CN1901880A - Compositions and dosage forms for enhanced absorption of gabapentin and pregabalin - 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

Be used to increase compositions and the dosage form that metformin absorbs

Invention field

The present invention relates to be used to discharge the compositions and the dosage form of metformin.More particularly, the present invention relates to the complex of metformin and transhipment part, wherein complex provides metformin at gastrointestinal tract, more particularly the absorption of infra gastrointestinal increase.

Background of invention

The development of conventional pharmaceutical dosage forms is based on two aspects, on the one hand for obtaining stabilizer type, on the other hand for obtaining to have in upper gastrointestinal the dosage form of absorption maximum.Because most of pharmaceutical dosage form is designed for direct release medicine, dosage form is designed to be dissolved in preferably in gastrointestinal (G.I.) road, because upper gastrointestinal has much bigger drug absorption surface area than lower gastrointestinal tract.Lower gastrointestinal tract or colon lack the microvillus that exists in the upper gastrointestinal.Microvillares existence increases the surface area of drug absorption greatly, and upper gastrointestinal surface area is 480 times that colon surface is amassed.

The difference of upper gastrointestinal and lower gastrointestinal tract cell characteristic also causes the deficiency of lower gastrointestinal tract molecule absorption.Fig. 1 illustrates the 2 kind conventional route of transhipment chemical compound by the gastrointestinal tract epithelium.The individual epithelial cell of being represented by 10a, 10b, 10c forms barrier cell along small intestinal and large intestine.Individual cells is by aquaporin or closely connection (for example 12a, 12b) separation.Transhipment by epithelium both can also can all can through parietal cell passage or both through striding cell passage.The cell passage (as the arrow 14 of Fig. 1) of striding of transhipment is meant that chemical compound moves by passive diffusion or carrier mediated transhipment and strides across epithelial cell wall and cyton.The parietal cell passage of transhipment is meant that molecule moves through each intercellular tight connection, and is as shown in arrow 16.Parietal cell passage specificity is lower but total capacity is much bigger, in part because it is present in whole gastrointestinal tract.But, closely connect along gastrointestinal tract distribution difference, close-connected effectively " compactness " is increase trend from near-end to far-end.Therefore, upper gastrointestinal duodenum is than upper gastrointestinal ileum more " leakiness ", ileum than the colon of lower gastrointestinal tract more " leakiness " (Knauf, H. etc., Klin.Wochenschr., 60(19): 1191-1200 (1982)).

Because medicine is from about 4 to 6 hours in the upper gastrointestinal common time of staying, so only 4 to 6 hour time period absorbed by body the medicine of colon absorption difference after oral absorption.What medically wish usually is that the medicine whole day of giving that appears in patient's blood flow keeps relative constant density.For reaching this point, the patient will need every day and take medicine 3 to 4 times during the conventional medicine preparation that absorbs with the minimum colon of performance.It is not a therapeutic regimen above this patient's of being not easy to the practical experience.Therefore, need to obtain the medicine of the long-term absorption of such whole day and 1 administration every day.

For the treatment of constant dosage is provided, the conventional medicine development has proposed various control and has discharged drug system.Such system plays a role by an elongated segment after administration discharges them in the time medicine payload.But the conventionally form that absorbs these Controlled Release System under the minimum situation at the medicine colon is invalid.Because medicine only absorbs and because medicine has only 4 to 6 hours in the upper gastrointestinal time of staying in upper gastrointestinal, do not mean and stop through upper gastrointestinal that body will continue absorption sustained release medicine after 4 to 6 hours so the sustained release dosage form dosage form in upper gastrointestinal that proposes still can discharge the fact of its payload after the time of staying.On the contrary, dosage form has entered the medicine that the sustained release dosage form discharges behind the lower gastrointestinal tract and has not absorbed usually, but discharges from body with other material of lower gastrointestinal tract.

The chemical compound that definite metformin is the colon absorption difference (Marathe, P. etc., Br.J.Clin.Pharmacol., 50: 325-332 (2000)).Metformin hydrochloride in essence poor permeability and in lower gastrointestinal tract or colon absorption difference, cause almost only absorbing in gastrointestinal top (upper gastrointestinal).

Metformin is the biguanides hyperglycemia medicine that is used for the treatment of type ii diabetes.Available its hydrochlorate is a metformin hydrochloride, and to be used for the treatment of the Glucophage of noninsulindependent diabetes (type ii diabetes) ^Sell.Because the relative constant dosage by metformin in the blood flow provides the pharmacodynamics advantage, the advantage outside metformin treatment once a day will facilitate for diabetics.For example, constant dosage can be improved glucose utilization and glucose tolerance relatively.

The prior art of realization SRM has concentrated on and has been increased in the upper gastrointestinal time of staying.For example, PCT publication No. WO 99/47128 describes based on metformin and absorbs the metformin delivery system that mainly occurs over just upper gastrointestinal and do not occur in the principle of lower gastrointestinal tract.Other prior arts great majority of attempting preparing the metformin preparation that is administered once every day are unsuccessful.For example, propose Glucophage XR ^As preparation once a day, but it is about 6 hours, far away from dosage form proposed once a day 15-20 hour in the time of release in vitro 90% dosage.Therefore, Glucophage XR ^Need be administered twice every day.Other people have proposed the prolongation release dosage form of metformin hydrochloride, and soak time under one's belt prolongs (United States Patent (USP) the 6th, 451, No. 808 by increasing the dosage form time of staying under one's belt; United States Patent (USP) the 6th, 723, No. 340).

Therefore, still need a kind of metformin sosimetric system once a day, this sosimetric system provides metformin infra gastrointestinal to absorb.

Summary of the invention

On the one hand, the present invention includes the material of being made up of metformin and transhipment part, metformin and transhipment part form complex.

In one embodiment, before complex formed, the transhipment part was CH ₃(C _nH _2n) fatty acid of COOH form, wherein n is 4-16.

In another embodiment, transhipment part is capric acid or lauric acid.

On the other hand, the present invention includes compositions, said composition comprises complex and the pharmaceutically acceptable carrier of being made up of metformin and transhipment part, and wherein compositions infra gastrointestinal is absorbed as at least four times of metformin hydrochloride.

On the other hand, the present invention includes the dosage form that contains above-mentioned composition.

On the other hand, the present invention includes the dosage form that contains above-mentioned substance.

In each embodiment, dosage form is an osmotic dosage form.

Exemplary dosage forms is the dosage form that comprises following several parts: (i) promoting layer (push layer); The medicine layer that (ii) contains metformin-transhipment part complex; (iii) center on the semi-permeable wall that promoting layer and medicine layer provide; (iv) outlet.

Another exemplary dosage forms is the dosage form that comprises following several parts: (i) semi-permeable wall that provides around the permeability preparation, and described preparation comprises metformin-transhipment part complex, penetrating agent (osmagent) and osmopolymer (osmopolymer); (ii) outlet.

In one embodiment, this dosage form provides the total daily dose between the 500-2550mg.

On the other hand, the invention provides the improvement dosage form that contains metformin and melbine salt.This improvement comprises the dosage form of the complex that comprises metformin and transhipment part.

On the other hand, the present invention includes the method that is used for the treatment of patient's hyperglycemia, this method comprises and gives above-mentioned composition.

In one embodiment, the compositions per os gives.

On the other hand, the present invention includes the method for preparing metformin-transhipment part complex, this method comprises provides metformin alkali; The transhipment part is provided; In the presence of the solvent of dielectric constant, make metformin alkali and the combination of transhipment part less than the dielectric constant of water; By the complex between combination formation metformin alkali and the transhipment part.

In one embodiment, at least in 1/2nd the solvent less than the water dielectric constant, make metformin and the combination of transhipment part at dielectric constant.Exemplary solvent is methanol, ethanol, acetone, benzene, dichloromethane and carbon tetrachloride.

On the other hand, the present invention includes the method that the gastrointestinal that improves metformin absorbs, this method comprises provides the complex of being made up of metformin and transhipment part, described complex be characterized as tight ion pair key (tight-ion pair bond); And give the patient this complex.

In one embodiment, improve absorption and comprise the absorption that improves lower gastrointestinal tract.

In another embodiment, improve absorption and comprise the absorption of improvement in upper gastrointestinal.

On the other hand, the present invention includes patient's the method that treatment suffers from type ii diabetes, this method comprises and gives the complex be made up of metformin and transhipment part; Give second kind of therapeutic agent.

In one embodiment, second kind of therapeutic agent comprises the second kind of therapeutic agent that gives to antidiabetic medicine.

In another embodiment, second kind of therapeutic agent is inhibitors of dipeptidyl IV.

In going back another embodiment, the complex of metformin and fatty acid transhipment part comprises complex and forms fatty acid before, and described fatty acid is CH ₃(C _nH _2n) the COOH form, wherein n is 4-16.Exemplary fatty acid is capric acid or lauric acid.

In another embodiment, complex and/or DPP IV inhibitor per os give.

Aspect another, the present invention includes the chemical compound that contains metformin and transhipment part, this chemical compound prepares through following method: metformin alkali (i) is provided; The transhipment part (ii) is provided; (iii) in the presence of the solvent of dielectric constant, make metformin alkali and the combination of transhipment part, wherein in conjunction with forming between metformin alkali and the transhipment part by the associating complex of tight ion pair key less than the dielectric constant of water.

When as detailed below of the present invention and accompanying drawing being united when understanding, can more fully understand these and other purposes of the present invention and feature.

Accompanying drawing describes in detail

Following accompanying drawing is not to draw in proportion, and the purpose of listing is for illustrating various embodiments of the present invention.

Fig. 1 is the curve of gastrointestinal tract epithelial cell, illustrates to stride cell passage and parietal cell (paracellular) passage by the epithelial cell transport molecule;

Fig. 2 shows the chemical constitution of metformin;

Fig. 3 is the logarithm of octanol/water partition coefficient and the pH functional arrangement of metformin hydrochloride;

Fig. 4 A shows the general synthetic reaction flow process that is used to prepare metformin-transhipment part complex;

Fig. 4 B shows the general synthetic reaction flow process that is used to prepare metformin-transhipment part complex, and wherein transhipment part comprises carboxyl;

Fig. 4 C shows the synthetic reaction flow process that is used to prepare metformin-fatty acid complex;

Fig. 5 A-5D is the physical mixture (Fig. 5 C) of metformin hydrochloride (Fig. 5 A), sodium laurate (Fig. 5 B), metformin hydrochloride and sodium laurate and HPLC trace (traces) figure of metformin-laruate complex (Fig. 5 D);

Fig. 6 A-6B is with little Siemens (microsiemens)/centimetre be electrical conductivity (the μ S/cm of unit, Fig. 6 A) and the percentage ratio of nonionic chemical medicine thing (Fig. 6 B) figure, for metformin hydrochloride (circle), with the function of the metformin concentration of succinate (del shape), caprate (square), laruate (prismatic), palmitate (triangle) and oleate (octagonal);

Fig. 7 show give rat with chemical compound per os tube feed after, be the metformin plasma concentration of unit with ng/mL in the rat, for metformin hydrochloride (circle) and metformin-laruate complex (prismatic) hour being the time function of unit;

Fig. 8 shows use flushing-ligation (flush-ligated) colon models, be the metformin plasma concentration of unit with ng/mL in the rat, for metformin hydrochloride (circle), with the metformin of succinate (prismatic), cetylate (triangle), oleate (inversion triangle), decanoin (square) and laurate (octagonal) complexation hour being the time function of unit;

Fig. 9 shows use flushing-ligation colon models, percentage ratio bioavailability in the rat plasma, is the metformin dose function of unit for the physical mixture (circle) of metformin hydrochloride and sodium laurate and lauric acid metformin complex (square) with mg alkali/kg;

Figure 10 is for using flushing ligation colon models, intravenous gives 2mg/kg metformin hydrochloride (triangle) afterwards and give the metformin hydrochloride (triangle) of every rat 10mg dosage or metformin lauric acid complex (prismatic) afterwards, and the metformin alkalemia slurry concentration that in the rat with ng/mL is unit is as hour being the time function figure of unit;

Figure 11 illustrates the exemplary osmotic dosage forms shown in the cutaway view;

Figure 12 explanation is suitable for giving once a day the another kind of exemplary osmotic dosage forms of metformin, and this dosage form comprises the filling dose (loading dose) of metformin-transhipment part complex and the outside coating appoplexy involving the collateral compound of choosing wantonly;

The embodiment of a kind of dosage form of metformin once a day of Figure 13 A explanation, this dosage form comprises metformin hydrochloride and metformin-laruate complex, with the optional metformin hydrochloride filling dose in coating;

Figure 13 B for show with mg/ hour be the bar diagram of the metformin rate of release of unit, this speed for the suitable dosage of 300mg metformin hydrochloride of Figure 13 A dosage form hour being the time function of unit;

Figure 14 A-14C explanation is giving the patient and comprising the dose delivery scheme that (Figure 14 A) before metformin-transhipment part complex, (Figure 14 B) on behind the absorption gastrointestinal tract and substrate fully corrode the band-like portions after separating (Figure 14 C) that has caused device in substrate.

Detailed Description Of The Invention

I. definition

With reference to as give a definition, accompanying drawing provided herein and exemplaryly openly can understand the present invention best.

" compositions " refers to one or more metformin-transhipment part complex, optional and other active pharmaceutical compositions make up, and/or optional and non-active ingredient combination, as pharmaceutically acceptable carrier, excipient, suspensoid, surfactant, disintegrating agent, binding agent, diluent, lubricant, stabilizing agent, antioxidant, penetrating agent, coloring agent, plasticizer etc.

" complex " refers to comprise the material by bonded drug moiety of tight ion pair key (as metformin) and transhipment part.Drug moiety-transhipment part complex can be different from the loose ion pair of drug moiety and transhipment part, and its difference is the distribution behavior in octanol/water, and its feature shows as following relation:

Δ LogD=LogD (complex)-LogD (loose ion pair) 〉=0.15 (equation 1)

Wherein, D, partition coefficient (apparent partition coefficient) is to set pH (about usually pH=5.0 is to about pH=7.0) and at 25 ℃ of following all kinds drug moieties with transport partly in capryl alcohol ratio with the equilibrium concentration of identical type in water (deionized water).Log D (complex) is used for determining according to the drug moiety of this paper indication preparation and the complex of transhipment part.Log D (loose ion pair) is the physical mixture that is used for determining deionized water Chinese medicine part and transhipment part.For example, can determine to infer the octanol/water apparent partition coefficient (D=C of complex (in deionized water 25 ℃) _{Capryl alcohol}/ C _Water) and with (mol/mol) physical mixture comparison in 1: 1 of transhipment part in 25 ℃ of deionized waters and drug moiety.If determine to infer complex (D+T-) Log D and 1: 1 (mol/mol) physical mixture (D+ ‖ T-) Log D between difference more than or equal to 0.15, so just confirm that the supposition complex is according to complex of the present invention.In preferred embodiments, Δ Log D 〉=0.20, and more preferably Δ Log D 〉=0.25, and more preferably Δ Log D 〉=0.35 still.

" dosage form " is meant in medium, carrier, vehicle or is fit to deliver medicine to Pharmaceutical composition in their patient's of needs the device.

" medicine " or " drug moiety " refers to provide medicine, chemical compound or the medicament of some pharmacological action or the residue of these medicines, chemical compound or medicament when giving the patient.Be suitable for using in forming complex, medicine comprises acidity, alkalescence or amphion constituent (element), or acidity, alkalescence or amphion residue constituent.

" fatty acid " refers to that general formula is CH ₃(C _nH _x) any organic acid group of COOH, wherein hydrocarbon chain be saturated (x=2n, as Palmic acid, C ₁₅H ₃₁COOH) or undersaturated (x=2n-2, as oleic acid, CH ₃C ₁₆H ₃₀COOH).

" intestinal " or " gastrointestinal tract " is meant the digestive tract part that extends to anus from the under shed of stomach, comprises small intestinal (duodenum, jejunum and ileum) and large intestine (ascending colon, transverse colon, descending colon, sigmoid colon and rectum).

" loose ion pair " be meant at physiology pH with in water environment, is easy to and may appears at a pair of ion that other loose pairing in the loose ion pair environment or free ions exchange mutually.With isotopic labeling and NMR or mass spectral analysis, can in experiment, find loose ion pair by the member and the another kind of ionic exchange that are recorded in loose ion pair in physiology pH and the water environment.Also available reversed-phase HPLC is found loose ion pair by being recorded in right being separated in of physiology pH and water environment intermediate ion in the experiment.Loose ion pair also can be called " physical mixture ", and by making ion pair physical mixed formation together in medium.

" lower gastrointestinal tract " or " following G.I. road " refers to large intestine.

Metformin refers to N, and (N, N-dimethylimidodicarbonimidicdiamide), molecular formula is C to N-dimethylimino diformazan imidic acid diamides ₄H ₁₁N ₅, molecular weight is 129.17.This chemical compound can have been bought with metformin hydrochloride.

" patient " refers to the animal that the needs treatment gets involved, preferred mammal, more preferably people.

" closely ion pair " refers in physiological pH and aqueous environments, is not easy and the ion pair of other loose free ions to exchanging that can exist in tight ion pair environment.Tight ion pair can detect with experimental technique, does not promptly have exchange to record by an ion and another ion that uses tight ion pair in isotope-labelling method and NMR or mass spectrum record physiological pH and the aqueous environments.Closely ion pair can be found with experimental technique, promptly by using reversed-phase HPLC record physiological pH and aqueous environments intermediate ion that isolating lacking found.

" transhipment part " refers to the residue that can form the chemical compound of complex with medicine or form the chemical compound of complex with medicine, and wherein transhipment part is compared with the transhipment of complexation medicine not, has improved the transhipment of the transepithelial tissue of medicine.The transhipment part comprises hydrophobic part and acidity, alkalescence or amphion constituent or acidity, alkalescence or amphion residue constituent.In preferred embodiments, hydrophobic part comprises hydrocarbon chain.In one embodiment, the pKa of alkaline structure composition or alkaline residue constituent is preferably greater than about 8.0 greater than about 7.0.

" Pharmaceutical composition " refers to be fit to the patient's of needs said composition compositions.

" constituent " refers to that (i) is the chemical group of macromole part and the chemical group that (ii) has recognizable chemical functional group.For example, acidic-group on the chemical compound or basic group are constituent.

" material " refers to have the chemical entities of concrete feature.

" residue constituent " refers to the constituent by modifying with the interaction or the reaction of another kind of chemical compound, chemical group, ion, atom etc.For example, carboxyl structure composition (COOH) interacts to form carboxylic acid sodium salt with sodium, and COO-is the residue constituent.

" upper gastrointestinal " or " going up the G.I. road " refers to comprise the gastrointestinal tract part of harmonization of the stomach small intestinal.

II. the formation of metformin complex and feature

As mentioned above, metformin is for being used for helping the biguanides hyperglycemia medicine of control noninsulindependent diabetes (type ii diabetes) blood sugar level.As shown in Figure 2, metformin is that to have pKa be 12.4 cation water-soluble chemical compound.The ionization form of medicine trends towards being adsorbed to negatively charged enterocyte, and research shown metformin in the colon of healthy population absorption difference (Vidon, N., etc., Diabetes Res.Clin.Pract., 4: 223-229 (1988)).The hydrophilic of metformin hydrochloride as shown in Figure 3, this figure has drawn the logarithm (logP) of octanol/water partition coefficient of metformin hydrochloride to the function of pH.When pH value less than 7.0, metformin hydrochloride is hydrophilic, and logP is less than-3.7.PH gradient scope in the gastrointestinal tract be from stomach pH about 1.2 pH to far-end ileum and the large intestine about 7.5 (Evans, D.F. etc., Gut, 29: 1035-1041 (1988)), this means that metformin hydrochloride is hydrophilic in the whole pH scope of gastrointestinal.In addition, metformin hydrochloride in these pH value for highly dissociated.Trend towards the uniting of hydrophilic and electric charge strictness and limit it through striding the absorption of cell passage transhipment, metformin hydrochloride absorbs non-constant in lower gastrointestinal tract as a result.

Therefore, on the one hand, the invention provides the material that is included in the metformin that absorption significantly improves in the lower gastrointestinal tract.This material is the complex of metformin and transhipment part, can prepare from melbine salt example hydrochloric acid metformin according to the general synthetic reaction flow process shown in Fig. 4 A.In brief, metformin is combined with the transhipment part, in the drawings with T-M ⁺Expression.Exemplary transhipment part is above-listed part, comprises fatty acid, benzenesulfonic acid, benzoic acid, fumaric acid and salicylic acid.As will discussing below, dielectric constant less than the organic solvent of water in the presence of, make two kinds of materials contacts to form metformin-transhipment part complex, wherein material closes by tight ion pair bond, in Fig. 4 A with metformin+(T)-represent.

Fig. 4 B explanation is used to form the flow process of synthetic reaction more specifically of metformin-transhipment part complex.In this flow process, the transhipment part has carboxyl (COO ^-), in the drawings with T-COO ^-Expression.Carboxylic transhipment part is T-COO ^-Mix in less than the solvent of water to form at dielectric constant by mixing the key or the tight complex of the associating metformin of ion pair and transhipment part, in the drawings with metformin+[(T COO) ₂]-expression.

Be provided for preparing the instantiation of the step of metformin-transhipment part complex among the embodiment 1, with Fig. 4 C explanation, wherein transhipment part is a fatty acid.Use ion-exchange process to prepare metformin alkali from hydrochlorate.Adipic acid solution contacts with metformin alkali to form metformin-fatty acid complex again in solvent.

In embodiment 1, complex is formed by the lauric acid as exemplary fatty acid transhipment part.Should understand lauric acid only for exemplary, its preparation process is equally applicable to be suitable as other materials of transhipment part, also is suitable for the fatty acid of any carbon chain lengths.For example, the salt formation complex of metformin and various fatty acid or fatty acid, described fatty acid has the 6-18 carbon atom, more preferably 8-16 carbon atom, even more preferably 10-14 carbon atom.Fatty acid or its salt can be saturated or unsaturated.Be expected at exemplary satisfied fatty acid that preparation uses in the complex comprise butanoic acid (butyric acid, 4C); Valeric acid (valeric acid, 5C); Caproic acid (caproic acid, 6C); Sad (sad, 8C); N-nonanoic acid (n-nonanoic acid, 9C); Capric acid (capric acid, 10C); Dodecoic acid (lauric acid, 12C); Tetradecylic acid (myristic acid, 14C); Hexadecylic acid (Palmic acid, 16C); Heptadecanoic acid (heptadecanoic acid, 17C) and stearic acid (stearic acid 18C), wherein is the carbon atom number in popular name and the fatty acid in the garden bracket after the system name.Unsaturated fatty acid comprises oleic acid, linoleic acid plus linolenic acid, and all acid have 18 carbon atoms.Linoleic acid plus linolenic acid is a polyunsaturated acid.

Also expect the salt formation complex of metformin and alkyl sulfate or alkyl sulfate, wherein alkyl sulfate can be saturated or unsaturated.Exemplary alkyl sulfuric ester or its salt (sodium, potassium, magnesium etc.) have the 6-18 carbon atom, more preferably 8-16 carbon atom, and even more preferably 10-14 carbon atom.Also expect metformin and benzenesulfonic acid, benzoic acid, fumaric acid and salicylic acid or these sour salt formation complex.

In one embodiment, do not comprise metformin-thioctic acid complex of (yet claiming alpha-lipoic acid) according to complex of the present invention.

Continue reference example 1, the complex of being made up of metformin-laruate prepares from acetone.Acetone only is exemplary solvent, and fatty acid can dissolved therein other solvents be suitable solvent.For example, fatty acid may be dissolved in chloroform, benzene, cyclohexane extraction, ethanol (95%), acetic acid and the methanol.Capric acid, lauric acid, myristic acid, Palmic acid and the stearic acid dissolubility (g/L) in these solvents is as shown in table 1.

Table 1: the dissolubility (g/L) of fatty acid under 20 ℃

Fatty acid (carbon number)	Chloroform	Benzene	Cyclohexane extraction	Acetone	Alcohol 95 %	Acetic acid	Methanol	Acetonitrile
									Capric acid (10)	3260	3980	3420	4070	4400	5670	5100	660
Lauric acid (12)	830	936	680	605	912	818	1200	76
									Myristic acid (14)	325	292	215	159	189	102	173	18
Palmic acid (16)	151	73	65	53.8	49.3	21.4	37	4
									Stearic acid (18)	60	24.6	24	15.4	11.3	1.2	1	＜1

In one embodiment, being used to form the used solvent of complex is the solvent of dielectric constant less than water, preferred at least less than 1/2nd of the dielectric constant of water, more preferably at least less than 1/3rd solvent of the dielectric constant of water.Dielectric constant is the measurement method of solvent polarity, and the dielectric constant of exemplary solvent is as shown in table 2.

Table 2: the feature of exemplary solvent

Solvent	Boiling point, ℃	Dielectric constant
			Water
	100	80
			Methanol	68	33
Ethanol	78	24.3
			The 1-propanol	97	20.1
The 1-butanols	118	17.8
			Acetic acid	118	6.15
Acetone	56	20.7
			Methyl ethyl ketone	80	18.5
Ethyl acetate	78	6.02
			Acetonitrile	81	36.6
N, dinethylformamide (DMF)	153	38.3
			Dimethyl sulfoxine (DMSO)	189	47.2
Hexane	69	2.02
			Benzene	80	2.28
Diethyl ether	35	4.34
			Oxolane (THF)	66	7.52
Dichloromethane	40	9.08
			Carbon tetrachloride	76	2.24

Aqueous solvent, methanol, ethanol, 1-propanol, 1-butanols and acetic acid are for having the hydrogen atom polar aprotic solvent that is connected to electronegative atom (being generally oxygen atom).Solvent acetone, ethyl acetate, methyl ethyl ketone and acetonitrile are dipolar aprotic solvent, in one embodiment, preferably use in forming the metformin complex.Dipolar aprotic solvent does not comprise the OH key, but because the multiple bond between carbon and oxygen or the nitrogen generally has the dipole moment of big key.Most of dipolar aprotic solvents comprise the two keys of C-O.The dielectric constant of the dipolar aprotic solvent of record is at least less than 1/2nd of water in table 2.

Used the reversed-phase HPLC analysis to state metformin-laruate complex as formation as described in the embodiment 1.Describe in the condition of the HPLC method part below.For relatively, also produced metformin hydrochloride, sodium laurate, and the HPLC trace of the physical mixture of metformin hydrochloride and sodium laurate, its result is as shown in Fig. 5 A-5D.Fig. 5 A has shown the trace of metformin hydrochloride, observes located in 1.1 minutes unimodal.Lauric salt form, sodium laurate between about 3-4 minute with single broad peak form eluting (Fig. 5 B).With two peak shape formula eluting, a peak of locating in 1.1 minutes is corresponding to metformin hydrochloride in water for 1: 1 mole of physical mixture of metformin hydrochloride and sodium laurate, and second peak locating in about 2.7-4 minute is corresponding to sodium laurate (Fig. 5 C).Fig. 5 D shows the HPLC trace of pressing the complex that step forms among the embodiment 2, observes 3.9-4.5 minute and has located single eluting peak.The HPLC trace shows that the complex that metformin alkali and lauric acid form is different from the physical mixture of these two kinds of compositions in water.This trace shows that also (water: 50: 50 v of acetonitrile: complex can not dissociate when v) being used for the HPLC analysis when this complex places solvent system.

In another research of describing metformin-laruate complex feature, measured the octanol/water apparent partition coefficient (D=C of complex _{Capryl alcohol}/ C _Water), and with metformin hydrochloride, metformin hydrochloride: 1: 1 (mol/mol) mixture of sodium lauryl sulphate and metformin hydrochloride: the octanol/water apparent partition coefficient of 1: 1 (mol/mol) mixture of sodium laurate is relatively.The result is as shown in table 3.

Table 3: octanol/water partition coefficient

Tester	*LogD
		Metformin hydrochloride	-2.64
1: 1, metformin hydrochloride: sodium lauryl sulphate	-0.05
		1: 1, metformin hydrochloride: sodium laurate	0.06
The lauric acid metformin	0.44

^*Log[C _{Capryl alcohol}/ C _Water]

The LogD of complex is 0.44, compares remarkable increase with metformin hydrochloride, and this shows that complex is more conducive to be distributed in the capryl alcohol than the salt form of metformin.Compare with the physical mixture of metformin hydrochloride in soap, complex also has higher logD.The difference of logD proves that further the complex of metformin-fatty acid is not the physical mixture of these two kinds of materials, that is to say not to be simple loose ion pair but tight ion pair.

Do not wish to be subjected to the concrete understanding of mechanism to fetter, the inventor's the reasons are as follows.When loose ion pair places the polar solvent environment, suppose the space that polar solvent molecule meeting insertion itself is occupied by ionic bond, thereby impel the ion of bonding to separate.Can form the solvation shell around the free ion, the solvation shell comprises static and is bonded to polar solvent molecule on the free ion.Thereby this solvation shell prevents this free ion and another free ion and forms any form, but is the ionic bond of loose ion pair.Under the polytype counter ion was present in condition in the polar solvent, any specific loose ion pair may be to the counter ion competing phase to sensitivity.

This effect is more obvious when polarity strengthens, and polarity is represented with the dielectric constant of solvent.Based on Coulomb's law, electrically charged (q1) and (q2) and the power between two kinds of ions that separated by the distance (r) in dielectric constant (e) medium be:

$F=-\frac{q_1{\mathrm{<figure-callout\; id="2"\; label="q"\; filenames="A20048003930400442.png,A20048003930400491.png"\; state="\{\{state\}\}">q</figure-callout>}}_2}{4{\mathrm{\&pi;\&epsiv;}}_0{\mathrm{\&epsiv;r}}^2\mathrm{}}$ (equation 2)

ε wherein ₀Be the spatial dielectric constant.Equation shows the importance of dielectric constant (ε) to loose ion pair stability in the solvent.In the aqueous solution of high-k (ε=80), if the ionic combination of hydrone attack and separate opposite charged ion, then electrostatic attraction is significantly reduced.

Therefore, the high dielectric constant solvent molecule can attack ionic bond and final this key that destroys near in a single day being present in ionic bond.So the ion of this not bonding freely moves in solvent.These property definitions are loose ion pair.

Closely the formation of ion pair is different with loose ion pair, thereby has the character that is different from loose ion pair.Form tight ion pair by the number that reduces polar solvent molecule in two interionic bonding spaces.This makes ion closely move together, and forms than the remarkable stronger key of loose ion pair key, but still thinks ionic bond.More completely open herein, use the polarity solvent littler to obtain tight ion pair with the embedding that reduces the interionic polar solvent than water.

As for the other discussion of loose and tight ion pair, see D.Quintanar-Guerrero etc., Pharm.Res., 14(2): 119-127 (1997).

Also can use the difference between the loose and tight ion pair of chromatographic process observation.Use reversed phase chromatography, Yu Buhui to separate under the condition of tight ion pair and can easily separate loose ion pair.

Also can be according to the present invention by selecting cation and the stronger chemical bond of anion prepared at concentrations relative to each other.Be under the situation of water for example, can select cation (alkali) and anion (acid) to reach stronger attracting each other at solvent.More weak if desired key then can be selected more weak attraction.

Stride the transhipment of this class film in order to understand molecule, the biomembrane partial simulation can be become the ground floor (first order) of approximate lipid bilayer.Because unsuitable portioning, the transhipment (opposite with active transport etc.) of striding the lipid bilayer part is unfavorable for ion.Each researcher these ionic electric charges of having advised neutralizing can increase transmembrane transport.

In " ion pair " theory, the ion medicine part is matched with " hiding " electric charge with transhipment part counter ion and is made the gained ion pair easier to be mobile in lipid bilayer.This method has caused a large amount of concerns and research, especially pays close attention to the raising per os and gives the absorption that medicine is striden enterocyte.

Although ion pair has caused many concerns and research, never obtain many successes.For example, the ion pair of finding two kinds of antiviral compounds causes to absorb and increases, be not because the effect of ion pair transcellular transport but since to the effect of monolayer integrity (J.Van Gelder etc., Int.J.of Pharmaceutics, 186: 127-136 (1999).The author infers that the formation of ion pair may not be very effective to the transepithelial cell traffic that improves charged hydrophilic compounds because find in vivo can destroy the beneficial effect of counter ion with other ionic competitions.Other authors have pointed out that the absorption experiment of ion pair always do not point to clear and definite mechanism (D.Quintanar-Guerrero etc., Pharm.Res., 14 (2): 119-127 (1997)).

The problem that the inventor has been surprised to find that these ion pair absorption experiment for they use loose ion pair rather than closely ion pair experimentize.Really, disclosed in the art many ion pair absorbs absorption experiment even does not clearly distinguish loose ion pair and the tight difference between the ion pair.The technical staff in fact has to by looking back the disclosed loose ion pair in open method district office of preparation ion pair, and indicates at loose ion pair but not closely ion pair of these disclosed preparation methoies.Loose ion pair is allowed the competition of counter ion relatively, and the cracking in conjunction with the ionic bond of loose ion pair by solvent mediation (as the water mediation) takes place easily.Therefore, when the drug moiety of ion pair arrives the membranous wall of enterocyte, can or cannot with the transhipment part with free ion to combining.Exist the probability of ion pair to depend on maintenance ion ionic bond together near the membranous wall, but depend on two kinds of ions local concentration separately more.When they during near the enterocyte membranous wall, if two parts do not have combination, the infiltration rate of non-complexation drug moiety may not can be subjected to the influence of non-complexation transhipment part.So compare with giving drug moiety separately, loose ion pair may be to absorbing only limited influence.

On the contrary, complex of the present invention has more stable key in the presence of polar solvent such as water.So inventor's inference, by forming complex drug moiety and transhipment part in close membranous wall, these parts will more may be associated with the ion pair form.This association can increase the electric charge of above-mentioned part by the chance of hidden (buried), makes the easier cell membrane that passes through of gained ion pair.

In one embodiment, complex comprises tight ion pair key between drug moiety and transhipment part.Discuss as this paper, closely ion pair is more stable than loose ion pair, thereby increases drug moiety and transport part near membranous wall the time, and described part can be with the associating probability of ion pair form.This association can increase the electric charge of above-mentioned part by hidden chance, makes the easier cell membrane that passes through of complex of tight ion pair bonding.

Should note drug moiety with respect to non-complexation, complex of the present invention can improve in whole gastrointestinal absorption, and just do not improve the absorption of lower gastrointestinal tract, because expect that general improvement of this complex strides the cell passage transhipment, and just do not improve the transhipment of lower gastrointestinal tract.For example, if drug moiety is for mainly coming across the proteic substrate of active transport in the upper gastrointestinal, then the complex that is formed by drug moiety still can be used as the substrate of transport protein.Therefore, total transhipment can be for being added the improved transhipment amount sum due to the cell of striding provided by the present invention by transport protein.In one embodiment, complex of the present invention improves at upper gastrointestinal, lower gastrointestinal tract, and the absorption at upper gastrointestinal and lower gastrointestinal tract two positions.

In the research of carrying out being subjected to support of the present invention, use fatty acid capric acid, lauric acid, Palmic acid and oleic acid to prepare metformin-fatty acid complex according to the step of describing among the embodiment 1.The complex that has also prepared metformin and ethylidene succinic acid.These complex are characterised in that its fusing point and dissolubility, and its data are summarised among the table 4A.In addition, each complex is at aqueous solution $(\mathrm{pH}\&cong;5.8)$ Electrical conductivity with CDM 83 conductometers (RadiometerCopenhagen) in 23 ℃ of mensuration.Its value is summarised among the table 4B and illustrates in Fig. 6 A.

Table 4A

Melbine salt or complex	Fusing point (℃)	H 2O dissolubility (4h)
			HCl	238	＞300
Succinate	243	95
			Cetylate	150	12
Oleate	138	53
			Decanoin	153	Gelation
Laurate	151	Gelation

Table 4B

Electrical conductivity (μ S/cm)
							Metformin concentration	Metformin hydrochloride	The succinic acid metformin	The capric acid metformin	The lauric acid metformin	The Palmic acid metformin	The oleic acid metformin
20(mM)	1850	1370	872	758	398	405
							10(mM)	958	741	461	450	237	235
5(mM)	452	355	233	225	144	136
							0(mM)	1.26	1.26	1.26	1.26	1.26	1.26

It is the electrical conductivity of unit that Fig. 6 A shows with little Siemens/cm (μ S/cm), is metformin hydrochloride (circle), and the concentration function of the metformin of succinate (del), caprate (square), laruate (prismatic), palmitate (triangle) and oleate (octagonal) complexation.Under all concentration, metformin hydrochloride has the highest electrical conductivity.Compare with metformin hydrochloride, complex has lower electrical conductivity, and electrical conductivity obviously increases and reduces along with the fatty acid carbons number.

Suppose that the concentration of electrical conductivity (k) and charged ion is proportional and metformin hydrochloride 100% is electrically charged, then estimate the percentage ratio of unionized medicine (f) by following equation.Also hypothesis is ignored the diffusion of different big or small fatty acid molecules.

F=(1-k/k _HCL) * 100 (equation 3)

Fig. 6 B is shown as the percentage ratio of unionized medicine of each complex of the function of metformin concentration, is determined by equation 3.Metformin hydrochloride (circle) ionization fully, and about 80% ionization of succinic acid-metformin (del).Complex capric acid-metformin (square) and about 50% ionization of metformin-laruate (prismatic), Palmic acid-metformin (triangle) and about 30% ionization of oleic acid-metformin (octagonal).These data are determined the difference between ion pair metformin hydrochloride and the metformin-fatty acid complex once more.

$f=(1-\frac{k}{k_{\mathrm{HCl}}})\&times;100$

The definition factor that dissociates is 100 to deduct the percent (f) of unionized medicine, in one embodiment, in $\mathrm{pH}\&cong;5.8$ Aqueous environments in, under the concentration of 20 mM metformin/every liter, complex of the present invention shows that the factor that dissociates is between the 5-90, more preferably 5-85, more preferably 10-70, even more preferably 20-65.

Colon absorbs and uses per os tube feed rat model to carry out characterized in the body of metformin-laruate complex.Described in embodiment 2, handle the fasting rat with every rat 40mg metformin hydrochloride or metformin-laruate complex.Taking a blood sample is used to analyze the concentration of metformin, and its result as shown in Figure 7.The plasma concentration of the rat of per os tube feed metformin hydrochloride (circle) reaches the plasma concentration maximum in about 1 hour after processing, and Cmax is about 4080ng/mL.The rat plasma concentration of the processing of per os tube feed metformin in about 1 hour-laruate complex (prismatic) reaches maximum after processing, and Cmax is about 5090ng/mL.During 1-8 hour after handling in all tests, the plasma concentration of the rat of handling with complex is higher.Data analysis shows for the bioavailability (100% bioavailability) of metformin when giving metformin hydrochloride with respect to vein, and the relative bioavailability of the metformin that gives with complex form is 151%.

Colon absorbs and also uses rat flush ligation colon models to estimate in the body of complex.Described in embodiment 3, give the different complexes of dosage 10mg/ rat to the ligation colon of rat through intubate.Rat (n=3) to each test group gives metformin hydrochloride, succinic acid metformin dimer, Palmic acid metformin, oleic acid metformin, capric acid metformin or lauric acid metformin.Another group rat vein gives 1mg metformin hydrochloride.Periodically take a blood sample and be used for the concentration of analyzing blood metformin alkali.Its data as shown in Figure 8.

It is the metformin plasma concentration of unit that Fig. 8 shows in the rat with ng/mL, its be metformin hydrochloride (circle), with the metformin of succinate (prismatic), palmitate (triangle), oleate (del), caprate (square) and laruate (octagonal) complexation hour being the time function of unit.Complex by lauric acid (circle) and capric acid (square) preparation reaches maximum plasma concentration.Be lower than the plasma concentration that complex reached with lauric acid and capric acid with the metformin plasma concentration that complex reached of Palmic acid (triangle) and oleic acid (del), but the plasma concentration that provides by metformin hydrochloride or succinic acid metformin is provided.

Table 5 shows the bioavailability (the 3rd row) that gives metformin hydrochloride with respect to vein, and the bioavailability (the 4th row) that gives the metformin hydrochloride of ligation colon through intubate is carried out the relative bioavailability of standardized relative Cmax (each complex is with respect to the maximum metformin alkalemia slurry concentration of metformin hydrochloride plasma concentration) and each complex.

Table 5

The metformin test compound	Relative Cmax	Area under curve (0-4 hour) based on 1mg alkali/rat	Bioavailability with respect to IV dosage 1(％)	Bioavailability with respect to IV dosage 2(increase multiple)
					HCl(i.v)	1.0	692.5	100	-
HCl		29.2	4.2	1
					Succinate	0.6	21.4	3.1	0.7
Cetylate	3.6	144.3	20.8	5
					Oleate	14.1	408.3	59.0	14
Decanoin	45.0	548.0	79.1	19
					Laurate	40.8	674.5	97.4	23

¹It is standardized by AUC that each complex reached to give the AUC of metformin hydrochloride with respect to intravenous; (ngh/mL-mg).

¹Standardized with respect to the AUC that gives metformin hydrochloride through intubate to ligation colon by AUC that each complex reached.

With the bioavailability that Palmic acid-the metformin complex reaches nearly 5 times of bioavailability of hydrochlorate, this shows, when metformin offered the colon absorption with metformin-transhipment part complex form, the bioavailability of metformin significantly improved.With respect to hydrochlorate, the bioavailability of oleate complex obtains 14 times improvement.With respect to hydrochlorate, capric acid-metformin complex provides nearly 18 times bioavailability of improving.With respect to hydrochlorate, the bioavailability of metformin-laruate complex obtains the improvement more than 20 times.Therefore, the present invention has designed the chemical compound that comprises the complex that is formed by metformin and transhipment part, the chemical compound that the perhaps basic complex that is formed by metformin and transhipment part is formed, the perhaps chemical compound formed of the complex that forms by metformin and transhipment part, wherein the colon with respect to metformin hydrochloride absorbs, complex is at least the former 5 times in the absorption of colon, more preferably at least 15 times, and more preferably at least 20 times, this obtains proof by the metformin bioavailability from the metformin determination of plasma concentration.Therefore, when metformin with metformin-when transhipment part complex form gives, significantly improve the colon that metformin enters blood and absorb.

Use flushing-ligation colon models of describing among the embodiment 3 to carry out another research, so that the bioavailability of metformin compares when the bioavailability of metformin provides with physical mixture form with metformin hydrochloride and sodium laurate (1: 1 mol ratio) will provide with complex form the time.With two kinds of test preparations (metformin-laruate complex and 1: 1 mol ratio metformin hydrochloride: sodium laurate) and the various dose of metformin hydrochloride send in the ligation colon through intubate.The analysed for plasma sample is with the concentration of measuring metformin and the bioavailability that gives the bioavailability of metformin with respect to vein.Its result as shown in Figure 9.

Fig. 9 show percent bioavailability, is the function of the metformin dosage of unit for the physical mixture (circle) of metformin hydrochloride and sodium laurate and lauric acid metformin complex (square) with mg alkali/kg.This complex has than higher bioavailability of physical mixture and lower transmutability.

Figure 10 shows the data of Table A, F and G among the embodiment 3, with explanation with give through intubation to the pharmacokinetics of the metformin hydrochloride (circle) of ligation colon or metformin hydrochloride (triangle) this complex (prismatic) relatively of giving through vein.This complex provides the colon higher than the salt form of medicine to absorb, and has the more persistent haemoconcentration that vein gives.

III. exemplary dosage forms and using method

Above-mentioned complex is provided at the particularly absorbance of the increase in the lower gastrointestinal tract of gastrointestinal tract.To describe the dosage form of this complex of use and the colon of Therapeutic Method and increase thereof now absorbs.Should understand following dosage form and only play the example effect.

Many dosage forms are suitable for the use of metformin-transhipment part complex.As mentioned above, provide the dosage form of administration once a day can reach therapeutic efficiency at least about 15 hours, more preferably at least 18 hours, even more preferably at least about 20 hours.Can make up and prepare dosage form according to any design that discharges the required dosage metformin.Generally, this dosage form per os gives, the tablet or the capsule of its size and the similar routine of shape.But can prepare the dosage form that per os gives according to one of various method.For example, this dosage form can be made into diffusion system and (comprises the associating as " regularly micropill (tiny time pills) " and pearl and stromatolysis system and diffusion/dissolution system and ion exchange resin system as storage storehouse device (reservoirdevice) or matrix device, dissolution system as wrapping capsular dissolution system, as Remington ' s Pharmaceutical Sciences, 18 ^ThEd., described in the pp.1682-1685 (1990).

The instantiation that is suitable for metformin-dosage form that transhipment part complex uses is osmotic dosage form.Usually, osmotic dosage form utilizes osmotic pressure to produce driving force, and liquid to small part is infiltrated in the compartment that is formed by semi-permeable wall, and described wall permission liquid freely spreads but do not allow medicine or penetrating agent (if existence) freely to spread.The advantage of osmosis system does not rely on pH for their running, thereby in whole time expand section, though when this dosage form through gastrointestinal tract and when running into different microenvironment with remarkable different pH value, continue to turn round with the speed of infiltration decision.At Santus and Baker, " Osmotic drug delivery:a review of the patentliterature (release of osmotic drug: the review of patent documentation), " Journal of ControlledRelease, 35: can find the commentary of relevant these dosage forms among the 1-21 (1995).Also describe osmotic dosage form in following United States Patent (USP) in detail, each document is attached to herein by reference: 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.

Be presented at the exemplary dosage forms of mentioning with primary osmotic pump (elementary osmoticpump) dosage form in the art among Figure 11.Dosage form 20 shown in the profile also is mentioned with the primary osmotic pump dosage form, by around with form around the semi-permeable wall 22 of interior compartment 24.Interior compartment comprises single component layer, is referred to herein as medicine layer 26, and this medicine layer comprises the mixture of metformin-transhipment part complex 28 and selected excipient.Adjust excipient so that the osmotically active gradient to be provided, this gradient is used for attracting liquid to enter through wall 22 from the external world, just forms releasable metformin-transhipment part complex preparation in case soak into liquid.Excipient can comprise suitable suspensoid (being also referred to as pharmaceutical carrier 30 herein), binding agent 32, lubricant 34 and be called the osmotically active agent of penetrating agent 36.The exemplary raw material of each composition in these compositions is provided below.

The semi-permeable wall 22 of osmotic dosage form can see through the liquid of outside process, as water and biofluid, but basically can not be through the composition of process in the interior compartment.The raw material that is used to form wall is not erodible in essence between the operating period and is insoluble to biological fluid substantially in dosage form.The representative polymers that forms semi-permeable wall is drawn together homopolymer and copolymer, as cellulose esters, cellulose ether and cellulose esters-ether.Channel modulators can form raw material with wall to be mixed to regulate the permeability for liquids of wall.For example, it usually is hydrophilic substantially that the infiltration of liquid such as water is produced the reagent that significantly increases, and is hydrophobic substantially and the infiltration of water is produced significantly reduced those reagent.The exemplary path regulator comprises polyhydric alcohol, poly alkylene glycol (glycol), poly alkylene glycol (polyalkylenediols), aklylene glycol polyester etc.

On-stream, because the osmotically active agent exists, the osmotic gradient of striding wall 22 causes that gastric juice passes wall and is absorbed, and makes the medicine layer swelling and form releasable metformin-transhipment part preparation (as solution, suspensoid, serosity or other flowable composition) in interior compartment.Releasable metformin when liquid continues to enter interior compartment-transhipment part preparation discharges through exporting 38.Even when pharmaceutical preparation discharged from dosage form, liquid continued to flow to interior compartment, thereby promoted that medicine continues to discharge.In this mode, metformin-transhipment part discharged in mode stable, that continue in stage time expand.

The preparation that is similar to dosage form shown in Figure 11 has been described among the embodiment 4.

Figure 12 is the sketch of another kind of exemplary osmotic dosage forms.At United States Patent (USP) the 4th, 612,008,5,082,668 and 5,091, describe this dosage form in detail in No. 190, above patent is attached to herein by reference.Briefly, the dosage form 40 of sectional view demonstration has the semi-permeable wall 42 of interior compartment of defining 44.Interior compartment 44 comprises the double-deck compressed core (core) with medicine layer 46 and promoting layer 48.Will describe below, promoting layer 48 is for being seated in transfer percolation (displacement) compositions in the dosage form, and promoting layer expands between the operating period, and the raw material that forms medicine layer is discharged from dosage form as exporting 50 through one or more outlets.Promoting layer can place the arrangement layering that contacts with medicine layer, and as shown in Figure 12, perhaps promoting layer can have the one or more intermediate layers that isolate promoting layer and medicine layer.

Medicine layer 46 comprises metformin-transhipment part complex, the selected mixed with excipients of this complex, as above-mentioned about those excipient that Figure 11 discussed.Exemplary dosage forms can comprise by the medicine layer that metformin-the laruate complex is formed, as the poly(ethylene oxide) of carrier, as the sodium chloride of penetrating agent, as the hydroxypropyl emthylcellulose of binding agent with as the magnesium stearate of lubricant.

Promoting layer 48 comprises the osmotically active composition, as drawing water liquid or biofluid and swollen one or more polymer, is called osmopolymer in the art.Osmopolymer is the hydrophilic polymer of swellable, and with water and aqueous biological fluids interaction, swelling or be extended to largely, the 2-50 that is generally its original volume doubly.Osmopolymer can be noncrosslinking or crosslinked, and osmopolymer is lightly crosslinked at least producing polymer network in preferred embodiments, and the very big and entanglement of this network is discharged from dosage form so that be not easy between the operating period.The examples of polymer that can be used as osmopolymer provides in the reference of foregoing detailed description osmotic dosage form.General osmopolymer is a polyalkylene oxide, and as poly(ethylene oxide) and poly-carboxymethyl cellulose alkali salt (poly (alkali carboxymethylcellulose)), wherein alkali is sodium, potassium or lithium.Other excipient such as binding agent, lubricant, antioxidant and coloring agent also can be included in the promoting layer.In the use, when liquid when semi-permeable wall absorbs, the osmopolymer swelling also promotes medicine layer and impels medicine to discharge through outlet from dosage form.

Promoting layer also can comprise the composition of mentioning with binding agent, is generally cellulose or polyvinyl as poly-positive vinylamide, poly-positive vinyl acetamide, polyvinylpyrrolidone, poly-positive vinyl caprolactone (caprolactone), poly-positive vinyl-5-N-methyl-2-2-pyrrolidone N-etc.Promoting layer also can comprise lubricant such as sodium stearate or magnesium stearate, and the antioxidant that suppresses the composition oxidation.Representative antioxidant includes, but are not limited to the mixture and the butylated hydroxytoluene of ascorbic acid, ascorbic palmitate, butylated hydroxyanisole, 2-and 3-t-Butyl-4-hydroxyanisole.

Penetrating agent also can mix the medicine layer and/or the promoting layer ester of osmotic dosage form.The osmotically active gradient of striding semi-permeable wall is set up in the existence of penetrating agent.Exemplary penetrating agent comprises salt such as sodium chloride, potassium chloride, lithium chloride etc., and sugar reaches carbohydrate as Raffinose, sucrose, glucose, lactose.

Continuation is with reference to Figure 12, and this dosage form can be chosen wantonly and comprise and be used for according to dosage coloured marking dosage form or the coatings (not shown) that provides metformin or another kind of medicine to discharge immediately is provided.

In the use, current enter promoting layer and medicine layer by wall.The promoting layer imbitition begins swelling, promotes medicine layer 44 subsequently, causes that the raw material in this layer is discharged through outlet, enters gastrointestinal tract.During dosage form placed gastrointestinal tract whole, promoting layer 48 was by predetermined design imbitition and continue swelling, thereby constantly discharges medicine from medicine layer.Like this, during 15-20 hour or this dosage form by gastrointestinal substantially whole during, this dosage form offers the metformin-transhipment part complex of gastrointestinal tract sustainable supply.Because metformin-transhipment part complex is absorbed in last lower gastrointestinal tract easily, so dosage form during transport at gastrointestinal tract 15-20 hour, the metformin that makes of this dosage form is passed in the blood flow.

Shown another kind of exemplary dosage forms among Figure 13 A.Osmotic dosage form 60 has trilaminar core 62, and this core comprises three layers: the second layer 66 of the ground floor 64 of metformin hydrochloride, metformin-transhipment part complex and be called the 3rd layer 68 of promoting layer.At United States Patent (USP) the 5th, 545,413,5,858,407,6,368,626 and 5,236, describe the dosage form of the type in No. 689 in detail, these patents are attached to herein by reference.As pointing out among the embodiment 5, three layers of dosage form of preparation have 85.0% weight metformin hydrochloride, 10.0% weight 100, the poly(ethylene oxide) of 000 molecular weight, 4.5% weight about 35,000-40, the ground floor of the polyvinylpyrrolidone of 000 molecular weight and 0.5% weight magnesium stearate.The second layer comprise 93.0% weight metformin-laruate complex (as describing preparation among the embodiment 1), 5.0% weight 5,000, about 35 of the poly(ethylene oxide) of 000 molecular weight, 1.0% weight, 000-40, the magnesium stearate of the polyvinylpyrrolidone of 000 molecular weight and 1.0% weight.

Promoting layer is made up of the poly(ethylene oxide) of 63.67% weight, the sodium chloride of 30.00% weight, the ferrum oxide of 1.00% weight, the hydroxypropyl emthylcellulose of 5.00% weight, the butylated hydroxytoluene of 0.08% weight and the magnesium stearate of 0.25% weight.Semi-permeable wall is made up of the cellulose acetate and the 20.0% poly(ethylene oxide)-poly(propylene oxide) copolymer of 80.0% weight with 39.8% acetyl content.

Metformin determines according to listed step the embodiment 5 from the dissolution rate of dosage form shown in Figure 13 A.Its result shown in Figure 13 B, wherein the rate of release of metformin (mg/ hour) show as the time (hour) function.Contact 12 hours subsequently after 4 hours with aqueous environments, dosage form begins to discharge the medicine of amount much at one, and greater than in 16 hours time, drug release begins minimizing after contact with aqueous environments.The metformin hydrochloride that is present near the medicine layer of outlet discharges at first.Contact in afterwards about 8 hours with aqueous environments, the release of metformin-transhipment part complex occurs, and continue to discharge 8 hours with abundant constant speed.Should understand this dosage form design for when when upper gastrointestinal is transported, discharge metformin hydrochloride in corresponding first eight hours of approximately transporting, shown in dotted line (dashed) post.When dosage form is transported by lower gastrointestinal tract, discharge metformin-transhipment part complex in the time of the about 8 little durations after the corresponding approximately picked-up, shown in point-like (dotted) post among Figure 13 B.This design utilizes the enhanced colon that is provided by complex to absorb.

Figure 14 A-14C illustrates another kind of exemplary dosage forms well known in the art, United States Patent (USP) the 5th, 534, and 263,5,667,804 and 6,020, this dosage form has been described in No. 000, these patents are attached to herein by reference.In brief, Figure 14 A is presented at the cross-sectional view of taking in gastrointestinal tract dosage form 80 before.This dosage form comprises the cylindric substrate 82 that comprises metformin-transhipment part complex.The two ends 84,86 of substrate 82 are preferably the circular convex shape so that guarantee light picked-up.Be with 88,90 and 92 with one heart around cylinder substrate, these bands are formed by the material that is insoluble to relatively in the aqueous environment.Among patent of Zhu Minging and the following embodiment 6 suitable material has been proposed in the above.

After dosage form 80 is taken in, begin ablations with substrate 82 zones between 88,90,92, as shown in Figure 14B.The ablation of substrate begins to cause that metformin-transhipment part complex is released in the gastrointestinal liquid environment.When dosage form continues when gastrointestinal tract transport, substrate continuation ablation is shown in Figure 14 C.At this moment, the ablation of substrate has developed into the degree that dosage form is broken into three fragments 94,96,98.Ablation is proceeded until the substrate of each fragment part fully by ablation.Be with 94,96,98 can discharge from gastrointestinal tract thereafter.

Should understand the osmotic dosage form of describing among Figure 11-14 and only be the exemplary dosage forms of many dosage forms, these dosage forms designed to be able to reach metformin-transhipment part complex are passed to the purpose of lower gastrointestinal tract.The technical staff of pharmaceutical field can confirm other suitable dosage form.

On the other hand, the present invention provides the method that is used for treating patient's hyperglycemia by compositions or the dosage form that comprises the metformin and the complex of transhipment part, and this complex is characterised in that and has heterodesmic (hybrid bond) or tight ion pair key between metformin and the transhipment part.This method finds to suffer from purposes among the patient of noninsulindependent diabetes (type ii diabetes) and/or insulin-dependent diabetes (type i diabetes) in treatment.To comprise complex and pharmaceutically acceptable vectorial compositions gives the patient, general per os gives.

Consider dosage form and required result, the dosage that gives is generally regulated according to patient's age, body weight and disease.In general, the recommended amounts that dosage form and compositions gave of metformin-transhipment part complex is with reference to the metformin hydrochloride (Glucophage that lists among the Physician ' s Desk Reference ^, Bristol-Myers Squibb Co.) consumption.For example, give the oral dose of metformin hydrochloride, and be no more than the highest day recommended dose of adult 2550mg and pediatric patients 2000mg based on the personalization of effectiveness and toleration.Metformin hydrochloride generally gives with meals with divided dose, begins with low dosage usually, is generally about 850mg/ days, increases to gradually then through the active required minimum treatment effective dose of the individual hyperglycemia of confirming to allow.Therefore, in one embodiment, provide and supply with the dosage form that dosage is the metformin of 500-2550mg every day, wherein metformin provides with metformin-transhipment part complex form.

On the other hand, the present invention design is united and is given metformin-transhipment part complex and second kind of therapeutic agent to treat hyperglycemia and controlling body weight, especially type ii diabetes patient.Preferred second kind of therapeutic agent is for being used for the treatment of especially type ii diabetes of obesity, diabetes, with the treatment of conditions agent relevant with diabetes.

Exemplary second kind of therapeutic agent includes but not limited to following chemical compound, and these compound classification are α glucosidase inhibitor, biguanide (not being metformin), Drugs Promoting Insulin Secretion, antidiabetic medicine or euglycemic agent.Exemplary α glucosidase inhibitor comprises acarbose, emiglitate, miglitol, voglibose.Suitable antidiabetic medicine is an insulin.Biguanide comprises buformin and phenformin.Suitable insulin succagoga comprises sulphanylureas such as glibenclamide (glibenclamie), glipizide, gliclazide, glimepiride, tolazamide, tolbutamide (tolbutamine), acetohexamide, carbutamide, chlorpropamide, glibornuride, gliquidone, Glisentide, glisolamide, glisoxepide, glyclopyramide (glyclopyamide), repaglinide, Nateglinide and glycyclamide.Euglycemic agent comprise PPAR-gamma agonist euglycemic agent (seeing WO97/31907) as 2-(1-carboxyl-2-{4-{2-(5-methyl-2-phenyl- azoles-4-yl)-ethyoxyl]-phenyl-ethylamino)-essence of Niobe and 2 (S)-(2-benzoyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl- azoles-4-yl)-ethyoxyl]-phenyl-propanoic acid.

Second kind of therapeutic agent is preferably antidiabetic compound such as insulin signaling pathway regulator, resemble Protein Tyrosine Phosphatases (PTPases) inhibitor, non-micromolecule simulation (mimetic) chemical compound and glutamine-D-fructose-6-phosphoric acid acylamino-transferring enzyme (GFAT) inhibitor, the chemical compound that the hepatic glucose of influence imbalance is produced, resemble G-6-Pase (G6Pase) inhibitor, fructose-1,6-diphosphatase (F-1,6-BPase) inhibitor, glycogen phosphorylase (GP) inhibitor, glucagon receptor antagonist and PCK (carboxykinase) be inhibitor (PEPCK), acetone acid dehydrogenation kinases (PDHK) inhibitor, insulin sensitivity enhancer, insulin secretion enhancers, alpha-glucosidase inhibitor, the gastric emptying inhibitor, the pharmaceutically acceptable salt of insulin and α 2-1 adrenergic antagonists or these chemical compounds and optional at least a pharmaceutically acceptable carrier, so that simultaneously, difference or sequential use, specifically be used for prevention, treatment is by the disease of DPP-IV adjusting or progress, especially impaired glucose tolerance (IGT) disease of delay disease, the impaired fasting glucose (IFG) disease, metabolic acidosis, ketosis, arthritis, obesity and the loose disease of sclerotin; Be preferably diabetes, especially type 2 diabetes mellitus.These unite preparation or the Pharmaceutical composition that is preferably combination.

In combinational therapeutic methods, with identical or different route of administration while or sequential metformin-transhipment part complex and second kind of therapeutic agent of giving.

In preferred embodiments, second kind of therapeutic agent is DPP IV (DPP-IV) inhibitor.Post-proline/alanine cracking the serine protease of DPP IV for finding in each tissue that comprises kidney, liver and intestinal at health.This protease from the position 2 protein with proline or alanine remove two N-end group aminoacid.DPP-IV can be used for controlling the metabolism of glucose, because its substrate comprises insulinotropic hormone glucagon-like peptide-1 (GLP-1) and Gastric inhibitory polypeptide (GIP).GLP-1 and GIP only have activity in its complete form; Two N-end group aminoacid removing them then make its deactivation (Holst, J. etc., Diabetes, 47: 1663 (1998)).

Therefore, for example United States Patent (USP) the 6th, 124, and 305,6,107, among No. 317 and PCT publication No. WO99/61431, WO98/19998, WO95/15309, the WO98/18736 DPP-IV inhibitor has been described.This inhibitor can be peptide class or non-peptide class, as the amino ethylamino of 1-[2-(5-cyanopyridine-2-yl)] acetyl group-2-cyano group-(S)-pyrrolidine and (2S)-1-[(2S)-2-amino-3,3-dimethyl butyrate acyl group]-2-pyrrolidine nitrile.

Designed a kind of method of suffering from the II diabetics that is used for the treatment of, wherein the patient uses DPP-IV inhibitor and metformin-transfer part complex therapeutic alliance.The advantageous effects that this combination medicine produces is stronger than the effect that the independent metformin associating that reach or DPP-IV inhibitor and non-complex form of each medicine is reached.This metformin-transfer part complex preferably gives with dosage form per os once a day, absorbs so that the enhanced colon that is provided by complex to be provided.The DPP-IV inhibitor can be given by any approach that is suitable for chemical compound and patient's use.

In one embodiment, combined treatment is to be used to alleviate the overweight or obese patient's who suffers from type ii diabetes body weight or to prevent its weight increase.Be presented at recently in the Zuckerfa/fa rat therapeutic alliance of metformin and DPP-IV inhibitor cause ingest reduce and the weight increase minimizing (Yasuda, N. etc., J.Pharmacol.Experimental Therap., 310(2): 614 (2004)).The present invention strengthens the scheme for combining that colon absorbs provides improvement by the metformin that gives metformin-transfer part complex form to reach.

From aforementioned content as seen, various purpose of the present invention and feature are met.Metformin and transhipment part are associated by heterodesmic or tight ion pair key, and the complex of being made up of metformin and transhipment part provides with respect to the viewed enhanced metformin colon absorption of metformin hydrochloride.This complex is prepared by new method, and wherein the metformin of alkali form partly contacts with transhipment in being dissolved in organic solvent, and the polarity of organic solvent for example can be passed through provable its low polarity of low-k less than water.Metformin alkali forms with the complex that contacting of transhipment part-solvent mixture causes between metformin and the transhipment part, and wherein these two kinds of materials associate by key, and this key is not that ionic bond neither covalent bond but heterodesmic or tight ion pair key.

IV. embodiment

Following examples further specify the present invention described herein, never plan to limit the scope of the invention.

Method

1.HPLC: by Hewlett Packard 1100 liquid chromatograph of being furnished with the evaporative light scattering detection instrument and use the C3 post (3.0 * 75mm) carry out anti-phase detection for Agilent Zorbax SB C3,5 μ m.Make water: 50: 50 v of acetonitrile: the mobile phase of v.Column temperature is 40 ℃, and flow velocity is 0.5mL/min.

Embodiment 1

The preparation of metformin-transhipment part complex

Raw material:

Metformin hydrochloride 13.0g

Lauric acid 16.0g

Methanol 675mL

Acetone 300mL

Demineralized water 14mL

Resin anion (R.A.) (Amberlyst A-26 (OH)) 108g

The preparation of metformin alkali

1. fill ion exchange column with resin anion (R.A.) Amberlyst A-26 (OH), obtain net weight.

2. at first use deionization (DI) water (oppositely (backflush)) to wash post,, note not allowing pillar drain off then with the methanol wash that contains 2%v/v DI water.

3. metformin hydrochloride is dissolved in the eluent of forming by the 365mL methanol of the DI water that contains 2% volume.

With the solution of step 3 with dropwise flow through pillar and collect eluent of separatory funnel.The metformin hydrochloride total amount that calculating is passed through makes its equilibrium point less than ion exchange resin (capacity).With about isopyknic eluent washing pillar.Collect the metformin alkali eluent of total amount 690mL.

5. the eluent that evaporation merges under 40 ℃ external temperature, vacuum is warming up to 65 ℃ to remove all residual water to doing when concentration step finishes.Because metformin alkali instability, carry out this concentration step in mode the most rapidly.

Complex forms

6. the 16.0g lauric acid is dissolved in the 300mL acetone with preparation lauric acid-acetone soln.Use several times the acetone washing liquid with the concentrated metformin alkali dissolution in the step 5, in the presence of filter aid, these eluents are filtered to remove any metformin hydrochloride that does not change immediately.Filtrate collection is also stirred in conical flask, be added dropwise to lauric acid-acetone soln rapidly with separatory funnel.Continue down to stir to spend the night in ambient temperature (20-25 ℃).

7. solvent and the sedimentary mixture of lauric acid metformin are filtered through buchner funnel.Filter cake descended dry one hour in vacuum pump then with 4 * 200mL washing with acetone.Wipe filter cake off and weigh from filter paper.In capillary tube, measure fusing point.Under ambient temperature, final drying is 3 hours in the vacuum drying oven.

This program causes the formation of lauric acid metformin complex, and its fusing point is 150-153 ℃.The fusing point of report metformin hydrochloride is 225 ℃.With respect to from used metformin hydrochloride and the stoichiometric Theoretical Calculation amount of lauric acid, gross production rate=75%.

Embodiment 2

Use the interior colon of body of per os tube feed rat model to absorb

8 rats arbitrarily are divided into two processed group.After fasting 12-24 hour, the metformin hydrochloride of first group of per os tube feed and 40mg/kg free alkali equivalent.Second group of per os tube feed with press the lauric acid metformin complex of describing the 40mg/kg free alkali equivalent for preparing among the embodiment 1.15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours are from tail vein blood sample collection behind the per os tube feed.Analyze the metformin plasma concentration by LC/MS/MS.The result as shown in Figure 7.

When research finishes, put to death rat, the gastrointestinal tract of experimental animal is carried out visual assessment to seek the stimulation sign.Observe in the rat of handling and do not have stimulation with complex or metformin hydrochloride.

Embodiment 3

In rat, use colon absorption in the body that washes the ligation colon models

Adopt the animal model that is known as " colonic ligation model " usually.With the 0.3-0.5kg Sprague-Dawley male rat after fasting anesthesia and separate sections near colon.The Excreta raw material of flushing colon.With the two ends ligation of this colon sections, simultaneously conduit is placed in the chamber and takes out in the abdomen and place on the skin so that transmit test preparation.Rinse the content of colon well and colon is put back to the abdominal cavity of animal.According to the experiment of setting, in sections, add test preparation after the 20mM sodium phosphate buffer of filling 1mL/kg pH7.4, imitate the actual colonic environment in the clinical setting more accurately.

After operation is prepared, be exposed to each test preparation before, make rat keep balance about 1 hour.Inject in the per rectum and give metformin hydrochloride or metformin-fatty acid complex, dosage is 10mg metformin hydrochloride/rat or 10mg metformin complex/rat.Rat is with as describing among the embodiment 1, and with fatty acid such as capric acid, lauric acid, Palmic acid and oleic acid, and the metformin-fatty acid complex of succinic acid dimer preparation is handled.After giving test preparation, taked blood sample, the metformin concentration of analyzing blood from the jugular vein conduit in 0,15,30,60,90,120,180 and 240 minute.Shown in following Table A-F, measure with nanograms/milliliter at each complex and the metformin alkali concn in each rat plasma that each time point detects.

Table A

Metformin hydrochloride
						Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Meansigma methods	Standard deviation
0	0	0	0	0.0	0.0
						0.25	48.9	30.7	52.3	44.0	11.6
0.5	48.4	22.2	61.2	43.9	19.9
						1	16.5	56.6	67.5	46.9	26.9
1.5	14	79	99	64.0	44.4
						2	27.3	124	96.6	82.6	49.8
3	28.6		81	54.8	37.1
						4	28.2		83.9	56.1	39.4

Table B

The succinic acid metformin
						Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Meansigma methods	Standard deviation
0	0	0	0	0.0	0.0
						0.25	19.9	42.6	19	27.2	13.4
0.5	19.5	53.6	18.9	30.7	19.9
						1	24.3	89.8	19	44.4	39.4
1.5	26.2	78.4	15.7	40.1	33.6
						2	44.1	59.1	13.2	38.8	23.4
3	38.9	48.3	15.8	33.7	16.5
						4	62.4	60.4	19	47.3	24.5

Table C

The Palmic acid metformin
						Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Meansigma methods	Standard deviation
0	0	0	0	0.0	0.0
						0.25	535	126	233	298.0	212.1
0.5	393	145	245	261.0	124.8
						1	147	43.6	212	134.2	84.9
1.5	103	116	110	109.7	6.5
						2	86.3	115	92.5	97.9	15.1
3	52	77.7	76.6	68.8	14.5
						4	57.9	105	118	93.6	31.6

Table D

The oleic acid metformin
						Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Meansigma methods	Standard deviation
0	0	0	0	0.0	0.0
						0.25	262	788	2450	1166.7	1142.1
0.5	218	552	1350	706.7	581.6
						1	79.3	426	1040	515.1	486.5
1.5	87.3	342	626	351.8	269.5
						2	59.3	399	219	225.8	170.0
3	27.9	163	79.3	90.1	68.2
						4	30.2	122	37.3	63.2	51.1

Table E

The capric acid metformin
						Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Meansigma methods	Standard deviation
0	0	0	0	0.0	0.0
						0.25	2750	3390	5020	3720.0	1170.4
0.5	1850	1430	2040	1773.3	312.1
						1	613	447	876	645.3	216.3
1.5	264	222	502	329.3	151.0
						2	177	243	193	204.3	34.4
3	51.8	97.9	100	83.2	27.2
						4	40.9	68	66.7	58.5	15.3

Table F

The lauric acid metformin
						Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Meansigma methods	Standard deviation
0	0	0	0	0.0	0.0
						0.25	3570	3270	3280	3373.3	170.4
0.5	2060	1950	1100	1703.3	525.4
						1	960	1590	544	1031.3	526.6
1.5	494	1150	287	643.7	450.5
						2	237	378	112	242.3	133.1
3	102	171	58.3	110.4	56.8
						4	68.1	77.5	47.4	64.3	15.4

For relatively, be in the blood flow of the direct intravenous injection to three of a metformin hydrochloride test rat of 2mg/kg rat body weight with dosage.Regular blood sample collection is so that analyze metformin alkali during four hours.Its result is shown in table G.

Table G

Metformin hydrochloride (iv)
						Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Meansigma methods	Standard deviation
0	0	0	0	0.0	0.0
						0.033333	1430	2370	3650	2483.3	1114.3
0.25	133	545	276	318.0	209.2
						0.5	262	331	94.7	229.2	121.5
1	35.5	N/A	25.2	30.4	7.3
						1.5	0	66.3	0	22.1	38.3
2	0	0	0	0.0	0.0
						3	0	0	0	0.0	0.0

In Fig. 8 with the result among the graphic formula display list A-F.Cmax and relative bioavailability are as above shown in the table 5.

Embodiment 4

Contain the preparation of the dosage form of metformin-transhipment part complex

Install by being prepared as follows shown in Figure 11.It is about 5,000,000 poly(ethylene oxide) and 0.5% silicon dioxide that the compartment forming composition comprises 92.25% (percentage by weight) metformin-transhipment part complex, 5% carboxypolymethylene potassium, 2% molecular weight, and they are mixed.Then mixture is crossed 40 order stainless steels sieve, dry type is mixed 30 minutes to obtain the mixture of homogeneous in the V-blender then.Then 0.25% magnesium stearate is crossed 80 order stainless steels sieve, again with mixture mixing 5-8 minute.Then, be placed on the blended powder of homogeneous dry type in the funnel and be supplied to compartment shaping press, the mixture of known quantity is compressed to being designed to 5/8 inch the oval outward appearance that per os uses.Then at Accela-Cota ^Use the wall forming composition with the pre-compartment of ellipse (precompartments) coating (coated) in the wall shaping coating machine, this forming composition comprises 91% cellulose acetate and 9% Polyethylene Glycol 3350 with 39.8% acetyl content.After the coating, the drug compartment of wall coating is removed and is transferred to the drying baker to remove the residual organic solvent that uses in the wall forming process from coating machine.Then, plater is transferred in 50 ℃ of air dry ovens dry about 12 hours.Then, thus use laser in the wall of device, to form passage getting out two passages on the major axis of each face of distributor.

Embodiment 5

Contain the preparation of the dosage form of metformin-transhipment part complex

Prepare the dosage form that comprises metformin hydrochloride layer and metformin-laruate complex layer shown in Figure 13 A as follows.

The poly(ethylene oxide) of 10 gram metformin hydrochloride, 1.18g 100,000 molecular weight and polyvinylpyrrolidone dry type in the blender of routine that 0.53g has about 38,000 molecular weight are mixed 20 minutes to obtain the mixture of homogeneous.Then, in the dry mixture of three kinds of compositions, slowly add the dehydrated alcohol of 4mL degeneration, continue to mix with agitator.Continued restir 5-8 minute.Blended wet compositions is crossed 16 mesh sieves and spend the night in drying at room temperature.Then, dried granule is crossed 16 mesh sieves and added the 0.06g magnesium stearate, all the components dry type was mixed 5 minutes.Prepare fresh granule with the initial ghe layer (dosage layer) in the preparation dosage form.These granules are about 35 by having of the poly(ethylene oxide) of 100,000 molecular weight of the metformin hydrochloride of 85.0% weight, 10.0% weight, 4.5% weight, 000-40, and the magnesium stearate of the polyvinylpyrrolidone of 000 molecular weight and 0.5% weight is formed.

By the metformin-lauric acid salt deposit that is prepared as follows in the dosage form.At first, will be by the 9.30 gram lauric acid metformin complex, the 0.50g 5 that describe preparation among the embodiment 1, the poly(ethylene oxide) of 000,000 molecular weight, 0.10g have polyvinylpyrrolidone dry type in conventional whisk of about 38,000 molecular weight and mix 20 minutes to obtain the mixture of homogeneous.Then in mixture, slowly add the degeneration dehydrated alcohol and continue and stirred 5 minutes.Blended wet compositions is crossed 16 mesh sieves and spend the night in drying at room temperature.Then, dried granule is crossed 16 mesh sieves and added the 0.10g magnesium stearate, all dry ingredient dry types were mixed 5 minutes.Said composition is about 35 by having of the poly(ethylene oxide) of 5,000,000 molecular weight of the lauric acid metformin of 93.0% weight, 5.0% weight, 1.0% weight, 000-40, and the magnesium stearate of the polyvinylpyrrolidone of 000 molecular weight and 1.0% weight is formed.

By being prepared as follows the promoting layer that comprises the osmopolymer hydrogel composition.At first, 58.67g is contained 7,000, the pharmaceutically receivable poly(ethylene oxide) of 000 molecular weight, 5gCarbopol  974P, 30g sodium chloride and 1g ferrum oxide are crossed 40 mesh sieves respectively.The hydroxypropyl emthylcellulose of the composition that sieves and 5g 9,200 molecular weight is mixed to obtain the mixture of homogeneous.Then, in mixture, slowly add 50mL degeneration dehydrated alcohol and continuation stirring 5 minutes.Then, add the 0.080g butylated hydroxytoluene and continue restir.The granule of prepared fresh crossed 20 mesh sieves and make it in dry 20 hours of room temperature (ambient temperature).Dry ingredient is crossed 20 mesh sieves and added the 0.25g magnesium stearate, all the components was mixed 5 minutes.Last compositions is made up of the poly(ethylene oxide) of 58.7% weight, the sodium chloride of 30.0% weight, the Carbopol  of 5.0% weight, the hydroxypropyl emthylcellulose of 5.0% weight, the ferrum oxide of 1.0% weight, the magnesium stearate of 0.25% weight and the butylated hydroxytoluene of 0.08% weight.

By being prepared as follows three layers of dosage form.At first, in stamping machine and mould, add 118mg metformin hydrochloride compositions and make firm by ramming, add 427mg lauric acid metformin compositions as the second layer and make firm by ramming again to mould then.Add the 272mg hydrogel composition then, in the diel of these three layers to 9/32 inch (0.714cm) diameter of compression stress lower compression of 1.0 tons (1000kg), form three layers of core (tablet) closely.

With composition by 80: thereby the 20wt/wt component ratio is dissolved in and makes 5.0% solid solution preparation semi-permeable wall forming composition in the acetone, the cellulose acetate with 39.8% acetyl content and 20.0% that said composition comprises 80.0% weight has the poly(ethylene oxide)-poly(propylene oxide) copolymer of 7680-9510 molecular weight.The solution vessel are placed in the tepidarium, quicken the dissolving of composition during this step.With the wall forming composition be injected into three layers of core around so that the semi-permeable wall of 93mg thickness to be provided.

Then, in the tri-layer tablets of semi-permeable wall, get out the outlet opening of 40mil (1.02mm), so that contacting of metformin layer and releasing device outside to be provided with laser.With this dosage form drying to remove any residual solvent and water.

Dosage form is placed on the external dissolution rate of measuring this dosage form in the sample fixer of metal gauze, on the USP VII type body lotion analyzer (bath indexer) of this holder attached to the water-bath that places 37 ℃ of steady temperatures.The aliquot of release medium is injected in the chromatographic system, determines that in each test interval medicine is released into the quantity in the mimic artificial gastric juice of medium (AGF).Test three kinds of dosage forms, its average dissolution rate is shown in Figure 13 B.

Embodiment 6

Contain the preparation of the dosage form of metformin-transhipment part complex

By being prepared as follows the dosage form shown in Figure 14 A-14C.Be used to prolong the unit dosage forms that metformin-laruate complex discharges by being prepared as follows.The metformin dosage that needs in metformin-laruate complex form is crossed the sieve of 40 silk screen/inches.The hydroxypropyl emthylcellulose that 20 grams is had the methoxyl content of hydroxypropyl content, 22% weight of 8% weight and number-average molecular weight 27,800 gram/moles is crossed the sieve of 100 silk screen/inches.With a certain size powder tumble mixed 5 minutes.In mixture, add dehydrated alcohol and stirring until forming wet group.With this wet sieve of rolling into a ball 20 silk screen/inches.With gained wet granular air dried overnight, and then cross 20 mesh sieves.2 gram tabletting magnesium stearate lubricants are crossed the sieve of 80 silk screen/inches.A certain size magnesium stearate is mixed in the dried granule to form last granule.

It is in 0.281 inch the die cavity that the final granule of 705mg part is placed on internal diameter.The pressure head of this part in 1 ton compressed to form vertical capsule-shaped tablets with the stamping machine of dark concave surface down.

With capsule place Tait Capsealer Machine (Tait Design and Machine Co., Manheim, Pa.) in, wherein three bands are stamped on each capsule.The raw material that forms band is ethylcellulose dispersion (Surelease , Colorcon, the West Point of 50% weight, Pa.) and the ethyl acrylate of 50% weight-methacrylate methyl ester (Eudragit  NE 30D, RohmPharma, Weiterstadt, Germany) mixture.These bands are as aqueous dispersion, and unnecessary water is removed in stream of warm air.The diameter of band is 2 millimeters.

Although the present invention is described with reference to specific embodiments, should be conspicuous to those skilled in the art not deviating from the various changes under the situation of the present invention and revising.

Claims (37)

1. material of being made up of metformin and transhipment part, described metformin and described transhipment partly form complex.

2. the material of claim 1, wherein said transhipment part was CH before complex forms ₃(C _nH _2n) fatty acid of COOH form, wherein n is 4-16.

3. the material of claim 2, wherein said fatty acid is capric acid or lauric acid.

4. compositions, it comprises

The complex of forming by metformin and transhipment part and

Pharmaceutically acceptable vehicle,

The absorption of wherein said compositions in lower gastrointestinal tract is at least 4 times of metformin hydrochloride.

5. the compositions of claim 4, wherein said transhipment part was CH before complex forms ₃(C _nH _2n) fatty acid of COOH form, wherein n is 4-16.

6. the compositions of claim 5, wherein said fatty acid is capric acid or lauric acid.

7. dosage form, it comprises the compositions of claim 4.

8. dosage form, it comprises the material of claim 1.

9. the dosage form of claim 8, wherein said dosage form is an osmotic dosage form.

10. the dosage form of claim 9, it comprises with the lower part: (i) promoting layer; The medicine layer that (ii) contains metformin-transhipment part complex; (iii) center on the semi-permeable wall that promoting layer and medicine layer provide; (iv) outlet.

11. the dosage form of claim 9, it comprises with the lower part: (i) semi-permeable wall that provides around the infiltration preparation that contains metformin-transhipment part complex, penetrating agent and osmopolymer; (ii) outlet.

12. the dosage form of claim 9, wherein said dosage form provide total daily dose of 500-2550mg.

13. an improvement that contains the dosage form of metformin or melbine salt, described improvement comprise the dosage form of being made up of the complex of metformin and transhipment part.

14. the improvement dosage form of claim 13, wherein said transhipment part was CH before complex forms ₃(C _nH _2n) fatty acid of COOH form, wherein n is 4-16.

15. the improvement dosage form of claim 14, wherein said fatty acid are capric acid or lauric acid.

16. a method for the treatment of patient's hyperglycemia, this method comprises:

Give the compositions of claim 4.

17. the method for claim 16, wherein said giving gives for per os.

18. a method for preparing metformin-transhipment part complex, this method comprises:

Metformin alkali is provided;

The transhipment part is provided;

Dielectric constant less than the solvent of water in the presence of, make metformin alkali and the combination of transhipment part;

Thereby it is described in conjunction with forming the complex of forming by metformin alkali and transhipment part.

19. the method for claim 18, wherein said combination are included in dielectric constant and contact in 1/2nd the solvent less than the dielectric constant of water at least.

20. the method for claim 19, wherein said solvent is selected from methanol, ethanol, acetone, benzene, dichloromethane and carbon tetrachloride.

21. a method of improving the metformin gastrointestinal absorption, this method comprises:

The complex of being made up of metformin and transhipment part is provided, and described complex is characterised in that tight ion pair key; With

Give the patient this complex.

22. the method for claim 21, the absorption of wherein said improvement comprises the absorption of the lower gastrointestinal tract of improvement.

23. the method for claim 21, the absorption of wherein said improvement comprise the upper gastrointestinal absorption of improvement.

24. a method for the treatment of the type ii diabetes patient, this method comprises:

Give the complex formed by metformin and transhipment part;

Give second kind of therapeutic agent.

25. the method for claim 24 wherein saidly gives second kind of therapeutic agent and comprises the second kind of therapeutic agent that gives antidiabetic medicine.

26. the method for claim 25 wherein saidly gives second kind of therapeutic agent and comprises and give inhibitors of dipeptidyl IV.

27. the method for claim 24, wherein said administration comprise the complex that gives metformin and fatty acid transhipment part, described fatty acid had CH before complex forms ₃(C _nH _2n) the COOH form, wherein n is 4-16.

28. the method for claim 27, wherein said fatty acid are capric acid or lauric acid.

29. the method for claim 24, the per os that comprises of wherein said complex gives complex.

30. the method for claim 27, wherein said per os give to finish by the complex in the orally give osmotic dosage form.

31. the method for claim 30, it comprises with the lower part: (i) promoting layer; The medicine layer that (ii) contains metformin-fatty acid complex; (iii) center on the semi-permeable wall that promoting layer and medicine layer provide; (iv) outlet.

32. the method for claim 30, it comprises: (i) semi-permeable wall that provides around the infiltration preparation that contains metformin-fatty acid complex, penetrating agent and osmopolymer; (ii) outlet.

33. the method for claim 29, wherein said dosage form provide total daily dose of 500-2550mg.

34. the method for claim 24, the giving of wherein said DPP IV inhibitor gives for per os.

35. a chemical compound that comprises metformin and transhipment part, described chemical compound prepares as follows: metformin alkali (i) is provided; The transhipment part (ii) is provided; (iii) in the presence of the solvent of dielectric constant, make metformin alkali and the combination of transhipment part less than the dielectric constant of water; Wherein said being combined between metformin alkali and the transhipment part forms by the associating complex of tight ion pair.

36. the chemical compound of claim 35, wherein said transhipment partly are CH ₃(C _nH _2n) fatty acid of COOH form, wherein n is 4-16.

37. the chemical compound of claim 36, wherein said fatty acid are capric acid or lauric acid.

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