MXPA06004955A - Compositions and dosage forms for enhanced absorption of metformin - Google Patents

Abstract

A complex comprised of metformin and a transport moiety, such as a fatty acid, is described. The complex has an enhanced absorption in the gastrointestinal tract, particularly the lower gastrointestinal tract. The complex, and compositions and dosage forms prepared using the complex, provide for absorption by the body of the drug through a period of ten to twenty-four hours, thus enabling a once-daily dosage form for metformin.

Description

COMPOSITIONS AND DOSAGE FORMS FOR INTENSIFIED ABSORPTION OF METFORMIN FIELD OF THE INVENTION This invention relates to compositions and dosage forms for the delivery of metformin. More particularly, the invention relates to a metformin complex and a transport portion, wherein the complex provides an enhanced absorption of metformin in the gastrointestinal tract, and more particularly, in the lower gastrointestinal tract.

BACKGROUND OF THE INVENTION The conventional pharmaceutical development of dosage forms is based on obtaining, on the one hand, a stable dosage form, and on the other hand, a dosage form that maximizes absorption in the upper gastrointestinal tract. Since most drug dosage forms are designed for immediate release of the drug, the dosage form is designed to be well dissolved in the upper gastrointestinal tract (G.l.), because the G.l. superior has a much greater surface area for drug absorption than the G.l. lower. The tract G.l. inferior, or colon, 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 of the colon. 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. lower (Knauf, H. et al., Klin. Wochenschr., 60 (19): 1191-1200 (1982)). Since the typical residence time of a drug in the G.l. If the upper one is approximately four to six hours, the drugs that have malabsorption 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 colonic absorption, 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, the conventional pharmaceutical development has suggested several systems of 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 inferior is generally not absorbed and, rather, is expelled from the body with another matter of the tract G.l. lower. Metformin is a compound that has been established to have colonic malabsorption (Marathe, P. er al., Br. J. Clin Pharmacol 50: 325-332 (2000)). Metformin hydrochloride has intrinsically poor permeability and absorption in the G.l. lower, or colon, leading to absorption almost exclusively in the upper part of the gastrointestinal tract (upper tract G.l.). Metformin is an antihyperglycaemic agent of the biguanide class used in the treatment of type II diabetes. It is commercially available as a hydrochloride salt, metformin hydrochloride, and is marketed as Glucophage® for the treatment of non-insulin-dependent diabetes mellitus (type II diabetes). For patients with diabetes, treatment with metformin once a day would provide advantages beyond convenience, since a relatively constant dosage of metformin in the blood stream provides pharmacodynamic benefits. For example, a relatively constant dosage could improve the use of glucose and glucose tolerance. The prior art methods for sustained release of metformin have focused on increasing the residence time in the G.l. higher. For example, PCT publication WO 99/47128 describes metformin delivery systems that proclaim on the principle that absorption of metformin occurs mainly only in the G.l. tract. superior, and not in the G.l. lower. Other attempts of the prior art to formulate a dose for metformin once a day have been largely unsuccessful. For example, Glucophage XR® is proposed as a once-a-day formulation, but it releases 90% of its dose in about six hours in vitro, much less than a proposed dosage form of 15 to 20 hours once a day. In this way, a dosage of Glucophage XR® twice a day is required. Others have proposed an extended release dosage form of metformin hydrochloride, wherein the absorption time in the stomach is extended by increasing the retention time of the dosage form in the stomach (see U.S. Patent No. 6,451, 808; and patent of E.U.A. No. 6,723,340). Thus, there is a need for a metformin dosing system once a day, wherein the dosing system provides metformin absorption in the G.l. lower.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, in one aspect, the invention includes a substance comprising metformin and a transport portion, metformin and the transport portion forming a complex. In one embodiment, the transport portion, prior to complex formation, is a fatty acid of the CH3 (CnH2n) COOH form, wherein n is 4 to 16. In another embodiment, the transport portion is capric acid or lauric acid. In another aspect, the invention includes a composition comprising a complex formed of metformin and a transport portion, and a pharmaceutically acceptable carrier, wherein the composition has an absorption in the lower gastrointestinal tract at least four times greater than the hydrochloride of metformin. In another aspect, the invention includes a dosage form comprising the composition described above. In another aspect, the invention includes a dosage form comprising the substance described above. In various embodiments, the dosage form is an osmotic dosage form. An example of a dosage form is one comprising (i) a push layer; (ii) drug layer comprising a complex of metformin-transport portion; (iii) a semipermeable wall provided around the push layer and the drug layer; and (v) an exit. Another example of a dosage form is one comprising (i) a semipermeable wall provided around an osmotic formulation comprising a metformin complex-transport portion, an osmagent and an osmopolymer; and (ii) an exit. In one embodiment, the dosage form provides a total daily dose between 500-2550 mg. In another aspect, the invention provides an improvement in a dosage form comprising metformin or a metformin salt. The improvement comprises a dosage form that includes a metformin complex and a transport portion. In another aspect, the invention includes a method for the treatment of hyperglycemia in a subject, comprising administering the composition described above. In one embodiment, the composition is administered orally. In another aspect, the invention includes a method for preparing a metformin-transport portion complex, comprising providing metformin base; provide a portion of transportation; combining the metformin base and the transport portion in the presence of a solvent having a dielectric constant lower than that of water; whereby the combination forms a complex between the metformin base and the transport portion.

In one embodiment, metformin and the transport portion are combined in a solvent having a dielectric constant at least twice less than the dielectric constant of water. Examples of solvents are methanol, ethanol, acetone, benzene, methylene chloride and carbon tetrachloride. In another aspect, the invention includes a method for improving gastrointestinal absorption of metformin, which comprises providing a complex formed of metformin and a transport portion, said complex characterized by a tight ion-pair bond; and administering the complex to a patient. In one embodiment, the improved absorption comprises improved absorption in the lower gastrointestinal tract. In another embodiment, the improved absorption comprises improved absorption in the upper gastrointestinal tract. In another aspect, the invention includes a method for treating a subject having type II diabetes, comprising administering a complex formed of metformin and a transport portion; administering a second therapeutic agent. In one embodiment, the administration of a second therapeutic agent comprises administering a second therapeutic agent that is an antidiabetic agent. In another embodiment, the second therapeutic agent is an inhibitor of dipeptidyl peptidase IV.

In another embodiment, the metformin complex and a fatty acid transport portion comprise a fatty acid, wherein before the formation of the complex, the fatty acid is of the form CH3 (CnH2n) COOH, where n is 4 to 16. Examples of fatty acids are capric acid or lauric acid. In another embodiment, the complex and / or the DPP IV inhibitor is administered orally. In another aspect, the invention includes a compound comprising metformin and a transport portion, the compound prepared by a process that (i) provides metformin base; (ii) provides a portion of transportation; (iii) combines the metformin base and the transport portion in the presence of a solvent having a dielectric constant lower than that of water, wherein the combination forms a complex between the metformin base and the transport portion associated via a pair bond ionic tight. These and other objects and features of the invention will be more fully appreciated when reading the following detailed description of the invention in conjunction with the accompanying drawings.BRIEF DESCRIPTION OF THE FIGURES The following figures are not drawn to scale, and are set forth to illustrate various embodiments of the invention.

Figure 1 is a diagram of epithelial cells of the gastrointestinal tract, illustrating the transcellular pathway and the paracellular pathway for the transport of molecules through the epithelium; Figure 2 is a graph of the logarithm of the octanol / water partition coefficient as a function of pH for metformin hydrochloride; Figures 3A-3D are traces of CLAR of metformin hydrochloride (Figure 3A), sodium laurate (Figure 3B), and a physical mixture of metformin hydrochloride, sodium laurate (Figure 3C) and metformin-laurate complex (Figure 3D); Figures 4A-4B are conductivity graphs, in microsiemens / centimeter (μS / cm, Figure 4A), and percent non-ionized drug (Figure 4B), 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 5 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 priming prays ! from the compounds to rats; Figure 6 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 7 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 8 is a graph of the concentration of metformin base in plasma, in ng / mL, in rats, as a function of time, in hours, after the 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 9 illustrates an example osmotic dosage form shown in cropped view; Figure 10 illustrates another example of an osmotic dosage form for a metformin dosage once a day, the dosage form comprising a complex of metformin-transport portion with an optional loading dose of the complex in the outer coating; Figure 11A illustrates an embodiment of a once-a-day metformin dosage form comprising metformin hydrochloride and a metformin-laurate complex, with an optional loading dose of metformin hydrochloride by coating; Figure 11B is a bar graph showing the metformin release rate, in mg / hour, as a function of time, in hours, of an equivalent dose of 300 mg of metformin hydrochloride from the dosage form of Figure 11 A; Figures 12A-12C illustrate one embodiment of a dosage prior to administration to a subject, and comprising a complex of metformin-transport portion in a matrix (Figure 12A), in operation after ingestion in the gastrointestinal tract (FIG. 12B), and after sufficient erosion of the matrix has caused the separation of the banded sections of the device (Figure 12C).

DETAILED DESCRIPTION OF THE INVENTION I. Definitions The present invention is best understood by reference to the following definitions, the drawings and description examples that are provided herein. "Composition" means one or more complexes of metformin-transport portion, optionally in combination with additional active pharmaceutical ingredients, and / or optionally in combination with inactive ingredients, such as vehicles, excipients, suspending agents, surfactants, disintegrators, binders, diluents, lubricants, stabilizers, antioxidants, osmotic agents, dyes, plasticizers, and the like, pharmaceutically acceptable. By "complex" is meant a substance comprising a portion of drug (e.g., metformin) 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. 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 preferred embodiments,? Log D> 0.20, and more preferably? Log D> 0.25, more preferably still? Log D> 0.35 By "dosage form" is meant a pharmaceutical composition in a medium, vehicle, carrier or device suitable for administration to a patient in need of it, 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 structural element, basic or zwitterionic, or an acid, basic or zwitterionic residual structural element By "fatty acid" is meant any of the group of organic acids of the general formula CH3 (CnHx) COOH, wherein the hydrocarbon chain uro is saturated (x = 2n, for example, palmitic acid, C15H31COOH) or unsaturated (x = 2n-2, eg, oleic acid, CH3C16H30COOH). 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 ionic couple" is meant a pair of ions which are, at physiological pH and in an aqueous environment, easily interchangeable with other free-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" means the large intestine Metformin refers to N, N-dimethylimidodicarbonimide diamide, with molecular formula of C4H11N5 and molecular weight of 129.17 The compound is commercially available as metformin hydrochloride. "Patient" means an animal , preferably a mammal, more preferably a human, in need of therapeutic intervention. "Tight ion pair" means a pair of ions which, at physiological pH and in an aqueous environment, are not easily interchangeable with other freely paired 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 and NMR or mass spectroscopy can also be found experimentally tight ion pairs noting the lack of separation of the ion pair, 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 that has formed, a complex with a drug, wherein the transport portion serves to improve the transport of the drug through the tissue epithelial, compared with 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. By "pharmaceutical composition" is meant a composition suitable for administration to a patient in need thereof. 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 "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 "upper gastrointestinal tract" or "upper tract G.l." is meant that portion of the gastrointestinal tract that includes the stomach and small intestine.

II. Formation and characterization of the metformin complex As indicated above, metformin is an antihyperglycemic agent of the biguanide class used to help control blood sugar levels in non-insulin-dependent diabetes mellitus (type II diabetes). Metformin, shown in formula 1, is a cationic compound soluble in water with a pKa of 12.4. The ionized form of the drug tends to be absorbed towards the negatively charged intestinal epithelium, and studies have shown that metformin has poor colonic absorption in healthy human subjects (Vidon, N., et al., Diabetes Res. Clin. Pract, 4: 223 -229 (1988)). The hydrophilic character of metformin hydrochloride is shown in Figure 2, where the logarithm of the octanol / water partition coefficient (logP) is plotted as a function of pH for metformin hydrochloride. At pH values less than 7.0, metformin hydrochloride is hydrophilic, with a logP of less than -3.7. The pH gradient in the G.l. tract which varies from a pH of about 1.2 in the stomach to a pH of about 7.5 in the distal ileum and large intestine (Evans, DF et al., Gut, 29: 1035-1041 (1988)), means that metformin hydrochloride is hydrophilic on the pH scale in the Gl tract In addition, metformin hydrochloride is highly dissociated at these pH values. The combination of hydrophilic character and charge tends to severely limit its absorption by the transcellular pathways and, as a result, metformin hydrochloride is very poorly absorbed in the G.l. lower.

Accordingly, in one aspect, the invention provides a substance comprising metformin that has significantly improved absorption in the G.l. lower. The substance is a complex of metformin and a transport portion, and can be prepared from a metformin salt, such as metformin hydrochloride, according to the generalized synthesis reaction scheme shown as reaction scheme 1. In summary, the Metformin is combined with a transport portion, represented as TM + in the drawing. Examples of transport portions are listed above, and include fatty acids, benzenesulfonic acid, benzoic acid, fumaric acid and salicylic acid. The two species are contacted in the presence of an organic solvent having a dielectric constant less than that of water, as will be discussed below, to form a metformin-transport portion complex, where the species are associated by a link of tight ion pair, denoted in reaction scheme 1 by the representation metformin + (T) -.

REACTION SCHEME 1 Metformin + T -; - Metform? Na + T- sotvenle Reaction scheme 2 is a more specific synthesis reaction scheme for the formation of a metformin-transport portion complex. In this scheme, the transport portion has a carboxyl group (COO "), represented as T-COO" in the drawing. The carboxyl-containing transport portion, T-COO ", is mixed in a solvent having a dielectric constant less than that of water, to form a metformin complex, and the transport portion associated by a hybrid bond or an ion pair tight, denoted in the drawing as metformin + [(T COO) 2] -.

REACTION SCHEME 2 Metformin + T'COOH [Meiformine] + [tiOOC * TI- solvent A specific example of the process for preparing a metformin-transport portion complex, wherein the transport portion is a fatty acid, is provided in Example 1, and is illustrated in reaction scheme 3. Metformin base is prepared at from salt hydrochloride, using an ion exchange process. A solution of a fatty acid in a solvent is contacted with metformin base to recover the metformin-fatty acid complex.

REACTION SCHEME 3 exchange Remove Cl " etformin * laurate (n-ll) In Example 1, a complex was formed from lauric acid as an example of the fatty acid transport portion. It will be understood that lauric acid is only an example, and that the preparation process is equally applicable to other suitable species as a transport portion, and to fatty acids of any carbon chain length, for example, formation of the metformin complex with various fatty acids or salts of fatty acids, the fatty acids having from 6 to 18 carbon atoms, more preferably from 8 to 16 carbon atoms, and even more preferably from 10 to 14 carbon atoms. The fatty acids or their salts can be saturated or unsaturated. Examples of saturated fatty acids contemplated for use in complex preparation include butanoic (butyric, 4C); pentanoic (valeric, 5C); hexanoic (caproic, 6C); otanoic (caprylic, 8C), nonanoic (pelargonic, 9C); decanoic (capric, 10C); dodecanoic (lauric, 12C); tetradecanoic (myristic, 14C); hexadecanoic (palmitic, 16C); heptadecanoic (margaric, 17C); and octadecanoic (stearic, 18C), where the systematic name is followed in parentheses by the trivial name and the number of carbon atoms in the fatty acid. The unsaturated fatty acids include oleic acid, linoleic acid and linolenic acid, all having 18 carbon atoms. Linoleic acid and linolenic acid are polyunsaturated. Also contemplated is the formation of the metformin complex with alkyl sulfates or a salt of an alkyl sulfate, wherein the alkyl sulfate can be saturated or unsaturated. Examples of alkyl sulfates, or its salts (sodium, potassium, magnesium, etc.), have from 6 to 18 carbon atoms, more preferably from 8 to 16 carbon atoms, and even more preferably from 10 to 14 carbon atoms. The formation of the metformin complex with benzenesulfonic acid, benzoic acid, fumaric acid and salicylic acid, or the salts of these acids is also contemplated. In one embodiment, the complexes according to the invention exclude a complex of metformin-thiocytic acid (also known as alpha-lipoic acid). With continuous reference to example 1, the complex consisting of metformin-laurate was prepared from acetone. Acetone is only an example of a solvent, and other solvents in which the fatty acids are soluble are suitable. For example, fatty acids are soluble in chloroform, benzene, cyclohexane, ethanol (95%), acetic acid and methanol. The solubility (in g / L) of capric acid, lauric acid, myristic acid, palmitic acid and stearic acid in these solvents is indicated in table 1.

TABLE 1 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. The dielectric constant is a measure of the polarity of a solvent, and dielectric constants for solvent examples are shown in Table 2.

TABLE 2 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 metformin complex. 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.

The dipolar aprotic solvents included in Table 2 have a dielectric constant at least twice less than that of water. Inverted phase HPLC was used to analyze the metformin-laurate complex formed as described in Example 1. The HPLC conditions are described in the methods section below. For comparison, HPLC traces of metformin hydrochloride, sodium laurate, and a physical mixture of metformin hydrochloride and sodium laurate were also generated, and the results are shown in Figures 3A-3D. The trace for metformin hydrochloride is shown in Figure 3A, 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 3B). 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 3C). Figure 3D shows the CLAR trace for the complex formed by the procedure of Example 2, 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.

In another study to characterize the metformin-laurate complex, the apparent octanol / water partition coefficient (D = Coctapoi / Cagua) of the complex was measured and compared with metformin hydrochloride, a 1: 1 mixture (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 Log [Coctane | / Cagua] - 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 loose ion pair, but is a tight ion pair. 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 the polar solvent molecules will insert themselves in the space occupied by the ionic bond, thus moving the bound 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 Coulomb's law, 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: (equation 2) pe? er where in is the space permitivity constant. The equation shows the importance of the dielectric constant (e) on the stability of a loose ion pair in solution. In an 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 ions 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 ion pair bond, but is still considered as an ionic bond. As described more fully herein, tight ion 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., 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 said ions, can intensify the transport through the membrane. In the theory of "ion pair", ionic drug portions 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 ion pairing 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 (J. Van Gelder et al. ., Int. J. of Pharmaceutics, 186: 127-136 (1999) The authors concluded that ion pair formation may not be very efficient as a strategy to enhance the trans-epithelial transport of charged hydrophilic compounds, since the competition for other ions present in in vivo systems can suppress the beneficial effect of the counterions.Other authors have observed that absorption experiments with ion pairs have not always pointed towards well-defined mechanisms (D. Quintanar-Guerrero et al., 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 absorption experiments with ion pairs described in the art still do not 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. Loose ion pairs 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 probability that the charges of the portions are 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. above, the complex formed from the drug portion may still be a substrate for that carrier. Accordingly, the total transport can 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. In a study carried out in support of the invention, 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 4A.

TABLE 4A TABLE 4B Figure 4A 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 (diamonds) ), 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 as the apparent number of carbons of the fatty acid increased. Based on the assumption that the conductivity (k) is proportional to the concentration of charged ions, and that the metformin hydrochloride is 100% loaded, the percentage of un ionized drug (r) was calculated by the following equation. It was also assumed that the diffusion effects of the variable sizes of the fatty acid molecules were negligible. f = (1-K / KHCl) x 100 (equation 3) Figure 4B shows the percent of non-ionized drug for each of the complexes as a function of the concentration of metformin, determined from equation 3. The Metformin hydrochloride (circles) is completely ionized, while the metformin-succinate complex (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.

By defining a dissociation factor as one hundred minus the percent of non-ionized drug (f), in one embodiment, the complex of "the present invention exhibits a dissociation factor between 5 to 90, more preferably 5 to 85, more preferably 10 to 70, and even more preferably 20 to 65 in an aqueous environment of pH = 5.8 at concentrations of 20 millimoles of metformin per liter.Colonic absorption of the metformin-laurate complex was characterized in vivo, using an oral fattening model In rats, as described in example 2, fasting rats were treated with 40 mg / rat metformin hydrochloride or the metformin-laurate complex, blood samples were taken for analysis of metformin concentration, and the results are shown in Figure 5. The plasma concentration in rats given metformin hydrochloride (circles) by oral priming reached a maximum plasma concentration approximately 1 hr. 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). In vivo colonic absorption of the complexes was also evaluated using a ligated-washed colon model in rats. As described in example 3, a dose of 10 mg / rat of several complexes was intubated in the bound colon of rats. The rats (n = 3) in each test group were dosed with metformin hydrochloride, metformin succinate dimer, metformin palmitate, metformin oleate, metformin caprate or metformin laurate. Another group of rats was intravenously administered 1 mg of metformin hydrochloride. Blood samples were periodically removed for analysis of the concentration of metformin base in the blood. The data are shown in Figure 6. Figure 6 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 laurato (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 5 shows the relative C max (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 5 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 into the colon in the form of a metformin-transport portion complex, is significantly enhanced, as observed by the nearly 5-fold increase in bioavailability 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 bioavailability greater than 20 times compared to that of the hydrochloride salt. Accordingly, the invention contemplates a compound comprising, consisting essentially of, or consisting of, 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 an increase of at least 20 times in colonic absorption with respect to the colonic absorption of metformin hydrochloride, as evidenced by the bioavailability of metformin determined from the concentration of metformin in plasma. In this way, metformin when administered in the form of a metformin-transport portion complex, provides a significantly enhanced colonic absorption of metformin in the blood. Another study was carried out using the ligated-washed colon model described in Example 3, 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 laurate) or metformin hydrochloride were intubated in the bound colon. Plasma samples were analyzed for metformin concentration, and bioavailability was determined, with respect to the bioavailability of metformin administered intravenously. The results are shown in Figure 7. Figure 7 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 8 shows the data in Tables A, F and G 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. lll. Examples of dosage forms and methods of use The complex described above provides an intensified absorption regime in the G.I. tract, and in particular in the G.l. 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 metformin-transport portion complex. As discussed above, a dosage form that provides once-a-day dosing achieves therapeutic efficacy for at least about 15 hours, more preferably for at least 18 hours, and even more preferably for at least about 20 hours. The dosage form can be configured and formulated according to any design that delivers a desired dose of metformin. Typically, the dosage form is orally administrable, 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 dissolving systems, and diffusion / dissolution combination systems and ion exchange resin systems, as described in Remington's Pharmaceutical Sciences, eighteenth edition, p. 1682-1685 (1990). A specific example of a dosage form suitable for use with the metformin-transport portion complex 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 at the osmotically determined rate 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 Iiterature," Journal of Controlled Relay, 35: 1-21 (1995). Osmotic dosage forms are also described in detail in the following U.S. Patents, each of which is incorporated herein 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 9. Dosage form 20, shown in a cropped view, is also referred to as an elementary 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 the metformin-transport portion complex 28 in a mixture with excipients selected. 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 metformin complex formulation-transport portion available after fluid inclusion. 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 for each are provided below 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 esters-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 metformin- transportable portion (for example, a solution, suspension, slurry or other fluid composition) within the internal compartment. The metformin-transportable portion 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 metformin-transport portion formulation is released in a sustained and continuous manner over an extended period. The preparation of a dosage form such as that shown in Figure 9 is described in Example 4. Figure 10 is a schematic illustration of another example of an osmotic dosage form. This dosage form is 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 outlet orifices, as is the case with the outlet orifice 50. The push layer may be positioned in a layered contacting arrangement with the drug layer, as illustrated in FIG. 10, or it may have one or more intermediate layers separating the push layer and the drug layer. The drug layer 36 comprises a complex of metformin-transport portion in a mixture with selected excipients, such as those discussed above with reference to Figure 9. An example dosage form can have a drug layer formed of complex of metformin-laurate, a poly (ethylene) oxide 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 continuous reference to Figure 10, 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 metformin 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, thus continuously expelling drug 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 metformin complex-transport portion to the gastrointestinal tract for a period of 15 to 20 hours, or through substantially the entire period of the step of the dosage form through the Gl tract Since the metformin-transport portion complex is easily absorbed in the G.l. tracts. superior and inferior, the administration of the dosage form provides metformin delivery into the bloodstream during the period of 15 to 20 hours of transit of the dosage form in the G.l. Another example of dosage form is shown in Figure 11 A. The osmotic dosage form 60 has a three layer core 62 comprising a first layer 64 of metformin hydrochloride, a second layer 66 of a metformin complex-portion of transport, and a third layer 68 referred to as a push layer. Dosage forms of this type are described 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. As set forth in Example 5, three-layered dosage forms having a first layer of 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 were prepared. of polyvinylpyrrolidone with a molecular weight of about 35,000 to 40,000, and 0.5% by weight of magnesium stearate. The second layer comprised 93.0 wt% metformin-laurate complex (prepared as described in example 1), 5.0 wt% polyethylene oxide with a molecular weight of 5,000,000, 1.0 wt% polyvinylpyrrolidone with a molecular weight from about 35,000 to 40,000, and 1.0% by weight of magnesium stearate. The thrust layer consisted 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 hydroxytoluene, and 0.25% by weight of magnesium stearate. The semipermeable wall comprised 80.0% by weight of cellulose acetate with an acetyl content of 39.8%, and 20.0% of polyoxyethylene-polyoxypropylene copolymer. The rate of dissolution of metformin from the dosage form shown in Figure 11 A was determined according to the procedure set forth in Example 5. The results are shown in Figure 11 B, where the rate of release of metformin, 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 subsequent 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, is initially performed. Approximately 8 hours after contact with an aqueous environment, the release of the metformin complex-transport portion occurs, and continues to a substantially constant regime 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 8 hours of transit, as indicated by the dashed bars. The metformin-transit portion complex is released as the dosage form travels through the G.l. tract. lower, corresponding approximately to times greater than about 8 hours after ingestion, as indicated by the dotted bars in Figure 11 B. This design takes advantage of the increased colonic absorption provided by the complex. Figures 12A-12C illustrate another example of dosage form, known in the art and described in the U.S.A. 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 12A. The dosage form comprises a cylindrically shaped matrix 82 comprising a complex of metformin-transport portion. 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 indicated 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 12B. Erosion of the matrix initiates the release of the metformin-transport portion complex in the fluidic environment of the G.l. As the dosage form continues to transit through the G.I. tract, the matrix continues to erode, as illustrated in FIG. 12C. 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 osmotic dosage forms described in Figures 11 to 14 are only one example of a variety of dosage forms designed to, and capable of achieving, the delivery of a metformin-transport portion complex to the G.l. tract. lower. Those skilled in the pharmaceutical arts can identify other dosage forms that would be suitable. In another aspect, the invention provides a method for the treatment of hyperglycemia in a subject, by administering a composition or a dosage form containing a metformin complex and a transport portion, the complex characterized by a hybrid bond or a couple bond. Ionic gap between metformin and the transport portion. The method finds use in the treatment of people with non-insulin-dependent diabetes mellitus (type II diabetes) and / or insulin-dependent diabetes mellitus (type I diabetes). A composition comprising the complex and a pharmaceutically acceptable carrier is administered to the patient, typically 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 of the metformin-transport portion complex are administered in recommended amounts for metformin hydrochloride (Glucophage®, Bristol-Myers Squibb Co.), as set forth in The Physician's Desk Reference. For example, oral dosage of metformin hydrochloride is individualized on the basis of efficacy and tolerance, while not exceeding the maximum recommended daily dose of 2550 mg in adults and 2000 mg in pediatric patients. Metformin hydrochloride is typically administered in divided doses with food, and is often initiated at a low dose, typically about 850 mg / day, with gradual intensification that allows the identification of a minimum therapeutically effective amount required for antihyperglycemic activity of an individual. Thus, in one embodiment, a dosage form is provided that delivers a daily dose of metformin between 500-2550 mg, wherein metformin is provided in the form of a metformin-transport portion complex. In another aspect, the invention contemplates the administration of a complex of metformin-transport portion in combination with a second therapeutic agent, for the treatment of hyperglycemia and for weight control, particularly in subjects with type II diabetes. The second preferred therapeutic agents are those useful in the treatment of obesity, diabetes mellitus, especially type II diabetes, and conditions associated with diabetes mellitus. Examples of the second therapeutic agent include, but are not limited to, a compound classified as an alpha-giucosidase inhibitor, a biguanide (other than metformin), an insulin secretagogue, an anti-diabetic agent, or an insulin sensitizer. Examples of alpha-glucosidase inhibitors include acarbose, emiglitate, miglitol and voglibose. A suitable antidiabetic agent is insulin. The biguanides include buformin and phenformin. Suitable insulin secretagogues include sulfonylureas, such as glibenclamide, glipizide, gliclazide, glimepiride, tolazamide, tolbutamide, acetohexamide, carbutamide, chloropropamide, giibornuride, gliquidone, glisentide, glisolamide, glisoxepide, glyclophamide, repaglinide, nateglinide and glycyllamide. Insulin sensitizers include insulin sensitizers of PPAR-gamma agonist (see WO97 / 31907), such as 2- (1-carboxy-2-. {4- [2- (5-methyl-2-methyl) methyl ester. phenyl-oxazol-4-yl) -ethoxy] -phenyl] -ethylamino) -benzoic acid and 2 (S) - (2-benzoyl-phenylamino) -3-. { 4- [2- (5-methyl-2-phenyl-oxazoi-4-yl) -ethoxy] -phenyl} -propionic The second therapeutic agent is preferably an antidiabetic compound, as is the case with modulators of the insulin signaling pathway, as inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetics, and glutamine-fructose-e inhibitors. -phosphate amidotransferase (GFAT), compounds that influence dysregulated production of hepatic glucose, such as inhibitors of glucose-6-phosphatase (G6Pase), inhibitors of fructose-1, 6-bisphosphatase (F-1, 6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists, and phosphoenolpyruvate carboxykinase (PEPCK) inhibitors, pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, alpha-inhibitors, glucosidase, gastric emptying inhibitors, insulin and a2-adrenergic antagonists, or pharmaceutically acceptable salts of said compound, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use, in particular in the prevention, delay or progression or treatment of conditions mediated by DPP-1V, in particular conditions of impaired glucose tolerance (IGT), impaired fasting plasma glucose conditions, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis, and preferably diabetes, especially type II diabetes mellitus. Said combination is preferably a combined preparation or a pharmaceutical composition. In a combined treatment method, the metformin-transport portion complex and the second therapeutic agent are administered simultaneously or sequentially, by the same route of administration, or different administration routes. In a preferred embodiment, the second therapeutic agent is an inhibitor of dipeptidyl peptidase IV (DPP-IV). Dipeptidyl peptidase IV is a serine protease that post-digests proline / alanine present in various tissues of the body, including kidney, liver and intestine. The protease removes the two N-terminal amino acids from proteins that have proline or alanine at position 2. DPP-IV can be used in the control of glucose metabolism, because its substrates include the insulinotropic hormones glucagon such as peptide- 1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 and GIP are active only in their intact forms; the removal of their two N-terminal amino acids inactivates them (Holst, J. et al., Diabetes, 47: 1663 (1998)). In this way, DPP-IV inhibitors have been described, for example, in the patents of E.U.A. Nos. 6,124,305 and 6,107,317, and in PCT publications Nos. W099 / 61431, W098 / 19998, WO95 / 15309 and W098 / 18736. The inhibitors can be peptidic or non-peptidic, such as 1 [2- (5-cyanopyridin-2-yl) aminoethylamino] acetyl-2-cyano- (S) -pyrrolidine and (2S) -1 - [(2S) -2-amino -3,3-dimethylbutanoyl] -2-pyrrolidinecarbonitrile. A method for treating a subject having type II diabetes is contemplated, wherein the subject is treated with a DPP-IV inhibitor in combination with a metformin-transport portion complex. The combined agents produce a greater beneficial effect than that achieved by any agent alone, or by a combination of a DPP-IV inhibitor and metformin not in a combined form. The metformin-transport portion complex is preferably administered orally in a once-a-day dosage form, to take full advantage of the enhanced colonic absorption provided by the complex. The DPP-IV inhibitor can be administered by any suitable route for the compound and the patient. In one modality, the combined treatment regimen is for use in reducing or preventing body weight gain in overweight or obese patients with type II diabetes. It has recently been shown that a combination therapy of metformin with DPP-IV inhibitor leads to reduced feed ration and body weight gain in Zucker faifa rats (Yasuda, N. et al., J. Pharmacol, Experimental Therap. , 310 (2): 614 (2004)). The invention provides an improved combination regimen by administering metformin as a metformin-transport portion complex, to achieve enhanced colonic absorption. From the above, it can be seen how various objectives and characteristics of the invention are satisfied. A complex consisting of metformin and a transport portion, metformin and the transport portion associated by a hybrid link or by a tight ion pair bond, provides an enhanced colonic absorption of metformin, relative to that observed for metformin hydrochloride. The complex is prepared from a novel procedure, in which the metformin in base form is contacted with a transport portion solubilized in an organic solvent, the organic solvent being less polar than water, the lower polarity evidenced, by example, by a lower dielectric constant. The contact of metformin base with the mixture of transport-solvent portion, results in the formation of a complex between metformin and the transport portion, where the two species are associated by a bond that is not an ionic bond or a covalent bond, otherwise it is a hybrid link or a tight ion pair bond.

IV. EXAMPLES The following examples better illustrate the invention described herein, and are not intended in any way to limit the scope of the invention. invention.

Methods 1. CLAR: Inverted phase HPLC was performed on a Hewlett Packard 1100 liquid chromatograph with a scattering detector of evaporative light, and using a C3 column (Agilent Zorbax SB C3, 5 μm, 3. 0 x 75 mm). A mobile phase of water was used: acetonitrile 50: 5 in v: v. The temperature of the column was 40 ° C, and the flow rate was 0.5 mL / min.

EXAMPLE 1 Preparation of the metformin complex-transport portion Materials: Metformin hydrochloride 13.0 g Lauric acid 16.0 g Methanol 675 mL Acetone 300 mL Demineralised water 14 mL Anionic resin (Amberlyst A-26 (OH)) 108 g Preparation of metformin base 1. The ion exchange column was packed with the anionic resin , Amberlyst A-26 (OH), and a net weight was obtained. 2. 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. 3. Metformin hydrochloride was dissolved in an eluent comprising 365 ml of methanol containing deionized water at 2% by volume. 4. 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. 5. 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 6. A solution of lauric acid-acetone, 16.0 g of lauric acid dissolved in 300 mL of acetone was prepared. The concentrated metformin from step 5 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-iaurate was precipitated. Stirring was continued overnight at room temperature (20-25 ° C). 7. 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 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 yield = 75% with respect to the theoretical amount calculated from the stoichiometric amounts of metformin hydrochloride and lauric acid used.

EXAMPLE 2 Colonic absorption in vivo 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 5. At the end of the study, the rats were sacrificed, 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 3 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 were anesthetized in fasting, and a segment of the proximal 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 simulate more accurately the actual colon environment in a clinical situation. The rats were allowed to equilibrate 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. The following tables A to F show for each complex and for each rat, the concentration of metformin base detected in the blood plasma measured in nanograms per milliliter at each time point.

TABLE A TABLE B TABLE C TABLE D TABLE E TABLE F 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 G.

TABLE G The results of tables A to F are shown graphically in figure 6. The Cmax and the relative bioavailabilities were shown in table 5 above.

EXAMPLE 4 Preparation of a dosage form comprising a complex of metformin-transport portion A device such as the one shown in Figure 9 is prepared in the following manner. A composition forming compartments comprising, in percent by weight, 92.25% metformin complex-transport portion, 5% carboxypolymethylene potassium, 2% polyethylene oxide with a molecular weight of about 5,000,000, and 0.5 is mixed. % of silicon dioxide. The mixture is then passed through a 40 mesh stainless steel screen, and then mixed dry in a V mixer for 30 minutes to obtain a uniform mixture. Then, 0.25% magnesium stearate is passed through a 80 mesh stainless steel screen, and the mixture is mixed again for another 5 to 8 minutes. Then, the homogeneously dry mixed powder is placed in a hopper and fed to a press forming compartments, and known amounts of the mixture are compressed into 1.58 cm oval shapes designed for oral use. The pre-compartments of oval shape are then coated on a machine for applying Accela-Cota® wall-forming coating, with a wall-forming composition comprising 91% cellulose acetate with an acetyl content of 39.8% and 9% polyethylene glycol 3350. After coating, the wall-coated drug compartments are removed from the machine for coating, and transferred to a drying oven for the removal of the residual organic solvent used during the wall-forming process. Then, the coated devices are transferred to a forced air oven at 50 ° C for drying for approximately 12 hours. Then, passages are formed in the wall of the device using a laser to perforate two passages in the main axis of each face of the dispensing device.EXAMPLE 5 Preparation of a dosage form comprising a complex of metformin-transport portion A dosage form comprising a layer of metformin hydrochloride and a layer of metformin-laurate complex, as illustrated in Figure 11 A, 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 polyvinylpyrrolidone with a molecular weight of about 38,000, were 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 as follows: 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 were added to a punch and die set, and were damped, and then 427 mg of the metformin-laurate composition was added to the set of dies as the second layer, and again cushioned 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% of 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. - 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 11 B.

EXAMPLE 6 Preparation of a dosage form comprising a complex of metformin-transport portion A dosage form as illustrated in Figures 12A-12C is prepared as follows: A unit dose for prolonged release of the metformin-laurate complex is prepared as follows: The desired dose of metformin in the form of metformin-laurate complex, is passed through a sieve granulométrico having 40 wires per 2.54 cm. 20 g of a hydroxypropylmethyl cellulose having a hydroxypropyl content of 8% by weight, a methoxyl content of 22% by weight, and a number average molecular weight of 27,800 g per mole, are passed through a granulometric sieve with 100 wires per 2.54 cm. The screened powders are miby tumbling for 5 minutes. Anhydrous ethanol is added to the mixture with stirring, until a moist mass forms. The wet mass is passed through a granulometric screen with 20 wires per 2.54 cm. The resulting wet granules are air-dried overnight, and then passed through the 20 mesh screen again. 2 g of tableting lubricant, magnesium stearate, are passed through a 80-mesh granulometric screen. 2.54 cm. The screened magnesium stearate is miin the dried granules to form the final granulation. Portions of 705 mg of the final granulation are placed in the cavities of the dies with internal diameters of 0.713 cm. The portions are compressed with deep concave punches under a load of 1,000 kg, forming longitudinal tablets in the form of a capsule. The capsules are fed in a Tait Capsealer machine (Tait Design and Machine Co., Manheim, Pa.), Where three bands are printed on each capsule. The material forming the bands is a mixture of 50% by weight of ethylcellulose dispersion (Surelease®, Colorcon, West Point, Pa.) And 50% by weight of ethyl acrylate-methyl methacrylate (Eudragit® NE 30D, RohmPharma , Weiterstadt, Germany). The bands are applied as an aqueous dispersion, and the excess water is extracted in a stream of hot air. The diameter of the bands is 2 mm. Although the invention has been described with respect to particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made without departing from the invention.

Claims (37)

NOVELTY OF THE INVENTION CLAIMS

1. - A substance comprising metformin and a transport portion, said metformin and said transport portion form a complex.

2. The substance according to claim 1, further characterized in that said transport portion, before the formation of the complex, is a fatty acid of the CH3 (CnH2n) COOH form, where n is from 4 to 16.

3 The substance according to claim 2, further characterized in that said fatty acid is capric acid or lauric acid.

4. A composition, comprising, a complex formed of metformin and a transport portion, and a pharmaceutically acceptable carrier, wherein said composition has an absorption in the lower gastrointestinal tract at least four times greater than metformin hydrochloride.

5. The composition according to claim 4, further characterized in that said transport portion is a fatty acid, before the formation of the complex, of the CH3 (CpH2n) COOH form, wherein n is from 4 to 16.

6. - The composition according to claim 5, further characterized in that said fatty acid is capric acid or lauric acid.

7. A dosage form comprising the composition according to claim 4.

8. A dosage form comprising the substance according to claim 1.

9. The dosage form according to claim 8, further characterized in that the dosage form is an osmotic dosage form.

10. The dosage form according to claim 9, further characterized in that it comprises (i) a thrust layer; (ii) drug layer comprising a complex of metformin-transport portion; (iii) a semipermeable wall provided around the push layer and the drug layer; and (iv) an exit.

11. The dosage form according to claim 9, further characterized in that it comprises (i) a semipermeable wall provided around an osmotic formulation comprising a complex of metformin-transport portion, an osmagent and an osmopolymer; and (ii) an exit.

12. The dosage form according to claim 9, further characterized in that the dosage form provides a total daily dose between 500-2550 mg.

13. - An improvement in a dosage form comprising metformin or a metformin salt, the improvement comprises a dosage form formed by a metformin complex and a transport portion.

14. The improved dosage form according to claim 13, further characterized in that said transport portion, before the formation of the complex, is a fatty acid of the CH3 (CnH2n) COOH form, wherein n is 4 to

15. The improved dosage form according to claim 14, further characterized in that said fatty acid is capric acid or lauric acid.

16. The use of the composition according to claim 4, for preparing a medicament for the treatment of hyperglycemia in a subject.

17. The use as claimed in claim 16, wherein said medicament is formulated for oral administration.

18. A method for preparing a metformin-transport portion complex, comprising providing metformin base; provide a portion of transportation; combining the metformin base and the transport portion in the presence of a solvent having a dielectric constant lower than that of water; whereby said combination forms a complex comprising the metformin base and the transport portion.

19. The method according to claim 18, further characterized in that said combination comprises contacting in a solvent having a dielectric constant at least twice less than the dielectric constant of water.

20. The method according to claim 19, further characterized in that said solvent is selected from the group consisting of methanol, ethanol, acetone, benzene, methylene chloride and carbon tetrachloride.

21. The use of a complex comprising metformin and a transport portion, said complex is characterized by a tight ion-pair bond; to prepare a medication to improve the absorption of metformin in the G.l.

22. The use as claimed in claim 21, wherein the improved absorption comprises improved absorption in the lower gastrointestinal tract.

23. The use as claimed in claim 21, wherein the improved absorption comprises improved absorption in the upper gastrointestinal tract.

24.- The use of a complex formed of metformin and a portion of transport; and a second therapeutic agent, for preparing a medicament for treating a subject having type II diabetes.

25. The use as claimed in claim 24, wherein said second therapeutic agent is an antidiabetic agent.

26. The use as claimed in claim 25, wherein said second therapeutic agent comprises an inhibitor of dipeptidyl peptidase IV.

27. The use as claimed in claim 24, wherein said medicament comprises a metformin complex and a fatty acid transport portion, said fatty acid before the formation of the complex has the form CH3 (CnH2n) COOH , wherein n is from 4 to 16.

28.- The use as claimed in claim 27, wherein said fatty acid is capric acid or lauric acid.

29. The use as claimed in claim 24, wherein said complex is formulated for oral administration.

30. The use as claimed in claim 27, wherein said oral administration is achieved by formulating an osmotic dosage form.

31. The use as claimed in claim 30, wherein the osmotic dosage form comprises (i) a thrust layer; (ii) drug layer comprising a complex of metformin-transport portion; (iii) a semipermeable wall provided around the push layer and the drug layer; and (iv) an exit.

32. The use as claimed in claim 30, wherein the osmotic dosage form comprises (i) a semipermeable wall provided around an osmotic formulation comprising a complex of metformin-transport portion, an osmagent and a osmopolymer; and (ii) an exit.

33. - The use as claimed in claim 29, wherein the dosage form provides a total daily dose between 500-2550 mg.

34. The use as claimed in claim 24, wherein said DPP IV inhibitor is orally administrable.

35. A compound comprising metformin and a transport portion, said compound is prepared by a process that (i) provides metformin base; (ii) provides a portion of transportation; (iii) combines the metformin base and the transport portion in the presence of a solvent having a dielectric constant less than that of water, wherein said combination forms a complex between the metformin base and the transport portion associated via a pair bond ionic tight.

36. The compound according to claim 35, further characterized in that said transport portion is a fatty acid of the CH3 (CnH2n) COOH form, wherein n is from 4 to 16. 37.- The compound according to claim 36, further characterized in that said fatty acid is capric acid or lauric acid.