CN1901881A - Compositions and dosage forms for enhanced absorption - Google Patents

Abstract

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

Description

The compositions and the dosage form that are used for enhanced absorption

Technical field

The present invention relates to the controlled delivery and the method, dosage form and the device that are used for this purpose of medicine.Particularly, the present invention relates to be used for the enhancing absorption of medical compounds and preparation, dosage form, method and the device of controlled delivery.

Background technology

In the drug development of routine, selecting dosage form (as alkali or salt) is benchmark to obtain the most stable dosage form on the one hand, is benchmark with the absorption maximum that is provided at gastrointestinal (G.I.) road on the other hand.Be designed to the release immediately of drug dose as the dosage form of most drug, dosage form be manufactured to be dissolved in the G.I. road fully and usually in the G.I. of small intestinal and large intestine environment (the about 5-7 of pH=) for highly dissociated, that is, highly charged.

Owing in last G.I. road, be used for the much bigger surface area of drug absorption, drug development also typically targeting be used for pharmaceutical dosage form in absorption of last G.I. road rather than the absorption of infra G.I. road.Following G.I. does not go up in the road existing microvillus in the G.I. road.Microvillares existence increases the surface area that is used for drug absorption widely, and the surface area in last G.I. road is 480 times of following G.I. road.The difference of upper and lower G.I. road cell characteristic also causes the molecule absorption of the difference in the infra G.I. road.

Fig. 1 illustrates that chemical compound passes two common approach of the transhipment of G.I. road epithelium.Each epithelial cell of being represented by 10a, 10b, 10c forms barrier cell along small intestinal and large intestine.Each cell is opened by aquaporin or tight the connection as connecting 12a, 12b branch.Passing the transhipment of epithelium is undertaken by transcellular pathway or is undertaken by the other approach of cell.Relate to chemical compound by the transcellular transport approach of arrow among Fig. 1 14 expression and pass moving of epithelial cell wall and epithelial cell body by passive diffusion or by carrier mediated transhipment.Paracellular shunt pathway relates to molecule by close-connected the moving between each cell, and is as shown in arrow 16.The other transhipment of cell specificity is lower, but has much bigger overall capacity, partly is because it takes place on the whole length in G.I. road.Yet, closely connect along the length in G.I. road and change, have close-connected effectively " compactness " gradient that from the near-end to the far-end, increases.Therefore, the duodenum in the last G.I. road is than the ileum in the last G.I. road easier " seepage ", and ileum is than the colon in the following G.I. road easier " seepage " (Knauf, people such as H., Klin.Wochenschr., 60 (19): 1191-1200 (1982)).

Because medicine typical time of staying in last G.I. road is about four to six hours, following G.I. absorbs relatively poor medicine and is absorbed by health in only four to six hours the time after oral absorption.Frequently, medically expectation all is present in patient's the blood flow for the medicine of usefulness in a whole day with constant relatively concentration.Show conventional medicine preparation realization this purpose that minimum following G.I. road absorbs in order to use, needs of patients is taken in medicine three to four times every day.The practical experience that the patient is brought inconvenience shows that this is not best therapeutic scheme.Therefore, expecting that this medicine is administered once every day can be implemented in long-term absorption in a whole day.

For constant dosage treatment is provided, conventional drug development has proposed many sustained release drug systems.This system works by the medicine payload that discharges them in the time expand section after the administration.Yet the Controlled Release System of these conventionally forms is invalid when medicine shows the minimum knot intestinal absorption.Because medicine only absorbs in last G.I. road and because the time of staying of medicine in last G.I. road has only four to six hours, the sustained release dosage form of proposition can not mean that health continuation absorption sustained release medicine after G.I. stop on four to six hours in dosage form discharges its payload after the time of staying in last G.I. the fact.But the medicine that is discharged by the sustained release dosage form after the G.I. road under dosage form enters is not absorbed usually but is discharged from health.

For this reason, attempted providing remedial measure.These attempt failing usually to provide gratifying result.

Therefore, need exploitation chemical compound, method and product, realizing previous unknown enhanced drug absorption, thereby in whole gastrointestinal tract, have high absorption.

Summary of the invention

In one aspect, the present invention relates to comprise the material of complex (complex), complex comprises drug moiety and transhipment part.

In yet another aspect, the present invention relates to the production method for compositions, it comprises: the drug moiety that ionic species is provided; The transhipment part of ionic species is provided; Drug moiety and transhipment part are merged in the presence of less than the solvent of the dielectric constant of water at dielectric constant, to form complex; With from the separated from solvent complex.

In one aspect, the present invention relates to Therapeutic Method, it comprises: the drug moiety that ionic species is provided; The transhipment part of ionic species is provided; Drug moiety and transhipment part are merged in the presence of less than the solvent of the dielectric constant of water at dielectric constant, to form complex; From the separated from solvent complex; With with isolating complex to the patient's administration that needs is arranged.

In yet another aspect, the present invention relates to improve the method for the absorption of drug moiety, it comprises: the complex of drug moiety with the transhipment part is provided; With with complex to the patient's administration that needs is arranged.

Description of drawings

The following drawings is not to draw in proportion, and it is used to illustrate multiple embodiments of the present invention.

Fig. 1 is gastrointestinal tract epithelial cell figure, illustrates that medicine passes two kinds of transporting pathway of G.I. tract epithelial cell.

Fig. 2 represents the figure of primary osmotic pump (elementary osmotic pump) dosage form.

Fig. 3 represents the figure of osmotic dosage form (osmotic dosage form).

Fig. 4 represents the figure of trilaminar osmotic dosage form.

Fig. 5 A-5C represents the figure of sustained release dosage form.

Fig. 6 represents the chemical constitution of metformin.

Fig. 7 is that the logarithm value of octanol/water partition coefficient of metformin hydrochloride is as the figure of the function of its pH.

Fig. 8 A represents to prepare the general synthetic reaction flow chart of metformin-transhipment part complex.

Fig. 8 B represents to prepare the general synthetic reaction flow chart of metformin-transhipment part complex, and wherein transhipment part comprises carboxyl.

Fig. 8 C represents to prepare the synthetic reaction flow chart of metformin-fatty acid complex.

Fig. 9 A-9D is for the physical mixture (Fig. 9 C) of metformin hydrochloride (Fig. 9 A), sodium laurate (Fig. 9 B) and metformin hydrochloride and sodium laurate and the HPLC spectrogram of metformin-laurate complex (Fig. 9 D).

Figure 10 A-10B be for metformin hydrochloride (circle), with the metformin (del) of amber acid radical complexation, with the metformin (square) of decanoate complexation, with the metformin (rhombus) of laurate complexation, with the metformin (triangle) of Petiolus Trachycarpi acid group complexation and with the metformin (octagonal) of oleic acid root complexation, with the electrical conductivity of little Siemens/cm (μ S/cm) expression as the percentage ratio of the functional arrangement (Figure 10 A) of metformin concentration and unionized medicine functional arrangement (Figure 10 B) as metformin concentration.

Figure 11 represents for metformin hydrochloride (circle) and metformin-laurate complex (rhombus), with described chemical compound to rat after the oral tube feed metformin plasma concentration (ng/mL) in rat as the time (hour) function.

Figure 12 is illustrated in and uses in flushing-ligation (flush-ligated) colon models, for metformin hydrochloride (circle), with the metformin (rhombus) of amber acid radical complexation, with the metformin (triangle) of Petiolus Trachycarpi acid group complexation, with the metformin (del) of oleic acid root complexation, with the metformin (square) of decanoate complexation and with the metformin (octagonal) of laurate complexation, the metformin plasma concentration (ng/mL) in rat as the time (hour) function.

Figure 13 is illustrated in the colon models of using flushing-ligation, and the bioavailability percentage ratio in rat plasma of physical mixture of metformin hydrochloride and sodium laurate (circle) and lauric acid metformin complex (square) is as the metformin dosage (function of mg alkali/kg).

Figure 14 for the colon models intravenous administration 2mg/kg metformin hydrochloride (triangle) that uses flushing-ligation afterwards with every Mus with 10mg dosed administration metformin hydrochloride (circle) or lauric acid metformin complex (rhombus) afterwards the plasma concentration of metformin alkali (ng/mL) as the time (hour) functional arrangement.

The metformin average rate of release (mg/ hour) that Figure 15 represents dosage form of the present invention as the time (hour) function.

Figure 16 A represents the structure of gabapentin.

Figure 16 B represents the chemical constitution of lyrica.

Figure 16 C represents to prepare the synthetic reaction flow chart of gabapentin-alkyl sulfate complex.

Figure 16 D represents to prepare the synthetic reaction flowchart illustrations of lyrica-alkyl sulfate complex.

Figure 17 A-17D is the physical mixture (loose ion pair) (Figure 17 C) of gabapentin (Figure 17 A), sodium lauryl sulfate (Figure 17 B), gabapentin and sodium lauryl sulfate and the FTIR scintigram of gabapentin-lauryl sulfate root complex (Figure 17 D).

Figure 18 represents the gabapentin (triangle) for intravenous administration and is administered into the gabapentin (circle) in the ligation colon and is administered into gabapentin-lauryl sulfate root complex (rhombus) in the ligation colon by intubation by intubation, the gabapentin plasma concentration (ng/mL) in rat as the time (hour) function.

Figure 19 A represent intravenous administration gabapentin (triangle) and with 5mg (circle), 10mg (square) and 20mg (rhombus) dosed administration to the gabapentin plasma concentration (ng/mL) in rat of duodenal gabapentin as the time (hour) function.

Figure 19 B represent intravenous administration gabapentin-lauryl sulfate root complex (triangle) and with 5mg (circle), 10mg (square) and 20mg (rhombus) dosed administration to the gabapentin plasma concentration (ng/mL) in rat of duodenal gabapentin-lauryl sulfate ester complex as the time (hour) function.

Figure 19 C is to the bioavailability (%) of gabapentin after the rat preduodenal administration functional arrangement as dosage with gabapentin (del) or gabapentin-lauryl sulfate root complex (circle).

Figure 20 A-20C represents to prepare the synthetic reaction flow chart of ferrum-fatty acid complex.

Figure 21 A-21D represents the structure of exemplary DPP IV inhibitor.

Describe in detail

Definition

By with reference to the following definition that provides herein, accompanying drawing with exemplary open the present invention may be better understood.

" composition " refers to one or more in the complex compound of the present invention, its randomly with the combination of other active medicine component, and randomly with the inactive ingredients combination, such as pharmaceutically useful carrier, excipient, suspending agent, surfactant, disintegrant, adhesive, diluent, lubricant, stabilizing agent, antioxidant, bleeding agent, colouring agent, plasticizer etc.

" complex compound " refers to comprise by the drug moiety of tight ion pair key (tight-ion pair bond) combination and the material of transhipment part. Can be by the difference of in octanol/water, distributing behavior that is characterized by following relational expression, with drug moiety-transhipment part complex compound with drug moiety and transport loose ion pair partly and differentiate:

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

Wherein:

Partition coefficient (apparent partition coefficient) D is for setting the drug moiety and the equilibrium concentration of all substances of transhipment part and the ratio of the equilibrium concentration of same substance in water (deionized water) in capryl alcohol under the pH (typically being about pH=5.0 to about pH=7.0) under 25 ℃.Complex for drug moiety of instructing preparation according to this paper and transhipment part is measured Log D (complex).Physical mixture in deionized water is measured Log D (loose ion pair) to drug moiety and transhipment part.Log D can with experimental technique measure or for loose ion pair can use the prediction of commercially available software kit (as, ChemSilico, Inc., Advanced Chemistry Development Inc).

For example, can measure the octanol/water apparent partition coefficient (D=C of the complex (under 25 ℃, in deionized water) of supposition _{Capryl alcohol}/ C _Water), and its 1: 1 (mol/mol) physical mixture with the transhipment in deionized water under 25 ℃ part and drug moiety compared.If the complex (D of supposition ⁺T-) Log D and D ⁺‖ T ^-The Log D of 1: 1 (mol/mol) physical mixture between difference more than or equal to 0.15, confirm that then the complex of supposition is a complex of the present invention.

In preferred embodiments, Δ Log D 〉=0.20, more preferably Δ Log D 〉=0.25, more preferably Δ Log D 〉=0.35.

Term used herein " DPP IV " is meant DPP IV (EC 3.4.14.5), has another name called CD26." DPP IV inhibitor " is meant the molecule that shows the enzymatic activity that suppresses DPP-IV, yet this molecule also can have the activity of inhibition to other DPP enzyme.DPP IV inhibitor keeps the effect of substrate molecule, and substrate molecule includes but not limited to GLP-1, GIP, peptide histidine methionine, P material, neuropeptide tyrosine and comprises other molecule of alanine or proline residue usually in the second amino terminal position.In the context of the present invention, " DPP IV inhibitor " also comprises its active metabolite and prodrug.Exemplary DPP IV inhibitor comprises 1-[[(3-hydroxyl-1-adamantyl) amino] acetyl group]-2-cyano group-(S)-pyrrolidine; 1-{N-(5,6-dichloro nicotinoyl)-L-ornithyl]-3,3-difluoro pyrrolidine hydrochloride; With disclosed chemical compound in WO 2004032836, WO2004/024184, WO03/000250, it all is merged in this paper as a reference; With disclosed chemical compound in for example WO98/19998, DE19616 486 Al, WO00/34241, WO95/15309, WO01/72290, WO01/52825, WO93/10127, WO99/25719, WO99/38501, WO99/46272, WO99/67278 and WO99/67279.

" dosage form " is meant the Pharmaceutical composition that is in medium, carrier, excipient or the device that is fit to patient's administration that needs are arranged.

" medicine " or " drug moiety " is meant the residue that the medicine of some pharmacotoxicological effect (drug), chemical compound or medicament (agent) or this medicine, chemical compound or medicament are provided to the main body administration time.In order to form complex, medicine comprises acidity, alkalescence or zwitterionic structural elements, or comprises the residual construction unit of acidity, alkalescence or amphion.In embodiments of the invention, the drug moiety and the transhipment part complexation that comprises alkaline structure unit or alkaline residual construction unit that comprise acid construction unit or acid residual construction unit.In embodiments of the invention, the drug moiety and the transhipment part complexation that comprises acid construction unit or acid residual construction unit that comprise alkaline structure unit or alkaline residual construction unit.In embodiments of the invention, the drug moiety that comprises zwitterionic structural elements or the residual construction unit of amphion with comprise acidity or the alkaline structure unit is acid or the transhipment part complexation of alkaline residual construction unit.In one embodiment, the pKa of acid construction unit or acid residual construction unit is less than about 7.0, preferably less than about 6.0.In one embodiment, the pKa of alkaline structure unit or alkaline residual construction unit is preferably greater than about 8.0 greater than about 7.0.The residual construction unit of zwitterionic structural elements or amphion, form complex according to how with the transhipment part and decide, analyze according to their alkaline structure unit or alkaline residual construction unit or their acid construction unit or acid residual construction units separately.

" fatty acid " is meant general formula CH ₃(C _nH _x) COOH organic acid any, wherein hydrocarbon chain be saturated (x=2n, as Palmic acid, CH ₃C ₁₄H ₂₈COOH) or undersaturated (for monounsaturated, x=2n-2, as oleic acid, CH ₃C ₁₆H ₃₀COOH).

" gabapentin " is meant 1-(amino methyl) Cyclohexaneacetic acid, and its molecular formula is C ₉H ₁₇NO ₂, molecular weight is 171.24.It can trade name Neurontin ^And be purchased, its structure is as shown in Figure 16 A.

" intestinal " or " gastrointestinal tract (G.I.) road " is meant the digestive tract part that extends to anus from the lower ending opening of stomach, and it comprises small intestinal (duodenum, jejunum and ileum) and large intestine (ascending colon, transverse colon, descending colon, sigmoid colon and rectum).

" loose ion pair " is meant under physiology pH and in aqueous environment and can be easily can be present in the ion pair of loose pairing in the loose ion pair environment or free ions exchange with other.Can use isotopic labeling and NMR or mass spectrometry under physiology pH and in the aqueous environment, to find loose ion pair with experimental technique by showing member in the loose ion pair and another ionic exchange.Can also under physiology pH with in the aqueous environment, show separating of ion pair and find loose ion pair by using reversed-phase HPLC with experimental technique.Loose ion pair also can be described as " physical mixture " and for forming by in medium ion pair physically being mixed.

" lower gastrointestinal tract " or " following G.I. road " is meant large intestine.

" patient " is meant the animal that needs treatment to interfere, and preferred mammal is more preferably human.

" Pharmaceutical composition " is meant the compositions that is suitable for patient's administration that needs are arranged.

" lyrica " is meant (S)-(+)-3-(amino methyl)-5-methylhexanoic acid).Lyrica also refers to (S)-3-isobutyl group GABA or CI-1008 in the literature.The structure of lyrica is as shown in Figure 16 B.

" residual construction unit " is meant by with interactions such as another chemical compound, chemical group, ion, atom or reaction and adorned construction unit.For example, carboxyl structure unit (COOH) interacts with sodium and forms the sodium carboxylate, and then COO-is residual construction unit.

" solvent " is meant wherein can be fully or partly dissolve the material of various other materials.In the present invention, preferred solvent comprises aqueous solvent and the dielectric constant solvent less than water.The dielectric constant of preferred solvent is less than water.Dielectric constant is measuring of solvent polarity, and the dielectric constant of exemplary solvent is as shown in table 1.

Table 1: the characteristic 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 sulfoxide (DMSO)	189	47.2
Hexane	69	2.02
			Benzene	80	2.28
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 polar aprotic solvents, have the hydrogen atom that is connected with the elecrtonegativity atom, and the elecrtonegativity atom is generally oxygen.Solvent acetone, ethyl acetate, methyl ethyl ketone and acetonitrile are dipolar aprotic solvent, and in one embodiment, preferably it is used to form complex of the present invention.Dipolar aprotic solvent does not contain the OH key, but has the big bond dipoles by means of the multiple bond between carbon and oxygen or the nitrogen usually.Most of dipolar aprotic solvents comprise the two keys of C-O.Dielectric constant is particularly useful for forming complex of the present invention less than the solvent of water.The low twice at least of the permittivity ratio water of the dipolar aprotic solvent shown in the table 1, and its dipole moment near or greater than water.

" construction unit " is meant that (i) is as a chemical group more macromolecular part and that (ii) have the chemical functionality that can distinguish.For example, acidic-group on the chemical compound and basic group are construction unit.

" material " is meant the chemical entities with special characteristic.

" closely ion pair " is meant under physiology pH and in aqueous environment and can not be easily may be present in the ion pair of loose pairing in the environment of tight ion pair or free ions exchange with other.Can use isotopic labeling and NMR or mass spectrometry not to have the member of tight ion pair and another ionic exchange and find tight ion pair by demonstration under physiology pH and in the aqueous environment with experimental technique.Can also under physiology pH with in the aqueous environment, not have separating of ion pair and find tight ion pair by using reversed-phase HPLC with experimental technique by showing.

" transhipment part " is meant the residue that can form the chemical compound of complex with drug moiety or form the chemical compound of complex with drug moiety, wherein, compares with complexation medicine not, and the transhipment part is used to improve the transhipment of the transepithelial tissue of medicine.Transhipment partly comprises hydrophobic parts and acid, alkaline or zwitterionic structural elements, or acid, alkaline or the residual construction unit of amphion.In preferred embodiments, hydrophobic parts comprises hydrocarbon chain.In one embodiment, the pKa of alkaline structure unit or alkaline residual construction unit is preferably greater than about 8.0 greater than about 7.0.The residual construction unit of zwitterionic structural elements or amphion according to how to form complex with drug moiety is decided, and analyzes according to their alkaline structure unit or alkaline residual construction unit or their acid construction unit or acid residual construction units separately.

In a more preferred embodiment, the transhipment part comprises pharmaceutically useful acid, includes but not limited to carboxylic acid and salt thereof.In embodiments, transhipment part comprises fatty acid or its salt, benzenesulfonic acid or its salt, benzoic acid or its salt, fumaric acid or its salt or salicylic acid or its salt.In preferred embodiments, fatty acid or its salt comprise 6 to 18 carbon atoms (C6-C18), more preferably 8 to 16 carbon atoms (C8-C16), more preferably 10 to 14 carbon atoms (C10-C14), most preferably 12 carbon atoms (C12).

In a more preferred embodiment, the transhipment part comprises alkyl sulfate (saturated or undersaturated) and salt thereof, as potassium, magnesium and sodium salt, specifically comprises sodium octyl sulfate, sodium decyl sulfate, sodium lauryl sulfate and sodium tetradecyl sulfate.In preferred embodiments, alkyl sulfate or its salt comprise 6 to 18 carbon atoms (C6-C18), more preferably 8 to 16 carbon atoms (C8-C16), more preferably 10 to 14 carbon atoms (C10-C14), most preferably 12 carbon atoms (C12).Other anion surfactant also is available.

In another preferred embodiment, the transhipment part comprises pharmaceutically useful primary amine or its salt, is specially Armeen (saturated and unsaturated) or its salt, diethanolamine, ethylenediamine, procaine, choline, trometamol, meglumine, magnesium, aluminum, calcium, zinc, alkyl trimethyl ammonium hydroxide, alkyl trimethyl ammonium bromide, benzalkonium chloride and benzethonium chloride.Other comprises that the pharmaceutically useful chemical compound of secondary amine or tertiary amine and salt and cationic surfactant thereof also are available.

" upper gastrointestinal " or " going up the G.I. road " is meant the gastrointestinal tract part that comprises the harmonization of the stomach small intestinal.

The formation of complex and sign

Find surprisingly, absorb the relatively poor many common drug moiety of feature, in case transport the part complexation with some, just show remarkable enhanced absorption, particularly descend the G.I. road to absorb, the G.I. road absorbs though also can strengthen upward.More surprisingly, complex of the present invention is compared with comprising the ionic loose ion pair identical with complex of the present invention (promptly not form complexed), shows the absorption of improvement.

These beyond thought results have been applied to the drug moiety of many classifications, have comprised drug moiety with alkaline structure unit or alkaline residual construction unit.The example of using this drug moiety of the present invention comprises metformin, ferrum, ranitidine hydrochloride, cetirizine hydrochloride, Sumatriptan Succinate salt, oxycodone hydrochloride, tramadol hydrochloride, hydrochloric acid ciprofaxicin, DPP IV (DPP IV) inhibitor and cimetidine hydrochloride.Also beyond thought result of the present invention is applied to comprise the drug moiety of zwitterionic structural elements or the residual construction unit of amphion.The example of this drug moiety that the present invention uses is gabapentin and levodopa.Also beyond thought result of the present invention is applied to comprise the drug moiety of acid construction unit or acid residual construction unit.The example of this drug moiety that the present invention uses is a RABEPRAZOLE SODIUM.

The embodiment of the preferred embodiments of the invention below is provided.What provide is wherein to form the complex with metformin, ferrum and gabapentin with embodiment preferred.

Though do not wish to be bound by the concrete understanding to mechanism, the present inventor provides following reason:

When loose ion pair is placed in the polar solvent environment, suppose that polar solvent molecule itself will be inserted in the occupied space of ionic bond, thereby with bonded ion separately.Can around free ion, form the solvation shell, comprise that static is incorporated into the polar solvent molecule of free ion.This then solvation shell prevents that free ion and another free ion from forming any bonding except that loose ion pair ionic bond.Have multiple counter ion counterionsl gegenions to be present in the situation in the polar solvent therein, any loose ion pair that provides can be to the counter ion counterionsl gegenions competing phase to sensitivity.

This polarity (being expressed as the dielectric constant of solvent) that acts on is more obvious when increasing.According to Coulomb's law, have electric charge (q1) and two ions separating with distance (r) (q2) and in the medium of dielectric constant (ε) between power be:

$F=-\frac{q_1{q}_2}{{4\mathrm{\π\ϵ}}_0{\mathrm{\ϵr}}^2}$ (equation 2)

ε wherein _oBe permittivity of vacuum.This equation is represented the importance of dielectric constant (6) for the stability of the loose ion pair in solution.In the aqueous solution with high-k (ε=80), if hydrone is attacked ionic bond and with the ion of oppositely charged separately, then electrostatic attraction significantly reduces.

Therefore, in case be present in ionic bond near, then the high dielectric constant solvent molecule will be attacked key and its destruction the most at last.Unconjugated then ion freely moves in solvent everywhere.These property definitions loose ion pair.

Closely ion pair is different from loose ion pair on forming, and therefore has the character different with loose ion pair.Closely the polar solvent molecule number in the bonding space forms ion pair between two ions by reducing.This makes ion closely move together, produces than the remarkable stronger key of loose ion pair key, but thinks that still it is an ionic bond.As more abundant disclosed in this article, use the polarity solvent lower to obtain tight ion pair holding back with the polar solvent between the minimizing ion than water.

For loose ion pair and the closely other discussion of ion pair, referring to people such as D.Quintanar-Guerrero, Applications of the Ion Pair Concept to HydrophilicSubstances with Special Emphasis on Peptides, Pharm.Res.14 (2): 119-127 (1997).

Can also use chromatography to observe loose ion pair and the tight difference between the ion pair.Use reverse-phase chromatography, can be under the condition that can not separate tight ion pair easily separately with loose ion pair.

Also can make that key of the present invention is stronger by selecting cation and anion intensity relative to each other.For example, solvent is in the situation of water therein, can select cation (alkali) and anion (acid) to make and attract more consumingly each other.If wish more weak key, then can select more weak attraction.

The first approximation model of biomembrane part as lipid bilayer can be striden across the molecule transhipment of this film with understanding.Because disadvantageous distribution, the transhipment (opposite with active transport albumen etc.) that strides across the lipid bilayer part is disadvantageous for ion.Many research worker think that this ionic charging neutrality can strengthen transmembrane transport.

In " ion pair " theory, thus ionic drug moiety and transhipment part counter ion counterionsl gegenions pairing " hiding " electric charge and the easier lipid bilayer that moves through of ion pair that obtains.This method has caused great concern and research, particularly strides across the absorption of enterocyte about the medicine that strengthens oral administration.

Though ion pair causes a large amount of concerns and research, it does not obtain than ten-strike all the time.For example, find the ion pair of two antiviral compounds, be owing to the influence of ion pair to transcellular transport, not equal to be owing to the influence to the monolayer integrity, and produce the absorption that increases.The author infers, because other ionic competition of the interior system discovery of body may be eliminated the beneficial effect of counter ion counterionsl gegenions, the formation of ion pair is not the very effective strategy that strengthens charged hydrophilic compounds transepithelial transhipment.People such as J.Van Gelder, " Evaluation of thePotential of Ion Pair Formation to Improve the Oral Absorption of twoPotent Antiviral Compounds; AMD3100 and PMPA ", Int.J.ofPharmaceutics 186:127-136 (1999).Other author notices and uses the absorption experiment of ion pair always not work with clear and definite mechanism.D.Quintanar-Guerrero etc., Applications of the Ion Pair Concept to Hydrophilic Substances withSpecial Emphasis on Peptides, Pharm.Res.14 (2): 119-127 (1997).

The present inventor finds that unexpectedly the problem of these ion pair absorption experiment is that they are to use loose ion pair rather than tight ion pair to carry out.In fact, the disclosed many ion pair absorption experiment in this area are not distinguished loose ion pair and tight ion pair clearly.Those skilled in the art must be clear, and investigating disclosed ion pair production method disclosed by reality is loose ion pair, and what notice that this disclosed production method relates to is loose ion pair rather than tight ion pair.Loose ion pair is relative with the fracture of the bonded ionic bond of loose ion pair responsive to (as the water mediation) of counter ion counterionsl gegenions competition and solvent mediation.Therefore, when the drug moiety of ion pair arrived the enterocyte membranous wall, it may be combined in the loose ion pair with the transhipment part or may not be combined in the loose ion pair with the transhipment part.Near the chance that ion pair is present in the membranous wall is depending on two kinds of independent ionic local concentrations to a greater extent than maintenance ion ionic bond together.When they lack combined two parts during near the enterocyte membranous wall, the absorption rate of the drug moiety of complexation may not be subjected to the transhipment some effects of not complexation.Therefore, compare with individually dosed drug moiety, loose ion pair only produces limited influence to absorbing.

By contrast, complex of the present invention has more stable combination in the presence of polar solvent such as water.Therefore, the present inventor's inference, by forming complex, drug moiety and transhipment part more may be combined into ion pair key form during near membranous wall at them.The electric charge that this combination will increase them is hidden and makes the easier chance that moves through cell membrane of the ion pair that obtains.

In one embodiment, complex comprises the tight ion pair key between drug moiety and the transhipment part.As discussing herein, closely the ion pair key is more stable than loose ion pair key, is combined into the probability of ion pair thereby increase drug moiety and transhipment part during near membranous wall at them.The electric charge that this combination will increase them is hidden and makes the easier chance that moves through cell membrane of tight ion pair bonding complex.

It is pointed out that complex of the present invention can improve absorption by the G.I. road with respect to the drug moiety of not complexation, and G.I. road down just, because complex is intended to improve usually the transcellular transport in the infra G.I. road just.For example, if drug moiety is the proteic substrate of active transport that is used for mainly being present in the G.I. road, then may be still the substrate that is used for those transport proteins by the complex that drug moiety forms.Therefore, total transhipment can be transhipment flux that transport protein realizes and adds summation by the transcellular transport of improvement provided by the invention.In one embodiment, complex of the present invention be provided in the G.I. road, in the infra G.I. road and the absorption of the improvement in last G.I. road and following G.I. road.

Complex of the present invention can be made by multiple medicine and transhipment part.Generally speaking, at first select drug moiety, select suitable transhipment part then to form complex of the present invention.Those skilled in the art can consider many factors when selecting to transport part, include but not limited to transport toxicity partly and toleration, the construction unit of drug moiety or the polarity of construction unit residue, construction unit or the intensity of construction unit residue, the construction unit of transhipment part or intensity, the transhipment possible treatment benefit partly of construction unit residue of drug moiety.In some preferred embodiment, the hydrophobic parts of transhipment part comprises hydrophobic chain, more preferably alkyl chain.This alkyl chain can help lend some impetus to the stability of complex by the attack of spatially protecting ionic bond to avoid polar solvent molecule.

In preferred embodiments, the transhipment part comprises alkyl sulfate or its salt with 6 to 18 carbon atoms (C6-C18), more preferably 8 to 16 carbon atoms (C8-C16), more preferably 10 to 14 carbon atoms (C10-C14), most preferably 12 carbon atoms (C12).In other preferred embodiment, the transhipment part comprises fatty acid or its salt with 6 to 18 carbon atoms (C6-C18), more preferably 8 to 16 carbon atoms (C8-C16), more preferably 10 to 14 carbon atoms (C10-C14), most preferably 12 carbon atoms (C12).

Complex of the present invention can be combined in the multiple compositions, particularly in the Pharmaceutical composition.In one embodiment, the present invention includes compositions, it comprises complex of the present invention and pharmaceutically suitable carrier.In another embodiment, the present invention includes Pharmaceutical composition, it comprises complex of the present invention and pharmaceutically suitable carrier.The complex in the compositions of the present invention and the amount of other component, Pharmaceutical composition and dosage form can be by those skilled in the art according to pharmacology and similar requirement decisions.The preparation of this compositions can be carried out according to the pharmacy practice of routine, comprises grinding, mixes, extrudes, compresses, coating etc.

Complex of the present invention can be according to following Common Criteria production.Can use other strategy, such as for the illustrational strategy of disclosed iron complex in following examples.

At first, whether the needs assessment drug moiety comprises the acid construction unit or the acid residual construction unit of the part that is used to form complex (closely ion pair key).If comprise, then whether be acidic residues or sour residue to the next one if being evaluated as construction unit.If there is sour residue, then next step is for determining whether it is strong acid or faintly acid residue." weak acid " is for having less than about 10 ^-4The chemical compound of acidolysis constant.Usually, as used in this article, weak acid is for forming the chemical compound of gentle acid solution when soluble in water, that is, the pH value of solution is about 3-6.Exemplary weak acid comprises formic acid, acetic acid, propanoic acid, butanoic acid, valeric acid and replacement form thereof." strong acid " typically refers to the chemical compound that has greater than 1 acidolysis constant.If residue is characterized as being strong acid, then can use the ion-exchange treatment drug moiety to obtain the drug moiety of sour form, use conventional chemical technology that it is separated then.In one embodiment, the solvent that uses in ion exchange process comprises the mixture of water and organic solvent.If residue is faintly acid residue, then can use the pH titration to handle drug moiety, to reduce the drug moiety that environment pH obtains sour form, use conventional chemical technology that it is separated from aqueous medium then.

Then with the drug moiety of sour form, no matter initially exist as acid construction unit or the acid residual construction unit handled as described herein with the drug moiety that obtains sour form, in the presence of the low solvent of permittivity ratio water with transhipment part (its can its alkaline form exist) reaction.Suitable transhipment partly comprise disclosed herein those, and preferably include cationic surfactant or amine and salt thereof.Then with complex from separated from solvent.

If construction unit be alkalescence or alkaline residue, then next step is whether measure it be highly basic and weakly alkaline residue.Usually and as used in this article, weak base is for forming the chemical compound of gentle alkaline solution, the i.e. solution of the about 8-11 of pH value when soluble in water." highly basic " typically refers at the dissociative alkali compounds of aqueous solution camber.If residue is alkaline residue, then can use the ion-exchange treatment drug moiety, to obtain the drug moiety of alkali form, use conventional chemical technology that it is separated then.In one embodiment, the solvent that uses in ion exchange process comprises the mixture of water and organic solvent.If residue is weakly alkaline residue, then can use the pH titration to handle drug moiety, to improve environment pH, obtain the drug moiety of alkali form, use conventional chemical technology that it is separated from aqueous medium then.

Then with the drug moiety of alkali form, the alkaline residue construction unit that no matter initially exists as the alkaline structure unit or handle as described herein with the drug moiety that obtains the alkali form exists, subsequently in the presence of the low solvent of permittivity ratio water with transhipment part (its can its sour form exist) reaction.Suitable transhipment partly comprise disclosed herein those, and preferably include fatty acid and salt, anion surfactant or comprise other pharmaceutical excipient of carboxyl.Then with complex from separated from solvent.

If construction unit is amphion or amphion residue, then next step determines that acidic-group or basic group will form complex with the complementary ion on the transhipment part.Can the group sealing of complex will do not formed by combination and transhipment part.Seal non-binding construction unit or residual construction unit preferable methods and be the pH that regulates environment, make the not ionizing of non-binding construction unit.For example, in order to seal acid construction unit, reduce environment pH, make the not ionizing of acid construction unit, but the ionizing of alkaline structure unit.In order to seal the alkaline structure unit, improve pH, make alkaline structure not ionizing of unit but acid construction unit ionizing.In case the desired results unit is closed, the separate drug part, then in the presence of the low solvent of permittivity ratio water with its with the transhipment partial reaction.Then with complex from separated from solvent.

In the selectivity scheme of zwitterionic structural elements or the residual construction unit of amphion, use ion-exchange treatment transhipment part, to obtain transporting the sour form and the alkali form of part, depend on that acidic-group still is that basic group will be and the group of transporting the complementary ion formation complex on the part.Can the group sealing of complex will do not formed by combination and transhipment part.The sour form of transhipment part or the ionized form of alkali form and drug moiety are reacted, to form complex in water-bearing media or water-bearing media and the mixture of dielectric constant less than the solvent of water.Use then conventional chemical technology with complex from aqueous medium or mixture separation.

In the selectivity scheme, can utilize the different dissolubilities of the drug moiety and the counter ion counterionsl gegenions of transhipment part.For example, if the loose ion pair that is made of counter ion counterionsl gegenions is water insoluble, then it separates out precipitation, stays drug moiety and transhipment part in solution.Can form complex then, or with the solvent extraction of dielectric constant less than water.This tactful example is provided as the part of following ferrum embodiment.

Can select different solvents to be used for the present invention.Choice of Solvent can be based in part on the drug moiety and/or the transhipment physical characteristic partly that will be dissolved in wherein.Exemplary solvent is a methanol; Other solvent also is suitable.For example, fatty acid dissolves in chloroform, benzene, cyclohexane extraction, ethanol (95%), acetic acid and the acetone.Capric acid, lauric acid, myristic acid, Palmic acid and the stearic acid dissolubility (being expressed as g/L) in these solvents is represented in table 2.

Fatty acid dissolubility (G/L) under 20 ℃ in the table 2

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, the solvent that is used to form complex is the solvent of dielectric constant less than water, and is preferably than the little twice at least of dielectric constant of water, more preferably little at least three times than the dielectric constant of water.

Can be based in part on solvent/interaction of molecules selective solvent, particularly low dielectric solvent that wherein exists with form of mixtures is mutually and in the embodiment of water.Preferred solvent not with drug moiety or transhipment partial reaction, and after forming complex relatively easily with complex separation.Compare with the hydrophobicity of complex, the relative hydrophilic of solvent also is important.Compare with the hydrophobicity of complex, if solvent is too hydrophilic, then complex can not leave water and goes forward side by side into solvent phase.Complex needs to enter low dielectric solvent phase (if existence) after forming, but free ions (having quite high polarity) preferably is excluded outside low dielectric solvent phase (if existence).

If complex is a precipitate, then by the isolated by filtration complex, and with its washing and drying.If the complex dissolving, then can use one or more methods: (1) is evaporating solvent under vacuum condition, (2) crystallization, or (3) solvent extraction is evaporated subsequently.Can carry out the condition of these operations by those skilled in the art's optimization.

Exemplary dosage form and usage

Can be with complex of the present invention to the patient's administration that needs be arranged.In embodiments, be configured to can be to there being the dosage form of the patient's administration that needs for complex of the present invention.In preferred embodiments, complex is formulated as the compositions comprising dosage form, more preferably Pharmaceutical composition.

Described herein complex is provided in the enhanced absorption speed in the G.I. road, particularly infra G.I. road.The colon of the dosage form of the complex of description use now and the increase of Therapeutic Method and complex absorbs.Should be appreciated that dosage form as described below is exemplary.

There is multiple dosage form to be suitable for using with complex of the present invention.Owing to realized that by complex enhanced down G.I. road absorbs, provide allow dosed administration once a day with realize at least about 12 hours, preferably at least about 15 hours, more preferably at least about 18 hours, more preferably at least about the dosage form of 20 hours therapeutic efficacy.Dosage form can be according to any design construction and the preparation of the drug moiety of sending required dosage.Usually, dosage form be Orally-administrable and its size be suitable for being configured as conventional tablet or capsule.According to a kind of dosage form of producing Orally-administrable in the multiple distinct methods.For example, dosage form can be produced for diffusion system, as depot device or matrix type device; Digestion series is as the digestion series (for example comprising " trace is pill (tiny timepill) regularly " and globule) and the substrate digestion series of capsule envelope; And the combination of diffusion/digestion series and ion exchange resin system, as Remington ' s Pharmaceutical Sciences, the 18 edition, 1682-1685 page or leaf (1990) is described.

Important consideration is the physical state of the complex that will be sent by dosage form in the practice of the present invention.In certain embodiments, complex of the present invention can be sticks with paste attitude or liquid state, and solid dosage forms may not be suitable for practice of the present invention in such cases.In this case, should use the dosage form that to send paste attitude or liquid.Perhaps, in certain embodiments, can use the fusing point of different transhipment parts, thereby make complex of the present invention more likely exist with solid-state with the raising material.

The object lesson that is applicable to dosage form of the present invention is an osmotic dosage form.Usually, osmotic dosage form does not allow medicine or permeability reagent (if existence) freely to spread at least in part by allowing fluid freely to spread semi-permeable wall utilizes osmotic pressure to produce driving force, is used for fluid is drawn into the chamber of formation.Therefore the advantage of osmosis system is that the non-pH of being operating as of they is dependent, keeps by the determined speed of osmotic pressure in during whole prolongation, even also be like this by gastrointestinal tract in dosage form when running into the different microenvironment with remarkable different pH value.At Santus and Baker, " Osmotic drug delivery:a review of thepatent literature " finds among the Journal of Controlled Release, 35:1-21 (1995) to the summary of this dosage form.Osmotic dosage form is also in following United States Patent (USP) 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, describe in detail in 397 and 5,156,850, each patent is all incorporated into this paper as a reference in full.

The exemplary dosage form that is known as the primary osmotic pump dosage form in the art as shown in Figure 2.Dosage form 20 shown in the cutaway view is also referred to as primary osmotic pump, and it comprises the semipermeable wall 22 of encirclement and seal inner chamber 24.Inner room comprises the one pack system layer that is called medicine layer 26 herein, and it comprises the complex 28 with the mixed with excipients of selecting.Excipient is suitable for providing the permeability active gradient, and the fluid of the environment that is used to attract to come from the outside is by wall 22 and be used for forming when fluid infiltrates the complex preparation that can send.Excipient can comprise suitable suspending agent, is also referred to as pharmaceutical carrier 30, binding agent 32, lubricant 34 herein and is called as the osmotically active agent 36 of penetrant (osmagent).The exemplary materials of each in these components provides following.

The semipermeable wall 22 of osmotic dosage form can see through outside fluid such as water and biological fluid, but can not see through the component in the inner room basically.Can be used for forming the difficult basically erosion of material of wall and in the life span of dosage form, being insoluble to biological fluid basically.The typical polymers that is used to form semipermeable wall comprises homopolymer and copolymer, as cellulose esters, cellulose ether and cellulose esters-ether.Flux regulator and wall can be formed material mixing, to regulate the fluid permeability of wall.For example, the remarkable reagent that increases of permeability that produces fluid such as water often is hydrophilic basically, and significantly reduced those of permeability of generation water are essentially hydrophobic.Exemplary flux regulator comprises the polyester of polyhydric alcohol, poly-alkane glycol, ployalkylene glycol, alkylene glycol etc.

In operation, osmotic gradient owing to the existence of osmotically active agent in wall 22 both sides causes that gastric juice is passed through wall by infiltration, make the medicine layer swelling, and the complex preparation (as solution, suspension, slurry or other flowable composition) that can send in interior indoor formation.Along with fluid continues to enter inner room, the complex preparation that can send is released by exporting 38.Even along with pharmaceutical preparation is discharged from dosage form, fluid continues to be inhaled in the inner room, thereby promote lasting release.Like this, complex of the present invention is to continue and successive mode discharges in the time expand section.

Fig. 3 is the sketch map of another exemplary osmotic dosage forms.Such dosage form is at United States Patent (USP) 4,612, describes in detail in 008,5,082,668 and 5,091,190, and it all is merged in this paper as a reference.Briefly, the dosage form 40 shown in the cutaway view has semipermeable wall 42, and it defines inner room 44.Inner room 44 comprises double-deck compressed core, and double-deck compressed core comprises medicine layer 46 and push layer 48.As described below, push layer 48 is the set of displacements compound, and it is arranged in the dosage form, makes that along with the expansion of push layer in use, the material that forms medicine layer is discharged from dosage form by one or more outlet openings such as outlet opening 50.Push layer can be arranged as shown in Figure 3 make layered arrangement contact medicine layer, perhaps push layer can have one or more interposed layer that push layer and medicine layer are separated.

Medicine layer 46 comprises the complex with the mixed with excipients of selecting, the excipient of selection such as above with reference to Fig. 2 discussed those.Exemplary dosage form can have comprise complex, as poly-(oxirane) of carrier, as the sodium chloride of penetrant, as the hydroxypropyl methylcellulose of binding agent with as the medicine layer of the magnesium stearate of lubricant.

Push layer 48 comprises the osmotically active component, and as being called one or more polymer of osmopolymer (osmopolymer) in the art, it draws aqueous fluid or biofluid and swelling.Osmopolymer is expandable hydrophilic polymer, and itself and water and aqueous biological fluids interact and swelling or expand into very high degree, show 2-50 volumetric expansion doubly usually.Osmopolymer can be uncrosslinked or crosslinked, and in preferred embodiments, osmopolymer is lightly crosslinked at least, is used in use producing derivatized polymers very big and that tangle, easily to discharge dosage form.Can be used as in the list of references of example when the foregoing detailed description osmotic dosage form of polymer of osmopolymer provides.Typical osmopolymer is for gathering (alkylene oxide) as poly-(oxirane) and poly-(carboxymethyl cellulose alkali), and wherein alkali is sodium, potassium or lithium.Also can in push layer, comprise other excipient such as binding agent, lubricant, antioxidant and coloring agent.In use, along with fluid is drawn by semipermeable wall, the osmopolymer swelling also promotes medicine layer, to cause that medicine is via the release of outlet opening from dosage form.

Push layer can also comprise the component that is called as binding agent, it typically is cellulose or vinyl class in polymer, as poly-n-vinylamide, poly-n-vinyl acetamide, poly-(vinyl pyrrolidone), poly-n-vinyl caprolactone, poly-n-vinyl-5-N-methyl-2-2-pyrrolidone N-etc.Push layer can also comprise lubricant such as sodium stearate or magnesium stearate and be used for the antioxidant of constituents for suppressing oxidation.Representative antioxidants includes but not limited to the mixture and the butylated hydroxytoluene of ascorbic acid, anti-bad blood acyl cetylate, butylated hydroxyanisole, 2-and 3-tertiary butyl-4-hydroxy methoxybenzene.

Also penetrant can be combined in the medicine layer and/or push layer of osmotic dosage form.The osmotically active gradient of striding semipermeable wall has been established in the existence of penetrant.Exemplary penetrant comprises that salt such as sodium chloride, potassium chloride, lithium chloride etc. and sugar are as Raffinose, sucrose, glucose, lactose and carbohydrate.

Continuation is with reference to figure 2 or 3, and this dosage form can randomly comprise the outer coatings (not shown), is used for dosage form is carried out color coding according to dosage, or is used to provide the release immediately of complex of the present invention or another kind of medicine.

In use, water flow stride across wall and enter push layer and medicine layer in.The push layer draw fluid also begins swelling, thereby and promote medicine layer 44, make that the material in the layer is discharged from and enters into gastrointestinal tract by outlet opening.Push layer 48 is designed to draw fluid and continues swelling, thereby in dosage form is in whole process in the gastrointestinal tract complex of the present invention is discharged from medicine layer continuously.Like this, dosage form is provided in time of 12 to 20 hours or is interim during by G.I. road whole basically in dosage form, and complex is without interruption to gastrointestinal.Because complex can easily absorb in upper and lower G.I. road, the using of dosage form is provided at drug moiety the sending in the blood flow in dosage form 12-20 hour by the G.I. road.

In embodiments, dosage form of the present invention comprises the drug moiety (as loose ion pair salt) of the complex of the present invention and second form, makes the medicine of second form to be obtained and to provide complex to be used for infra G.I. road to absorb by the absorption of last G.I. road.Wherein need can promote different characteristic with the optimal absorption of optimization in the situation of the absorption in whole G.I. road like this.

Comprise the complex of the present invention and second form drug moiety (as loose ion pair salt) concrete exemplary dosage forms as shown in Figure 4.Such three layers of dosage form are at United States Patent (USP) 5,545, describe in detail in 413,5,858,407,6,368,626 and 5,236,689, and it all is merged in this paper as a reference.Osmotic dosage form 60 has trilaminar core 62, it comprise the drug moiety salt that exists with loose ion pair ground floor 64, comprise the second layer 66 of the drug moiety that exists with complex form of the present invention and be called the 3rd layer 68 of push layer.Three layers of dosage form are prepared as has ground floor, it comprises that the drug moiety salt of the 85.0 weight % that exist with loose ion pair salt, the molecular weight of 10.0 weight % are 100, the molecular weight of 000 poly(ethylene oxide), 4.5 weight % about 35, the magnesium stearate of 000 to 40,000 polyvinylpyrrolidone and 0.5 weight %.The second layer comprises that the complex of 93.0 weight %, the molecular weight of 5.0 weight % are 5,000,000 poly(ethylene oxide), about 35,000 to 40,000 the polyvinylpyrrolidone of molecular weight of 1.0 weight % and the magnesium stearate of 1.0 weight %.

Push layer is made up of hydroxypropyl methylcellulose, 0.08 weight % butylated hydroxytoluene and the 0.25 weight % magnesium stearate of the poly(ethylene oxide) of 63.67 weight %, 30.00 weight % sodium chloride, 1.00 weight % ferrum oxides, 5.00 weight %.Semipermeable wall is made up of the cellulose acetate with 39.8% acetyl content of 80.0 weight % and polyoxyethylene-polyoxypropylene copolymer of 20.0 weight %.

The dissolution rate of those dosage forms as shown in Fig. 2-4 can be measured according to the method described in the embodiment 6.Usually, pharmaceutical preparation is after being released in of dosage form contacts aqueous environment.In the dosage form of Fig. 2 explanation, the drug moiety-transhipment part complex that is present in the layer of contiguous outlet opening discharges after the contact aqueous environment and lasting release in useful life's process of device.Dosage form illustrated in fig. 4 provides the initial release of the drug moiety salt in the medicine layer that is present in contiguous outlet opening, and the release of drug moiety-transhipment part complex takes place subsequently.Should be appreciated that this dosage form design is for discharging drug moiety salt during the G.I. road on passing through, approximately corresponding in first eight hours that pass through.Complex is along with dosage form discharges by following G.I. road, corresponding to than taking in the about 8 hours time more of a specified duration of back.This design has utilized the following G.I. road of the increase that is provided by complex to absorb.

Fig. 5 A-5C explanation is as known in the art and at United States Patent (USP) 5,534, another exemplary dosage form of describing in 263,5,667,804 and 6,020,000, and it is all incorporated into this paper as a reference particularly.The cutaway view of the dosage form 80 before briefly, having represented among Fig. 5 A in the gastrointestinal tract that is ingested.This dosage form comprises the cylindrical substrate 82 that contains complex.The end 84,86 of preferred substrate 82 is circular and is the shape of convex surface, to guarantee easy absorption.Ribbon 88,90 and 92 surrounds cylindrical substrate with one heart and forms by have relative insoluble material in aqueous environment.Suitable material proposes in aforesaid patent and following embodiment 6.

After dosage form 80 was ingested, the zone of the substrate 82 between ribbon 88,90,92 began etch, as illustrating among Fig. 5 B.The etch of substrate causes the release of complex in the fluid environment in G.I. road.Along with dosage form continues by the G.I. road, substrate continues etch, as illustrating among Fig. 5 C.At this moment, the etch of substrate has proceeded to the degree that dosage form is divided into three parts 94,96,98.Etch will be proceeded the substrate part etch fully up to each sheet.Thereafter ribbon 94,96,98 is discharged from the G.I. road.

Should be appreciated that the dosage form described in Fig. 2-5 just is designed for and can realizes the exemplary illustration of drug moiety complex of the present invention to the multiple dosage form of sending in G.I. road.The pharmaceutical field technical staff can discern other suitable dosage form.

Complex of the present invention, compositions and dosage form can be used for treating multiple indication.Usually, can use the indication number of complex of the present invention, compositions and dosage form treatment identical with the number of the drug moiety that can be used for the present invention's practice.In one aspect, the invention provides the compositions or the indication among the dosage form treatment patient such as the method for disease or disease that comprise complex of the present invention by administration, complex is characterised in that hybrid bond or the tight ion pair key between drug moiety and transhipment part.In one embodiment, by the oral compositions of complex and pharmaceutically acceptable excipient that will comprise to patient's administration.

The dosage of administration is usually according to patient's age, body weight and situation, and considers dosage form and required result and regulate.Usually, can a certain amount of dosage form and compositions that comprises complex of the present invention of administration, it provides the drug moiety in the order of magnitude of a certain amount of not complexation drug moiety that is in common releasing pattern immediately.Because the enhanced absorption that is provided by complex, the dosage of complex can be lower than the dosage that uses the conventional therapy of complexation drug moiety not to recommend usually.The amount of the drug moiety that typical dosage can comprise is that about 0.01 microgram drug moiety is to about 5000mg drug moiety, preferred about 1 microgram drug moiety is to about 2500mg drug moiety, more preferably from about 10 microgram drug moieties are to about 2000mg drug moiety, more preferably from about 100 microgram drug moieties are to about 1500mg drug moiety, and more preferably from about 500 microgram drug moieties are to the drug moiety of about 1000mg.The amount of the complex of the present invention that typical dosage can comprise is that about 0.01 microgram complex of the present invention is to about 5000mg complex of the present invention, preferred about 1 microgram complex of the present invention is to about 2500mg complex of the present invention, more preferably from about 10 micrograms complex of the present invention is to the complex of the present invention of about 2000mg, more preferably from about 100 micrograms complex of the present invention is to about 1500mg complex of the present invention, and more preferably from about 500 micrograms complex of the present invention is to about 1000mg complex of the present invention.

How to satisfy different purpose of the present invention and characteristics as can be seen from noted earlier.Comprise that the complex by tight ion pair key or bonded drug moiety of hybrid bond and transhipment part can provide with respect to the not colon absorption of the viewed enhanced drug moiety of complexation drug moiety.This complex prepares from new technology, wherein with drug moiety be dissolved in transhipment part in the solvent as fatty acid response, polarity of solvent is lower than water, hanging down polarity proves by for example lower dielectric constant.This reaction causes between drug moiety and transhipment part and forms complex, and wherein two kinds of materials close by bond, and this key is not an ionic bond, neither covalent bond, but tight ion pair key.

The present invention relates to comprise the material of complex, complex comprises drug moiety and transhipment part.In preferred embodiments, transhipment part comprises acidity, alkalescence or zwitterionic structural elements; Or with transhipment part in the residual construction unit of acidity, alkalescence or amphion of ion pairing.In preferred embodiments, transhipment part comprises fatty acid or its salt, benzenesulfonic acid or its salt, benzoic acid or its salt, fumaric acid or its salt or salicylic acid or its salt.In other preferred embodiment, fatty acid or its salt comprise C6-C18 fatty acid or its salt, and more preferably, C6-C18 fatty acid or its salt comprise C12 fatty acid or its salt.In preferred embodiments, the transhipment part comprises alkyl sulfate or its salt, and more preferably alkyl sulfate or its salt comprise C6-C18 alkyl sulfate or its salt, and more preferably C6-C18 alkyl sulfate or its salt are sodium lauryl sulfate.In preferred embodiments, transhipment part comprises pharmaceutically useful primary amine, secondary amine or tertiary amine or its salt.In a more preferred embodiment, drug moiety comprises acidity, alkalescence or zwitterionic structural elements; Or with the salifiable acidity of ion pairing shape, alkalescence or the residual construction unit of amphion.The present invention relates to the compositions that comprises this material and inactive ingredients in addition and relates to the dosage form that comprises said composition.The present invention relates to treat the method for disease or disease, it comprises: to this material of patient's administration of needs is arranged.In preferred embodiments, this material is by oral, intravenous, subcutaneous, intramuscular, transdermal, intra-arterial, intraarticular or intradermal routes administration.

The present invention relates to the production method for compositions, it comprises: the drug moiety that ionic species is provided; The transhipment part of ionic species is provided; Drug moiety and transhipment part are made up in the presence of less than the solvent of water at dielectric constant, to form complex; With from the separated from solvent complex.In preferred embodiments, transhipment part comprises acidity, alkalescence or zwitterionic structural elements; Or with transhipment part in the residual construction unit of acidity, alkalescence or amphion of ion pairing.In preferred embodiments, drug moiety comprises acidity, alkalescence or zwitterionic structural elements; Or with transhipment part in the residual construction unit of acidity, alkalescence or amphion of ion pairing.In preferred embodiments, drug moiety comprises acid construction unit or acid residual construction unit; And drug moiety is through processing to obtain the drug moiety of sour form.In preferred embodiments, drug moiety comprises alkaline structure unit or alkaline residual construction unit; And drug moiety is through processing to obtain the drug moiety of alkali form.In preferred embodiments, drug moiety comprises zwitterionic structural elements or the residual construction unit of amphion; And non-binding construction unit or residual construction unit with zwitterionic structural elements or the residual construction unit of amphion before drug moiety and transhipment partial reaction seal.

The present invention relates to Therapeutic Method, it comprises: the drug moiety that ionic species is provided; The transhipment part of ionic species is provided; Drug moiety and transhipment part are made up in the presence of less than the solvent of water at dielectric constant, to form complex; From the separated from solvent complex; With with isolating complex to the patient's administration that needs is arranged.In preferred embodiments, transhipment part comprises acidity, alkalescence or zwitterionic structural elements; Or with the salifiable acidity of ion pairing shape, alkalescence or the residual construction unit of amphion.In preferred embodiments, drug moiety comprises acidity, alkalescence or zwitterionic structural elements; Or with the salifiable acidity of ion pairing shape, alkalescence or the residual construction unit of amphion.In preferred embodiments, drug moiety comprises acid construction unit or acid residual construction unit; And drug moiety is through processing to obtain the drug moiety of sour form.In preferred embodiments, drug moiety comprises alkaline structure unit or alkaline residual construction unit; And drug moiety is through processing to obtain the drug moiety of alkali form.In preferred embodiments, drug moiety comprises zwitterionic structural elements or the residual construction unit of amphion; And non-binding construction unit or residual construction unit with zwitterionic structural elements or the residual construction unit of amphion before drug moiety and transhipment partial reaction seal.In preferred embodiments, complex is by oral, intravenous, subcutaneous, intramuscular, transdermal, intra-arterial, intraarticular or intradermal routes administration.

The present invention relates to the method for the absorption that improves drug moiety in addition, and it comprises: the complex of drug moiety with the transhipment part is provided; With with complex to the patient's administration that needs is arranged.In preferred embodiments, the complex oral administration, and the absorption that improves comprises the oral absorption of improvement.In preferred embodiments, the oral absorption of improvement comprises that the lower gastrointestinal tract of improvement absorbs.In preferred embodiments, the oral absorption of improvement comprises that the upper gastrointestinal of improvement absorbs.In preferred embodiments, complex transdermal administration, and the Transdermal absorption of improving that is absorbed as improvement.In preferred embodiments, complex subcutaneous administration, and the subcutaneous absorption that is absorbed as improvement that improves.

Though describe by the present embodiment and pointed out characteristics of the present invention and advantage, field of medicaments the technical staff should be appreciated that, can improve, change, augment and abridge and do not break away from spirit of the present invention the method described in the description.

Embodiment

Following examples are just illustrative for claimed the present invention, and it is restrictive never in any form.

Metformin

Metformin is meant N, N-dimethyl imido grpup two carbon imidic acid diamides, and its molecular formula is C ₄H ₁₁N ₅, molecular weight 129.17.The commercial form of this chemical compound is a metformin hydrochloride.Fig. 6 represents the chemical constitution of metformin.

Embodiment 1

The preparation of metformin-transhipment part complex

Material

Metformin hydrochloride 13.0g

Lauric acid 16.0g

Methanol 675mL

Acetone 300mL

Demineralization water 14mL

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

The preparation of metformin alkali

Ion exchange column is loaded and the weighing net weight with resin anion (R.A.) Amberlyst A-26 (OH).

Post is at first used deionization (DI) water rinse (backwash), with the methanol rinse that comprises 2%v/vDI water, post is parched then.

Metformin hydrochloride is dissolved in by 365mL comprises in the eluent that the methanol of 2 volume %DI water forms.

Use solution that separatory funnel makes step 3 dropwise by post and collect eluent.Calculate the equilibrium point (capacity) that the total metformin hydrochloride that passes through is lower than ion exchange resin.With the isopyknic approximately eluent rinsing of post.Collect the eluent of the metformin alkali of 690mL altogether.

Eluent evaporated in vacuo under 40 ℃ ambient temperature with merging raises the temperature to 65 ℃ to remove whole surplus waters when concentration step finishes.Because the unstability of metformin alkali, carry out this concentration step in mode the most rapidly.

Complex forms

The 16.0g lauric acid is dissolved in the 300mL acetone prepares lauric acid-acetone soln.Use some acetone washing liquids will derive from the spissated metformin alkali dissolution of above-mentioned steps 5 and these washing liquids are filtered in the presence of filtration adjuvant immediately, to remove any unconverted metformin hydrochloride.In taper (Erlenmeyer) flask, also under agitation use separatory funnel to add lauric acid-acetone soln filtrate collection in the mode of quick dropping.Lauric acid metformin precipitation is separated out.Continue down to stir to spend the night in ambient temperature (20-25 ℃).

The mixture of solvent and sedimentary lauric acid metformin is filtered by buchner funnel.Filter cake is with the rinsing of 4 * 200mL acetone, under the vacuum draw condition dry one hour then.Filter cake is scraped and weighs from filter paper.In capillary tube, measure fusing point.Final drying 3 hours in vacuum drying oven at ambient temperature.

It is 150-153 ℃ lauric acid metformin complex that said method obtains fusing point.The fusing point of metformin hydrochloride is reported as 225 ℃.With respect to the theoretical value that stoichiometric metformin hydrochloride and lauric acid from use calculate, total recovery=75%.

Fig. 8 A represents to prepare the general synthetic reaction scheme of metformin-transhipment part complex.Fig. 8 B represents to prepare the general synthetic reaction scheme of metformin-transhipment part complex, and wherein transhipment part comprises carboxyl.Fig. 8 C represents the synthetic reaction scheme as the preparation metformin-fatty acid complex that illustrates in the present embodiment.

Embodiment 2

The sign of metformin-transhipment part complex

HPLC characterizes

Use reversed-phase high pressure liquid chromatography (RP-HPLC) to analyze the metformin-laurate complex that forms described in the embodiment 1.For relatively, also generated the HPLC spectrogram of the physical mixture of metformin hydrochloride, sodium laurate and metformin hydrochloride and sodium laurate.Carry out reversed phase chromatography on Hewlett Packard 1100 chromatograph of liquid of evaporative light scattering detector and use C3 post (Agilest Zorbas SB C3,5 μ m, 3.0 * 75mm) having.The mobile phase of using is water: acetonitrile=50: 50v: v.Column temperature is 40 ℃, and flow velocity is 0.5mL/min.

The result is as shown in Fig. 9 A-9D.The spectrogram of metformin hydrochloride was observed unimodal at 1.1 minutes as shown in Fig. 9 A.Laruate form-sodium laurate-, be the broad peak (Fig. 9 B) of list at about 3-4 minute eluting.Metformin hydrochloride and sodium laurate 1: 1 molar mixture eluting in water is two peaks, and peak is being equivalent to 1.1 minutes of metformin hydrochloride, and second peak is at about 2.7-4 minute (Fig. 9 C) of sodium laurate.Fig. 9 D represents the HPLC spectrogram of the complex that the method by embodiment 1 forms, and wherein observes unimodal at 3.9-4.5 minute eluting.The HPLC spectrogram shows that metformin alkali is different with the physical mixture of two kinds of components in water with the complex that lauric acid forms.Spectrogram shows that also (water: acetonitrile=50: 50v: in the time of v), complex is disassociation not with solvent system in process HPLC analysis.

The octanol/water partition coefficient

In another research that characterizes metformin-laurate complex, measured the octanol/water partition coefficient (D=C of complex _{Capryl alcohol}/ C _Water) and with itself and metformin hydrochloride, metformin hydrochloride: 1: 1 (moles/mole) mixture of sodium lauryl sulfate and metformin hydrochloride: 1: 1 (moles/mole) mixture of sodium laurate is compared.The result is as shown in table 3.

Table 3: octanol/water partition coefficient

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

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

Complex has 0.44 log D, compares remarkable increase with metformin hydrochloride, shows that complex more advantageously is assigned in the capryl alcohol than the salt form of metformin.Complex also has the log D higher than the physical mixture of metformin hydrochloride in soap.This log D difference confirms that further the complex of metformin-fatty acid is not the physical mixture of two kinds of materials, that is, and and simple ion pair, but another kind of form.Fig. 7 is that the logarithm value of octanol/water partition coefficient of metformin hydrochloride is as the figure of the function of its pH.

Dissociation property

Use fatty acid capric acid, lauric acid, Palmic acid and oleic acid, prepare metformin-fatty acid complex according to the method described in the embodiment 1.The complex that also prepares metformin and succinic acid.Complex characterizes by fusing point and dissolubility, and data are summarised among the table 4A.In addition, also use CDM 83 conductometers (Radiometer Copenhagen) to measure different complex at aqueous solution at 23 ℃ $(\mathrm{pH}\≅5.8)$ In electrical conductivity.Values summarized the table 4B in and in Figure 10 A, present in diagrammatic form.

Table 4A

Melbine salt or complex	Fusing point (℃)	H 2O dissolubility (4h)
			HCl	238	＞300
Amber acid radical	243	95
			The Petiolus Trachycarpi acid group	150	12
The oleic acid root	138	53
			Decanoate	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

Figure 10 A represent metformin hydrochloride (circle), with the metformin (del) of amber acid radical complexation, with the metformin (square) of decanoate complexation, with the metformin (rhombus) of laurate complexation, with the metformin (triangle) of Petiolus Trachycarpi acid group complexation and with the metformin (octagonal) of oleic acid root complexation with the electrical conductivity of little Siemens/cm (μ S/cm) expression function as metformin concentration.Metformin hydrochloride all has the highest electrical conductivity under all concentration.Complex has the electrical conductivity lower than metformin hydrochloride, and the electrical conductivity reduction becomes obvious with the increase of fatty acid carbon number.

Figure 10 B represents the function of the unionized percent of drug of every kind of complex measuring from equation 3 as metformin concentration.Metformin hydrochloride (circle) ionizing fully, and about 80% ionizing of metformin-amber acid radical (del).Complex metformin-decanoate (square) and about 50% ionizing of metformin-laurate (rhombus), metformin-Petiolus Trachycarpi acid group (triangle) and metformin-about 30% ionizing of oleic acid root (octagonal).Establish difference between ion pair metformin hydrochloride and the metformin-fatty acid complex once more according to these data.

Embodiment 3

Use the interior G.I. road down of body of oral tube feed rat model to absorb

Eight rats are divided into two treatment groups at random.After by fasting 12-24 hour, first group gives the 40mg/kg free alkali normal metformin hydrochloride by oral tube feed.The normal metformin laurate complex of preparation as described in example 1 above of the 40mg/kg free alkali that second winding is given by oral tube feed.

15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours are from tail vein taking blood sample after oral tube feed.Analyze the metformin plasma concentration by LC/MS/MS.

The result as shown in Figure 11.Give plasma concentration in the rat of metformin hydrochloride (circle) by oral tube feed and reached maximum in about 1 hour after treatment, Cmax is about 4080ng/mL.Had the plasma concentration of maximum in about 1 hour with the rat of the oral tube feed of metformin-laurate complex (rhombus) treatment after treatment, Cmax is about 5090ng/mL.After treatment in 1-8 hour time, all be that the plasma concentration of the rat treated with complex is higher in all testing sites.The analysis showed that of data, the bioavailability (100% bioavailability) of the metformin with respect to the metformin hydrochloride administration time, the relative bioavailability of the metformin during with the complex form administration is 151%.

When research finishes, with the G.I. road of painless execution of rat and perusal evaluation test animal, to seek the sign of inflammation.In with complex or rat, do not observe inflammation with the metformin hydrochloride treatment.

Embodiment 4

Absorb in the body of the flushing-ligation colon models of use in rat

Preparation for test adopts the animal model that is commonly called " colonic ligation model ".The following operation of carrying out the 0.3-0.5kg Sprague-Dawley male rat of fasting anesthesia is prepared.Separate nearly colon section and clean Excreta from colon.Simultaneously conduit is placed the chamber that organ is taken out to be positioned at by abdomen in the two ends ligation section and be used for sending of test preparation more than the skin.The content of colon cleaned out and colon sent and return in the animal abdominal cavity.Decide according to test setting,, add test preparation after the pH 7.4, to simulate colonic environment actual in the clinical setting more accurately at the 20mM sodium phosphate buffer that section is full of 1mL/kg.

After operation is prepared and before being exposed under every kind of test preparation, made the rat balance about 1 hour.With metformin hydrochloride or metformin-fatty acid complex with the dosed administration of colonic bullet form with 10mg metformin hydrochloride/rat or 10mg metformin complex/rat.With the metformin-fatty acid complex treatment of rat, use fatty acid capric acid, lauric acid, Palmic acid and oleic acid, and use the succinic acid dimer with preparation described in the embodiment 1.After the test preparation administration 0,15,30,60,90,120,180 and 240 minute from jugular vein conduit taking blood sample and analyzing blood metformin concentration.Following table 5-10 represents for every kind of complex and every rat, metformin alkali concn in the blood plasma of representing with the millimicro grams per milliliter that each time point records.

Table 5

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	3g.4

Table 6

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	36.9	48.3	15.8	33.7	16.5
						4	62.4	60.4	19	47.3	24.5

Table 7

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 8

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 9

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 10

The lauric acid metformin
						Time (h)	Rat1(ng/ml)	Rat2(ng/ml)	Rat3(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	55.8
						4	68.1	77.5	47.4	64.3	15.4

For relatively, in the blood flow with the direct intravenous injection to three of the metformin hydrochloride test rat of the dosage of 2mg/kg rat body weight.Regular taking blood sample is analyzed metformin alkali in four hours.The result is as shown in table 11.

Table 11

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	2092
						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

Result among the table 5-10 presents in diagrammatic form in Figure 12.Figure 12 represent metformin hydrochloride (circle), with amber acid radical (rhombus), with Petiolus Trachycarpi acid group (triangle), with oleic acid root (del), with decanoate (square) and with the rat of the metformin of laurate (octagonal) complexation in plasma concentration (ng/mL) as the time (hour) function.Obtain the highest plasma concentration at complex from lauric acid (circle) and capric acid (square) preparation.The metformin plasma concentration that realizes with the complex of Palmic acid (triangle) and oleic acid (del) preparation is than low with the complex of lauric acid and capric acid preparation, but it is higher by metformin hydrochloride or the plasma concentration that provided by the succinic acid metformin.

The relative Cmax of every kind of complex of table 12 expression is (with respect to the plasma concentration of metformin hydrochloride, the metformin alkali maximal plasma concentration of every kind of complex) with respect to the bioavailability (the 4th row) by metformin hydrochloride that the ligation intubate is obtained with respect to the relative bioavailability of the normalized every kind of complex of bioavailability (the 3rd row) of the metformin hydrochloride of intravenous administration.

Table 12

The metformin test compound	Relative Cmax	Area under curve (0-4 hours is based on 1 mg alkali/rat)	Bioavailability with respect to IV dosage 1(％)	Bioavailability with respect to IV dosage 2(multiple of increase)
					HCl(i.v.)	1.0	692.5	100	-
HCl		29.2	4.2	1
					Amber acid radical	0.6	21.4	3.1	0.7
The Petiolus Trachycarpi acid group	3.6	144.3	20.8	5
					The oleic acid root	14.1	408.3	59.0	14
Decanoate	45.0	548.0	79.1	19
					Laurate	40.8	674.5	97.4	23

¹By AUC that every kind of complex is obtained AUC normalization with respect to the metformin hydrochloride of intravenous administration; (ng-h/mL-mg).

²By AUC that every kind of complex is realized with respect to by the AUC normalization of intubate to the metformin hydrochloride of ligation colon administration.

When the form with metformin-transhipment part complex is provided for down the absorption in G.I. road, the bioavailability that realizes with respect to hydrochlorate from metformin-Petiolus Trachycarpi acid group complex near 5 times increase, the metformin of metformin-transhipment part complex significantly strengthens.Oleic acid root complex is realized the improvement with respect to 14 times bioavailability of hydrochlorate.Metformin-decanoate complex provides 18 times the improvement of bioavailability nearly with respect to hydrochlorate.Metformin-laurate complex realizes surpassing with respect to hydrochlorate the improvement of 20 times bioavailability.Therefore, the present invention has considered to comprise the chemical compound of the complex that is formed by metformin and transhipment part, wherein the following G.I. road that provides of complex absorbs with respect to 5 times the increase of being absorbed with in the metformin hydrochloride infra G.I. road at least, more preferably at least 15 times increase, more preferably at least 20 times increase, this metformin bioavailability from the metformin determination of plasma concentration is proved.Therefore, when with the form administration of metformin-transhipment part complex, metformin provides significantly enhanced and absorbs metformin to blood from G.I. road down.

Embodiment 5

Use washes in rat-absorbs in the body of ligation colon models

Use the flushing-ligation colon models described in the embodiment 4 to carry out another research, the bioavailability of the metformin that will provide with complex form is compared with the bioavailability of the metformin that the physical mixture with metformin hydrochloride and sodium laurate (1: 1 mol ratio) provides.With two test preparations of various dose (metformin hydrochloride of metformin-laurate complex and 1: 1 mol ratio: sodium laurate) or the metformin hydrochloride intubate in the ligation colon.Plasma sample is analyzed metformin concentration and measured bioavailability with respect to the bioavailability of the metformin of intravenous administration.The result as shown in Figure 13.

The physical mixture (circle) that Figure 13 represents metformin hydrochloride and sodium laurate and the bioavailability percentage ratio of lauric acid metformin complex (square) are as the metformin dosage (function of mg alkali/kg).Complex has the bioavailability higher than physical mixture, and undulatory property is littler.

Figure 14 represents from the table 5 of embodiment 3,11 and 12 data, is used for the pharmacokinetics of explanation and the complex (rhombus) of comparing to the metformin hydrochloride of ligation colon (circle) or intravenous (triangle) administration by intubate.Complex provides the colon higher than the salt form of medicine to absorb, and has than the more persistent haemoconcentration of intravenous administration.

Embodiment 6

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

Be prepared as follows the dosage form that comprises metformin hydrochloride layer and metformin-laurate complex layer.

With the molecular weight of metformin hydrochloride, the 1.18g of 10 grams is that the molecular weight of 100,000 poly(ethylene oxide) and 0.53 gram is about 38,000 a polyvinylpyrrolidone dry blending 20 minutes in the blender of routine, to obtain the blend of homogeneous.Then, add 4mL degeneration dehydrated alcohol at leisure, under the continuous mixing of blender, three kinds of dry component are mixed.Mix and continued other 5 to 8 minutes.Make blended wet compositions by 16 eye mesh screens and dried overnight at room temperature.Then, make dried granule by 16 eye mesh screens and add the magnesium stearate of 0.06g, and with all components dry blending 5 minutes.The predose layer that freshly prepd granule can be used as in the dosage form is used for preparation.This granule comprises that the metformin hydrochloride of 85.0 weight %, the molecular weight of 10.0 weight % are that 100,000 poly(ethylene oxide), the molecular weight of 4.5 weight % are the magnesium stearate of about 35,000 to 40,000 polyvinylpyrrolidone and 0.5 weight %.

Be prepared as follows the metformin-laurate layer in the dosage form.At first, with the metformin laurate complex of preparation described in the embodiment 1 of 9.30 grams, the molecular weight of 0.50g is 5,000,000 poly(ethylene oxide), the molecular weight of 0.10g are about 38,000 polyvinylpyrrolidone dry blending 20 minutes in the blender of routine is to obtain the blend of homogeneous.Then, in blend, add at leisure degeneration dehydrated alcohol and continuous the mixing 5 minutes.Make blended wet compositions by 16 eye mesh screens and dried overnight at room temperature.Then, make dried granule by 16 eye mesh screens and add the magnesium stearate of 0.10g, and all dried dry component were mixed 5 minutes.Compositions comprises that the metformin laurate of 93.0 weight %, the molecular weight of 5.0 weight % are that 5,000,000 poly(ethylene oxide), the molecular weight of 1.0 weight % are the magnesium stearate of about 35,000 to 40,000 polyvinylpyrrolidone and 1.0 weight %.

Be prepared as follows the push layer that comprises the osmopolymer hydrogel composition.At first, the molecular weight with 58.67g is 7,000,000 pharmaceutically acceptable poly(ethylene oxide), the Carbopol of 5g ^The sodium chloride of 974P, 30g and the ferrum oxide of 1g sieve by 40 eye mesh screens respectively.With the molecular weight of the component of sieving and 5 grams is that 9,200 hydroxypropyl methylcellulose mixes, to produce the blend of homogeneous.Then, the degeneration dehydrated alcohol and continuous the mixing 5 minutes that in blend, add 50mL at leisure.Then, butylated hydroxytoluene and the continuation that adds 0.080g mixes.Freshly prepd granule is by 20 eye mesh screens and make its at room temperature (environment) dry 20 hours.Then, make exsiccant component by 20 eye mesh screens and add the magnesium stearate of 0.25g, and with all components dry blending 5 minutes.Final compositions comprises the poly(ethylene oxide) of 58.7 weight %, the sodium chloride of 30.0 weight %, the Carbopol of 5.0 weight % ^, the hydroxypropyl methylcellulose 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 %.

Be prepared as follows trilaminar dosage form.At first, join in the diel group metformin hydrochloride compositions of 118mg and compacting, the lauric acid metformin compositions that adds 427mg then in set of molds is as the second layer and compacting once more.Then, the hydrogel composition of adding 272mg also is reduced to three laminations in the diel group of 9/32 inch (0.714cm) diameter under the pressure of 1.0 tons (1000kg), forms three layers of core (tablet) closely.

By being formed to be dissolved in the acetone to form the preparation of 5.0% solid solution with 80: 20 w/w, component comprises that the acetyl content of 80.0 weight % is that the molecular weight of 39.8% cellulose acetate and 20.0% is that the semi-permeable wall of polyoxyethylene-polyoxypropylene copolymer of 7680-9510 forms compositions.In this step, place tepidarium to quicken the dissolving of component solution container.Wall is formed composition spray on three layers of core and all around, so that the semipermeable wall of 93mg thickness to be provided.

Then, form the outlet opening of 40 mils (1.02mm) being surrounded by laser drill on the tri-layer tablets of semi-permeable wall, so that contacting of metformin layer and delivery apparatus outside to be provided.With the dosage form drying to remove any residual solvent and water.

Bathe the dissolution rate in vitro of measuring dosage form in the wire coil sample holder of warm indicator by the USP Type VII that is connected in that dosage form is placed in 37 ℃ of waters bath with thermostatic control.The release medium of five equilibrium is expelled in the chromatographic system, to quantize in each test interval, to be discharged into the medication amount in the medium of simulating simulated gastric fluid (AGF).Test three dosage forms and average dissolution rate be illustrated among Figure 15 B, wherein metformin rate of release (mg/ hour) be expressed as the time (hour) function.After contact aqueous environment four hours, dosage form begins to discharge almost medication amount uniformly in subsequently 12 hours, and after the contact aqueous environment surpassed 16 hours, the release of medicine began to reduce.The metformin hydrochloride that is present in the contiguous medicine layer that exports discharges at first.After about 8 hours of contact aqueous environment, the release of metformin-transhipment part complex takes place, and continue to discharge 8 hours with the speed of substantial constant again.Should be appreciated that this dosage form design was about as much as first eight hours that pass through for discharge metformin hydrochloride during the G.I. road on passing through, shown in the line bar diagram.Metformin-transhipment part complex discharges during by following G.I. road with dosage form, be about as much as take in about 8 hours after the time, shown in the point-like bar diagram among Figure 15.The absorption of the increase in the infra G.I. road that is provided by complex has been provided in this design.

Gabapentin

Embodiment 7

The preparation of gabapentin-lauryl sulfate root complex

1. prepare the solution of 0.5mL 36.5% hydrochloric acid (5mmol HCl) in the 25mL deionized water.

2. add 5mmol gabapentin (0.86g) in the solution in step 1.Mixture at room temperature stirred 10 minutes.Form Gabapentin hydrochloride.

3. the sodium lauryl sulfate (1.4g) that in the aqueous solution of step 2, adds 5mmol.Mixture at room temperature stirred 20 minutes.Form the loose ion pair of gabapentin and lauryl sulfate ester.

4. in the solution of step 3, add the 50mL dichloromethane.Mixture at room temperature stirred 2 hours.

5. transfer to the mixture of step 4 in the separatory funnel and it was left standstill 3 hours.Form biphasely, lower floor is the dichloromethane phase, and the upper strata is a water.

6. separating step 5 is biphase up and down.Dichloromethane below reclaiming is mutually and at room temperature with the dichloromethane evaporate to dryness, subsequently in vacuum drying oven 40 ℃ dry 4 hours down.Obtain gabapentin-lauryl sulfate root complex (1.9g).With respect to the theoretical value that gabapentin and sodium lauryl sulfate from primary quantity calculate, total recovery is 87%.

Figure 16 C represents to prepare the synthetic reaction scheme of gabapentin-alkyl sulfate complex.

Embodiment 8

The sign of gabapentin-lauryl sulfate root complex

Use fourier transform infrared spectroscopy (FTIR) to analyze the gabapentin-lauryl sulfate root complex that forms among the embodiment 7.Use is formed Perkin-Elmer Spectrum 2000FTIR spectrophotometer system by the detector of attenuated total reflectance (ATR) adnexa and the refrigerative MCT of liquid N2 (cadmium mercury telluride) and is obtained FTIR spectrum.Also generated the FTIR scintigram of the physical mixture of gabapentin, sodium lauryl sulfate and gabapentin and sodium lauryl sulfate.Also generated the FTIR/ATR spectrum of 1: 1 mol ratio physical mixture (is solid film in methanol and at air drying with two components dissolved) of gabapentin, sodium lauryl sulfate and gabapentin and sodium lauryl sulfate, the result is as shown in Figure 17 A-17D.The spectrum of gabapentin has been represented the peak corresponding to NH and COO part as shown in Figure 17 A.The spectrum of sodium lauryl sulfate is observed corresponding to the master of S-O part bimodal between 1300-1200cm-1 as shown in Figure 17 B.Gabapentin HC1 and sodium lauryl sulfate 1: 1 molar mixture in water is observed the decay of distinct pattern characteristics of gabapentin and S-O peak (1300-1200cm-1) broadening of sodium lauryl sulfate as shown in Figure 17 C.Figure 17 D represents the FTIR spectrum by the complex of the method formation of embodiment 7, wherein disappear and replaced, show the electric charge sealing of COO-by the peak of the COOH group in the gabapentin lauryl sulfate root complex corresponding to two peaks of the COO-group of gabapentin.In the spectrum of gabapentin-lauryl sulfate root, observe the distortion of the N-H 15cm-1 displacement partly of gabapentin.This displacement of the bands of a spectrum of N-H key shows the protonated of N-H group in the complex that obtains.As shown in the spectrum of gabapentin complex, the peak shift 30cm-1 of the 1250cm-1 that expression S-O absorbs in the sodium lauryl sulfate spectrum, the interaction of the sulfate groups of expression gabapentin and sodium lauryl sulfate.The FTIR scintigram shows that the complex that is formed by gabapentin is different with the physical mixture of two components.

Embodiment 9

Colon absorbs in the body of the flushing ligation colon models of use in rat

Use is commonly called the animal model of " flushing-ligation colon models " or " colonic ligation model ".With the anesthesia of the 0.3-0.5kg Sprague-Dawley male rat of fasting and separate nearly colon section.Clean Excreta from colon.Simultaneously conduit is placed the chamber that organ is taken out to be positioned at by abdomen in the two ends ligation section and be used for sending of test preparation more than the skin.The content of colon cleaned out and colon sent and return in the animal abdominal cavity.Decide according to test setting,, add test preparation after the pH 7.4, to simulate colonic environment actual in the clinical setting more accurately at the 20mM sodium phosphate buffer that section is full of 1mL/kg.

After operation is prepared and before being exposed under every kind of test preparation, make about 1 hour of rat (n=3) balance.Gabapentin-lauryl sulfate root complex or gabapentin are sent with the form administration of colonic bullet and with the dosage of 10mg gabapentin-lauryl sulfate root complex/rat or 10mg gabapentin/rat.At 0,15,30,60,90,120,180 and 240 minute from jugular vein conduit taking blood sample and analyze gabapentin concentration.When 4 hours experimental periods, finish, with rat with the painless execution of excessive pentobarbital.Excise the colon section of every rat and vertically open along antimesenteric border.Whether each section of perusal has inflammation and any unusual.The colon of excision is placed on the scale paper and measures about colon surface area.In the mucosa of any test rat, all there is not macroscopic tissue pathologies change.

Control rats (n=3) is treated with the dosage intravenous administration gabapentin of 1mg/ rat.With the identical decimation in time blood sample of above analysis gabapentin used time of concentration.

The mean plasma concentration of the gabapentin plasma concentration of every test animal and the animal of each test group is represented in table 13-15.

Table 13

Gabapentin-intravenous administration
						Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Meansigma methods (ng/mL)	Standard deviation
0	0	0	0	0.0	0.0
						0.03	3340	2170	2330	2613.3	634.4
0.167	1420	1280	1080	1260.0	170.9
						0.5	933	868	855	8853	41.8
1	878	867	779	841.3	54.3
						1.5	714	770	648	710.7	61.1
2	573	690	518	593.7	87.8
						3	505	558	415	492.7	72.3

Table 14

Gabapentin-colon intubate
						Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Meansigma methods (ng/mL)	Standard deviation
0	0	0	0	0.0	0.0
						0.25	40.6	53.8	32	42.1	11.0
0.5	82.5	100	64.8	82.4	17.6
						1	189	210	83.8	160.9	67.6
1.5	266	240	78.6	194.9	101.5
						3	413	265	92.9	257.0	160.2
4	279	322	94.7	231.9	120.7

Table 15

Gabapentin lauryl sulfate ester-colon intubate
						Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Meansigma methods (ng/mL)	Standard deviation
0	0	0	0	0.0	0.0
						0.25	2160	2380	2790	2443.3	319.7
0.5	2110	2710	4440	3086.7	1209.8
						1	2990	3280	3960	3410.0	497.9
1.5	3050	3270	3750	3356.7	358.0
						3	2170	2410	2140	2240.0	148.0
4	1380	1520	1380	1426.7	80.8

Figure 18 represents that average gabapentin concentration in each test group is as the function of time.The gabapentin of intravenous administration (triangle) provide high initial plasma concentration and in first 15 minutes concentration sharply reduce.When gabapentin during with the form administration of colonic bullet (circle), the slow absorption of medicine takes place.On the contrary, when medicine during to G.I. canal drug administration down, drug absorption rapidly takes place with the form (rhombus) of gabapentin-lauryl sulfate root complex, after intubate, observed Cmax in one hour.

The pharmacokinetic parameter that derives from this research is represented in table 16.For each gabapentin dosage, based on 1mg gabapentin/rat infinitely great area under curve (AUC) of measuring from the time zero to time, wherein the time infinity is estimated by supposing that log-linear descends.The bioavailability of gabapentin is expressed as the percentage ratio of giving the gabapentin concentration that obtains with medicine from intravenous.

Table 16

Medicament forms (route of administration)	AUC∞ (ng-h/mL-mg)	Bioavailability (%)
			Gabapentin (iv)	6090.3	100
Gabapentin (colonic)	301.4	4.9
			Gabapentin lauryl sulfate ester (colonic)	3854.1	63.3

When with complex form during to following G.I. canal drug administration, from medicine with respect to the bioavailability of the remarkable improvement of pure medicine as seen, the enhanced colon absorption that is provided by the complex of gabapentin and lauryl sulfate ester is tangible.It is the improvement of 13 times bioavailability that gabapentin lauryl sulfate root complex provides with respect to pure medicine.Therefore, the chemical compound that the present invention has considered to comprise, consist essentially of or has been made up of the complex that gabapentin (or lyrica) and transhipment part form, wherein the complex colon that provides colon with respect to gabapentin (or lyrica) to be absorbed as at least 5 times of increases, more preferably at least 10 times of increases, more preferably at least 12 times of increases absorbs, and this gabapentin (or lyrica) bioavailability from gabapentin (or lyrica) determination of plasma concentration is proved.Therefore, when with gabapentin (or lyrica)-transhipment part complex form administration, gabapentin (or lyrica) provides remarkable enhanced gabapentin (or lyrica) to absorb to the colon in the blood.

Embodiment 10

Absorb in the body

28 rats are divided into seven test group (n=4) at random.With gabapentin or the gabapentin that described in embodiment 1A, prepares or gabapentin-lauryl sulfate root complex with the dosage of 5mg/ rat, 10mg/ rat and 20mg/ rat by intubation catheter in the beginning part of rat preduodenal.Remaining test group intravenous gives the gabapentin of 1mg/kg.

In four hour time from every animal taking blood sample and analyze gabapentin content.The result is as shown in table 17-22 and Figure 19 A-19C.

Table 17

Gabapentin lauryl sulfate ester, duodenal administration dosage, 5mg/ rat
							Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Rat 4 (ng/mL)	Meansigma methods	Standard deviation
0	0	0	0	0	0	0
							0.25	1490	1410	2130	2400	1857.5	484.4
0.5	2690	2080	3210	3700	2920	695.5
							1	2380	2720	2750	4640	3122.5	1025.5
1.5	2500	2620	2470	4010	2900.0	742.8
							2	1970	2740	1520	3620	2462.5	921.5
3	1580	1670	1230	2860	1835.0	709.2
							4	967	1120	696	1710	1123.25	428.8

Table 18

Gabapentin lauryl sulfate ester, duodenal administration dosage, 10mg/ rat
							Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Rat 4 (ng/mL)	Meansigma methods	Standard deviation
0	0	0	0	0	0	0
							0.25	2260	2510	2440	3080	2572.5	354.3
0.5	3210	4010	3220	4350	3697.5	574.2
							1	3670	3150	4010	4910	3935	740.0
1.5	2890	4590	4240	6370	4522.5	1433.3
							2	2310	3880	4200	5190	3895	1194.8
3	1410	3630	5210	3400	3412.5	1558.7
							4	981	2230	2430	1760	1850.2	644.0

Table 19

Gabapentin lauryl sulfate ester, duodenal administration dosage, 20mg/ rat
							Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Rat 4 (ng/mL)	Meansigma methods	Standard deviation
0	0	0	0	0	0	0
							0.25	5570	4270	5910	3420	4792.5	1156.2
0.5	5320	4680	6410	4820	5307.5	784.7
							1	7370	6610	7000	6550	6882.5	381.4
1.5	6770	6820	7830	8380	7450	789.3
							2	5670	6980	8100	9410	7540	1593.842
3	3720	5970	5880	7210	5695	1449.793
							4	2570	4980	3330	4060	3735	1029.061

Table 20

Gabapentin, duodenal administration dosage, 5mg/ rat
							Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Rat 4 (ng/mL)	Meansigma methods	Standard deviation
0	0	0	5.71	0	1.4275	2.855
							0.25	3920	2590	3110	4020	3410	681.8
0.5	7500	4420	4400	6850	5792.5	1618.3
							1	10800	7610	6350	7870	8157.5	1882.6
1.5	11400	8410	7260	7740	8702.5	1859.2
							2	9390	6800	9370	6670	8057.5	1528.0
3	6350	5830	5640	5370	5797.5	413.9
							4	4710	3490	3900	3350	3862.5	611.3

Table 21

Gabapentin, duodenal administration dosage, 10mg/ rat
							Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Rat 4 (ng/mL)	Meansigma methods	Standard deviation
0	0	0	5.62	0	1.405	2.81
							0.25	5690	2760	5740	5110	4825	1406.1
0.5	7560	4480	8490	9260	7447.5	2096.9
							1	7600	7320	Missing	11400	8773.333	2279.1
1.5	7150	6170	10500	14900	9680	3943.0
							2	8020	11000	12500	14800	11580	2841.6
3	6580	12900	9740	14100	10830	3377.8
							4	4610	12400	6820	8660	8122.5	3297.5

Table 22

Gabapentin, duodenal administration dosage, 20mg/ rat
							Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Rat 4 (ng/mL)	Meansigma methods (ng/mL)	Standard deviation
0	0	0	0	0	0	0
							0.25	5560	6720	7910	8050	7060	1164.5
0.5	7360	9850	13100	11800	10527.5	2498.6
							1	7970	13500	13700	15800	12742.5	3347.4
1.5	10300	13400	13500	16200	13350	2411.8
							2	9530	12500	14100	17600	13432.5	3362.2
3	6530	9070	10200	16900	10675	4424.7
							4	4370	5900	6050	13900	7555	4297.6

Figure 19 A is illustrated in the gabapentin plasma concentration (ng/mL) in the animal for the treatment of with intravenous mode administration (triangle), to the pure gabapentin of duodenal administration 5mg (circle), 10mg (square) and 20mg (rhombus).Increase for accepting to observe with dosage by intubate animal of administration in the duodenum, haemoconcentration increases.Naturally, the low plasma drug level of animal (triangle) for intravenous therapy is because low drug dose.

Figure 19 B represents to derive from the result that intravenous is accepted gabapentin-lauryl sulfate root complex (triangle) and directly is administered into duodenal animal with the dosage of 5mg (circle), 10mg (square) and 20mg (rhombus).Though accepting the absolute haemoconcentration of the animal of gabapentin-lauryl sulfate root complex compares with the animal of gabapentin treatment low, but data show derives from the absorption that the gabapentin of complex absorbs with respect to pure medicine to be strengthened, perhaps in part because L-amino acid transport system do not have saturated and/or increase transhipment by other mechanism that complex provides.Between this 5mg in comparison diagram 6A and 6B and the 10mg dosage and apparent during the haemoconcentration between 10mg and the 20mg dosage, wherein for the gabapentin with the complex form administration, along with the increase of dosage, the haemoconcentration increase is bigger.

Figure 19 C represent gabapentin as pure medicine (del) or as gabapentin-lauryl sulfate root complex (circle) percentage ratio of the gabapentin bioavailability during to the rat preduodenal administration.Gabapentin with respect to intravenous administration is measured bioavailability percentage ratio.At the dosage of 20mg, gabapentin-lauryl sulfate root complex shows the bioavailability higher than pure medicine.The bioavailability that increases under higher dosage may be the enhanced absorption that provides owing to by complex, and wherein the absorption in the G.I. road is not limited to by the absorption of the L-amino acid transport system of complex, also takes place by striding the other mechanism of cell and cell.

The pharmacokinetic analysis of table 23 expression the research has wherein been measured 0 to 4 hour area under curve and has been normalized to 1mg gabapentin/kg rat.With the relevant gabapentin of the 4th little time point (iv) data supposition be to derive from the log-linear of the data of measuring in first three hours to descend.Bioavailability percentage ratio is with respect to the bioavailability of the gabapentin of intravenous administration.

Table 23

Pharmaceutical dosage form	Dosage (mg/kg ± s.d.)	AUC(0-4h，ng h/ml-mg±s.d.) *	Bioavailability (%)
				Gabapentin (iv)	1	2727.1±259.1	100.0
Gabapentin (duodenum)	14.8±0.1	1705.2±257.2	62.5±9.4
				Gabapentin (duodenum)	30.6±1.7	1205.7±276.3	44.2±10.1
Gabapentin (duodenum)	59.8±1.7	726.1±223.9	26.2±8.2
				Gabapentin lauryl sulfate ester (duodenum)	14.0±0.1	1604.3±479.1	58.8±17.6
Gabapentin lauryl sulfate ester (duodenum)	29.1±1.1	1182.2±267.9	43.3±9.8
				Gabapentin lauryl sulfate ester (duodenum)	58.1±2.3	1033.9±88.9	37.9±3.3

Normalize to the dosage of 1mg gabapentin/kg

AUC and bioavailability data show, along with dosage increases, when medicine provided with the form of gabapentin-transhipment part complex, the colon of gabapentin absorbed improvement.

Embodiment 11

The preparation of lyrica-transhipment part complex

1. prepare the solution of 0.5mL 36.5% hydrochloric acid (5mmol HCl) in the 25mL deionized water.

2. add 5mmol lyrica (0.80g) in the solution in step 1.Mixture at room temperature stirred 10 minutes.Form the lyrica hydrochlorate.

3. the sodium lauryl sulfate (1.4g) that adds 5mmol to the aqueous solution of step 2.Reactant mixture was at room temperature stirred 20 minutes.

4. in the solution of step 3, add the 50mL dichloromethane.Mixture at room temperature stirred 2 hours.

5. transfer to the mixture of step 4 in the separatory funnel and it was left standstill 3 hours.Form biphasely, lower floor is the dichloromethane phase, and the upper strata is a water.

6. separating step 5 is biphase up and down.The dichloromethane that reclaims lower floor is mutually and with dichloromethane evaporate to dryness at room temperature, under 40 ℃ in vacuum drying oven dry 4 hours subsequently.Obtain lyrica-lauryl sulfate root complex (2.1g).

Figure 16 D represents to prepare the synthetic reaction scheme of lyrica-alkyl sulfate complex.

Embodiment 12

Colon absorbs in the body of the flushing ligation colon models of use in rat

Employing is commonly called the animal model of " colonic ligation model ".The 0.3-0.5kg Sprague-Dawley male rat of fasting is anaesthetized and is separated the section of nearly colon.Clean Excreta from colon.Simultaneously conduit is placed the chamber that organ is taken out to be positioned at by abdomen in the two ends ligation section and be used for sending of test preparation more than the skin.The content of colon cleaned out and colon sent and return in the animal abdominal cavity.Decide according to test setting,, add test preparation after the pH 7.4, to simulate colonic environment actual in the clinical setting more accurately at the 20mM sodium phosphate buffer that section is full of 1mL/kg.

After operation is prepared and before being exposed under every kind of test preparation, make about 1 hour of rat (n=3) balance.Lyrica-lauryl sulfate root complex or lyrica are sent with the form administration of colonic bullet and with the dosage of 10mg lyrica/rat.Be used to analyze lyrica concentration at 0,15,30,60,90,120,180 and 240 minute from jugular vein conduit taking blood sample.When 4 hours experimental periods, finish, with rat with the painless execution of excessive pentobarbital.Excise the colon section of every rat and vertically open along antimesenteric border.Whether each section of perusal has inflammation and any unusual.The colon of excision is placed on the scale paper and measures about colon surface area.

Control rats (n=3) is treated with the intravenous administration lyrica of the dosage of 1mg/ rat.At above-mentioned identical decimation in time blood sample.

Embodiment 13

Absorb in the body of lyrica

28 rats are divided into seven test group (n=4) at random.Lyrica that will be in water or as the lyrica-lauryl sulfate root complex of preparation as described in the embodiment 1B with 5mg/ rat, 10mg/ rat and 20mg/ rat by intubation catheter in the beginning part of rat preduodenal.Remaining test group intravenous gives the lyrica of 1mg/kg.

In four hour time from every animal taking blood sample and analyze lyrica content.Be used for similar calculating mensuration dosage, AUC and bioavailability that gabapentin calculates among use and the embodiment 10.

Ferrum

Term " ferrum " comprise with its any state of oxidation and with the ferrum (Fe) of any salt combination." ferrous " is meant to have+ferrum (also being expressed as Fe2+, Fe++, ferrum (II) in the art) of 2 electric charges." ferric iron " is meant to have+ferrum (also being expressed as Fe3+, Fe+++, ferrum (III) in the art) of 3 electric charges.That exemplary ferrous salt and iron salt include but not limited to is vitriolic, fumaric acid, succinic acid, the ferrous salt and the iron salt of gluconic acid, or the like.

Figure 20 represents to prepare the synthetic reaction scheme of ferrum-fatty acid complex.

Embodiment 14

The preparation of ferrum-fatty acid complex

Carry out following steps ferrous to form-the fatty acid complex.Be reflected among Figure 20 A-20C and illustrate.

1. 9.15 FeSO47H2O that restrain are dissolved in the 300mL methanol in beaker.

2. 14.64 gram sodium laurates (sodium laurate) are dissolved in second the 300mL methanol in the beaker.

3. the drips of solution with step 1 is added in the solution of step 2.Mixture at room temperature stirred 1-5 hour, to produce the precipitation of Na2SO4.Solution stirring is spent the night.

4. by using #42 Whatman filter paper vacuum filtration to remove the precipitate of step 3, filtrate collection is in funnel.Precipitate methanol wash three times; Filtrate collection is in funnel.

5. the filtrate solution with step 4 places crystallizing dish and places fume hood with evaporating solvent.Form the ecru precipitate.Precipitate placed on the vacuum filter and by vacuum filtration remove remaining solvent.Filter cake is placed crystallizing dish and places vacuum drying oven to spend the night to drying.

Measuring sedimentary fusing point is 38-38 ℃.

Embodiment 15

Colon absorbs in the body of the flushing ligation colon models of use in rat

The following G.I. that use is commonly called the animal model evaluation ferrum-transhipment part complex of " colonic ligation model " absorbs and bioavailability.The following operation of carrying out the 0.3-0.5kgSprague-Dawley male rat of fasting anesthesia is prepared.Separate the section of nearly colon and clean Excreta from colon.Simultaneously conduit is placed the chamber that organ is taken out to be positioned at by abdomen in the two ends ligation section and be used for sending of test preparation more than the skin.The content of colon cleaned out and colon sent and return in the animal abdominal cavity.Decide according to test setting,, add test preparation after the pH 7.4, to simulate colonic environment actual in the clinical setting more accurately at the 20mM sodium phosphate buffer that section is full of 1mL kg.

After operation is prepared and before being exposed under every kind of ferrum-transhipment part complex, made the rat balance about 1 hour.Test compound is sent with the form administration of colonic bullet and with the dosage of 10mg ferrum (as the Fe+2/ rat).At 0,15,30,60,90,120,180 and 240 minute from jugular vein conduit taking blood sample and analyzing blood concentration of iron.When 4 hours experimental periods finish, rat is put to death with excessive pentobarbital.Excise the colon section of every rat and vertically open along antimesenteric border.Whether each section of perusal has inflammation and any unusual.The colon of excision is placed on the scale paper and measures about colon surface area.

Use said method to estimate the absorption of ferrous sulfate, ferrous-the laurate complex, ferrous-the decanoate complex, ferrous-oleic acid root complex and ferrous-Petiolus Trachycarpi acid group complex.

Embodiment 16

28 rats are divided into seven test group (n=4) at random.With ferrous sulfate or as the ferrous-lauryl sulfate root complex of preparation as described in the embodiment 11 with 5mg/ rat, 10mg/ rat and 20mg/ rat by intubation catheter in the beginning part of rat preduodenal.Remaining test group intravenous gives the ferrous sulfate of 1mg/kg.

Inhibitors of dipeptidyl IV

DPP IV inhibitor is the chemical compound of the enzymatic activity of inhibition DPP-IV, yet these chemical compounds also can have the activity of inhibition to other DPP enzyme.Identified multiple DPP-IV inhibitor, its four exemplary chemical compounds are as shown in Figure 21 A-21D.

Figure 21 A represents DPP IV inhibitor 1-[[(3-hydroxyl-l-adamantyl) amino] acetyl group]-structure of 2-cyano group-(S)-pyrrolidine; be accredited as chemical compound (Villhauer, people such as E.B., the Journal of Medicinal Chemistry of LAF-237; 46,2774-2789 (2003)).Figure 21 B is illustrated in the structure of the aminoacyl Triazolopyrazine DPP IV inhibitor of describing in detail among the WO2004032836, and described patent is merged in this paper as a reference.Figure 21 C is illustrated in the structure of another exemplary DPP IV inhibitor of describing among the WO2004/024184.Figure 21 D is illustrated in DPP IV inhibitor 1-[N-(5,6-dichloro nicotinoyl)-L-ornithyl of describing among the WO03/000250]-3, the structure of 3-difluoro pyrrolidine hydrochloride, described patent is merged in this paper as a reference.This chemical compound is also referred to as " difluoro pyrrolidine compound " in this article.

Be prepared as follows complex with DPPIV inhibitor.

Embodiment 17

The preparation of DPP IV inhibitor-fatty acid complex

Use two fluoropyrrolidine DPP IV inhibitor to prepare complex

By being dissolved in the 100mL acetone, 16.0g oleic acid prepares oleic acid-acetone soln.

The DPPIV inhibitor of 22.0 grams as the free alkali that is accredited as difluoro pyrrolidine compound (Figure 21 D) is dissolved in the 200mL acetone.

Under agitation oleic acid-acetone soln is added drop-wise in the solution that comprises DPP IV inhibitor.Continuing stirring in ambient temperature (20-25 ℃) spends the night.Difluoro pyrrolidine compound-oleic acid root complex compound sediment is come out.

The mixture of solvent and sedimentary difluoro pyrrolidine compound-oleic acid root complex is filtered by buchner funnel.Filter cake is with the rinsing of 4 * 200mL acetone, under vacuum draw dry one hour then.Filter cake is scraped and weighs from filter paper.

Use Cyanopyrolidine DPP IV inhibitor to prepare complex

1. by being dissolved in 100mL acetone, 16.0g oleic acid prepares oleic acid-acetone soln.

2. the DPP IV inhibitor of 16.9 grams as the free alkali that is accredited as cyanopyrrole hydride compounds (Figure 21 A) is dissolved in the 200mL acetone.

3. under agitation oleic acid-acetone soln is added drop-wise in the solution that comprises DPP IV inhibitor.Continuing stirring in ambient temperature (20-25 ℃) spends the night.Form cyanopyrrole hydride compounds-oleic acid root complex.

4. use suitable technology to reclaim cyanopyrrole hydride compounds-oleic acid root complex, be filtration or extraction as form according to complex from solution.

Use homophenylalanin (Homophenylalanine) DPP IV inhibitor to prepare complex

By being dissolved in the 100mL acetone, 16.0g oleic acid prepares oleic acid-acetone soln.

The DPPIV inhibitor of 22.7 grams as the free alkali that is accredited as homophenylalanin chemical compound (Figure 21 B) is dissolved in the 200mL acetone.

Under agitation oleic acid-acetone soln is added drop-wise in the solution that comprises DPP IV inhibitor.Continuing stirring in ambient temperature (20-25 ℃) spends the night.Form homophenylalanin chemical compound-oleic acid root complex.

According to the form of complex, use suitable technology as filtering or extracting from solution and reclaim homophenylalanin chemical compound-oleic acid root complex.

Claims (33)

1. material, it comprises:

The complex that comprises drug moiety and transhipment part.

2. the material of claim 1 is wherein transported part and is comprised acidity, alkalescence or zwitterionic structural elements; Or with ion pairing with the salifiable acidity of shape, alkalescence or the residual construction unit of amphion.

3. the material of claim 2 is wherein transported part and is comprised fatty acid or its salt, benzenesulfonic acid or its salt, benzoic acid or its salt, fumaric acid or its salt or salicylic acid or its salt.

4. the material of claim 3, wherein fatty acid or its salt comprise C6-C18 fatty acid or its salt.

5. the material of claim 4, wherein C6-C18 fatty acid or its salt comprise C12 fatty acid or its salt.

6. the material of claim 2 is wherein transported part and is comprised alkyl sulfate or its salt.

7. the material of claim 6, wherein alkyl sulfate or its salt comprise C6-C18 alkyl sodium sulfate or its salt.

8. the material of claim 7, wherein C6-C18 alkyl sodium sulfate or its salt comprise sodium lauryl sulfate.

9. the material of claim 2 is wherein transported part and is comprised pharmaceutically useful primary amine, secondary amine or tertiary amine or its salt.

10. the material of claim 1, wherein drug moiety comprises acidity, alkalescence or zwitterionic structural elements; Or with ion pairing with the salifiable acidity of shape, alkalescence or the residual construction unit of amphion.

11. a compositions, it comprises the material and the inactive ingredients of claim 1.

12. a dosage form, it comprises the compositions of claim 11.

13. the method for treatment disease or disease, it comprises:

To the material of the patient's administration claim 1 that needs is arranged.

14. the method for claim 13, wherein material is by oral, intravenous, subcutaneous, intramuscular, transdermal, intra-arterial, intraarticular or intradermal routes administration.

15. the production method for compositions, it comprises:

The drug moiety of ionic species is provided;

The transhipment part of ionic species is provided;

Drug moiety and transhipment part are made up in the presence of less than the solvent of water at dielectric constant, to form complex; With

From the separated from solvent complex.

16. the method for claim 15, wherein transhipment part comprises acidity, alkalescence or zwitterionic structural elements; Or with ion pairing with the salifiable acidity of shape, alkalescence or the residual construction unit of amphion.

17. the method for claim 15, wherein drug moiety comprises acidity, alkalescence or zwitterionic structural elements; Or with ion pairing with the salifiable acidity of shape, alkalescence or the residual construction unit of amphion.

18. the method for claim 17, wherein drug moiety comprises acid construction unit or acid residual construction unit; And drug moiety is through processing to obtain the drug moiety of sour form.

19. the method for claim 17, wherein drug moiety comprises alkaline structure unit or alkaline residual construction unit; And drug moiety is through processing to obtain the drug moiety of alkali form.

20. the method for claim 15, wherein drug moiety comprises zwitterionic structural elements or the residual construction unit of amphion; And non-binding construction unit or residual construction unit with zwitterionic structural elements or the residual construction unit of amphion before drug moiety and transhipment partial reaction seal.

21. Therapeutic Method, it comprises:

The drug moiety of ionic species is provided;

The transhipment part of ionic species is provided;

Drug moiety and transhipment part are made up in the presence of less than the solvent of water at dielectric constant, to form complex;

From the separated from solvent complex; With

With isolating complex to the patient's administration that needs is arranged.

22. the method for claim 21, wherein transhipment part comprises acidity, alkalescence or zwitterionic structural elements; Or with ion pairing with the salifiable acidity of shape, alkalescence or the residual construction unit of amphion.

23. the method for claim 21, wherein drug moiety comprises acidity, alkalescence or zwitterionic structural elements; Or with ion pairing with the salifiable acidity of shape, alkalescence or the residual construction unit of amphion.

24. the method for claim 23, wherein drug moiety comprises acid construction unit or acid residual construction unit; And drug moiety is through processing to obtain the drug moiety of sour form.

25. the method for claim 23, wherein drug moiety comprises alkaline structure unit or alkaline residual construction unit; And drug moiety is through processing to obtain the drug moiety of alkali form.

26. the method for claim 23, wherein drug moiety comprises zwitterionic structural elements or the residual construction unit of amphion; And non-binding construction unit or residual construction unit with zwitterionic structural elements or the residual construction unit of amphion before drug moiety and transhipment partial reaction seal.

27. the method for claim 21, wherein complex is by oral, intravenous, subcutaneous, intramuscular, transdermal, intra-arterial, intraarticular or intradermal routes administration.

28. improve the method for the absorption of drug moiety, it comprises:

The complex of drug moiety with the transhipment part is provided; With

With complex to the patient's administration that needs is arranged.

29. the method for claim 28, complex oral administration wherein, and the absorption that improves comprises the oral absorption of improvement.

30. the method for claim 29, wherein the oral absorption of Gai Shaning comprises that the lower gastrointestinal tract of improvement absorbs.

31. the method for claim 29, wherein the oral absorption of Gai Shaning comprises that the upper gastrointestinal of improvement absorbs.

32. the method for claim 28, wherein complex transdermal administration, and the Transdermal absorption of improving that is absorbed as improvement.

33. the method for claim 28, wherein complex subcutaneous administration, and the subcutaneous absorption that is absorbed as improvement that improves.

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