation as the initial dosage layer in the dosage form. The granules comprised 85.0% by weight of metformin hydrochloride, 10.0% by weight of polyethylene oxide with a molecular weight of 100,000, 4.5% by weight of polyvinylpyrrolidone with a molecular weight of about 35,000 to 40,000, and 0.5% by weight of stearate of magnesium. The metformin-laurate layer in the dosage form was prepared as follows: First, 9.30 g of metformin laurate complex, prepared as described in Example 1, 0.50 g of polyethylene oxide with a molecular weight of 5,000,000 , and 0.10 g of polyvinylpyrrolidone with a molecular weight of about 38,000, were dry blended in a conventional mixer for 20 minutes, to give a homogeneous mixture. Then, denatured anhydrous ethanol was slowly added to the mixture with continuous mixing for 5 minutes. The mixed wet composition was passed through a 16 mesh screen, and dried overnight at room temperature. Then, the dried granules were passed through a 16 mesh screen and 0.10 g of magnesium stearate was added, and all dry ingredients were dry mixed for 5 minutes. The composition comprised 93.0% by weight of metformin-laurate, 5.0% by weight of polyethylene oxide with a molecular weight of 5,000,000, 1.0% by weight of polyvinylpyrrolidone with a molecular weight of about 35,000 to 40,000, and 1.0% by weight of stearate of magnesium. A pusher layer comprising an osmopolymer hydrogel composition was prepared in the following manner: First, 58.67 g of pharmaceutically acceptable polyethylene oxide with a molecular weight of 7,000,000, 5 g of Carbopol® 974P, 30 g of sodium chloride and 1 g of ferric oxide were screened separately through a 40 mesh screen. The sieved ingredients were mixed with 5 g of hydroxypropylmethylcellulose with a molecular weight of 9,200 to give a homogeneous mixture. Then, 50 mL of denatured anhydrous alcohol was slowly added to the mixture with continuous mixing for 5 minutes. Then, 0.080 g of butylated hydroxytoluene was added, followed by further mixing. The freshly prepared granulation was passed through a 20 mesh screen, and allowed to dry for 20 hours at room temperature. The dried ingredients were passed through a 20 mesh screen and 0.25 g of magnesium stearate was added, and all ingredients were mixed for 5 minutes. The final composition comprised 58.7% by weight of polyethylene oxide, 30.0% by weight of sodium chloride, 5.0% by weight of Carbopol®, 5.0% by weight of hydroxypropylmethylcellulose, 1.0% by weight of ferric oxide, 0.25% by weight of magnesium stearate, and 0.08% by weight of butylated hydroxytoluene. The three layer dosage form was prepared as follows: First, 118 mg of the metformin hydrochloride composition was added to a punch and die set, and they were buffered, and then 427 mg of the metformin-laurate composition was added to the set of dies as the second layer, and again they were damped. Then, 272 mg of the hydrogel composition was added, and the three layers were compressed under a compression force of 1000 kg in a 0.714 cm diameter die and punch kit, forming a three layer intimate core (tablet). A semipermeable wall-forming composition comprising 80.0% by weight of cellulose acetate with an acetyl content of 39.8% and 20.0% polyoxyethylene-polyoxypropylene copolymer with a molecular weight of 7680-9510 was prepared by dissolving the ingredients in acetone in a composition 80:20 in p / p, to obtain a solids solution at 5.0%. The placement of the solution container in a hot water bath during this step accelerated the dissolution of the components. The wall-forming composition was sprayed on and around the three-ply core, to provide a semi-permeable wall of 93 mg thickness. Then, a 1.02 mm exit orifice was laser drilled in the three-layer semi-permeable wall tablet to provide contact of the metformin layer with the exterior of the delivery device. The dosage form was dried to remove any residual solvent and water. The in vitro dissolution regimens of the dosage form were determined by placing a dosage form on metal coil sample holders attached to a Vil type bath cataloger of USP in a constant temperature water bath at 37 ° C. Aliquots of the release medium were injected into a chromatographic system to quantitate the amounts of drug released in a medium simulating artificial gastric fluid (AGF) during each testing interval. Three dosage forms were tested and the average dissolution rate is shown in Figure 13, where the metformin release rate, in mg / hour, is shown as a function of time, in hours. Four hours after contact with an aqueous environment, the dosage form begins to release an almost uniform amount of drug for the next 12 hours, with drug release beginning to decrease in times greater than 16 hours after contact with an aqueous environment. The release of metformin hydrochloride, present in the drug layer adjacent to the exit orifice, occurs initially. Approximately 8 hours after contact with an aqueous environment, the release of the metformin-transport portion complex occurs, and continues at a substantially constant rate for 8 more hours. It will be appreciated that this dosage form is designed to release metformin hydrochloride while transiting in the G.l. superior, which corresponds approximately to the first eight hours of transit, as indicated by the dashed bars. The metformin-transport portion complex is released as the dosage form travels through the G.l. tract. lower, corresponding approximately to times longer than about 8 hours after ingestion, as indicated by the dotted bars in Figure 13. This design takes advantage of the increased absorption in the G.l. lower provided by the complex.

Gabapentina EXAMPLE 7 Preparation of gabapentin-lauryl sulfate complex 1. A solution of 0.5 mL of 36.5% hydrochloric acid (5 mmol of HCl) in 25 mL of deionized water was prepared. 2. 5 mmol of gabapentin (0.86 g) was added to the solution from step 1. The mixture was stirred for 10 minutes at room temperature. Gabapentin hydrochloride was formed. 3. 5 mmoles of sodium lauryl sulfate (1.4 g) was added to the aqueous solution from step 2. The mixture was stirred for 20 minutes at room temperature. A loose ion pair of gabapentin and lauryl sulfate was formed. 4. 50 mL of dichloromethane was added to the solution of step 3. The mixture was stirred for 2 hours at room temperature. 5. The mixture from step 4 was transferred to a separatory funnel, and allowed to settle for 3 hours. Two phases were formed, a lower phase of dichloromethane, and an upper phase of water. 6. The upper and lower phases of step 5 were separated. The lower phase of dichloromethane was recovered, and the dichloromethane was evaporated to dryness at room temperature, followed by drying in a vacuum oven for 4 hours at 40 ° C. A complex of pregabalin-lauryl sulfate (1.9 g) was obtained. The total yield was 87% with respect to the theoretical amount calculated from the initial amounts of gabapentin and sodium lauryl sulfate. Reaction scheme 4 shows a synthesis reaction scheme for the preparation of a gabapentin-alkyl sulfate complex.

REACTION SCHEME 4 Gabapentyria Gafeapentipa HCl extraction EXAMPLE 8 Characterization of the gabapentin-lauryl sulfate complex Infrared Fourier transformation spectroscopy was used (FTIR), to analyze the gabapentin-lauryl sulfate complex formed as described in Example 7. FTIR spectra were obtained using a Perkin-Elmer Spectrum 2000 FTIR spectrometer system, consisting of the attenuated total reflectance accessory ( ATR) and MCT detector (cadmium-mercury telluride) cooled in liquid nitrogen. FTIR scans of gabapentin, sodium lauryl sulfate, and a physical mixture of gabapentin and sodium lauryl sulfate were also generated. FTIR / ATR spectra were also generated from gabapentin, sodium lauryl sulfate, and from a 1: 1 molar ratio physical mixture of gabapentin and sodium lauryl sulfate (two components were dissolved in methanol, and dried in air as a film solid), and the results are shown in Figures 14A-14D. The spectrum for gabapentin is shown in Figure 14A, and the maximum values corresponding to the NH and COO portions are indicated. The spectrum for sodium lauryl sulfate is shown in Figure 14B, and a maximum value of the main doublet corresponding to the S-0 portion is observed between 1300-1200 cm -1. A 1: 1 molar mixture of gabapentin hydrochloride and sodium lauryl sulfate in water is shown in Figure 14C, and an attenuation of the distinct characteristic pattern of gabapentin is apparent, and a widening of the maximum value of S-0 is observed ( 1300-1200 cm-1) from sodium lauryl sulfate. Figure 14D shows the FTIR spectrum for the complex formed by the procedure of Example 7, where two maximum values corresponding to the COO- group of gabapentin disappeared, and were replaced by a maximum value of the COOH group in the gabapentin complex -lauryl sulfate, indicating the blocking of COO- charges. The deformation of the N-H portion of gabapentin was observed by changing 15 cm-1 in the gabapentin-lauryl sulfate spectra.

This change of bands for the N-H bond indicates the protonation of the N-H groups in the resulting complex. The maximum value at 1250 cm-1 which is indicative of the absorption of S-0 in the sodium lauryl sulfate spectra changed 30 cm -1, as shown in the spectrum of the gabapentin complex, suggesting the interaction of gabapentin with the sulfate group of sodium lauryl sulfate. The FTIR scans showed that the complex formed of gabapentin is different from the physical mixture of the two components.

EXAMPLE 9 Colonic absorption in vivo using the ligated-washed colon model in rats An animal model commonly known as the "ligated-washed colon model" was used. Sprague-Dawley male rats weighing 0.3-0.5 kg were anesthetized in fasting, and a proxmal segment of colon was isolated. The colon was washed to remove the stool. The segment was ligated at both ends, while a catheter was placed in the lumen and externalized on the skin for delivery of the test formulation. The colonic contents were washed away, and the colon was returned to the abdomen of the animal. Depending on the experimental arrangement, the test formulation was added after the segment was filled with 1 mL / kg of pH buffer of 20 mM sodium phosphate, pH 7.4, to more accurately simulate the actual colon environment in a clinical situation. The rats (n = 3) were allowed to reach equilibrium for approximately 1 hour after the surgical preparation and before exposure to each test formulation. The gabapentin-lauryl sulfate or gabapentin complex was administered as an intracolonic bolus, and was administered to 10 mg of gabapentin-lauryl sulfate / rat complex or 10 mg of gabapentin / rat. Blood samples obtained from the jugular catheter were taken at 0, 15, 30, 60, 90, 120, 180 and 240 minutes, and analyzed for gabapentin concentration. At the end of the 4 hour trial period, the rats were subjected to euthanasia with an overdose of pentobarbital. Colonic segments of each rat were excised and opened longitudinally along the anti-mesenteric border. Each segment was observed macroscopically for irritation, and any abnormality was noted. The removed colons were placed on graph paper, and were measured for approximate colonic surface area. There was no histopathological change visible to the naked eye in the mucosa of the rats put to the test. A control group of rats (n = 3) was treated intravenously with gabapentin, at a dose of 1 mg / rat. Blood samples were taken at the same times indicated above, for analysis of the concentration of gabapentin.

The concentration of gabapentin in plasma for each test animal, and the average plasma concentration for the animals in each test group, are shown in Tables 13 to 15.

TABLE 13 TABLE 14 TABLE 15 Figure 15 shows the average concentration of gabapentin in each test group, as a function of time. Gabapentin administered intravenously (triangles), gives a high concentration in initial plasma with a sharply decreasing concentration during the first 15 minutes. When gabapentin is administered as an intracolonic bolus (circles), a slow absorption of the drug occurs. In contrast, when the drug is administered to the G.l. In the form of a gabapentin-lauryl sulfate complex (diamonds), a rapid drug uptake occurs, with a CmaX observed one hour after intubation. The pharmacokinetic parameters of this study are shown in table 16. The area under the curve (AUC) is determined from time zero to infinite time based on 1 mg of gabapentin / rat for each of the dosages of gabapentin, where the Infinite time was calculated assuming a linear logarithmic decrease. The bioavailability of gabapentin is expressed as a percent of the concentration of gabapentin that results from the intravenous administration of the drug.

TABLE 16 The enhanced colonic absorption provided by the gabapentin and lauryl sulfate complex is evident from the remarkably improved bioavailability of the drug when administered to the G.l. tract. lower in the form of the complex with respect to the pure drug. The gabapentin-lauryl sulfate complex provided a 13-fold improvement in bioavailability over that of the pure drug. Accordingly, the invention contemplates a compound comprising, which consists essentially of, or consisting of, a complex formed of gabapentin (or pregabalin) and a transport portion, wherein the complex provides at least a 5-fold increase, more preferably at least a 10-fold increase , and more preferably at least a 12-fold increase in colonic absorption with respect to the colonic absorption of gabapentin (or pregabalin), as evidenced by the bioavailability of gabapentin (or pregabalin) determined from the concentration of gabapentin (or pregabalin) in plasma. In this way, gabapentin (or pregabalin) when administered in the form of a complex of gabapentin (or pregabalin) -portion of transport, provides a significantly enhanced colonic absorption of gabapentin (or pregabalin) in the blood.

EXAMPLE 10 Absorption in vivo Twenty-eight rats were randomized into seven test groups (n = 4). Gabapentin or gabapentin-lauryl sulfate complex prepared as described in example 1A, was intubated by catheter at the beginning of the duodenum of the rats, at dosages of 5 mg / rat, 10 mg / rat and 20 mg / rat. The remaining test group was intravenously administered 1 mg / kg gabapentin. Blood samples were taken from each animal for a period of four hours, and analyzed for gabapentin content. The results are shown in tables 17 to 22 and in figures 16A-16C.

TABLE 17 TABLE 18 TABLE 19 TABLE 20 TABLE 21 TABLE 22 Figure 16A shows the concentration of gabapentin in plasma, in ng / mL, in the animals treated with pure gabapentin, administered intravenously (triangles), and to the duodenum, at dosages of 5 mg (circles), 10 mg (squares) and mg (diamonds). Increasing blood concentration with increasing dose was observed for the animals that received drug by intubation in the duodenum. Naturally, the lowest concentration of drug in plasma for the treated animals intravenously (triangles), is due to the lower dose of drug. Figure 16B shows the results for the animals that received intravenously gabapentin-lauryl sulfate complex (triangles), and directly to the duodenum, at dosages of 5 mg (circles), 10 mg (squares) and 20 mg (diamonds). While the absolute blood concentrations of the animals that received gabapentin-lauryl sulfate complex are lower than for the animals treated with gabapentin, the data show that the gabapentin absorption of the complex is enhanced with respect to absorption of the pure drug, perhaps because in part because the L-amino acid transport system is not being saturated and / or the transport is increased by other mechanisms provided by the complex. This is evident from a comparison of the blood concentration between the dose of 5 mg and 10 mg, and between the dose of 10 mg and 20 mg in Figures 16A and 16B, where the increase in blood concentration with increased dose it is greater for gabapentin administered in the complex form. Figure 16C shows the percent bioavailability of gabapentin administered as the pure drug (inverted triangles) or as gabapentin-lauryl sulfate complex (circles), to the duodenum of the rats. The percent bioavailability is determined with respect to gabapentin administered intravenously. At a dosage of 20 mg, the gabapentin-lauryl sulfate complex exhibited greater bioavailability than the pure drug. The increased bioavailability at higher doses is probably due to the enhanced absorption offered by the complex, where the uptake in the G.l. it is not limited to the uptake by the transport system of L-amino acids by the complex, but is also occurring through transcellular and paracellular mechanisms. Table 23 shows the pharmacokinetic analysis of the study, where the area under the curve was determined from 0 to 4 hours, and normalized to a dose of 1 mg of gabapentin / kg of the rat. The data regarding the 4-hour point for gabapentin (v), suppose a linear logarithmic decrease of the data measured for the first three hours. The percentage of bioavailability is related to the bioavailability of gabapentin administered intravenously.

TABLE 23 Normalized at the dose of 1 mg gabapentin / kg.

The AUC and the bioavailability data show that as the dose increases, gabapentin colonic absorption is improved when the drug is provided in the form of a gabapentin-transport portion complex.

EXAMPLE 11 Preparation of pregabalin complex-transport portion 1. Prepare a solution of 0.5 mL of hydrochloric acid at 36.5% (5 mmole of HCl) in 25 mL of deionized water. 2. Add 5 mmoles of pregabalin (0.80 g) to the solution in step 1. The mixture is stirred for 10 minutes at room temperature. Pregabalin hydrochloride is formed. 3. Add 5 mmoles of sodium lauryl sulfate (1.4 g) to the aqueous solution from step 2. The mixture is stirred for 20 minutes at room temperature. 4. Add 50 mL of dichloromethane to the solution of step 3.

The mixture is stirred for 2 hours at room temperature. 5. The mixture from step 4 is transferred to a separatory funnel, and allowed to settle for 3 hours. Two phases are formed, a lower phase of dichloromethane, and an upper phase of water. 6. The upper and lower phases of step 5 are separated. The lower phase of dichloromethane is recovered, and the dichloromethane is evaporated to dryness at room temperature, followed by drying in a vacuum oven for 4 hours at 40 ° C. A complex of pregabalin-lauryl sulfate (2.1 g) is obtained. The reaction scheme 5 shows a synthesis reaction scheme for the preparation of a pregabalin-alkyl sulfate complex.

REACTION SCHEME 5 Pregab aliña extraction, EXAMPLE 12 Colonic absorption in vivo using the ligated-washed colon model in rats An animal model commonly known as the "ligated-washed colon model". Male Sprague-Dawley rats weighing 0.3-0.5 kg are anesthetized in fasting, and a segment of the proximal colon is isolated. The colon is washed to remove stool. The segment is ligated at both ends, while a catheter is placed in the lumen and exteriorized on the skin for delivery of the test formulation. The colonic contents are washed away, and the colon is returned to the abdomen of the animal. Depending on the experimental setup, the test formulation is added after the segment is filled with 1 mL / kg of pH buffer of 20 mM sodium phosphate, pH 7.4, to more accurately simulate the actual colon environment in a clinical situation. The rats (n = 3) are allowed to reach equilibrium for approximately 1 hour after the surgical preparation and before exposure to each test formulation. Pregabalin-lauryl sulfate or pregabalin complex is administered as an intracolonic bolus, and delivered to 10 mg of pregabalin / rat. Blood samples obtained from the jugular catheter are taken at 0, 15, 30, 60, 90, 120, 180 and 240 minutes for the analysis of the concentration of pregabalin. At the end of the 4 hour trial period, the rats are subjected to euthanasia with an overdose of pentobarbital. Colonic segments of each rat are excised and opened longitudinally along the anti-mesenteric border. Each segment is observed macroscopically for irritation, and any abnormality is noted. The removed colons are placed on graph paper, and are measured for approximate colonic surface area. A control group of rats (n = 3) is treated intravenously with pregabalin, at a dose of 1 mg / rat. Blood samples are drawn at the same times indicated above.

EXAMPLE 13 In vivo absorption of pregabalin Twenty-eight rats are randomized into seven test groups (n = 4). Pregabalin or pregabalin-lauryl sulfate complex prepared as described in example 1B, in water, was intubated by catheter at the beginning of the duodenum of rats, at dosages of 5 mg / rat, 10 mg / rat and 20 mg / rat. The remaining test group is administered intravenously 1 mg / kg of pregabalin. Blood samples are taken from each animal for a period of four hours, and analyzed for pregabalin content. The dose, AUC and bioavailability are determined using calculations similar to those used for gabapentin in Example 10.

Iron The term "iron" includes iron (Fe) in any of its oxidative states, and in combination with any salt. The term "ferrous" refers to iron with a +2 charge (also denoted in the art as Fe2 +, Fe ++, iron (II)). The term "ferric" refers to iron with a +3 charge (also denoted in the art as Fe3 +, Fe +++, iron (III)). Examples of ferrous salts and ferric salts include, but are not limited to, sulfate, fumarate, succinate, giuconate, etc. ferrous and ferric. Reaction schemes 6 to 8 show synthetic reaction schemes for the preparation of an iron-fatty acid complex.

REACTION SCHEME 6 Fe + * T2 + 2 TM * Fe + Tv +, and solvent REACTION SCHEME 7 jF ^? ye + 2T * € 0aM * ñtette? e + Kr'COOfc) - * MSY REACTION SCHEME 8 B SQj * 11.04- 2 C-I3 < a-2) HCQ (- + "'" Fe + [Cfí5 { CH2)? COO] 2-' 4- Ka, 5? / / 7 = 2-20 EXAMPLE 14 Preparation of iron-fatty acid complex The following steps are carried out to form a ferrous salt-fatty acid complex. The reaction is illustrated in the reaction 6 to 8. 1. 9.15 grams of FeS04-7H20 were dissolved in 300 mL of methanol, in a beaker. 2. 14.64 g of sodium lauric acid (sodium laurate) were dissolved in 300 mL of methanol in a second beaker. 3. The solution from step 1 was added dropwise to the solution of step 2. The mixture was stirred for 1-5 h at room temperature to produce a precipitate of Na 2 SO. The solution was stirred overnight. 4. The precipitate from step 3 was removed by vacuum filtration using # 42 Whatman filter paper; the filtrate was captured in a funnel. The precipitate was washed three times with methanol; the filtrate was captured in the funnel. 5. The filtrate solution from step 4 was placed in a crystallizer, and placed in a laboratory hood to evaporate the solvent. A beige precipitate formed. The precipitate was placed on a vacuum filter, and the remaining solvent was removed by vacuum filtration. The filter cake was placed in a crystallizer, and placed in a vacuum oven overnight to dry. It was determined that the melting point of the precipitate is between 38-38 ° C.

EXAMPLE 15 Colonic absorption in vivo using the ligated-washed colon model in rats The absorption in the G.l. tract is evaluated. And the bioavailability of iron-transport complexes, using an animal model commonly known as the "ligated-wash colon model". The surgical preparation of male Sprague-Dawley rats of 0.3-0.5 kg in an anesthetized fast proceeds as follows. A segment of the proximal colon is isolated, and the colon is washed to remove fecal material. The segment is ligated at both ends, while a catheter is placed in the lumen and exteriorized on the skin for the delivery of test formulations. The colonic contents are washed away, and the colon is returned to the abdomen of the animal. Depending on the experimental setup, the test formulation is added after the segment is filled with 1 mL / kg of pH buffer of 20 mM sodium phosphate, pH 7.4, to more accurately simulate the actual colon environment in a clinical situation. The rats are allowed to reach equilibrium by approximately 1 hour after surgical preparation and before exposure to each iron-transport portion complex. The test compounds are administered as an intracolonic bolus, and are supplied to 10 mg of iron (as Fe + 2 / rat). Blood samples obtained from the jugular catheter are taken at 0, 15, 30, 60, 90, 120, 180 and 240 minutes, and analyzed for the concentration of iron in blood. At the end of the 4 hour trial period, the rats are subjected to euthanasia with an overdose of pentobarbital. Colonic segments of each rat are excised and opened longitudinally along the anti-mesenteric border. Each segment is observed macroscopically for irritation, and any abnormality is noted. The removed colons are placed on graph paper, and are measured for approximate colonic surface area. The above procedure is used to evaluate the absorption of ferrous sulfate salt, and ferrous-laurate sulfate salt complex, ferrous sulfate-caprate salt complex, ferrous sulfate-oleate salt complex, and ferrous sulfate salt complex -palmitate.

EXAMPLE 16 It is randomly distributed to 28 rats in seven test groups (n = 4). Ferrous sulfate or ferrous laurate sulfate complex prepared as described in example 11, was intubated by catheter at the beginning of the duodenum of the rats, at dosages of 5 mg / rat, 10 mg / rat and 20 mg / rat. The remaining test group is intravenously administered 1 mg / kg of ferrous sulfate.

Inhibitors of dipeptidyl peptidase IV The inhibitors of DPP IV are compounds that inhibit the enzymatic activity of DPP-IV; however, the compounds may also have inhibitory activity on other DPP enzymes. A large number of DPP-IV inhibitors have been identified, and four examples of compounds are shown in formulas 4 to 7.

Formula 4 shows the structure of the DPP inhibitor IV 1 - [[(3-hydroxy-1-adamyl) amino] acetyl] -2-cyano- (S) -pyrrolidine, a compound identified as LAF-237 (Villhauer, EB, et al., Journal of Medicinal Chemistry, 46, 2774-2789 (2003)). Formula 5 shows the structure of an aminoacyl triazolopyrazine DPP IV inhibitor described in detail in WO2004032836, incorporated herein by reference. Formula 6 shows the structure of another example of DPP IV inhibitor, described in WO2004 / 024184. Formula 7 shows the structure of a DPP IV inhibitor, 1- [N- (5,6-dichloronicotinoyl) -L-omitinyl] -3,3-difluoropyrrolidine hydrochloride, described in WO03 / 000250, which is incorporated herein by reference. This compound is also referred to herein as the "difluoropyrrolidine compound". Complexes are prepared with DPP IV inhibitors, as follows: EXAMPLE 17 Preparation of DPP inhibitor complexes IV-fatty acid Preparation of the complex using the difluoropyrrolidine inhibitor DPP IV A solution of oleic acid-acetone, 16.0 g of oleic acid dissolved in 100 mL of acetone is prepared. 22.0 g of the DPP IV inhibitor is dissolved as the free base identified as the difluoropyrrolidine compound (formula 7), in 200 mL of acetone. The oleic acid-acetone solution is added dropwise to the solution containing the DPP IV inhibitor, with stirring. Stirring is continued overnight at room temperature (20-25 ° C). A complex of difluoropyrrolidine-oleate compound is precipitated. The mixture of solvent and precipitated complex of difluoropyrrolidine-oleate compound is filtered through a Buchner funnel. The filter cake is rinsed with 4x 200 mL of acetone, and then dried under suction in vacuum for one hour. The filter cake is scraped off the filter paper, and weighed.

Preparation of the complex using a cyanopyrrolidine DPP IV inhibitor 1. Prepare a solution of oleic acid-acetone, 16.0 g of oleic acid dissolved in 100 mL of acetone. 2. 16.9 g of the DPP IV inhibitor is dissolved as the free base identified as the cyanopyrrolidine compound (formula 4), in 200 mL of acetone. 3. The oleic acid-acetone solution is added dropwise to the solution containing the DPP IV inhibitor, with stirring. Stirring is continued overnight at room temperature (20-25 ° C). A complex of cyanopyrrolidine-oleate compound is formed. 4. The cyanopyrrolidine-oleate compound complex is recovered from the solution using a suitable technique, such as filtration or extraction, depending on the shape of the complex.

Preparation of the complex using a homophenylalanine DPP IV inhibitor A solution of oleic acid-acetone, 16.0 g of oleic acid dissolved in 100 mL of acetone is prepared. 22.7 g of the DPP IV inhibitor are dissolved as the free base identified as the homophenylalanine compound (formula 5), in 200 mL of acetone. The oleic acid-acetone solution is added dropwise to the solution containing the DPP IV inhibitor, with stirring. Stirring is continued overnight at room temperature (20-25 ° C). A complex of homophenylalanine-oleate compound is formed. The homophenylalanine-oleate compound complex is recovered from the solution using a suitable technique, such as filtration or extraction, depending on the shape of the complex.

Claims (33)

NOVELTY OF THE INVENTION CLAIMS

1. - A substance, comprising: a complex comprising a drug portion and a transport portion.

2. The substance according to claim 1, further characterized in that the transport portion comprises an acid, basic or zwitterionic structural element; or an acid, basic or zwitterionic residual structural element, paired with an ion, to form a salt.

3. The substance according to claim 2, further characterized in that the transport portion comprises fatty acids or their salts, benzenesulfonic acid or its salts, benzoic acid or its salts, fumaric acid or its salts, or salicylic acid or its salts .

4. The substance according to claim 3, further characterized in that the fatty acids or their salts comprise a C6-C18 fatty acid, or its salt.

5. The substance according to claim 4, further characterized in that the C6-C18 fatty acid or its salt comprises a C12 fatty acid or its salt.

6. The substance according to claim 2, further characterized in that the transport portion comprises an alkyl sulfate or its salt.

7. The substance according to claim 6, further characterized in that the alkyl sulfate or its salt comprises a C6-C18 sodium alkyl sulfate or its salt.

8. The substance according to claim 7, further characterized in that the C6-C18 sodium alkyl sulfate or its salt, comprises sodium lauryl sulfate.

9. The substance according to claim 2, further characterized in that the transport portion comprises a pharmaceutically acceptable primary, secondary or tertiary amine, or salts thereof.

10. The substance according to claim 1, further characterized in that the drug portion comprises an acid, basic or zwitterionic structural element; or an acid, basic or zwitterionic residual structural element, paired with an ion, to form a salt.

11. A composition comprising the substance according to claim 1, and an inactive ingredient.

12. A dosage form comprising the composition according to claim 11.

13. The use of the substance as defined in claim 1, for preparing a medicament for the treatment of a disease or condition.

14. The use claimed in claim 13, wherein the medicament is administrable by an oral, intravenous, subcutaneous, intramuscular, transdermal, intraarterial, intraarticular or intradermal route.

15. A method for obtaining a composition, comprising: providing a portion of drug in an ionic form; provide a transport portion in an ionic form; combining the drug portion and the transport portion, in the presence of a solvent having a dielectric constant less than that of water, to form a complex; and separate the solvent complex.

16. The method according to claim 15, further characterized in that the transport portion comprises an acid, basic or zwitterionic structural element; or an acid structural element, basic or zwitterionic, paired with an ion, to form a salt.

17. The method according to claim 15, further characterized in that the drug portion comprises an acid, basic or zwitterionic structural element; or an acid, basic or zwitterionic residual structural element, paired with an ion, to form a salt.

18. The method according to claim 17, further characterized in that the drug portion comprises an acid structural element or an acidic residual structural element; and the drug portion is processed to obtain the acid form of the drug portion.

19. The method according to claim 17, further characterized in that the drug portion comprises a basic structural element or a basic residual structural element.; and the drug portion is processed to obtain the basic form of the drug portion.

20. The method according to claim 15, further characterized in that the drug portion comprises a zwitterionic structural element or residual zwitterionic structural element; and a structural element or residual structural element that does not bind, the zwitterionic structural element or residual zwitterionic structural element, is blocked before the drug portion and the transport portion react.

21. The use of a portion of drug in an ionic form; combined with a transport portion in an ionic form; in the presence of a solvent having a dielectric constant lower than that of water, to form a complex separate from the solvent; to prepare a medicine useful for the treatment of a disease or condition.

22. The use claimed in claim 21, wherein the transport portion comprises an acid, basic or zwitterionic structural element; or an acid, basic or zwitterionic residual structural element, paired with an ion, to form a salt.

23. The use claimed in claim 21, wherein the drug portion comprises an acid, basic or zwitterionic structural element; or an acid, basic or zwitterionic residual structural element, paired with an ion, to form a salt.

24. - The use claimed in claim 23, wherein the drug portion comprises an acidic structural element or an acidic residual structural element; and the drug portion is processed to obtain the acid form of the drug portion.

25. The use claimed in claim 23, wherein the drug portion comprises a basic structural element or a basic residual structural element; and the drug portion is processed to obtain the basic form of the drug portion.

26. The use claimed in claim 23, wherein the drug portion comprises a zwitterionic structural element or residual zwitterionic structural element; and a structural element or residual structural element that does not bind, the zwitterionic structural element or residual zwitterionic structural element, is blocked before the drug portion and the transport portion react.

27. The use claimed in claim 21, wherein the medicament is administrable by an oral, intravenous, subcutaneous, intramuscular, transdermal, intraarterial, intraarticular or intradermal route. 28.- The use of a complex of the drug portion and a transport portion, to prepare a medicament improve the absorption of a portion of drug. 29. The use claimed in claim 28, wherein the medicament is orally administrable, and the improved absorption comprises improved oral absorption. 30. The use claimed in claim 29, wherein the improved oral absorption comprises improved absorption in the lower gastrointestinal tract. 31. The use claimed in claim 29, wherein the improved oral absorption comprises improved absorption in the upper gastrointestinal tract. 32. The use claimed in claim 28, wherein the medicament is transdermally administrable, and the improved absorption is improved transdermal absorption. 33. The use claimed in claim 28, wherein the medicament is subcutaneously administrable, and the improved absorption is improved subcutaneous absorption.