CN101217942A - Bioenhanced compositions - Google Patents

Abstract

The invention relates to a method for improving bioavailability of receptor blocking pharmacon (ARBs) of angiotensin II by preparing a combination of ARB and at least one solubility intensifier. The invention especially relates to the solubility intensifier which not only plays the function of solubility intensifier, but also can improve the dissolution rate in acid or faintly acid medium, wherein ARB has minimum dissolution rate in medium. In combination, ARB can stay with the solubility intensifier in a manner of physical mixture, solid dispersion, solid solution, or complex. The combination of the ARB and the solubility intensifier can be added into quick-release or controlled-release preparation or other suitable improved-release preparation. The in vitro release of the quick-release preparation containing ARB combination in acid medium (PH value is smaller than 3) is at least 40%. Therefore, the bioavailability of the ARB combination can at least be improved by 20% like the measurement of Cmax, AUC(0-t), and AUC(0-infinitude).

Description

Bioenhanced compositions

The application advocates that Indian patent application number is 477/MUM/2005, and the applying date is on April 18th, 2005, and application number is 0315/MUM/2006, and the applying date is the priority on March 6th, 2006, incorporates its disclosed content into this paper at this in the reference mode.

Technical field

The present invention relates to improve the method for angiotensin-ii receptor blockers (ARBs) bioavailability, realize by the compositions for preparing ARB and at least one solubility enhancing agent.The present invention is absorbed in especially provides a kind of new or improved dissolution curve, and wherein the release of ARB in the GI road does not rely on the physiological pH environment.

Background of invention

Angiotensin II is very effective end-product chemicals, and it can cause the blood vessel contraction of muscle on every side, and blood vessel is significantly dwindled.Thisly dwindle that to have improved arteries intrinsic pressure, (hypertension) causes elevation of the blood pressure.Angiotensin receptor blocker (ARBs) is to block the active medicine of Angiotensin II.Therefore, arteries expansion and blood pressure drops make that thus cardiac pumping is more prone to.So ARBs also can be used to improve heart failure and hypertension.In addition, they have slowed down the process of the kidney disease that is caused by hypertension or diabetes.

The importance of controlling undue blood pressure is mathematical, but the focus for the treatment of at present expands the protection to end-organ (end-organ) to, the therapeutic goal of its conduct and reduction BP no less important.Like this, ARBs is slowing down because the value in the kidney disease gait that hypertension or diabetes cause is exactly to become very positive medicine and have commercial significance.

This class medicine comprise Candesartan (Atacand, Astra-Zeneca), Eprosartan (Teveten, Solvay﹠amp; Biovail), irbesartan (Avapro, BMS), losartan (Cozaar, Merck), Olmesartan (Benicar, Medoxomil; Sankyo ﹠amp; Forest), telmisartan (Micardis, Boehringer Ingelheim), valsartan (Diovan, Novartis) and pratosartan (Kotobuki).ARBs can use separately or comprise that with other class antihypertensive thiazide diuretic, beta blocker, calcium channel blocker, hypertension fibrinogen inhibitor and ACE inhibitor are used in combination, and are used for the treatment of hypertension and congestive heart failure together.

Valsartan, optionally ARB is a kind of known antihypertensive.Valsartan can be rapidly from gastrointestinal absorption behind oral administration.The absolute bioavailability of valsartan is about 25% (10-35%).This low relatively bioavailability of valsartan mainly ascribes its dissolubility relatively poor in the gastrointestinal tract acid medium to.Valsartan is acid, therefore, o'clock good dissolubility is arranged in pH＞5, and dissolubility is lower under gastrointestinal tract (GI) sour environment.Valsartan is from little intestinal absorption, and it is lower at that solvent degree.

United States Patent (USP) 5399578 (' 578 patent) has been put down in writing the synthetic of valsartan and has been used.WO 04083192, WO 04087681 and WO 03066606 have put down in writing the various polymorphs and the salt form of valsartan.

WO 04101535 relates to pharmaceutical composition and reduces the method for the risk of the M ﹠ M that the depleted patient with sympotoms of heart rate is arranged, it comprises the valsartan that gives this patient's effective dose, or its pharmaceutically acceptable salt, it uses separately or makes up with other therapeutic agent, chooses wantonly to have pharmaceutically acceptable carrier.This patent has been described the new purposes or the novel crystal forms of valsartan, but does not have to handle and the low relevant problem of bioavailability of valsartan.

U.S. Patent number 6,294, the patent of 197 (' 197 patents) and Application No. 2003/0035832 has been put down in writing the solid oral dosage form of valsartan, and it uses separately or makes up with hydrochlorothiazide (HCTZ), prepares the required pharmacy additive of solid dosage forms by pressing in addition.In preparation, comprise active component according to the solid dosage forms of this invention greater than 35% weight.It also discloses and has used rolling process to prepare the method for this solid dosage forms.

At United States Patent (USP) 6,485, in 745 (' 745), put down in writing the solid dosage forms of valsartan, it can quicken release of active ingredients in pH is 6.8 phosphate buffer.Yet, in 0.1N HCl, but can not present the dissolubility minimum of valsartan under this environment.

U.S. Patent Application Publication No. 2002/0132839 and U.S. Patent Application Publication No. 2003/0152620 have been discussed valsartan tablet medicine compositions, and its biological effectiveness is higher at least 1.2 times than conventional valsartan capsule.Comprising concentration level according to the tablet formulation of this invention is the disintegrating agent that accounts for compositions gross weight 10-80%.High-load disintegrating agent guarantees that the hydrophobicity valsartan can be in the well moistening of granulation stage quilt.This tablet can be dispersed into granule rapidly in dissolution medium can dissolve and have the bioavailability of improvement better than conventional formulation thus.Yet this invention is not documented in the method that improves valsartan autolysis under the gastric environment, and therefore, the dissolubility of valsartan in 0.1N HCl is still very low, and this causes bioavailability also lower.

Candesartan Cilexetil (Candesartan cilexitil) as valsartan, is the hydrophobic molecule that has than low aqueous solubility, and this causes its oral administration biaavailability also lower (about 14%).WO 2005/070398A2 has required the pharmaceutical composition of tablet form, and it comprises Candesartan, fatty glyceride, surfactant, cosolvent and pharmaceutically acceptable additive.This preparation is also by the film coating of film forming polymer and Polyethylene Glycol formation.The use of cosolvent has only improved the stability of Candesartan, does not change its dissolubility and dissolution rate under sour environment.

U.S. Patent Application Publication No. 2005/0220881 provides the method for improving the Eprosartan stripping, and it is realized by the association complex for preparing itself and one or more solid poloxamers.Yet, but need a large amount of poloxamers to realize deliquescent remarkable increase.This complex dosage form that exploitation can reach high oral administration biaavailability is owing to the restriction of the weight very difficulty that becomes.In addition, use a large amount of poloxamers also can not be allowed to for a long time.

The low bioavailability relevant with low aqueous solubility causes and need give heavy dose of ARBs to keep the therapeutic activity of expection.Like this, the ARB preparation is improved, to obtain and in the pH scope of GI road broad, to carry the preparation of active medicine form with dissolved form and expected mode with regard to still needing and having an opportunity.

Summary of the invention

The present invention relates to predictability ground and improve the particularly bioavailability of valsartan of ARBs, and in the wide pH scope in GI road, guarantee the method for stable absorption.The present invention has improved the absorption of ARBs in the GI road, reduced thus between the patient and the patient in diversity, these are different with oral formulations in the market, the absorption difference opposite sex of these oral formulations in the patient and between the patient is bigger.Compare with the commercially available prod, the present invention has also significantly reduced the time (T that ARB reaches maximum plasma concentration _Max) and degree of absorption (AUC).

The invention still further relates to the preparation of physics and chemically stable ARBs preparation, particularly valsartan, wherein used the adjuvant that is known as safety (GRAS).The invention still further relates to the oral formulations of valsartan, it can reduce in the patient and the absorption difference opposite sex between the patient, particularly under low GI pH.C _MaxThe coefficient of variation of maximum plasma concentration is less than about 35%, preferably less than about 30%.The coefficient of variation of AUC is less than about 45%, and is preferred 40%, and most preferably 30%.

Have been found that ARB, valsartan particularly, when combining, can significantly improve with solubility enhancing agent its in sour environment (pH＜3) dissolubility and improve dissolution rate, these are obviously different with ARB preparation in the market.Its bioavailability also will improve, and absorb on the position because there is more medicine to be present in dissolved form.The raising of bioavailability has reduced and has produced a desired effect ARB dosage required and the diversity between the patient, and the treatment that has therefore strengthened ARB is used.Solid dosage forms can use preparation solid dosage forms conventional production process and standard production equipment commonly used to make.

One aspect of the present invention provides the method that improves the ARB bioavailability, by itself and at least one solubility enhancing agent are realized jointly.

In one aspect of the method, this new compositions of valsartan provides at least 40% dissolution in acid and faintly acid dissolution medium." acidity " refers to pH less than about 3 as used herein.As used herein " faintly acid " to refer to pH be about 3 to 5.

Valsartan composition of the present invention can be used for the treatment of the disease of following record and also can carry the medicine of dissolved form to improve bioavailability in the wide pH scope in GI road.Therefore, compare, just can reduce dosage and frequency with the administration of conventional valsartan.In addition, between the patient relevant with the present preparation of valsartan and the diversity in the patient also can be lowered.Therefore, expect that valsartan composition of the present invention can improve therapeutic effect.

The example of disease that this medicament is controlled comprises 1. blood circulation diseasess, for example hypertension, heart disease (heart failure, myocardial infarction, valvulopathy), peripheral circulation functional defect; 2. kidney disease, for example glomerulonephritis, renal insufficiency; 3. cerebral function obstacle, for example apoplexy, Alzheimer, depression, amnesia, dementia; 4. diabetic complications, for example retinopathy, nephropathy; 5. the arteriosclerosis that occurs by hypertension, apoplexy, heart attack, angina pectoris or gastrointestinal (GI) road or extremity ischemia; 6. orphan disease, for example aldosteronism, multiple system organ failure, scleroderma; With 7. anxiety neurosises, catatonia and dyspepsia.The vasoconstriction that many these diseases are all expressed by the Angiotensin II secondary causes or aggravates.

The accompanying drawing summary

Fig. 1 has compared the dissolution rate of valsartan itself and with the dissolution rate of solubility enhancing agent as the valsartan of solid dispersion.

Fig. 2 has shown embodiment 4Diovan ^Release in vitro curve to preparation #1.

Fig. 3 has shown the release in vitro curve of embodiment 6 valsartan preparation #2.

Fig. 4 has shown the release in vitro curve of embodiment 7 valsartan preparation #3.

Fig. 5 has compared embodiment 8 valsartan preparation #4 and Diovan ^Blood distiller line.

Fig. 6 has compared the stripping curve of valsartan preparation under the different pH.

The specific embodiment

According to the ultimate principle of drug absorption, the medicine in the solution only could pass through the lipid cell membrane under neutral form.Therefore, be that medicine should be neutral lipophilic, and enough strippings are arranged in the GI medium for can better absorbing very crucial.Usually, from chemical terms, most of ARBs have a general character, and at least one free carboxy is promptly arranged, and this makes ARBs can not dissolve in sour environment and be ionized (dissolved form) under alkaline environment.For example, valsartan has a carboxyl, and therefore, it is difficult for dissolving in acid medium.So the absorption of valsartan in sour environment is with regard to owing to its low solubility becomes lower, yet under alkaline environment, valsartan is the ionization form, and this is lipophilic unlike neutral free acid, therefore abundant permeate through cell membranes.In other words, valsartan has less absorption also because the dissolubility of free acid form permeability low and dissolving (ion) form is low in acidity/faintly acid GI medium at gastrointestinal tract.The result is the low bioavailability that produces 10-25%.The dissolubility of these ARBs in acidity/weak acidic medium even without carboxylic acid function's property is also lower.

Ionizing under the high pH is the inherent character of ARB molecule itself, and this parameter is unalterable.Unique probability is dissolubility and/or the dissolution rate that improves under sour environment.It has surprisingly been found that with commercially available finished product and compare that the compositions of ARB or its salt refers to solubility enhancing agent at this in the presence of predetermined substance, can under the pH of broad scope, improve dissolubility and improve dissolution rate and improve bioavailability thus.

In addition, have the chemical substance of free carboxy, ARBs for example is considered to be used for the substrate of the reverse transportation system of p-glycoprotein usually.Overflowing of this p-glycoprotein mediation also is the partly cause that causes the ARBs bioavailability to reduce.The solubility enhancing agent of using among the present invention has also been brought into play the effect of p-glycoprotein inhibitors, and it helps further to improve the bioavailability of ARB.

Active component

The active component that is used for the object of the invention is ARB, and it can be, but be not limited to Candesartan, Eprosartan, irbesartan, losartan, Olmesartan, telmisartan, valsartan or pratosartan.Active component of the present invention can exist with crystal or unbodied form.Crystal form can be different polymorph.All different polymorphs, solvate, hydrate, salt are all within the scope of the invention.Preferred active component is a valsartan.

In dosage form of the present invention, one or more in addition except that ARB, two or three active component for example.Can include but not limited to antihypertensive with the therapeutic agent of ARB combination, for example hydrochlorothiazide (HCTZ), calcium channel blocker, beta blocker, ACE inhibitor, inotropic agent, hypolipidemic, antiadipositas drug, feritin enzyme inhibitor, and/or antidiabetic drug.

The present invention also is applicable to other active pharmaceutical ingredient, and these compositions have the low solubility relevant with the bioavailability problem equally.

The amount of active component in compositions can be about 1-80% weight, preferred 5-50% weight, more preferably 10-30% weight.

Solubility enhancing agent

According to the present invention, the increase of the instantaneous dissolubility of ARB realizes by using one or more suitable solubility enhancing agent in the compositions.Solubility enhancing agent can comprise one or more surfactants, solubilizing agent, chelating agent, hydrotropic solvent etc.The solubility enhancing agent that is used for different AR B ' s can be identical or different.The present invention is focussed in particular on provides new or improved solubility curve, wherein ARB to be released under the whole physiological pH environment of gastrointestinal all be similar, i.e. the release of medicine does not rely on the physiological pH environment basically.

Solubility enhancing agent can be, but be not limited to hydrophilic surfactant active, lipophilic surfactant, its mixture.Surfactant can be anion, nonionic, cation, amphion or amphipathic.The relative hydrophilic of surfactant and hydrophobicity are by HLB (hydrophil lipophil balance) value representation.The hydrophilic surfactant active comprises HLB greater than 10 surfactant, with and the HLB scope be not blanket anion, cation, amphipathic or zwitterionic surfactant.Similarly, the lipophilic surfactant is the HLB value less than 10 surfactant.

Hydrophilic non-ionic surfactant can be, but be not limited to Polyethylene Glycol sorbitan aliphatic ester, polyethylene glycol fatty acid monoesters, PEG-fatty acid diester, alcohol or polyhydric alcohol and at least one hydrophilic transesterification products natural and/or hydrogenated oil and fat.The most frequently used oil is Oleum Ricini or castor oil hydrogenated, or edible vegetable oil for example Semen Maydis oil, olive oil, Oleum Arachidis hypogaeae semen, palm-kernel oil, almond oil.Preferred polyhydric alcohols comprises glycerol, propylene glycol, ethylene glycol, Polyethylene Glycol, sorbitol and tetramethylolmethane.Preferred this class hydrophilic surfactant active comprises PEG-35 Oleum Ricini, polyoxyethylene-polypropylene copolymer, and (Lutrol is BASF) with the PEG-40 castor oil hydrogenated.

The amphiphilic surfactant includes, but not limited to d-alpha-tocopherol base cetomacrogol 1000 succinate and d-alpha-tocopherol hydrochlorate for example succinate, hydrochlorate etc.

The ionic surfactant can be, but be not limited to alkylammonium salt; Fusidic acid (fusidic acid) salt; The derivative of fatty acid of aminoacid, oligopeptide or polypeptide; The glyceride ester derivatives of aminoacid, oligopeptide or polypeptide; Lecithin or hydrolecithin; LYSOLECITHIN SUNLECITHIN A or hydrogenation LYSOLECITHIN SUNLECITHIN A; The phospholipid or derivatives thereof; The lysophosphatide or derivatives thereof; The fatty acid ester salt of carnitine; The salt of alkyl sulfate; Soap; Docusate sodium; Acyl lactylates (lactylates); Single-or the list of two-glyceride-or two-acetylation tartrate; The list of succinylation-or two-glyceride; Single-or the citrate of two-glyceride; Or its mixture.

The lipotropy surface activity can be, but be not limited to aliphatic alcohol; Fatty acid glyceride; Acetylated glycerol fatty acid esters; Lower alcohol fatty acid esters; Methyl glycol fatty acid ester; Sorbitan aliphatic ester; The Polyethylene Glycol sorbitan aliphatic ester; Sterone and sterone derivant; Polyoxyethylene sterol or sterol derivative; Polyethylene glycol alkyl ether; Sugar ester; Sugar ether; Single-or the lactic acid derivative of two-glyceride; The hydrophobicity transesterification products of polyhydric alcohol and at least one following material: glyceride, vegetable oil, hydrogenated vegetable oil, fatty acid and sterol; Oil-soluble vitamin/vitamin derivant; Polyethylene Glycol (PEG) sorbitan aliphatic ester; The PEG fatty acid glyceride; The bound to polyglycerol fatty acid; Polyox-yethylene-polyoxypropylene block copolymer; Sorbitan aliphatic ester; Or its mixture.

Solubility enhancing agent is PEG-20-glyceryl stearate (Capmul  byAbitec) preferably; PEG-40 castor oil hydrogenated (Cremophor RH 40  by BASF); PEG 6 Semen Maydis oil (Labrafil  by Gattefosse); lauryl Polyethylene Glycol-32 glyceride (Gelucire 44/14  by Gattefosse); stearoyl polyethyleneglycol glyceride (Gelucire 50/13  by Gattefosse); the single dioleate of polyglyceryl-10 (Caprol  PEG 860 by Abitec); propylene glycol oleate (Lutrol OP  by BASF); propylene glycol dicaprylate (Captex  by Abitec); propylene glycol caprylate/decanoin (Labrafac  by Gattefosse); glyceryl monooleate (Peceol  byGattefosse); single glyceryl linoleate (Maisine  by Gattefosse); glyceryl monostearate (Capmul  by Abitec); PEG-20 sorbitan monolaurate (Tween20  by ICI); PEG-4 Laurel ether (Brij 30  by ICI); distearyl acid sucrose ester (Sucroester 7  by Gattefosse); single Palmic acid sucrose ester (Sucroester 15  by Gattefosse); polyox-yethylene-polyoxypropylene block copolymer (Lutrol  seriesBASF); Polyethylene Glycol 660 hydroxy stearic acid esters (Solutol  by BASF); sodium laurylsulfate; sodium lauryl sulphate; dioctyl suphosuccinate; the L-hydroxypropyl cellulose; hydroxyethyl-cellulose; hydroxypropyl cellulose; propylene glycol alginate; Bile Salts; sodium glycocholate; sodium deoxycholate; betanin; Polyethylene Glycol (Carbowax  by DOW); d-alpha-tocopherol cetomacrogol 1000 succinate (Vitami E TPGS  by Eastman), or its mixture.

Solubility enhancing agent is PEG-40 castor oil hydrogenated (Cremophor RH 40  by BASF-HLB-13) more preferably, lauryl Polyethylene Glycol-32 glyceride (Gelucire44/14  by Gattefosse-HLB-14), stearoyl polyethyleneglycol glyceride (Gelucire 50/13  by Gattefosse-HLB-13), PEG-20 sorbitan monolaurate (Tween 20  by ICI-HLB-17), PEG-4 Laurel ether (Brij30  by ICI-HLB-9.7), polyox-yethylene-polyoxypropylene block copolymer (Lutrol  series BASF, different HLB with 15-30), sodium laurylsulfate (HLB-40), Polyethylene Glycol (Carbowax  by DOW), d-alpha-tocopherol cetomacrogol 1000 succinate (Vitamin E TPGS  by Eastman-HLB-15), or its mixture.

Solubilizing agent also can comprise the pH regulator agent, for example buffer agent, aminoacid and aminoacid sugar.

Chelating agent comprises the cyclodextrin molecule, for example comprises cyclodextrin, particularly alpha-cyclodextrin, beta-schardinger dextrin-, the gamma-cyclodextrin of six to 12 glucose units, or derivatives thereof, for example hydroxypropyl beta cyclodextrin, or its mixture.Chelating agent can also comprise cyclic amides, hydroxybenzoic acid derivative and gentisic acid.In the complexation process, can also additionally add hydrophilic polymer further to strengthen dissolubility together with chelating agent.

In compositions of the present invention, ARB and one or more solubility enhancing agent can be used in varing proportions.Selected ratio depends on the dissolubility that expection will improve and the type of used solubility enhancing agent.Expection within the scope of the invention, the ratio of ARB and solubility enhancing agent is about 20: 1 to about 1: 20, preferred about 10: 1 to about 1: 10, most preferably from about 5: 1 to about 1: 5.The compositions that can also comprise solubility enhancing agent, wherein total consumption of solubility enhancing agent remains in the aforementioned proportion.

The solubilising of ARBs

In compositions, ARB and solubility enhancing agent can exist with the form of physical mixture, solid dispersion, solid solution or complex.Can use distinct methods to prepare the compositions of ARB and solubility enhancing agent.Expection within the scope of the invention, these methods can include, but not limited to use melt granulation, solvent processing, physical mixed or carry out spray drying and come solubilising being dissolved in medicine in the solvent and solubility enhancing agent.

In melt granulation, solubility enhancing agent is melted.Add ARB then and mix, solidify, then granule is separated to form granule with fused mass.In another exemplary of this system, use the solubility enhancing agent of fusing that ARB is granulated.In some cases, ARB and solubility enhancing agent can be melted and cool to room temperature together.

In using the method for solvent processing, solubility enhancing agent or ARB, or they the two, can be dissolved in the solvent, then evaporation or spray drying.The gained material is the mixture of ARB and solubility enhancing agent, and the dissolubility of ARB just has been enhanced like this.The solvent that uses in this system can be an aqueous or nonaqueous.

In physical mixed, preferably use Hobart blender, V-agitator or high speed shear granulator with ARB and solubility enhancing agent dry mixed fully.

In the complexation method, can use different technology to prepare the ARB complex, for example ball milling, solvent evaporated method it comprise spray drying and lyophilization, slurry method, paste method etc.

Expection can be used in combination preceding method within the scope of the invention.For example, can be used in combination hot melt, physical mixed and solvent treatment method.Under this situation, ARB can be earlier granulates with the solubility enhancing agent of one or more fusings, and it can also further be handled in solvent with identical or different solubility enhancing agent, or carries out single physical mixed or vice versa.Expection within the scope of the invention, the method for any usually suitable pharmaceutical compositions known in the art can be used to purpose of the present invention.

Melt granulation and complete physical mixed are the most preferred method of preparation according to valsartan of the present invention.The raising of dissolubility can be determined by research actual solubility of valsartan in the presence of solubility enhancing agent, or determine by the dissolubility of research in the suitable solvent medium.The preferred dissolution method is because it can play the meltage of valsartan to come the rate of dissolution of the different preparations of comparison by measuring different time at interval.

Compositions can be made into various pharmaceutical dosage forms, and it includes but not limited to, under one's belt the tablet of disintegrate, tablet that can disintegrate in mouth, can be in liquid (water) tablet by the effervescence disintegrate, tablet that can disintegrate in liquid (for example water), coated tablet, according to dosage be packaged in the powder in the sachet, suspensoid, gelatine capsule, Perle, semisolid dosage form, and other drug delivery system.

The preferred dosage form of the present invention is a solid dosage forms, preferred tablet, and it can be a different shape, includes but not limited to ellipse, triangle, Semen Armeniacae Amarum type, Semen arachidis hypogaeae type, parallelogram, pentagonal.Expection within the scope of the invention, this dosage form can be by encapsulated.

Can use conventional tabletting technology known in the art to prepare according to tablet of the present invention, such as but not limited to, direct compression, wet granulation, dry granulation, or extrude/melt granulation.

Can comprise conventional adjuvant known in the art, for example filler, binding agent and lubricant according to dosage form of the present invention.Can use filler, for example include but not limited to, lactose monohydrate, microcrystalline Cellulose, dicalcium phosphate, calcium silicates, aluminium-magnesium silicate (magnesiumaluminometasilicate) are (Neusillin) etc.Can use binding agent, for example include but not limited to, polyvinylpyrrolidone (PVP), copolyvidone (copovidone) etc.Can make with lubricator, for example include but not limited to Aerosil-200, magnesium stearate, hydrogenated vegetable oil, the triglyceride of stearic acid, Palmic acid etc.

Disintegrating agent can be, but be not limited to following material: starch, carboxymethyl starch sodium, pregelatinized Starch, crospolyvinylpyrrolidone, cross-linked carboxymethyl cellulose or ion exchange resin, most preferably carboxymethyl starch sodium.The amount of disintegrating agent be the compositions gross weight about 0.25 to about 30%, more preferably from about 0.5 to about 20.0%, most preferably from about 0.75-10% weight.

In an exemplary, dosage form can be chosen wantonly by coating.For attractive in appearance or, can use surface coatings for the purpose of stablizing tabletting dosage size.Any conventional coating materials that is suitable for orally using can be used to carry out surface coatings.Can use any routine techniques of using conventional ingredient to carry out coating.For example, surface coatings can use the instant film of conventional polymer to obtain, and polymer for example is hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl alcohol polymethacrylates etc.

In an exemplary, can will be joined in the capsule with liquid form by the ARB of solubilising.In this embodiment, in will incapsulating with the blended ARB of solubility enhancing agent of fusing, wherein add or do not add other adjuvant.Composition in the capsule keeps liquid state or semisolid in storage period, the liquid in perhaps incapsulating can exist with the form of entity in capsule.Optional disintegrating agent, lubricant or the diluent of comprising in the preparation.

In another exemplary, can be dispersed in the adjuvant by the ARB of solubilising, for example general other adjuvant that uses in microcrystalline Cellulose, lactose, mannitol, calcium silicates, aluminium-magnesium silicate (Neusillin) or the peroral dosage form.Dispersive mixture can be loaded in the capsule or be pressed into tablet.

In another exemplary, be introduced in the slow releasing preparation by the ARB of solubilising.Solubility enhancing agent can guarantee that the controlling slow release curve also can be finished drug release in the interval of expection better.

In another exemplary, be introduced in the lasting release matrix preparation by the ARB of solubilising, wherein comprise one or more polymerizations or non-polymeric release retardant in the preparation.Operable examples of polymer includes but not limited to, the polyalkenyl oxide; Cellulosic polymer; Acrylic acid, methacrylic acid copolymer and ester thereof; Copolymer-maleic anhydride; Poly; Poly-(acrylamide); Poly-(enol); Poly-(N-vinyl lactam); Polyhydric alcohol; Polyoxy ethylization sugar (polyoxyethylated saccharides);  azoles quinoline; Polyvinylamine; Polyvinylacetate; Poly-imines; Starch and based on the polymer of starch; Polyurethane hydrogel; Chitosan; Polysaccharide glue; Zein; Polymer based on Lac; Poly(ethylene oxide); Hydroxypropyl cellulose; Hypromellose; Hydroxyethyl-cellulose; Sodium carboxymethyl cellulose; Carboxymethylcellulose calcium; Methylcellulose; Polyacrylic acid; Maltodextrin; Pregelatinized Starch and polyvinyl alcohol; Copolymer; And composition thereof.

Also can use one or more hydrophilic polymers to prepare the dosage form that continues release.The preferably poly-oxireme of these polymer, hydroxypropyl cellulose, hypromellose, hydroxyethyl-cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, methylcellulose, polyacrylic acid, maltodextrin, pregelatinized Starch, polyvinyl alcohol, or its mixture.The percetage by weight of hydrophilic polymer is about 5 to about 90 percentage by weights in the dosage form, and preferred about 10 to about 70 percentage by weights, and most preferably from about 15 to about 50 percentage by weights.

In another exemplary, solid composite medicament can be used for oral administration with the form of multilayer system.This system can be suitable for carrying two kinds of different active matters, for example is by the ARB of solubilising in one deck, is hydrochlorothiazide in another layer.

In another exemplary, the solid composite medicament that is used for the multilayer system form of oral administration can be suitable for carrying first active agents from ground floor immediately when reaching gastrointestinal tract, and carries from the second layer and the second identical or different medicament of first medicament with controllable mode in concrete time bar.

In another exemplary, the solid composite medicament that is used for the expansion multilayer system form of oral administration is suitable for carrying first active agents from ground floor immediately when reaching gastrointestinal tract, and carries from the second layer and the second identical or different medicament of first medicament with controllable mode in concrete time bar.The second layer also is suitable for being provided for the expansion characteristics of dosage form system, makes the dosage form system that better stop is arranged under one's belt thus.

In another exemplary, be introduced in the drug-supplying system of controlling by osmotic pressure by the ARB of solubilising.Solubility enhancing agent can guarantee that release profiles is controlled better, and also can finish drug release in the interval of expection.

In acid and weak acid environment, the solubility enhancing agent of using in the compositions can improve dissolubility and the stripping of ARBs, particularly valsartan.The fast dissolving dosage form that contains said composition can provide at least 40% dissolution in acid and weak acid environment.Dissolving in acid and weak acid environment strengthen and better stripping make have more medicine to see through the GI film and cause the bioavailability raising.The increase of dissolubility also can produce the drug release curve that does not rely on pH, and wherein this medicine has the dissolubility that depends on pH.The drug absorption diversity that the present invention has also reduced between the patient and the patient is interior.

The invention provides the oral dosage form of ARBs, it is than high about 1.2 to 4 times of the bioavailability of conventional fast dissolving dosage form.The raising of bioavailability proves by following evidence: T _Max(reaching the time of maximum plasma concentration) reduces, C _Max(maximum plasma concentration), AUC _0-tAnd AUC _0-∞(degree of absorption, or the area under curve of blood drug level and time) increases.Because relative bioavailability increases, so this new compositions also will reduce the diversity typically relevant with ARB, and particularly wherein ARB is a valsartan.This compositions also can reach peak blood drug level in less than 4 hours time, preferably in less than 3 hours, more preferably reach in less than 2 hours.The T of gained _MaxBe worth also fast than conventional quick releasing formulation.

Although invention has been described by concrete exemplary, some improves and equivalent will be conspicuous to those skilled in the art, and comprises within the scope of the invention.Details of the present invention, its purpose and advantage will be described in detail hereinafter in the mode of non-limiting example explanation.

The solubilising of embodiment 1-valsartan

Valsartan is joined under mixing continuously in the material of fusing to obtain uniform dispersion, thus the valsartan solid dispersion that contains the different solubilities reinforcing agent that exists in varing proportions of preparation.In 0.1N HCl, measure the dissolubility of gained solid dispersion.

Table 1: the dissolubility of valsartan in 0.1N HCl that contains the different solubilities reinforcing agent

Solid dispersion	The HLB of solubility enhancing agent	Dissolubility mcg/ml
			Valsartan		84.60
Valsartan: hard ester acyl polyethyleneglycol glyceride USP (Gelucire 50/13) 1: 0.5	13	73.51 *
			Valsartan: vitamin e T.P.G.S.USP/NF1: 0.5	15	230.40
Valsartan: vitamin e T.P.G.S.USP/NF1: 1	15	337.10
			Valsartan: hard ester acyl polyethyleneglycol glyceride, USP (Gelucire 50/13) 1: 1	13	167.19
Valsartan: polyoxyethylene (polyoxyl) 40 castor oil hydrogenated, USP (Cremophor RH40) 1: 1	13	181.24
			Valsartan: polyethylene glycol 6000, USP1: 1		82.54 *

T.P.G.S.-alpha-tocopherol cetomacrogol 1000 succinate

The HLB-hydrophile-lipophile balance value

^*Because the interference the possibility of result of measuring is underestimated

In the different solubility enhancing agent of research, vitamin e TPGS, Gelucire 50/13 under 1: 1 ratio and the maximum that in cremophor RH 40, has reached dissolubility increase.

Embodiment 2-uses the solubilising of the valsartan of surface activator composition

Valsartan is joined under mixing continuously in the integration material of surface activator composition to obtain uniform dispersion, prepare thus to have the valsartan solid dispersion of different solubilities enhancer compositions.In 0.1N HCl, measure the dissolubility of gained solid dispersion.

Table 2: the dissolubility of valsartan in 0.1N HCl with different solubilities enhancer compositions

Solid dispersion	The HLB of solubility enhancing agent compositions	Dissolubility mcg/ml
			Valsartan		84.60
Valsartan: stearoyl polyethyleneglycol glyceride, USP (Gelucire 50/ 13): SLS *，USP1∶0.5∶0.1	17.5	140
			Valsartan: stearoyl polyethyleneglycol glyceride, USP (Gelucire 50/ 13): SLS, US P1: 1: 0.1	15.5	171.19
Valsartan: polyoxyl 40 hydrogenated castor oil USP (Cremophor RH40): SLS, USP1: 0.5: 0.1	17.5	123.7
			Valsartan: polyoxyl 40 hydrogenated castor oil USP (Cremophor RH40): SLS, USP1: 1: 0.1	15.5	173.9

^*The SLS-sodium lauryl sulfate

In the compositions of surfactant, the maximum that the compositions of Cremophor RH 40 and SLS has reached dissolubility increases.

The preparation of embodiment 3-valsartan solid dispersion and the research of dissolution rate thereof

Having on the hot plate of thermoregulator under about 50 ℃ in beaker fusing Gelucire and (valsartan: ratio Gelucire) joined in the valsartan of fusing amount and mixes a period of time with 1: 0.5.In this mixture, add 2 parts of microcrystalline Cellulose and stir and reach room temperature until it.The disintegrating agent (is 280mg at this) that directly adds weighed amount in the stripping cylinder carries out stripping.

External stripping research

External stripping research is carried out according to following explanation:

Dissolution medium: 0.1N HCl, contain 0.5%SLS

Stripping experimental provision: USP II type

Temperature: 37.5 ± 0.5 ℃

RPM：50

Sampling interval: 5,10,15,30,60 and 120 minutes

Sample volume: 10ml

Table 3: the external stripping research of valsartan and valsartan solid dispersion separately

Time (minute)	Valsartan (% builds up stripping)	Valsartan solid dispersion (% builds up stripping)
			0 5 10 15 30 60 120	0 1.0 4.1 6.7 6.5 9.7 15.7	0 32.2 32.9 36.6 40.6 43.7 42.7

The valsartan that contains solubility enhancing agent in solid dispersion has been realized the remarkable increase of dissolution rate.When last, only there was 15% pure valsartan to be dissolved at 120 minutes.Yet the valsartan that in solid dispersion, contains solubility enhancing agent in 5 minutes with regard to stripping greater than 30% medicine (Fig. 1).

Embodiment 4-adds in quick-release tablet by the valsartan of solubilising (preparation #1)

The quick releasing formulation of table 4: valsartan-BEx (preparation #1)

Composition	The mg/ sheet
		The solid dispersion bulk phase
Valsartan	160
		The stearoyl polyethyleneglycol glyceride, USP (Gelucire50/13)	80
Microcrystalline Cellulose, USP (Avicel PH102)	320
		Outside
Microcrystalline Cellulose, USP (Avicel PH200)	160
		Silica sol, USP (Aerosil 200)	8
Magnesium stearate, USP	8
		Crosslinked-polyvidone, USP (Kollidon.CL)	22.08

The solid dispersion of valsartan and solubility enhancing agent is according to the method preparation of embodiment 3.Then solid dispersion is mixed with other adjuvant, lubricated and be pressed into tablet.

Dissolution rate in vitro research

External stripping research is carried out according to following explanation:

Stripping experimental provision: USP II type

Temperature: 37.5 ± 0.5 ℃

Dissolution medium: (900ml) carried out in stripping research in 0.1N HCl

Rpm：75

Sampling interval: 15,30,60 and 120 minutes

Sample volume: 10ml

The stripping curve of preparation #1 (table 4) and Diovan among the table 5:0.1N HCl

Time (minute)	160mg fast-release tablet (% builds up stripping)	Preparation #1 (% builds up stripping)
			0	0	0
15	5.5	28.7
			30	9.5	39.9
60	16.3	42.7
			120	26.8	51.0

Preparation of the present invention is compared with Diovan and is demonstrated higher and drug release curve (Fig. 2) faster.

Embodiment 5-joins the valsartan of solubilising in the tablet formulation that continues to discharge

Table 6: the tablet composition that continues release

Composition	The mg/ sheet
		The solid dispersion bulk phase
Valsartan	160.0
		The stearoyl polyethyleneglycol glyceride, USP (Gelucire50/13)	80.0
Microcrystalline Cellulose, USP (Avicel PH102)	320.0
		Outside
Hypromellose, USP (Methocel K100M)	50.0
		Lactose monohydrate, USP	250.0
Polyvinylpyrrolidone, USP	75.0
		Magnesium stearate, USP	9.35

Except valsartan solid dispersion and other adjuvant dry mixed that will contain Gelucire 50/13, magnesium stearate, and granulate with the alcoholic solution of polyvinylpyrrolidone.Dried particles in fluid bed dryer, lubricated and be pressed into tablet.

External release research

External stripping research is carried out according to following explanation:

Stripping experimental provision: USP I type

Temperature: 37.5 ± 0.5 ℃

Dissolution medium: 0.1N HCl, contain 0.5%SLS

RPM：100

Sampling interval: 1,2,3,4,6,8,10,12 and 18 hours

Sample volume: 10ml

Table 7: the release in vitro of valsartan in the extended release preparation

Time (hour)	% accumulates stripping
		0	0
1	2.8
		2	7.6
3	9.5
		4	12.9
6	21.6
		8	28.7
10	40.5
		12	53.8
18	97.4

Embodiment 6

In the fast-release tablet preparation, add by the valsartan of solubilising (preparation #2)

The quick releasing formulation of table 8: valsartan-BEx (preparation #2)

Composition	The mg/ sheet
		Solid dispersed phase
Valsartan	80.0
		Vitamin e TPGS, USP/NF	80.0
Microcrystalline Cellulose, USP (Avicel PH102)	240.0
		Outside
Microcrystalline Cellulose, USP (Avicel PH200)	400.0
		Silica sol, USP (Aerosil 200)	18.0
Magnesium stearate, USP	6.0
		Crosslinked-polyvidone, USP (Kollidon.CL)	25.0

The valsartan solid dispersion that contains vitamin e TPGS according to the method preparation of embodiment 3.Then that solid dispersion and other is all adjuvants mix, lubricated and be pressed into tablet.

Dissolution rate in vitro research

Dissolution rate in vitro research is carried out according to following explanation:

Stripping experimental provision: USP II type

Temperature: 37.5 ± 0.5 ℃

Dissolution medium: (900ml) carried out in stripping research in 0.1N HCl

RPM：75

Sampling interval: 15,30,60 and 120 minutes

Sample volume: 10ml

Table 9: the stripping curve (table 8) of preparation #2 in 0.1N HCl

Time (hour)	% accumulates stripping
		0	0
15	62.6
		30	77.6
60	80.3
		120	83.6

With the valsartan preparation of commercially available Diovan sheet and other research and development, preparation #1 compares with #3, and the preparation of this exploitation has higher and drug release curve (Fig. 3) faster.

Embodiment 7-adds in the fast-release tablet preparation by the valsartan of solubilising (preparation #3)

The quick releasing formulation of table 10: valsartan-BEx (preparation #3)

Composition	The mg/ sheet
		Physical mixture
Valsartan	80.0
		Poloxamer 407, USP (LutrolF 127)	80.0
Outside
		Microcrystalline Cellulose, USP (Avicel PH102)	320.0
Silica sol, USP (Aerosil200)	14.4
		Magnesium stearate, USP	9.6
Crosslinked-polyvidone, USP	29.0

Valsartan and Lutrol F 127 are carried out physical mixed.Then this mixture is further mixed with other all adjuvant, lubricated and be pressed into tablet.

Dissolution rate in vitro research

Dissolution rate in vitro research is carried out according to following explanation:

Stripping experimental provision: USP II type

Temperature: 37.5 ± 0.5 ℃

Dissolution medium: (900ml) carried out in stripping research in 0.1N HCl

RPM：75

Sampling interval: 15,30,60 and 120 minutes

Sample volume: 10ml

Table 11: the stripping curve of preparation #3 in 0.1N HCl

Time (hour)	% accumulates stripping
		0	0
15	38.9
		30	51.9
60	58.8
		120	65.5

Compare with commercially available Diovan sheet, the preparation of this exploitation has higher and drug release curve (Fig. 4) faster, but similar to the preparation #1 of research and development, and is slower than the preparation #2 of research and development.

Embodiment 8-join in the quick-release capsules dosage form by the research of solubilising valsartan preparation (80mg) (preparation #4) and oral relatively availability.

The quick-release capsules preparation of table 12: valsartan-BEx (preparation #4)

Sequence number	Composition	The Mg/ capsule
				Solid dispersed phase
1.	Valsartan	80.0
			2.	Vitamin-E TPGS, USP/NF	40.0
3.	Poloxamer 407, USP/NF (Lutrol F127)	40.0
			4.	Microcrystalline Cellulose, USP/NF (Avicel PH102)	240.0
	Outside
			5.	Microcrystalline Cellulose USP (AvicelPH102)	100.00
6.	Crosslinked-polyvidone, USP (Killidon.CI)	15.0
			7.	Crosslinked-polyvidone, USP (Killidon.VA64)	5.00
8.	Magnesium stearate, USP	6.00

A. step

With vitamin e TPGS and Lutrol 127MP (poloxamer 407, USP) fusing together under about 60 ℃.Under continuing mixing, valsartan is joined in this fusion mixture.In this material, add microcrystalline Cellulose (Avicel PH102) and cool to room temperature with the preparation solid particle.

Microcrystalline Cellulose (Avicel PH102) and partial cross-linked-polyvidone (Kollidon CL) are mixed with above-mentioned solid aggregate.These aggregates be dissolved in isopropyl alcohol: the copolyvidone in pure water (7: the 3) mixture is granulated.This wet stock is also dry by the #12 mesh screen.

Dried granules is mixed with the crosslinked-polyvidone (Kollidon.CL) of remainder, lubricated and incapsulate with magnesium stearate.

External stripping research: the actual conditions according to embodiment 7 carries out.

Table 13: preparation #4 and the relative stripping curve of Diovan in 0.1N HCl

Time (minute)	Preparation #4% accumulation stripping (avg ± S.D.)	Diovan  80% accumulation stripping (avg ± S.D.)
			0	0.0	0.0
15	70.4±7.0	4.1±0.3
			30	84.0±3.9	10.7±1.4
60	89.5±3.6	18.3±0.8
			120	92.4±2.8	29.4±1.7

Oral relatively availability research

The design crossing research shows in the body under quick condition in healthy male volunteers with respect to Diovan  (R) to estimate preparation #4 (T) valsartan capsule.According to data computation following pharmacokinetic parameters: T _Max(reaching the time of maximum plasma concentration), C _Max(maximum plasma concentration), AUC _0-t(0 hour the lower area of blood concentration-time curve of sample time) to the end and AUC _0-∞(0 hour lower area of blood concentration-time curve) to infinitely great (degree of absorption).

Table 14: the statistical summaries of pharmacokinetic parameters

		Unconverted data		The T/R ratio
					Parameter	Statistics	With reference to (R)	Test (T)
C max(ng/mL)	Meansigma methods (C.V.%)	4405.7(41.25)	7215.2(26.2)						1.637
				AUC 0-t(hr.ng/mL)	Meansigma methods (C.V.%)	29357.4(48.9)	44710.2(41.6)	1.523
AUC 0-∞(hr.ng/mL)	Meansigma methods (C.V.%)	29907.0(49.8)	45484.6(42.7)						1.521
				T max(hr)	Intermediate value (C.V.%)	2.66(37.2)	1.66(41.6)

C of the present invention _Max, AUC _0-tAnd AUC _0-∞Than commercially available prod height (Fig. 5).Therefore test the biological effectiveness of product than commercially available prod height.This tests the rapid-action of product.And this experiment product has been realized more uniform blood level and has been reduced mobility.Just obtained better preparation thus, it can reduce mobility, may allow to reduce dosage, can also quick acting, and this can improve patient's compliance.

The stripping that does not rely on pH of embodiment 9-tablet of the present invention (preparation #5)

The quick releasing formulation of table 15: valsartan-BEx, preparation #5

Sequence number	Composition	The Mg/ sheet
				Solid dispersed phase
1.	Valsartan	80.0
			2.	Poloxamer 407, USP/NF (Lutrol F127)	80.0
3.	Microcrystalline Cellulose, USP/NF (AvicelPH102)	240.0
				Outside
4.	Microcrystalline Cellulose USP (AvicelPH102)	400.00
			5.	Crosslinked-polyvidone, USP (Killidon.CI)	24.0
6.	Silica sol, USP (Aerosil200)	8.0
			7.	Magnesium stearate, USP	8.0

Step

With the poloxamer 407 of medicine and fusing, USP mixes, and material is being continued add microcrystalline Cellulose under the mixing then, and USP (Avicel PH102) also with the dispersion cool to room temperature, prepares solid dispersion with this.With the microcrystalline Cellulose of this solid dispersion and weighed amount, USP and copolyvidone are mixed lubricated then and tabletting.

Dissolution rate in vitro research

Dissolution rate in vitro research is carried out under different pH medium, is described as follows:

Stripping experimental provision: USP II type

Temperature: 37.5 ± 0.5 ℃

Dissolution medium: stripping is studied in the phosphate buffer USP of the acetate buffer of 0.1N HCl, pH4.5 and pH6.8 and is carried out

RPM:75 (for the buffer of 0.1N HCl and pH4.5) and 50 (for the buffer of pH6.8)

Sampling interval: 15,30,60 and 120 minutes (for the buffer of 0.1N HCl and pH4.5) and 10,20,30 and 45 minutes (for the buffer of pH6.8).

Sample volume: 10ml

Table 16: hypermedia stripping data

Time (minute)	0.1N HCl (pH～1.2) (% builds up stripping)	PH4.5 buffer (% builds up stripping)	PH6.8 buffer (% builds up stripping)
				0	0.0	0.0	0.0
10	-	-	71.7
				15	53.1	82.7	-
20	-	-	78.6
				30	78.8	90.7	81.9
45	-	-	86.3
				60	92.9	96.4	-

Said preparation provides the stripping curve that does not rely on pH, and above harmony in the exterior Fig. 6 is card.

The solubilising of embodiment 10-Eprosartan methylsulfonyl ester (mesylate)

The solubility enhancing agent of medicine and solubility enhancing agent or fusing is mixed with the Eprosartan methylsulfonyl ester of different proportion and the solid dispersion of different solubilities reinforcing agent.In 0.1NHCl, measure the dissolubility of gained solid dispersion.

Table 17: the solid dispersion of Eprosartan methylsulfonyl ester and the dissolving of acquisition enhancing property

Solid dispersion	Dissolubility in 0.1N HCl (mcg/ml)
		Eprosartan methylsulfonyl ester	712.0
Eprosartan methylsulfonyl ester: vitamin e TPGS 1: 0.2	958.3
		Eprosartan methylsulfonyl ester: PEG6000,1: 0.5	876.9
Eprosartan methylsulfonyl ester: Gelucire 50/13: SLS 1: 0.5: 0.2	1292.4
		Eprosartan methylsulfonyl ester: Gelucire50/13: Gelucire43/01 1: 0.5: 0.5	1003.9
Eprosartan methylsulfonyl ester: Gelucire50/13: Capmul MCM 1: 0.5: 0.5	967.8
		Eprosartan methylsulfonyl ester: Polyethylene Glycol 660 hydroxy stearic acid esters, USP (Solutol HS15): SLS 1: 1: 0.2	1245.6
Eprosartan methylsulfonyl ester: vitamin e TPGS: SLS 1: 0.5: 0.2	1025.9

The compositions of finding solubility enhancing agent provides higher dissolving enhancing property.Find to add SLS and can significantly improve dissolubility.

The solubilising of embodiment 11-Candesartan Cilexetil (candesartan cilexetil)

The adjuvant (as Solutol HS 15) of medicine and adjuvant (for example capryl caproyl (Caprylocaproyl) Polyethylene Glycol-8 glyceride, EP (Labrasol)) or fusing is mixed dispersion with preparation Candesartan Cilexetil and different auxiliary material.In 0.1N HCl, measure dispersions obtained dissolubility.

Table 18: the dissolving of candesartan cilexetil ester dispersion and acquisition enhancing property

Solid dispersion	0.1N the dissolubility among the HCl (mcg/ml)
		Candesartan Cilexetil	0.51
Candesartan Cilexetil: Polyethylene Glycol 660 hydroxy stearic acid esters, USP (Solutol HS 15) 1: 10	98.6
		Candesartan Cilexetil: capryl caproyl Polyethylene Glycol-8 glyceride, EP (Labrasol) 1: 10	8.9

The dissolubility of Solutol HS 15 or Labrasol all is significantly increased.

Although the at present preferred particular of the present invention is described at this, but, be conspicuous to those skilled in the relevant art of the present invention at the variation and the variant that do not deviate from shown here and contained various embodiments under the spirit and scope of the present invention.Therefore, the present invention only is subject to desired scope of accessory claim and the suitable needed degree of rules.

Claims (65)

1. compositions, it comprises

Valsartan or its salt, and

Solubility enhancing agent.

2. the compositions of claim 1, wherein solubility enhancing agent is selected from surfactant, solubilizing agent, chelating agent, hydrotropic solvent and cyclodextrin molecule.

3. the compositions of claim 1, wherein solubility enhancing agent is selected from PEG-40 castor oil hydrogenated, lauryl Polyethylene Glycol-32 glyceride, stearoyl polyethyleneglycol glyceride, PEG-20 sorbitan monolaurate, PEG-4 lauryl ether, polyox-yethylene-polyoxypropylene block copolymer, sodium lauryl sulfate, Polyethylene Glycol, d-alpha-tocopherol cetomacrogol 1000 succinate, and composition thereof.

4. the compositions of claim 1, wherein the amount of valsartan in compositions is about 1-80%.

5. the compositions of claim 1, wherein the amount of valsartan in compositions is about 5-50%.

6. the compositions of claim 1, wherein the amount of valsartan in compositions is about 10-30%.

7. the compositions of claim 1, wherein the ratio of valsartan and solubility enhancing agent is about 20: 1 to about 1: 20.

8. the compositions of claim 1, wherein the ratio of valsartan and solubility enhancing agent is about 10: 1 to about 1: 10.

9. the compositions of claim 1, wherein the ratio of valsartan and solubility enhancing agent is about 5: 1 to about 1: 5.

10. the compositions of claim 1, it further contains filler, binding agent or lubricant.

11. the compositions of claim 1, it further contains microcrystalline Cellulose, lactose, calcium silicates, aluminium-magnesium silicate and mannitol.

12. the compositions of claim 1, it further contains lasting release matrix.

13. the compositions of claim 12, wherein continue release matrix and be selected from the polyalkenyl oxide, cellulosic polymer, acrylic acid, methacrylate polymer, the ester of acrylic acid and methacrylate polymer, the maleic anhydride polymer, poly, poly-(acrylamide), poly-(enol), poly-(N-vinyl lactam), polyhydric alcohol, polyoxy ethylizes sugared, poly- azoles quinoline, polyvinylamine, polyvinylacetate, poly-imines, starch, the polymer of starch matrix, polyurethane hydrogel, chitosan, polysaccharide glue, zein, the Lac matrix polymer, poly(ethylene oxide), hydroxypropyl cellulose, hypromellose, hydroxyethyl-cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, methylcellulose, polyacrylic acid, maltodextrin, pregelatinized Starch, polyvinyl alcohol, copolymer, and composition thereof.

14. the compositions of claim 1, wherein compositions is tablet or capsule.

15. the compositions of claim 1, wherein the stripping under 60 minutes inherent pH＜3 is at least 40%.

16. the compositions of claim 1, wherein the stripping in 0.1N HCl should be at least 20% in 5 minutes, was at least 25% in 15 minutes, was at least 30% in 30 minutes, was at least 35% in 45 minutes, and was at least 40% in 60 minutes.

17. the compositions of claim 1, wherein stripping does not rely on pH basically.

18. the compositions of claim 1, wherein T _MaxBe about 1-2 hour.

19. the compositions of claim 1, wherein T _MaxBe about 1-2 hour, C _MaxBe at least the every mg valsartan of about 80ng/ml dosage.

20. the compositions of claim 1, wherein T _MaxBe about 1-2 hour, AUC is at least the every mg valsartan of 500nghr/ml dosage.

21. the compositions of claim 1, wherein the coefficient of variation of AUC (CV) is no more than 45%.

22. the compositions of claim 1, wherein the coefficient of variation of AUC (CV) is no more than 40%.

23. the compositions of claim 1, wherein C _MaxThe coefficient of variation (CV) be no more than 35%.

24. the compositions of claim 1, wherein C _MaxThe coefficient of variation (CV) be no more than 30%.

25. the compositions of claim 1, it further comprises other antihypertensive, antiadipositas drug, antidiabetic drug, beta blocker, inotropic agent, hypolipidemic, or its combination.

26. the compositions of claim 25, wherein other antihypertensive is selected from HCTZ, calcium channel blocker, beta blocker, ACE inhibitor, inotropic agent, hypolipidemic, renin inhibitor, and combination.

27. prepare the method for valsartan composition, be used to improve the dissolubility of valsartan, improve the absorption of valsartan, or reduce the absorption difference opposite sex of valsartan between the patient or in the patient, described method comprises following steps:

(a) provide valsartan or its salt

(b) provide solubility enhancing agent, and

(c) valsartan is mixed with solubility enhancing agent.

28. the method for claim 27, wherein step (c) comprises melt granulation, direct physical mixing, spray drying or solvent evaporation.

29. the method for claim 27, wherein solubility enhancing agent is selected from surfactant, solubilizing agent, chelating agent, hydrotropic solvent and cyclodextrin.

30. the method for claim 27, wherein solubility enhancing agent is selected from PEG-40 castor oil hydrogenated, lauryl Polyethylene Glycol-32 glyceride, stearoyl polyethyleneglycol glyceride, PEG-20 sorbitan monolaurate, PEG-4 lauryl ether, polyox-yethylene-polyoxypropylene block copolymer, sodium lauryl sulfate, Polyethylene Glycol, d-alpha-tocopherol cetomacrogol 1000 succinate, and composition thereof.

31. the method for claim 27, wherein the ratio of valsartan and solubility enhancing agent is about 10: 1 to about 1: 10.

32. the method for claim 27, wherein the ratio of valsartan and solubility enhancing agent is about 5: 1 to about 1: 5.

33. the method for claim 27, it further comprises the step that adds filler, binding agent or lubricant.

34. the method for claim 27, it further comprises the step that adds microcrystalline Cellulose, lactose, calcium silicates, aluminium-magnesium silicate or mannitol.

35. the method for claim 27, it further comprises and adds the step that continues release matrix.

36. the method for claim 35, wherein continue release matrix and be selected from the polyalkenyl oxide, cellulosic polymer, acrylic acid, methacrylate polymer, the ester of acrylic acid and methacrylic acid copolymer, the maleic anhydride polymer, poly, poly-(acrylamide), poly-(enol), poly-(N-vinyl lactam), polyhydric alcohol, polyoxy ethylizes sugared, poly- azoles quinoline, polyvinylamine, polyvinylacetate, poly-imines, starch, the starch matrix polymer, polyurethane hydrogel, chitosan, polysaccharide glue, zein, the Lac matrix polymer, poly(ethylene oxide), hydroxypropyl cellulose, hypromellose, hydroxyethyl-cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, methylcellulose, polyacrylic acid, maltodextrin, pregelatinized Starch, polyvinyl alcohol, copolymer, and composition thereof.

37. the method for claim 27, it further comprises the step with the mixture tabletting.

38. the method for claim 27, it further comprises antihypertensive, antiadipositas drug, antidiabetic drug, beta blocker, inotropic agent, the hypolipidemic that adds other, or the step of its combination.

39. the method for claim 27, wherein other antihypertensive is selected from HCTZ, calcium channel blocker, beta blocker, ACE inhibitor, inotropic agent, hypolipidemic, renin inhibitor, and combination.

40. the method for treatment disease, wherein disease is selected from blood circulation diseases, kidney disease, cerebral function obstacle, diabetic complications, arteriosclerosis, aldosteronism, multiple system organ failure, scleroderma, anxiety neurosis, catatonia and dyspepsia; Described method comprises the step of claim 1 compositions of the mammal treatment effective dose that needs this treatment.

41. the method for claim 40, wherein blood circulation diseases is hypertension, heart disease or peripheral circulation functional defect.

42. the method for claim 40, wherein kidney disease is glomerulonephritis or renal insufficiency.

43. the method for claim 40, wherein the cerebral function obstacle is apoplexy, Alzheimer, depression, amnesia or dementia.

44. the method for claim 40, wherein diabetic complications is retinopathy or nephropathy.

45. the method for claim 40, wherein arteriosclerosis is caused by hypertension, apoplexy, heart attack, angina pectoris or gastrointestinal tract ischemia or extremity ischemia.

46. the method for claim 40, wherein compositions further contains other antihypertensive, antiadipositas drug, antidiabetic drug, beta blocker, inotropic agent, hypolipidemic, or its combination.

47. the compositions of claim 46, wherein other antihypertensive is selected from HCTZ, calcium channel blocker, beta blocker, ACE inhibitor, inotropic agent, hypolipidemic, renin inhibitor, and combination.

48. a compositions, it comprises

Angiotensin-ii receptor blockers (ARB) or its salt, and solubility enhancing agent.

49. the compositions of claim 48, wherein solubility enhancing agent is selected from surfactant, solubilizing agent, chelating agent, hydrotropic solvent and cyclodextrin molecule.

50. the compositions of claim 48, wherein solubility enhancing agent is selected from PEG-40 castor oil hydrogenated, lauryl Polyethylene Glycol-32 glyceride, stearoyl polyethyleneglycol glyceride, PEG-20 sorbitan monolaurate, PEG-4 lauryl ether, polyox-yethylene-polyoxypropylene block copolymer, sodium lauryl sulfate, Polyethylene Glycol, d-alpha-tocopherol cetomacrogol 1000 succinate, and composition thereof.

51. the compositions of claim 48, wherein the amount of ARB in compositions is about 1-80%.

52. the compositions of claim 48, wherein the amount of ARB in compositions is about 5-50%.

53. the compositions of claim 48, wherein the amount of ARB in compositions is about 10-30%.

54. the compositions of claim 48, wherein the ratio of ARB and solubility enhancing agent is about 20: 1 to about 1: 20.

55. the compositions of claim 48, wherein the ratio of ARB and solubility enhancing agent is about 10: 1 to about 1: 10.

56. the compositions of claim 48, wherein the ratio of ARB and solubility enhancing agent is about 5: 1 to about 1: 5.

57. the compositions of claim 48, it further contains filler, binding agent or lubricant.

58. the compositions of claim 48, it further contains microcrystalline Cellulose, lactose, calcium silicates, aluminium-magnesium silicate and mannitol.

59. the compositions of claim 48, it further contains lasting release matrix.

60. the compositions of claim 59, wherein continue release matrix and be selected from the polyalkenyl oxide, cellulosic polymer, acrylic acid, methacrylate polymer, the ester of acrylic acid and methacrylate polymer, the maleic anhydride polymer, poly, poly-(acrylamide), poly-(enol), poly-(N-vinyl lactam), polyhydric alcohol, polyoxy ethylizes sugared, poly- azoles quinoline, polyvinylamine, polyvinylacetate, poly-imines, starch, the starch matrix polymer, polyurethane hydrogel, chitosan, polysaccharide glue, zein, the Lac matrix polymer, poly(ethylene oxide), hydroxypropyl cellulose, hypromellose, hydroxyethyl-cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, methylcellulose, polyacrylic acid, maltodextrin, pregelatinized Starch, polyvinyl alcohol, copolymer, and composition thereof.

61. the compositions of claim 48, wherein compositions is tablet or capsule.

62. the compositions of claim 48, wherein ARB is selected from Candesartan, Eprosartan, irbesartan, losartan, Olmesartan, telmisartan, valsartan and pratosartan.

63. the compositions of claim 48, it further contains other antihypertensive, antiadipositas drug, antidiabetic drug, beta blocker, inotropic agent, hypolipidemic, or its combination.

64. the compositions of claim 63, wherein other antihypertensive is selected from HCTZ, calcium channel blocker, beta blocker, ACE inhibitor, inotropic agent, hypolipidemic, and combination.

65. the compositions of claim 48, wherein the oral administration biaavailability of ARB than this height of ARB 1.2-4 doubly.

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