CN102647978A

CN102647978A - Pharmaceutical composition comprising poorly soluble active ingredient and hyperbranched polymer

Info

Publication number: CN102647978A
Application number: CN2010800550800A
Authority: CN
Inventors: S·雷文; E·扎加尔
Original assignee: Lek Pharmaceuticals dd
Current assignee: Lek Pharmaceuticals dd
Priority date: 2009-10-07
Filing date: 2010-10-06
Publication date: 2012-08-22
Also published as: WO2011042463A3; WO2011042463A2; EP2485716A2

Abstract

The present invention belongs to the field of pharmaceutical industry and relates to a pharmaceutical composition comprising at least one hyperbranched polymer and at least one pharmaceutically active ingredient, wherein the polymer and the pharmaceutically active ingredient are present in a specific weight ratio, and to a process for the preparation of said pharmaceutical composition. The present invention is also directed to a powder or granulate comprising at least one hyperbranched polymer and at least one pharmaceutically active ingredient in a specific weight ratio, to a process for the preparation of said powder or granulate, and to a pharmaceutical dosage form comprising the pharmaceutical composition, powder or granulate. Furthermore, the present invention relates to a process for preparing a solid dispersion of a hyperbranched polymer and at least one API. Moreover, it relates to the use of a crystalline carrier for the preparation of a mixture of hyperbranched polymer and a pharmaceutically active ingredient, as well as to the use of polyesteramide hyperbranched polymers for the preparation of a pharmaceutical composition, to the use of a hydrophilic or hydrophobic carrier for the preparation of said composition comprising a specific group of API, and to the use of a specific API and at least one hyperbranched polymer for the preparation of a pharmaceutical composition.

Description

Comprise the poorly soluble active component and the pharmaceutical composition of hyper branched polymer

Invention field

The invention belongs to the pharmaceuticals industry field; And relate to and comprise at least a hyper branched polymer and at least a pharmaceutical composition that in aqueous solvent, shows poorly soluble active constituents of medicine, wherein hyper branched polymer and active constituents of medicine (API) exist with specific weight ratio; Relate to said preparation of drug combination method.The invention still further relates to and comprise at least a hyper branched polymer and at least a powder or the granule that in aqueous solvent, shows poorly soluble active constituents of medicine, wherein polymer and API exist with specific weight ratio; Relate to said powder or particulate method for preparing and comprise said compositions, powder or particulate pharmaceutical dosage forms.The invention still further relates to the method for preparing and the purposes of crystallization carrier in the mixture of preparation hyper branched polymer and active constituents of medicine of the solid dispersion of hyper branched polymer and at least a API.In addition, the invention still further relates to the purposes of polyesteramide hyper branched polymer in pharmaceutical compositions, hydrophilic carrier purposes and specific API and the purposes of at least a hyper branched polymer in pharmaceutical compositions in the compositions of the described API that comprises particular group of preparation.

Background technology is described

Active constituents of medicine can only not be applied to the patient usually individually to be prevented or treats, but usually active constituents of medicine is mixed with pharmaceutical composition such as powder or tablet, for example coating or the single or multiple lift sheet of coating not.According to route of administration separately, ad hoc the designer drug compositions is to provide the dissolution characteristic of expection.Demonstrate the pharmacological activity of expection in order to ensure active constituents of medicine, it must reach enough concentration at site of action.This means that active constituents of medicine must demonstrate certain minimum dissolubility, this transfers the dissolubility that requirement usually improves each active constituents of medicine.

In this regard, can utilize multiple solubilising technology as adding cosolvent, carrying out the micelle solubilising, use cyclodextrin, change pH, solvent recrystallization, spray drying etc. so that in aqueous or other expection solvent, make insoluble or poorly soluble medicament solubilization through surfactant.

In addition, US 2009/0041813A1 discloses and has comprised at least a slightly water-soluble active substance and at least a compositions that comprises the hyper branched polymer of nitrogen-atoms.

Patent application WO 2004/072153 discloses multi-functional dendroid and the hyper branched polymer as effective medicine and genes delivery system.

Yet; Although there is above-mentioned composition, as far as improvedly comprising the pharmaceutical composition of active constituents of medicine, particularly still having demand with regard to the improved pharmaceutical composition that comprises active constituents of medicine of the dissolubility of active constituents of medicine and to the method for improved this type of preparation pharmaceutical composition.

Summary of the invention

The invention provides following aspect, theme and embodiment preferred, they have contribution to solving the object of the invention respectively alone or in combination:

(1) pharmaceutical composition comprises:

A) at least a hyper branched polymer; With

B) at least aly in the aqueous medium of pH6.8 and 37 ℃, demonstrate less than the dissolubility of 1mg/ml

Active constituents of medicine; Wherein said at least a hyper branched polymer: the weight ratio of described at least a active pharmaceutical ingredient is 99:1w/w to 11:1w/w; Perhaps wherein wt compares even can be 99:1w/w to 4:1w/w, and condition is that active pharmaceutical ingredient is selected from phosphodiesterase inhibitor, preferably phosphoric acid diesterase III inhibitor or Phosphodiesterase V inhibitors; Non-thiazine sulfonamide medicine (non-thiazide sulphonamides); Sulfonyl urea derivates; And hydroxyl-1, the 4-naphthoquinone derivatives; Perhaps the wherein wt ratio is 99:1w/w to 4:1w/w, and the high branched polyamide ester that condition is high branched polyamide ester, preferably have tertiary amine end groups or have a hydroxyl end groups is used as hyper branched polymer.Preferably, hyper branched polymer and active constituents of medicine form solid dispersion.

Preferred phosphodiesterase iii inhibitor is a pimobendan, and preferred Phosphodiesterase V inhibitors is a tadanafil; Preferred non-thiazine sulfonamide medicine is an indapamide; Preferred sulfonyl urea derivates is a glimepiride; Preferred hydroxyl-1, the 4-naphthoquinone derivatives is an atovaquone.In preferred embodiments, use have tertiary amine end groups high branched polyamide ester so that best API dissolubility to be provided.In another embodiment of the present invention, use high branched polyamide ester so that minimum pharmaceutical composition, powder or particulate wettability to be provided with hydroxyl end groups.

The weight ratio of hyper branched polymer/active medicine of the present invention is preferably 99:1 to 11:1.In preferred embodiments, weight ratio is 99:1 to 14:1, and going back preferred weight ratio is 99:1 to 17:1, even to go back preferred weight ratio be 99:1 to 18:1.In another embodiment preferred, weight ratio is 80:1 to 11:1, and going back preferred weight ratio is 55:1 to 11:1, even to go back preferred weight ratio be 24:1 to 11:1.In another embodiment, weight ratio is 80:1 to 14:1, and going back preferred weight ratio is 55:1 to 17:1, even to go back preferred weight ratio be 24:1 to 18:1.Preferably; For example when active pharmaceutical ingredient was glimepiride or indapamide, the weight ratio of hyper branched polymer and said active pharmaceutical ingredient was 80:20w/w to 98:2w/w, preferred 88:12w/w to 98:2w/w; More preferably 90:10w/w to 98:2w/w; Also more preferably 93:7w/w to 98:2w/w, particularly 98:2w/w to 95:5w/w, also preferred 98:2w/w to 95:2w/w.

(2) pharmaceutical composition of (1) item, wherein the mixture of hyper branched polymer and active constituents of medicine also comprises at least a water-dispersible or water solublity pharmaceutically suitable carrier.Preferably, described hyper branched polymer and described at least a active pharmaceutical ingredient form solid dispersion or solid solution.Preferably, solid dispersion forms between described hyper branched polymer and described at least a active constituents of medicine.Also preferred solid dispersion or solid solution obtain through adopting known technology (for example high shear mixing, spray drying or fluidized bed granulation).In intended scope of the present invention, solid dispersion is represented the solid-state dispersion of one or more chemical compounds in inert carrier.The solid solution of one or more solutes in solvent represented in term " solid solution ", and wherein mixture remains single homogeneous phase.

(3) pharmaceutical composition of (1) or (2) item; Wherein said at least a hyper branched polymer comprises hydroxyl, ester group, acylamino-and/or carboxyl; Preferred described at least a hyper branched polymer comprises ester or acylamino-; Preferred hyper branched polymer is a polyesteramide, if the weight ratio of hyper branched polymer and said active pharmaceutical ingredient is 11:1 or higher.

The pharmaceutical composition of (4) (2)-(3) item; Wherein water-dispersible or water-solubility carrier are selected from modification or unmodified carbohydrate; Preferred monomers, oligomeric or poly carbohydrate, preferred modification or unmodified monomer, oligomeric or poly monosaccharide or straight or branched oligosaccharide or polysaccharide; Wax; Natural gum; Organic or inorganic acid or alkali or its salt; Surfactant; Synthetic polymer; Modification or unmodified silicon dioxide; Mineral pharmaceutical excipient or its combination; Preferred vector is crystalline.

(5) pharmaceutical composition of (4) item, wherein organic acid is aminoacid or citric acid.

(6) above-mentioned each pharmaceutical composition, wherein carrier is sucrose, maltose, lactose, glucose, mannose, mannitol, sorbitol, xylitol, erythritol, lactitol, maltose alcohol, starch or modified starch such as pregelatinized Starch, corn starch, potato starch or corn starch; Alginate, gelatin, carrageenin, glucosan, maltodextrin (maltodextran), dextrates, dextrin, polydextrose or tragakanta; Arabic gum, guar gum, xanthan gum; Cellulose such as carboxymethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, Powderd cellulose or microcrystalline Cellulose; Polyacrylic acid, modification or unmodified alginate or chitosan, gelatin, pectin, polyethylene, glycol Polyethylene Glycol (glycolpolyethylene glycol), polyvinylpyrrolidone, polyvinyl alcohol, polyoxyethylene copolymer, polyoxypropylene copolymer or PEO; Arginine, meglumine, lysine, MEA, diethanolamine, triethanolamine, Propanolamine, dipropanolamine, thiamine, sodium salicylate or its mixture.

(7) pharmaceutical composition of (6) item; Wherein carrier is selected from lactose, sucrose, maltose, mannitol, sorbitol, xylitol, erythritol, lactitol, maltose alcohol, starch and cellulose; Preferred lactose, maltose, mannitol, sorbitol, starch and cellulose; More preferably lactose and cellulose, also more preferably carrier is a lactose.

(8) powder or granule comprise

A) at least a hyper branched polymer;

Active constituents of medicine;

Wherein said at least a hyper branched polymer: the weight ratio of described at least a active pharmaceutical ingredient is 99:1w/w to 11:1w/w; Perhaps wherein wt compares even can be 99:1w/w to 4:1w/w, and condition is that active pharmaceutical ingredient is selected from phosphodiesterase inhibitor, preferably phosphoric acid diesterase III inhibitor or Phosphodiesterase V inhibitors; Non-thiazine sulfonamide medicine; Sulfonyl urea derivates; And hydroxyl-1, the 4-naphthoquinone derivatives; Perhaps the wherein wt ratio is 99:1w/w to 4:1w/w, and the high branched polyamide ester that condition is high branched polyamide ester, preferably have tertiary amine end groups or have a hydroxyl end groups is used as hyper branched polymer; With

C) hydrophilic or hydrophobic carrier, the preferred hydrophilic carrier, more preferably carrier is crystalline.

(9) powder or the granule of (8) item, wherein said hyper branched polymer and described at least a active constituents of medicine form solid dispersion or solid solution, and preferred solid dispersion or solid solution and active constituents of medicine and solid or dissolved carrier merge.Preferred vector is a solid carrier.Can carrier and solid dispersion or solid solution be merged through adopting mixing, high shear mixing, spray drying, fluidized bed granulation or lyophilization.Preferably the solution with step b) is sprayed on the carrier granular.

Preferred solid dispersion forms between described hyper branched polymer and described at least a active constituents of medicine.

(10) above-mentioned each pharmaceutical composition, wherein in the compositions amount of included carrier respectively based on pharmaceutical composition and powder or particulate weight be calculated as 10% to 90%, preferred 30% to 60%, more preferably 50% to 80%, also more preferably 70% to 80%.

(11) above-mentioned each pharmaceutical composition, powder or granule; Wherein said at least a active constituents of medicine is selected from glimepiride, gliclazide, glipizide, glibenclamide, pimobendan, tadanafil, atovaquone and indapamide; Preferred glimepiride, pimobendan, tadanafil, atovaquone and indapamide, more preferably active constituents of medicine is a glimepiride.

(12) above-mentioned each pharmaceutical composition, powder or granule also comprises other active constituents of medicine.Preferably, described other active constituents of medicine is selected from thiazolidinedione (thiazolidinone) type medicine, biguanides, statins, Bei Te (fibrate) type medicine, phenothiazine drug and acarbose, miglitol, voglibose, orlistat, sibutramine, Rimonabant, Exenatide (exenatide) and AC-137; Preferably, described other active constituents of medicine is selected from biguanides, thiazolidinediones medicine and phenothiazine drug; More preferably, it is selected from the thiazolidinediones medicine.Active constituents of medicine from the thiazolidinediones medicine for example has pioglitazone, Li Gelie ketone (rivoglitazone), rosiglitazone, troglitazone.Preferably the active constituents of medicine from the thiazolidinediones medicine has pioglitazone or rosiglitazone, more preferably pioglitazone.Active constituents of medicine from biguanides for example has phenformin, buformin or metformin, preferred metformin.Active constituents of medicine from statins for example has atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, Pitavastatin, pravastatin, rosuvastatin or simvastatin.Preferred statins active component has atorvastatin, pravastatin, rosuvastatin or simvastatin, more preferably rosuvastatin.

In another embodiment preferred, pharmaceutical composition of the present invention, powder or granule comprise the active constituents of medicine of one or more (11) item and the active constituents of medicine of one or more (12) item.In another embodiment preferred, pharmaceutical composition of the present invention comprises the active constituents of medicine of a kind of being selected from (11) item and the active constituents of medicine of a kind of being selected from (12) item.

(13) each pharmaceutical composition, powder or granule of (2)-(11), the composition that wherein forms solid dispersion or solid solution is deposited on pharmaceutically suitable carrier.

Preferably, said composition forms solid dispersion.

(14) above-mentioned each pharmaceutical composition, powder or granule, wherein pharmaceutical composition, powder or granule randomly with pharmaceutically acceptable mixed with excipients.Preferably, excipient is a filler, for example lactose, mannitol, cellulose derivative and sucrose; Disintegrating agent, for example cross-linking sodium carboxymethyl cellulose, calcium carbonate, carboxymethylcellulose calcium; Binding agent, for example polyvinylpyrrolidone; Lubricant, for example magnesium stearate, stearic acid and silicon dioxide; Aromatic, for example vanilla extract (vanilla extract); Coloring agent, for example titanium dioxide; Sweeting agent, for example glucide; Coating polymer, for example hydroxypropyl emthylcellulose; Or solvent, for example water and organic solvent.Preferably, pharmaceutical composition, powder or granule do not contain surfactant (surfactant).

(15) comprise aforementioned each pharmaceutical composition, powder or particulate pharmaceutical dosage forms, pharmaceutical dosage forms solid dosage form preferably wherein, the form of pill, tablet, capsule, sachet preferably, preferred said dosage form is a tablet.

(16) pharmaceutical dosage forms of (15) item, wherein tablet is the form of single-layer sheet, double-layer tablet, multilayer tablet and/or coated tablet; Capsule is the coating capsule.

(17) each pharmaceutical composition, powder, granule or pharmaceutical dosage forms of (2)-(17), wherein pharmaceutically suitable carrier is crystalline.

(18) preparation of drug combination method, this method comprises the following steps:

A) provide at least a hyper branched polymer, preferably as in 3 defined hyper branched polymer and at least a in the aqueous medium of pH6.8 and 37 ℃, demonstrate active pharmaceutical ingredient less than the dissolubility of 1mg/ml, preferred at least a as (11) and/or (12) in defined active constituents of medicine; Its weight ratio is 99:1w/w to 11:1w/w, preferably as 1 in defined weight ratio; Perhaps wherein wt is than being 99:1w/w to 4:1w/w, and condition is that active pharmaceutical ingredient is selected from phosphodiesterase inhibitor, non-thiazine sulfonamide medicine, sulfonyl urea derivates and hydroxyl-1, the 4-naphthoquinone derivatives; Perhaps wherein wt is than for 99:1w/w to 4:1w/w, and the high branched polyamide ester that condition is high branched polyamide ester, preferably have tertiary amine or a hydroxyl is used as hyper branched polymer;

B) mixture of formation described at least a hyper branched polymer, described at least a active pharmaceutical ingredient and organic solvent randomly mixes; With

C) except that desolvating.Preferably, described at least a hyper branched polymer and described at least a active pharmaceutical ingredient are dissolved in the organic solvent fully.Preferably, in first method, remove organic solvent, form solid dispersion and/or solid solution, preferred solid dispersion.More preferably, through adopt mixing, spray drying, fluidized bed granulation or lyophilization, more preferably spray drying and fluidized bed granulation are removed organic solvent.

(19) powder of the present invention or particulate method for preparing, this method comprises the following steps:

A) at least a hyper branched polymer and at least aly in the aqueous medium of pH6.8 and 37 ℃, demonstrate the active pharmaceutical ingredient less than the dissolubility of 1mg/ml is provided; Weight ratio is 99:1w/w to 11:1w/w; Perhaps or even weight ratio be 99:1w/w to 4:1w/w, condition is that active pharmaceutical ingredient is selected from phosphodiesterase inhibitor, preferably phosphoric acid diesterase III inhibitor or Phosphodiesterase V inhibitors; Non-thiazine sulfonamide medicine; Sulfonyl urea derivates; And hydroxyl-1, the 4-naphthoquinone derivatives; Perhaps weight ratio is 99:1w/w to 4:1w/w, and the high branched polyamide ester that condition is high branched polyamide ester, preferably have tertiary amine end groups or have a hydroxyl end groups is used as hyper branched polymer;

B) mixture of formation described at least a hyper branched polymer, described at least a active pharmaceutical ingredient and organic solvent; With

C) except that desolvating and preparing powder or granule, wherein step b) or step c) also comprise mixture and hydrophilic or hydrophobic carrier, preferred hydrophilic carrier, more preferably the crystallization carrier merges.Preferably, organic solvent is removed and allows effectively formation solid solution and/or solid dispersion, preferred solid dispersion.

(20) method of (18) or (19) item, wherein organic solvent is selected from C ₂-C ₄Alkanol, for example ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutanol; Aliphatic series or alicyclic ethers, for example ether, Di Iso Propyl Ether, methyl tertiary butyl ether(MTBE), two

Alkane, oxolane; Ketone, for example acetone, methyl ethyl ketone; Dimethyl sulfoxine and dimethyl formamide; Or its mixture.

(21) each method of (18)-(20) wherein adds water-dispersible or water solublity pharmaceutically suitable carrier, preferably as above-mentioned defined carrier in each in step b).

(22) each method of (18)-(21) is wherein mixed and can during step b) and/or step c), be carried out.

(23) each method of (18)-(22), wherein step c) is carried out through adopting mixing, high shear mixing, spray drying, fluidized bed granulation or lyophilization.

(24) each method of (18)-(23) also comprises drying steps.In preferred embodiments, drying can be in vacuum drying oven be lower than 60 ℃, preferably be lower than under 50 ℃ the temperature, most preferably under 40 ℃ or following temperature, carrying out.

(25) each method of (20)-(26), wherein powder or granule are pressed into tablet or are packed in the capsule.

(26) each method of (18)-(25) also comprises adding other active constituents of medicine.Preferably; Other active constituents of medicine is selected from thiazolidinediones medicine, biguanides, statins, fibrate, phenothiazine drug, acarbose, miglitol, voglibose, orlistat, sibutramine, Rimonabant, Exenatide and AC-137; Be preferably selected from biguanides, thiazolidinediones medicine and phenothiazine drug, more preferably be selected from the thiazolidinediones medicine.

(27) method for preparing of the solid dispersion of hyper branched polymer and at least a active constituents of medicine and/or solid solution, this method comprises the following steps:

A) mixture of formation described at least a hyper branched polymer, described at least a active pharmaceutical ingredient and organic solvent, preferred described at least a hyper branched polymer and described at least a active pharmaceutical ingredient are dissolved in the organic solvent fully;

B) through adopting high shear mixing, spray drying or fluidized bed granulation that solid dispersion and/or solid solution from the dispersion/solution of step a) are provided, wherein the solid dispersion of mixture in the step a) or step b) and/or solid solution are randomly with hydrophilic or hydrophobic carrier, preferred hydrophilic carrier, more preferably the crystallization carrier merges.

(28) method of (27), the weight ratio of wherein said at least a hyper branched polymer and described at least a active pharmaceutical ingredient in the above-mentioned item definition.

(29) the crystallization carrier comprises the purposes in the pharmaceutical composition of hyper branched polymer and active constituents of medicine in preparation.

(30) purposes of (29) item, wherein hyper branched polymer and ingredient form solid dispersion.

(31) polyesteramide hyper branched polymer, the polyester hyper branched polymer that preferably has tertiary amine or a hydroxyl end groups comprise the purposes in the pharmaceutical composition of at least a active pharmaceutical ingredient in preparation; The weight ratio of wherein said hyper branched polymer and described at least a active pharmaceutical ingredient is 99:1w/w to 11:1w/w; Perhaps wherein wt compares even can be 99:1w/w to 4:1w/w, and condition is that active pharmaceutical ingredient is selected from phosphodiesterase inhibitor, preferably phosphoric acid diesterase III inhibitor or Phosphodiesterase V inhibitors; Non-thiazine sulfonamide medicine; Sulfonyl urea derivates; And hydroxyl-1, the 4-naphthoquinone derivatives.

(32) hydrophilic or the hydrophobic carrier purposes in pharmaceutical compositions; Said pharmaceutical composition comprises and blended phosphodiesterase inhibitor, non-thiazine sulfonamide medicine, sulfonyl urea derivates and hydroxyl-1, the active constituents of medicine of 4-naphthoquinone derivatives, preferred non-thiazine sulfonamide medicine of being selected from of at least a hyper branched polymer.

(33) purposes of hydrophilic carrier in pharmaceutical compositions; Said pharmaceutical composition comprises and blended phosphodiesterase inhibitor, non-thiazine sulfonamide medicine, sulfonyl urea derivates and hydroxyl-1, the active constituents of medicine of 4-naphthoquinone derivatives, preferred non-thiazine sulfonamide medicine of being selected from of at least a hyper branched polymer.

(34) be selected from phosphodiesterase inhibitor, non-thiazine sulfonamide medicine, sulfonyl urea derivates and hydroxyl-1; The active pharmaceutical ingredient of 4-naphthoquinone derivatives comprises the purposes in the pharmaceutical composition of at least a hyper branched polymer in preparation; Wherein said at least a active constituents of medicine demonstrates the dissolubility less than 1mg/ml in the aqueous medium of pH6.8 and 37 ℃, and the weight ratio of wherein said at least a hyper branched polymer and described at least a active pharmaceutical ingredient is 99:1w/w to 4:1w/w.

(35) purposes of (34) item, wherein ingredient is selected from pimobendan, tadanafil, indapamide, glimepiride and atovaquone.

Detailed Description Of The Invention

Describe the present invention in more detail through embodiment preferred and embodiment now, still, these embodiments and embodiment only are used for purpose of explanation, limit scope of the present invention by any way and should not be construed as.

One of the most challenging difficult problem is that (active pharmaceutical ingredient API) is delivered to the site of action of expection with the active constituents of medicine of treatment effective dose in pharmaceutics.But in order to demonstrate the pharmacological activity of expection, API must reach enough concentration at site of action.For the site of action in expection reaches effective API concentration, API should demonstrate the dissolubility that allows to reach valid density.

Therefore, pharmaceutical composition of the present invention provides effective needed active constituents of medicine concentration in physiological environment.For example, when comprising the pharmaceutical composition of active constituents of medicine, the dissolubility of said API is enough high to reach required concentration or when absorbing, to reach essential haemoconcentration at target site such as gastrointestinal tract Orally administered.Therefore, pharmaceutical composition of the present invention need not contain more a large amount of API, and this is normally required in order to compensate API poor solubility in aqueous solution.This then cause pharmaceutical composition not demonstrate size increasing, the latter can influence patient's compliance unfriendly.In addition, pharmaceutical composition of the present invention and this preparation of drug combination method are effectively many with regard to cost: the dissolubility based on the API that exists in the pharmaceutical composition improves, and needed API measures less for effective API concentration that expection is provided at target site.

In addition, through using method of the present invention, can avoid load limit, solubilizing agent toxicity (for example nephrotoxicity), when surfactants based solubilising, keep the requirement of certain critical micelle concentration and in pH changes, select limited.

In context of the present invention, unexpectedly observe: the dissolubility of poorly soluble active pharmaceutical ingredient can obtain increasing especially, and condition is to use the specified weight ratio of described hyper branched polymer and described at least a active pharmaceutical ingredient.

For specific API as described herein, can obtain the extra high relative increase (comparing) of dissolubility with independent API.Wherein, this contribution allows to use the weight ratio widely of hyper branched polymer: API.As can be from Fig. 3-7 resulting; API of the present invention provides very high dissolution rate especially in preceding 5 minutes of dissolution test, wherein said API is selected from phosphodiesterase inhibitor, preferably phosphoric acid diesterase III inhibitor or Phosphodiesterase V inhibitors; Non-thiazine sulfonamide medicine; Sulfonyl urea derivates; And hydroxyl-1, the 4-naphthoquinone derivatives.Therefore, the mixture of hyper branched polymer and API of the present invention provides quick stripping, and it causes the medicine blood plasma level in the object of the medicine composite for curing that comprises this mixture, advantageously to increase fast.Preferred especially API is a pimobendan, and it demonstrates the highest dissolution rate increases (map 7).

If described hyper branched polymer and described at least a active pharmaceutical ingredient form solid dispersion, then dissolubility can further be increased.Also have been found that: polyesteramide hyper branched polymer, the polyesteramide hyper branched polymer that particularly has tertiary amine or a hydroxyl end groups are particularly advantageous (map 3 and 4) to the dissolubility that increases API.Yet; Use have hydroxyl end groups polyesteramide (for example

aspect the pharmaceutical composition, powder, granule or the pharmaceutical dosage forms that obtain to have extremely low wettability be preferred (referring to Fig. 8, if

used in its demonstration as hyper branched polymer water absorption would be minimum).

Also have been found that: when using hydrophilic or hydrophobic carrier, preferred hydrophilic carrier, the powder or the granule (referring to Fig. 8) that can prepare the described hyper branched polymer that comprises the specified weight ratio and described at least a active pharmaceutical ingredient and have the characteristic (for example low wettability) of improvement.This confession choosing or select parallel technical contribution to allow to use the weight ratio widely of hyper branched polymer: API once more with API.But also observe: in the situation of using the crystallization carrier, the stability of API and dissolubility can even increase manyly.If when pharmaceutical composition should be the form of powder or granule or dosage form, this was particularly advantageous.Have been found that: adopt the crystallization carrier to cause the wettability of pharmaceutical composition to descend, avoided the liquefaction of powder or granule thus.In addition, in context of the present invention, unexpectedly find: the ratio of hyper branched polymer/at least a active pharmaceutical ingredient should be at least 11:1 or with regard to specific API, be at least 4:1, so that the dissolubility of remarkable increase is provided.Yet when the amount of hyper branched polymer was too high, dissolubility descended.Do not hope to be entangled in any theory, the dissolubility of inferring corresponding API increases, because the former unconjugated poorly soluble active pharmaceutical ingredient and hydroxyl, ester, acylamino-and/or the carboxyl of hyper branched polymer interact.When the weight ratio of hyper branched polymer: API is higher than 99:1, possibly exists and when the H-key between the hyper branched polymer self is preponderated above the intermolecular interaction between active component and the polymer, cause the closed and situation that no longer the dissolubility that increases active component is contributed of polymer.On the other hand, when the ratio of hyper branched polymer/active constituents of medicine during less than 11:1, the intermolecular interaction of active constituents of medicine can cause the active constituents of medicine crystallization, thereby reduces dissolubility.

One of most important main points that when the designer drug compositions, must satisfy be the composition of said compositions be biocompatibility and suit in live organism, to use.

As for example for multiple cationic systems, comprise liposome with the surface group that carries cationic charge and micelle viewed, these cationic systems can easily be damaged cell membrane, cause lysis.Therefore, before considering to use them, the hypotoxicity problem is that hyper branched polymer is correlated with, as for any other promising pharmaceutical excipient.Because the biocompatibility of hyper branched polymer, they are applicable to mammal.Especially, high branched polyamide ester had not only had amide, but also had had the ester link, and this causes amphipathic and biodegradability.High branched polyamide ester has the biodegradability of the excellent mechanical properties and the polyester of polyamide.Because the polarity of amide group and they form the ability of hydrogen bond, these polymer demonstrate good heat and mechanical property, even also are like this when low-molecular-weight.On the other hand, can be that polymer provides biodegradability through the ester bond of hydrolytic degradation.Report: the branching of polyesteramide has strengthened in alkalescence and the hydrolysis in phosphate buffered salt solution basically, has alleviated the load to live organism especially.

Pharmaceutical composition, powder or granule have been described hereinafter in more detail.Pharmaceutical composition, powder or granule comprise at least a hyper branched polymer, preferred specific hyper branched polymer as described herein.

In intended scope of the present invention; Term " hyper branched polymer " ordinary representation is known as dendritic (dendritic polymers), tree shaped polymer (dendrimers), arbor branch shape polymer (arborol), cascade polymers, cauliflower polymer or star polymer, polydispersion hyper branched polymer, connects the polymer very widely of branch polymer (dendrigraft polymers) or other heavy polymer; They all have the specific branched structure that comprises central atom or molecule; Can be monomer or polymeric, exhale three or more chains therefrom.Therefore hyper branched polymer is different from linear polymer, copolymer or graft polymers, crosslinked linear polymer or comb polymer.

Another marked feature of hyper branched polymer in intended scope of the present invention is that they have a large amount of functional end-groups.When having a large amount of terminal groups, the intermolecular interaction between the hyper branched polymer mainly depends on the type of functional end-group, causes glass transition temperature, dissolubility, one-tenth film characteristics etc. significantly to change.Especially, owing to there are a large amount of terminal groups, this hyper branched polymer has the characteristic that the general linear polymer is not had.The characteristic of fluid of hyper branched polymer significantly is different from the characteristic of fluid of the linear polymer with similar repetitive chemical constitution and same molecular amount.One of most important characteristics of high branching or dendritic is that they can not make polymer chain crystallization or winding, regardless of its molecular weight.Utilize existing understanding can not accurately predict the miscibilty of these polymer, because the interaction between the branched structure impact polymer chain to the linear polymer rule.In addition, hyper branched polymer can have a large amount of also along the functional group of side chain.According to the present invention, the preferred use comprises hydroxyl, ester group, acylamino-and/or the carboxyl hyper branched polymer as functional end-group (end group).Preferably, hyper branched polymer comprise ester group or acylamino-or they both, also preferred hyper branched polymer is a polyesteramide, also preferably has the polyesteramide of tertiary amine end groups.Also have been found that: when with the general linear polymer phase than the time, polyesteramide hyper branched polymer, the polyesteramide hyper branched polymer that particularly has tertiary amine or a hydroxyl end groups are particularly advantageous (contrast Figure 1B and Fig. 3 and 4) for the dissolubility that increases API.

Usually, can be according to the synthetic hyper branched polymer of any suitable method well known by persons skilled in the art.Preferably; Through identical or different monomer being coupled to central atom or molecule synthesizes hyper branched polymer in that one or many is in service; Wherein at least some monomers have three or more a plurality of functional group; Make coupling reaction subsequently on unreacted functional end-group, to carry out, cause forming a chain extension.Monomer in the intended scope of the present invention is can be with chemical mode and the micromolecule of other monomer bonding with the formation polymer.Monomer can be synthetic, for example hydrocarbon; Or natural, aminoacid for example.Said method can be used to produce at random or in order hyper branched polymer in various degree.In addition; From for example increasing functional group's number or replace them and with polymer and other molecule is covalently bound, the reason that promptly is used to send nutrient, vitamin or active pharmaceutical ingredient, the functional end-group that replacement that can be through subsequently or additive reaction customize hyper branched polymer.In addition, allow the protection hyper branched polymer when being applied to the human or animal, to avoid being detected as polymer chain Polyethylene Glycol by the monokaryon macrophage system.But can also introducing and receptor or organize complementary recognition group or introducing to help the part that cell membrane is passed in the hyper branched polymer transhipment.

The preferred hyper branched polymer that the present invention uses is the polydispersity hyper branched polymer, the also known in addition dendritic (in addition also have tree shaped polymer and connect the branch polymer) that belongs to as one of subclass.For example, tree shaped polymer is single stepwise branching macromole that disperses of terminal groups exponential growth when at every turn synthesizing generation.Disperse perfect structure in order to obtain list, necessary purified product behind each synthesis step, this makes and synthesizes costliness and limited its application in high value added product.Tree shaped polymer has low polydispersity, so would rather they be monodispersities.The ratio of the Mw/Mn of tree shaped polymer is about 1.0, preferably less than 1.01, their molecular weight can be through the mathematical method prediction.Opposite with tree shaped polymer, the polydispersity hyper branched polymer obtains through condensation reaction at random, causes it to control molecular weight and branching only is limited.The polydispersity hyper branched polymer has more than 1.1, the ratio of preferred about 2 Mw/Mn, but can even surpass 3, and for example 5.The polydispersity of polymer samples is the tolerance of molecular weight distribution in the said polymer samples.It is expressed as weight average molecular weight (Mw) divided by number-average molecular weight (Mn).The value of polydispersity can be equal to or greater than 1.Sample has the polydispersity value of the unit of approaching (1) more uniformly with regard to the polymer chain with homogeneous length more.The number-average molecular weight (Mn) of preferred polydispersity multi-branch polymer is 400 to 100000g/mol, preferred 700 to 60000g/mol, more preferably 1000 to 5000g/mol, particularly about 1200g/mol or about 1600g/mol.

Preferred hyper branched polymer of the present invention is that high branching is gathered imines, high branched polyurethanes, high branched polyamide, high branched polyester amine, high branched polyamide ester; Preferred especially high branched polyester amine and high branched polyamide ester, even further preferred high branched polyamide ester.Be understood that said hyper branched polymer can introduce different monomers in its structure, and functional end-group can be chosen and is changed wantonly.For example; Following obtain high branched polyamide ester, be preferred hyper branched polymer of the present invention: at first monomer is provided through making cyclic anhydride (for example succinic anhydride, hexahydrophthalic anhydride or phthalic anhydride) generate teritary amide with a COOH and two OH groups with the diisopropanolamine (DIPA) reaction, then under the gentle relatively condition, do not having catalyst in the presence of make it carry out polycondensation reaction via

azoles quinoline intermediate in batches.Through changing and merging anhydride and change, can obtain having a large amount of different structures of characteristic of coexisting with the end group of few types.Two instances representing hydrophilic, the high branched polyamide ester of water solublity are Hybrane S1200 (terminal hydroxyl) and HA1690 (terminal tertiary amine group).

Pharmaceutical composition, powder or granule also comprise at least a active pharmaceutical ingredient with low solubility.

A large amount of active pharmaceutical ingredients have the dissolubility less than 1mg/ml in the aqueous medium of pH6.8 and 37 ℃.Dissolubility as referred to herein be adopt USP apparatus 2 (American Pharmacopeia 32-NF27), under the stirring of 75RPM, maintaining in the dissolution medium of phosphate buffer of pH6.8 and 37 ℃ and measuring.The useful pharmaceutical composition that this low feasible preparation of dissolubility has acceptable size and effectiveness is especially difficult.

Pharmaceutical composition of the present invention contains and at least aly in the aqueous medium of pH6.8 and 37 ℃, demonstrates the active constituents of medicine less than the dissolubility of 1mg/ml.In preferred embodiments, this and its pharmacological effect that possibly have or its are used to the disease independent of preventing or treating.When stipulating active pharmaceutical ingredient used according to the invention, the dissolubility of this active pharmaceutical ingredient is measured through only adopting said active pharmaceutical ingredient, that is, said active pharmaceutical ingredient does not mix with any additives such as hyper branched polymer.In a preferred embodiment of the invention; The dissolubility of active pharmaceutical ingredient in the aqueous medium of pH6.8 and 37 ℃ is being equal to or less than 1mg/ml and the scope that is equal to or greater than 0.2mg/ml; Also preferably be equal to or less than 1mg/ml and the scope that is equal to or greater than 0.3mg/ml, even also preferably be equal to or less than 1mg/ml and the scope that is equal to or greater than 0.4mg/ml.

Preferred active pharmaceutical ingredient is selected from: phosphodiesterase inhibitor, preferably phosphoric acid diesterase III inhibitor or Phosphodiesterase V inhibitors; Non-thiazine sulfonamide medicine; Sulfonyl urea derivates; And hydroxyl-1, the 4-naphthoquinone derivatives.Preferred phosphodiesterase iii inhibitor is a pimobendan, and preferred Phosphodiesterase V inhibitors is tadalfil (tadanafil); Preferred non-thiazine sulfonamide medicine is an indapamide; Sulfonyl urea derivates as insulin secretion stimulators is acetohexamide, chlorpropamide, tolbutamide, tolazamide, glipizide, gliclazide, glibenclamide, gliquidone, glyclopyramide, glimepiride, lattice row piperazine special (glixosepid), 2-benzenesulfonamido-5-(.beta.-methoxyethoxy)pyrimidine (glimidine), glypinamide, glyhexamide, glybuzole (glibuzole) or glybuthiazole, is more preferably glimepiride, gliclazide, glipizide and glibenclamide; Preferred hydroxyl-1,4-naphthoquinone derivatives atovaquone, it has the protozoacide activity.Unexpectedly find: if use above-mentioned API; Particularly unite the weight ratio of preferred hyper branched polymer as described herein and preferred hyper branched polymer/API, can improve relative solubility (with respect to the dissolubility of independent API) more.

Unexpectedly find: the dissolubility of the dissolubility of above-mentioned API, preferably phosphoric acid diesterase III inhibitor such as pimobendan can be increased especially doughtily, even the weight ratio of hyper branched polymer/API is merely 4:1 or higher, and 50:1 (map 7) for example.Pimobendan and levosimendan are the selectivity phosphodiesterase iii inhibitor that is used to control heart failure.

Tadanafil is a phosphodiesterase E5 inhibitor, can be used for treating erection disturbance or pulmonary hypertension.Known atovaquone has anti-yeast and parasiticide is active.

Also unexpectedly find: if hydrophilic or hydrophobic carrier, preferred hydrophilic carrier are used to prepare the pharmaceutical composition that comprises with the blended non-thiazine sulfonamide medicine of at least a hyper branched polymer, the dissolubility of then non-thiazine sulfonamide medicine (diuresis chemical compound), preferred indapamide can be increased especially.

Each chemical compound is following at the dissolubility that pH is about in the aqueous medium of 7 (glimepiride has the dependent dissolubility of pH-at least): glimepiride 0.001mg/ml; Gliclazide 0.05mg/ml; Glipizide 0.037mg/ml; Glibenclamide 0.06mg/ml; Pimobendan 0.21mg/ml; Tadanafil 0.11mg/ml; Atovaquone 0.003mg/ml; Indapamide 0.7mg/ml.In a preferred embodiment of the invention, said active component under these conditions the dissolubility in aqueous medium increase to compare and be respectively 10,50,55,100 and 140 times with the dissolubility of pure API.Especially; If active pharmaceutical ingredient is selected from phosphodiesterase inhibitor, non-thiazine sulfonamide medicine, sulfonyl urea derivates and hydroxyl-1; The 4-naphthoquinone derivatives; Can reach maximum dissolubility increases, and when adopting glimepiride, pimobendan, tadanafil, atovaquone or indapamide as API, can reach even further increase.Though do not hope to be entangled in any theory, inferring this is because the intermolecular H-key that between the inside carboxyl of the molecular radical of API and hyper branched polymer, forms.Through interacting through infrared studies and using technological having made at least of attenuated total reflectance (ATR) and attempt illustrating the interaction (Figure 12) between API and the hyper branched polymer.

Pharmaceutical composition of the present invention, powder or granule comprise the hyper branched polymer/API of specified weight ratio.

The weight ratio of hyper branched polymer/active medicine of the present invention is preferably 99:1 to 11:1.In preferred embodiments, this weight ratio is 99:1 to 14:1, and further preferred this weight ratio is 99:1 to 17:1, even further preferred this weight ratio is 99:1 to 18:1.In another embodiment preferred, this weight ratio is 80:1 to 11:1, and further preferred this weight ratio is 55:1 to 11:1, even further preferred this weight ratio is 24:1 to 11:1.In another embodiment, this weight ratio is 80:1 to 14:1, and further preferred this weight ratio is 55:1 to 17:1, even further preferred this weight ratio is 24:1 to 18:1.Preferably; When active pharmaceutical ingredient was glimepiride or indapamide, the weight ratio of multi-branch polymer and said active pharmaceutical ingredient was 80:20w/w to 98:2w/w, preferred 88:12w/w to 98:2w/w; More preferably 90:10w/w to 98:2w/w; Also more preferably 93:7w/w to 98:2w/w, particularly 98:2w/w to 95:5w/w, further preferred 98:2w/w to 95:2w/w.As can from the experimental data that this paper comprised, finding out, use the weight ratio of 99:1 to 11:1 to provide than the high dissolubility (map 3-7) of weight ratio that uses 4:1.These figure also show: when using the weight ratio of 19:1, can reach the highest dissolubility increases.

Usually, the weight ratio of hyper branched polymer/API should be 11:1 or more than.Yet; As indicated above; Have been found that: when use is low to moderate the hyper branched polymer of 4:1 (or more than)/API weight ratio; Be selected from phosphodiesterase inhibitor, non-thiazine sulfonamide medicine, sulfonyl urea derivates and hydroxyl-1, the dissolubility of the given activity ingredient of 4-naphthoquinone derivatives also can significantly be increased.In addition, weight ratio can be low to moderate 4:1 (or more than), if use specific polyesteramide hyper branched polymer as described herein.Yet, represent the preferred embodiments of the invention like 11:1 defined herein and above preferred weight ratio, do not rely on the composition of use.

Comprise at least a hyper branched polymer and at least a in the aqueous medium of pH6.8 and 37 ℃, demonstrate less than pharmaceutical composition, powder and the granule of the active constituents of medicine of the dissolubility of 1mg/ml can through with as specified weight defined herein two kinds of compositions be provided than in organic solvent and prepare except that desolvating.Have been found that: if solid dispersion is through adopting known technology such as high shear mixing, spray drying or fluidized bed granulation to be provided by described at least a hyper branched polymer and the dispersion/solution of described at least a API in organic solvent; The highest said polymer and the intermolecular interaction between the said active component that maybe number can take place in the then said composition intimate admixture that becomes thus.Particularly preferably be, API is dissolved in the organic solvent fully.As described herein, preferably use hydrophilic or hydrophobic carrier, particularly hydrophilic carrier, if particularly prepare powder or the particulate words that comprise API.Dispersion liquid according to being solution or dispersion liquid, for example containing solid API and/or solid carrier particle is used to prepare mixture of the present invention or solid dispersion, and the those skilled in the art that considered the instruction that this paper provides can select the method for preparing that suits.

In intended scope of the present invention, term " solid dispersion " relates to the homogeneous mixture of active pharmaceutical ingredient (granule) in hyper branched polymer.Active pharmaceutical ingredient is dissolved in or is scattered in the polymer.Usually, solid solution is the solid solutions (in this case, " solvent " by hyper branched polymer representative) of one or more solutes in solvent.When the structure of solvent remains unchanged when adding solute and when this mixture remains single homogeneous phase, this mixture is regarded as solution rather than complex.Therefore, described at least a hyper branched polymer and described at least a active pharmaceutical ingredient are in contact with one another, and preferably on big surface area, are in contact with one another.Can obtain the solid dispersion of composition through adopting method as described herein.Preferably, obtain the solid dispersion of active pharmaceutical ingredient and hyper branched polymer through adopting solvent method, wherein active pharmaceutical ingredient and hyper branched polymer all are dissolved in the organic solvent fully, wherein when removing organic solvent, obtain solid dispersion.The technology that allows to remove fast organic solvent shows to help between polymer and API, form associates and/or compound the contact, randomly owing to have hydrophilic or hydrophilic carrier, particularly further strengthen owing to there is hydrophilic carrier.Preferably, organic solvent remove go through a couple of days, preferably go through 24 hours, more preferably in 10 hours, most preferably in 1 hour, accomplish.Do not hope to be entangled in any theory, believe that API-API associates, the API secondary granule forms and the API crystallization can by solvent so fast remove suppress, otherwise all this phenomenons all react on like the association of expection disclosed herein and/or compound.Through adopting known technology such as mixing, high shear mixing, spray drying, fluidized bed granulation or lyophilization to come to remove effectively to desolvate.Preferred high shear mixing, spray drying or the fluidized bed granulation of using.When on solid carrier particle, solid dispersion being provided, preferably solution or the dispersion liquid with hyper branched polymer/API is sprayed onto on the carrier granular through adopting known technology.

The hyper branched polymer major part is water miscible through functional end-group, and since they amorphous form but extremely hygroscopic.When hygroscopicity hyper branched polymer contact atmosphere, migrate in the polymer/migrate on the polymer from the water of steam, and some hydrones combine with polymer chain through molecular separating force.Can be known by one of skill in the art method measure the wettability of hyper branched polymer.These class methods comprise that mainly the quality (being 5-10mg) of measuring small amount of sample as the function of time, changes controlled relative humidity and/or temperature in the environment simultaneously.When the average indoor relative humidity of contact; The hygroscopicity of hyper branched polymer causes comprising the pharmaceutical composition suction of hyper branched polymer and active pharmaceutical ingredient; And for example when pharmaceutical composition was powder type, powder particle changed shape and finally causes compositions liquefaction.But it is desired that the characteristic of pharmaceutical composition (it for example is a powder type) does not change when storing.

Pharmaceutical composition of the present invention preferably comprises carrier.Powder of the present invention or granule also comprise carrier.

Unexpectedly find at present: in pharmaceutical composition, add water-dispersible or water solublity pharmaceutically suitable carrier, preferred hydrophilic or hydrophobic carrier, more preferably hydrophilic carrier, particularly preferred crystallization carrier have significantly reduced pharmaceutical composition and from atmosphere, absorb water and kept its primary characteristic such as powder-form (referring to for example Figure 11).Particularly preferably be the crystallization hydrophilic carrier.The characteristic of pharmaceutical composition of the present invention is the maintenance stable state with regard to suitable flowability, chemical stability and compressibility, particularly when using the crystallization carrier.Can pass through to adopt methods known in the art to measure flowability, chemical stability or compressibility like method of explaining in the 6th edition " European Pharmacopoeia ".Aspect chemical stability; Unexpectedly observe: when in pharmaceutical composition of the present invention, adding water-dispersible or water-solubility carrier, preferred hydrophilic, preferred crystallization carrier; Significantly degraded does not take place in water sensitivity API such as glimepiride in addition, even the relative humidity of the rising of the pharmaceutical composition that obtains thus contact 75%.Same method is suitable for dosage form disclosed by the invention.The existence of carrier also regulation pharmaceutical composition is suitable for mechanography.In powder, granule, small pieces, pill, tablet, capsule, use carrier, particularly crystallization carrier to increase the shelf life of dosage form thus.

In intended scope of the present invention, " water-dispersible or water solublity pharmaceutically suitable carrier " is interpreted as and can disperses or be dissolved in 37 ℃ of solid or any pharmaceutically acceptable excipient of semi-solid form in the water.

Said carrier can for example be modification or unmodified carbohydrate, and it can be monomer, oligomeric or poly; Wax; Natural gum; Organic or inorganic acid or alkali or its salt; Surfactant; Synthetic polymer; Modification or unmodified silicon dioxide; Mineral medicinal compound such as calcium phosphate, calcium sulfate, calcium chloride, magnesium carbonate, magnesium oxide, sodium chloride, aluminium-magnesium silicate, polacrilin potassium, Pulvis Talci, aluminium hydroxide, aluminium oxide or its combination.

Said carrier can also for example be a carboxymethylcellulose calcium; Sodium carboxymethyl cellulose; Cellulose acetate; CAP; Ceresine; Spermol; Chitosan; Cellulose; Ethyl cellulose; Gelatin; Glucose; Glyceryl behenate; Glyceryl palmitostearate; Methylcellulose; Hydroxyethyl-cellulose; Hydroxyethylmethyl-cellulose; Microcrystalline Cellulose; Silicified microcrystalline cellulose; Hydroxypropyl cellulose; Hypromellose; Phthalandione hypromellose ester; Cross-linking sodium carboxymethyl cellulose; Hydroxypropyl cellulose; Hydroxyl isomaltulose (isomalt); Maltose alcohol; Mannitol; Kaolin; Lactitol; Maltodextrin; Polydextrose; Dextrates; Dextrin; Dextrose; Methylcellulose; Polydextrose gathers (dl-lactic acid); Polyethylene glycol oxide polyethylene (polyethylene oxidepolyvinyl); Acetic acid phthalate ester (acetate phthalate); Polyvinyl alcohol; Lac; Sucrose; Fructose; Maltose; Trehalose; Sucrose octaacetate; Sugar; Lactose; Cyclodextrin; Corn starch; Pregelatinized Starch; Hydroxypropyl starch; Titanium dioxide; Wax (Brazil wax); Wax (microwax); Xylitol; Zein; Copolyvidone (copovidone); Simethicone; Crospovidone; Erythritol; Glyceryl palmitostearate; Sorbitol sulfobutyl ether beta-schardinger dextrin-; Vitamin e polyethanediol succinate; Arabic gum; Agar; Guar gum; Carbomer; Gelatin; Pectin; Carob (ceratonia); Chitosan; Copolyvidone; Polyethylene glycol oxide; Polymethacrylates; Polyvidone; Glyceryl behenate; Inulin; Cetylpyridinium chloride; Glyceryl monostearate; HYDROXYPROPYL BETA-CYCLODEXTRIN; Lecithin; Polyethylene Glycol 15 hydroxy stearic acid esters; Phospholipid; Poloxamer; Polyoxyethylene alkyl ether; Castor oil derivatives; The smooth fatty acid ester of polyoxyethylene Pyrusussuriensis; Myrj 45; Polyoxyethylene glyceride (polyoxylglycerides); Ketopyrrolidine; Sorbitan ester (the smooth fatty acid ester of Pyrusussuriensis); The sulfobutyl ether beta-schardinger dextrin-; Tricaprylin; Triolein; Vitamin e polyethanediol succinate; Wax; Benzalkonium chloride; Isoleucine; Alanine; Leucine; Agedoite; Lysine; Aspartic acid; Methionine; Cysteine; Phenylalanine; Glutamic acid; Threonine; Glutamine; Tryptophan; Glycine; Valine; Proline; Serine; Tyrosine; Arginine; Histidine; Stearic acid; Citric acid; Malic acid; Pentetic acid; Adipic acid; Alginic acid; Boric acid; Calcium lactate; Calcium phosphate; Monohydrate potassium; Maleic acid; Monosodium glutamate; Potassium citrate; Sodium acetate; Sodium alginate; Sodium borate; Sodium carbonate; Two hydration sodium citrates; Sodium hydroxide; Sodium lactate; Dibastic sodium phosphate; Sodium dihydrogen phosphate; Primojel; Calcium carbonate; Calcium lactate; Calcium phosphate; Calcium sulfate; Calcium chloride; Magnesium carbonate; Magnesium oxide; Sodium chloride; Aluminium-magnesium silicate; Polacrilin potassium; Pulvis Talci; Aluminium hydroxide; Aluminium oxide; The aluminum phosphate adjuvant; Attapulgite; Bentonite; Calcium silicates; Silica sol; Hectorite; Kaolin; Aluminium-magnesium silicate; Magnesium carbonate; Polycarbophil; Saponite; Aluminium-magnesium silicate or its mixture.

Preferred vector is a hydrophilic carrier, and said hydrophilic carrier is preferably selected from sugar and carbohydrate, and preferred vector is selected from modification or unmodified monosaccharide, straight or branched oligosaccharide and straight or branched polysaccharide or its mixture.Also preferred vector is selected from lactose, sucrose, maltose, mannitol, sorbitol, xylitol, erythritol, lactitol, maltose alcohol, starch or cellulose; Preferred lactose, maltose, mannitol, sorbitol, starch and cellulose; More preferably lactose and cellulose, also more preferably lactose.

Another advantage that pharmaceutically suitable carrier is joined in the pharmaceutical composition is that carrier is made contributions to powder or particulate formation.Based on the total weight of pharmaceutical composition, in the pharmaceutical composition amount of included carrier should be preferably 10% to 90%, preferred 30% to 60%, more preferably 50% to 80%, also more preferably 70% to 80%.Carrier prevents that compositions from increasing because of absorbing from environment such as airborne water weight.And carrier prevents the particulate size increase of compositions and it can be used to pass unaltered situation in time basically.The useful effect of limited distribution of sizes is the flowability of improving, particularly when extensive embodiment of the present invention.

For the pharmaceutical composition of a powder or a form, use like the defined hydrophilic carrier of preceding text.Carrier can be particle form and/or crystal form.

When using the carrier of crystal form, particularly advantageous effect can be provided.In this case, the most remarkable to the protective effect of compositions, this possibly be because the wettability of the carrier of crystal form is lower.Unexpectedly find: even solid dispersion of the present invention is deposited on the carrier surface, wettability also reduces.Therefore, solid dispersion is deposited on the carrier surface.For example, this can reach through adopting solvent method as described herein, wherein, at first hyper branched polymer and active constituents of medicine is dissolved in the organic solvent, and add carrier, preferred crystallization carrier in the solution this moment, removes then desolvate (solvent method).Perhaps, only carrier is added in hyper branched polymer and the active constituents of medicine after desolvating removing to desolvate or to remove at least in part.This can mix with carrier through the solid dispersion that comprises hyper branched polymer and active constituents of medicine with gained simply and reaches.Selection in addition is with carrier and said two kinds of compositions merging the time, to remove to desolvate.An instance of this generation is when being sprayed onto the solution/dispersion of hyper branched polymer and API on the carrier granular, cause evaporation to be desolvated with removing thus, and carrier being applied by the solid dispersion of generation.Those skilled in the art will appreciate that the order or the combination of the step that can select to add carrier as one sees fit; That is, can with described at least a hyper branched polymer and described at least a active constituents of medicine are provided in organic solvent or desolvate simultaneously or in turn add carrier with removing.Even can be at first the carrier of carrier, preferred crystal form be joined in the solution/dispersion, add once more after desolvating removing then.Preferably the solution/dispersion with hyper branched polymer and API is sprayed onto on the carrier granular as described herein.

Whether comprise the crystallization carrier in order to measure pharmaceutical composition, can carry out the analysis of X-ray powder diffraction.When the X-ray data demonstrated the peak of crystallization carrier material, pharmaceutical composition contained the crystallization carrier.When the X-ray data did not show any peak, pharmaceutical composition was unbodied and does not represent the pharmaceutical composition of the preferred embodiments of the invention.The characteristic peak of crystallization carrier can easily be obtained from the obtainable data base of the public by those skilled in the art.Can also at first carry out the X-ray powder diffraction of crystallization carrier self analyzes to identify the characteristic peak of carrier material.When analyzing unknown pharmaceutical composition, when failing to detect the peak, there is not the crystallization carrier.When detecting the peak, for example, can at first analyze pharmaceutical composition to find to have used which kind of specific carrier material.Can obtain the characteristic peak of this carrier material then by document or normal experiment.

According to the present invention, can use other excipient.This type excipient can add with carrier, is particularly adding before or after the mixture of hyper branched polymer that prepares solid form and API, preferred solid dispersion except that desolvate (according to solvent method as described herein).Removing when being added in the mixture before desolvating when them, also representing the drug excipient of carrier will be called as carrier according to above-mentioned definition.In the situation that this type excipient uses behind the preparation solid dispersion, for example, if excipient is added in the tablet coating, then this type excipient is not considered to be carrier.On the other hand, some carriers shown in preceding text are also suitable to removing the drug excipient that use the back of desolvating.

Suitable excipient is a pharmaceutically acceptable excipient commonly used arbitrarily.For example, excipient can be filler (lactose, mannitol, cellulose derivative, sucrose etc.), disintegrating agent (cross-linking sodium carboxymethyl cellulose, calcium carbonate, carboxymethylcellulose calcium etc.), binding agent (polyvinylpyrrolidone etc.), lubricant (magnesium stearate, stearic acid, silicon dioxide etc.), aromatic, coloring agent (titanium dioxide etc.), sweeting agent (glucide etc.), coating polymer (hydroxypropyl emthylcellulose etc.) or solvent (water, organic solvent etc.).

In another embodiment, pharmaceutical composition, powder or granule also comprise other active pharmaceutical ingredient.Can select the other active component of this type to provide aspects such as additive effect, synergism, complementary effect, minimizing side effect to replenish first kind of active pharmaceutical ingredient those pharmacological activity As mentioned above.

Preferably; Other active pharmaceutical ingredient is selected from thiazolidinediones medicine, biguanides, statins, fibrate, phenothiazine drug, acarbose, miglitol, voglibose, orlistat, sibutramine, Rimonabant, Exenatide and AC-137; Preferred its is selected from biguanides, thiazolidinediones medicine and phenothiazine drug, and more preferably it is selected from the thiazolidinediones medicine.Active pharmaceutical ingredient from the thiazolidinediones medicine for example has pioglitazone, Li Gelie ketone, rosiglitazone, troglitazone.Preferably the active pharmaceutical ingredient from the thiazolidinediones medicine has pioglitazone or rosiglitazone, more preferably pioglitazone.Active pharmaceutical ingredient from biguanides for example has phenformin, buformin or metformin.Preferred biguanides active pharmaceutical ingredient is a metformin.Active pharmaceutical ingredient from statins for example has atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, Pitavastatin, pravastatin, rosuvastatin or simvastatin.Preferred Statins active pharmaceutical ingredient has atorvastatin, pravastatin, rosuvastatin or simvastatin, more preferably rosuvastatin.

Active pharmaceutical ingredient from fibrate for example has bezafibrate, ciprofibrate, clofibrate, gemfibrozil or fenofibrate.The special type active pharmaceutical ingredient of preferred shellfish is gemfibrozil or fenofibrate, more preferably fenofibrate.Active pharmaceutical ingredient from phenothiazine drug for example has chlorothiazide or hydrochlorothiazide, preferred hydrochlorothiazide.

In embodiment preferred of the present invention; Pharmaceutical composition, powder or granule comprise at least a active pharmaceutical ingredient and at least a hyper branched polymer that is selected from glimepiride, gliclazide, glipizide, glibenclamide, pimobendan, tadanafil, atovaquone and indapamide, wherein said at least a active pharmaceutical ingredient and described hyper branched polymer with the weight ratio shown in preceding text, for example with 99:1w/w to 11:1w/w, preferred 80:20w/w to 98:2w/w, more preferably the weight ratio of 90:10w/w to 98:2w/w, particularly 98:2w/w to 95:2w/w mix, preferred intimate.In another particular, described at least a active pharmaceutical ingredient is glimepiride, pimobendan, tadanafil, atovaquone or indapamide, preferred glimepiride or pimobendan, more preferably glimepiride.In another preferred embodiment, said pharmaceutical composition also comprises water-dispersible or water solublity pharmaceutically suitable carrier, preferred lactose.

An embodiment of the present invention relates to powder or granule, and it comprises

A) at least a hyper branched polymer,

B) at least aly in the aqueous medium of pH6.8 and 37 ℃, demonstrate active constituents of medicine less than the dissolubility of 1mg/ml,

Preferably, described hyper branched polymer and described at least a ingredient form solid dispersion.Can prepare powder or granule through adopting mixing, high shear mixing and/or spray drying, fluidized bed granulation or lyophilization.Preferably through adopting high shear mixing and/or spray drying or fluidized bed granulation to prepare.Preceding text have been described the weight ratio of preferred hyper branched polymer, preferred API, preferred carrier and preferred hyper branched polymer/API etc.

The above-mentioned pharmaceutical composition of mentioning, powder and granule are suitable for preparing medicament.

Therefore; The invention still further relates to and comprise above-mentioned each pharmaceutical composition, powder or particulate pharmaceutical dosage forms; Pharmaceutical dosage forms solid dosage form preferably wherein, the form of preferred small pieces, tablet, capsule, sachet, the preferred dose form is a tablet.Tablet can have one deck or can be bilayer or multilayer tablet, preferably thin membrane coated tablet or cover coated tablet (mantle coated tablet).

Pharmaceutical composition, powder or granule and pharmaceutical dosage forms preferably do not contain surfactant.

The invention still further relates to the method for preparing of pharmaceutical composition of the present invention, powder, granule and pharmaceutical dosage forms.

Method of the present invention can adopt aforesaid specific hyper branched polymer, API, carrier, the preferably enforcements such as weight ratio of hyper branched polymer/API.

Usually, method of the present invention comprises in the first step described at least a hyper branched polymer and described at least a active pharmaceutical ingredient is joined in the organic solvent.Preferably, gained solution or dispersion liquid are mixed.At least a carrier of optional then adding.For solid composite medicament is provided, removes and desolvate.Perhaps can be only remove the back or remove of desolvating desolvate in carrier and two kinds of compositions merging.

Can desolvate through adopting standard technique to remove.Preferably, application has been enough under low relatively temperature, remove the technology of desolvating.Remove the step desolvate preferably 60 ℃ at the most, more preferably carry out under 50 ℃ the temperature at the most.This has further improved the stability of compositions.In solvent removal process, active constituents of medicine can solidify, and can be at least in part but preferably fully form solid solution with hyper branched polymer.It is amorphous that the solvent method of removing becomes composition, and this also helps to increase dissolubility, especially when implementing in short relatively time bar through appropriate technology such as spray drying, fluidized bed granulation or lyophilization, preferably spray drying or fluidized bed granulation.Preferably, method of the present invention comprises that also drying steps is to remove residual water and organic solvent.The temperature of in drying means, using preferably keeps below 60 ℃, preferably is lower than 50 ℃.In preferred embodiments, drying can be lower than 60 ℃, preferably be lower than 50 ℃, most preferably under 40 ℃ or following temperature, in vacuum drying oven, carry out.

In all methods of the present invention, preferably described at least a hyper branched polymer and described at least a active pharmaceutical ingredient are dissolved in the organic solvent fully.If the use carrier, then carrier can remove desolvate before or removing desolvate after with hyper branched polymer and API merging.Another kind of probability is that solution or the dispersion liquid with described at least a hyper branched polymer and described at least a API is sprayed onto on the carrier that kind as mentioned below.With regard to latter event, removing in same step of the merging of carrier and API/ hyper branched polymer and solvent carried out.Can also be as described herein through adopting high shear mixing, spray drying, fluidized bed granulation or lyophilization to remove the solvent in the step c).In this case, obtain the solid dispersion of API/ hyper branched polymer on carrier.If do not use carrier, then can also be as described herein through adopting mixing, high shear mixing, spray drying, fluidized bed granulation, lyophilization etc. to remove solvent in the step c) so that the solid dispersion of said composition to be provided.

Method of the present invention can be used to prepare solid pharmaceutical dosage form and gel or solution.Remove and to desolvate to provide as solid, preferably as powder or particulate mixture, preferred solid dispersion.When preparation gel or solution, can the solid that obtain for example be dissolved in acceptable solvent or the buffer solution again after desolvating removing.

The solvent that is suitable for pharmaceutical compositions can be any solvent that dissolves two constituents (API and hyper branched polymer) at least in part.Preferred organic solvent is selected from C ₂-C ₄Alkanol, for example ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutanol; Aliphatic series or alicyclic ethers, for example ether, Di Iso Propyl Ether, methyl tertiary butyl ether(MTBE), two

Alkane, oxolane; Ketone, for example acetone, methyl ethyl ketone; Dimethyl sulfoxine and dimethyl formamide; Or its mixture.Composition in the solvent can randomly mix.

In particular of the present invention, at least 50%w/w, preferred 80%w/w above, more preferably surpass 90%w/w, also more preferably whole two constituents are dissolved in the solvent.

A kind of method for preparing of pharmaceutical composition of the present invention comprises the following steps:

A) at least a hyper branched polymer to be provided like the defined weight ratio of preceding text and at least aly in the aqueous medium of pH6.8 and 37 ℃, to demonstrate active pharmaceutical ingredient less than the dissolubility of 1mg/ml;

B) described at least a hyper branched polymer and described at least a active pharmaceutical ingredient are joined in the organic solvent; With

C) except that desolvating.

Powder of the present invention or particulate method for preparing comprise the following steps:

A) provide at least a hyper branched polymer, preferably in the aqueous medium of pH6.8 and 37 ℃, demonstrate active pharmaceutical ingredient less than the dissolubility of 1mg/ml, preferred at least a like the defined specific medication active component of preceding text like the defined specific hyper branched polymer of preceding text and at least a; Weight ratio is 99:1w/w to 11:1w/w; Perhaps wherein wt compares even can be 99:1w/w to 4:1w/w, and condition is that active pharmaceutical ingredient is selected from phosphodiesterase inhibitor, preferably phosphoric acid diesterase III inhibitor or Phosphodiesterase V inhibitors; Non-thiazine sulfonamide medicine; Sulfonyl urea derivates; And hydroxyl-1, the 4-naphthoquinone derivatives; Perhaps wherein wt is than for 99:1w/w to 4:1w/w, and the high branched polyamide ester that condition is high branched polyamide ester, preferably have tertiary amine end groups or have a hydroxyl end groups is used as hyper branched polymer, preferably with as 1 in defined weight ratio;

B) described at least a hyper branched polymer and described at least a active pharmaceutical ingredient are dissolved in organic solvent and mix; With

C) remove and to desolvate, wherein step b) or step c) also comprise mixture and hydrophilic or hydrophobic carrier, preferred hydrophilic carrier, more preferably crystallization carrier even more preferably like the defined carrier merging of preceding text.

With regard to method productive rate and final preferably dissolubility, when described at least a active pharmaceutical ingredient and described hyper branched polymer were dissolved in the solvent, method of the present invention was particularly advantageous.In this case, and under the situation that satisfies the weight ratio requirement, obtain the active pharmaceutical ingredient of amorphous form, it contacts on high surface area with hyper branched polymer and interacts widely with polymer.Preferably obtain solid dispersion.

When preparation powder or granule, in step b), add hydrophilic or hydrophobic carrier, preferred hydrophilic carrier, more preferably like the defined carrier of preceding text.When carrier is particle form, preferably, hyper branched polymer and active pharmaceutical ingredient carry out step b) on the carrier particle surface through being deposited to.Preferably composition is deposited on the carrier through application technology such as high shear mixing, spray drying or fluidized bed granulation etc.For example when carrying out high shear mixing, still preferred ingredient partly is dissolved in the solvent when solvent arrives carrier, and is spreading on the carrier except that solvent before desolvating fully.On the other hand, the parameter of selecting to be used for spray drying technology makes solvent at component bump carrier granular front evaporator in principle.This condition is more not preferred.These technology generally include removes at least some solvents.Yet it possibly be essential being used for the other step that solvent removes.

Yet the step that deposits said at least a active constituents of medicine and said at least a hyper branched polymer can also and be removed to desolvate and carry out through the simple said composition of mixing in organic solvent, and wherein removing also of solvent preferably carried out under mixing.

Also preferably in procedure of the present invention, add other aforesaid active constituents of medicine.According to the present invention, other active constituents of medicine can add in the solid dispersion process of preparation hyper branched polymer, active constituents of medicine and carrier.Yet other active constituents of medicine can also add after preparing solid dispersion.And other active constituents of medicine can join in the tablet coating material or can mix with powder that contains solid dispersion of the present invention or granule.

In addition preferably, in procedure of the present invention, add other excipient.Suitable excipient is as described herein.

When using powder or preparation of granules pharmaceutical dosage forms such as tablet or capsule, preferably powder or granule are pressed into tablet or powder or particles filled is gone in the capsule.

Can be through will be at method step c) in the pharmaceutical composition as described herein, powder or the granule that obtain and optional other excipient directly be pressed into tablet and prepare the solid dosage form.Yet, can also pharmaceutical composition as described herein, powder or granule and optional other excipient at first be granulated, in tablet machine, suppress to obtain tablet then.In tablet machine, can use two or multilayered schema prepares double-layer tablet or multilayer tablet.And tablet machine can be used to obtain overlapping coating.Randomly, tablet is further overlapped coating or film coating.Film coating material can carry out as follows: with suitable coating polymer with plasticizer, stabilizing agent (antioxidant, acidity or alkaline reagent etc.) etc. are dissolved in or are scattered in the solvent and solvent is deposited on dosage form in addition if necessary.This method can for example be carried out through spray technique or dip coating.

The instance of used suitable equipment is a coating pan.The cover coating can carry out through around dosage form, compressing pharmaceutical preparation.Perhaps, can pharmaceutical composition of the present invention (randomly at first being converted into powder or granule) be packed in gelatin or the hypromellose capsule.And various round as a ball or extruding technologies can be used to prepare small pieces.Can small pieces and capsule be carried out further coating.

But the drying means of pharmaceutical composition, powder, granule or pharmaceutical dosage forms has further strengthened stability and operating characteristic.Drying means can be applied to prepare the arbitrary steps in compositions, powder, granule, tablet, small pieces, the capsule etc.

In addition, the present invention relates to the crystallization carrier and comprise the purposes in the pharmaceutical composition of hyper branched polymer and active constituents of medicine in preparation.That kind as discussed above, the application of crystallization carrier in pharmaceutical composition of the present invention provides favourable characteristic.

The invention still further relates to the polyesteramide hyper branched polymer and comprise the purposes in the pharmaceutical composition of at least a active pharmaceutical ingredient in preparation, the weight ratio of wherein said hyper branched polymer and said at least a active pharmaceutical ingredient is 99:1w/w to 4:1w/w.The weight ratios of operable further preferred polyesteramide hyper branched polymer, API, hyper branched polymer/API etc. are as indicated above.

In addition; The present invention relates to hydrophilic or hydrophobic carrier and comprise the purposes in the pharmaceutical composition with the blended active pharmaceutical ingredient of at least a hyper branched polymer in preparation; Said active constituents of medicine is selected from phosphodiesterase inhibitor, non-thiazine sulfonamide medicine, sulfonyl urea derivates and hydroxyl-1; The 4-naphthoquinone derivatives, preferred non-thiazine sulfonamide medicine, preferred especially indapamide.Preferred hydrophilic carrier and preferred non-thiazine sulfonamide medicine and other composition, weight ratio etc. are as indicated above.In addition, the present invention relates to hydrophilic carrier and preparing like preceding text the purposes in the defined pharmaceutical composition.

The invention still further relates to and be selected from phosphodiesterase inhibitor, non-thiazine sulfonamide medicine, sulfonyl urea derivates and hydroxyl-1; The active pharmaceutical ingredient of 4-naphthoquinone derivatives comprises the purposes in the pharmaceutical composition of at least a hyper branched polymer in preparation; Wherein said at least a active constituents of medicine demonstrates the dissolubility less than 1mg/ml in the aqueous medium of pH6.8 and 37 ℃, and the weight ratio of wherein said at least a hyper branched polymer and described at least a active pharmaceutical ingredient is 99:1w/w to 4:1w/w.Ingredient is preferably selected from pimobendan, tadanafil, indapamide, glimepiride and atovaquone.The weight ratios of operable preferred hyper branched polymer, API, hyper branched polymer/API etc. are as indicated above.

The following example only is used for example the present invention; They should not be regarded as with any-mode and limit scope of the present invention, because these embodiment, change and other equivalent will be conspicuous when considering disclosure and appended claims of the present invention to those skilled in the art.

Description of drawings

Figure 1A has shown the influence to the glimepiride dissolubility of surface active ingredient or non-active ingredient.

Figure 1B has shown the influence to the glimepiride dissolubility of linear polymer and amorphous glimepiride.

Fig. 2 has shown the influence of hyper branched polymer to the glimepiride dissolubility.

Fig. 3 A has shown the contrast dissolution study of sample (embodiment 9-13) glimepiride in the phosphate buffer of pH6.8 as far as containing

.

Fig. 3 B has shown the sample that contains (embodiment 14 – 16) the contrast dissolution study of glimepiride in the phosphate buffer of pH6.8.

Fig. 4 has shown the contrast dissolution study of sample (embodiment 17-19) glimepiride in the phosphate buffer of pH6.8 as far as containing

.

Fig. 5 has shown the contrast dissolution study of sample indapamide in the phosphate buffer of pH6.8 as far as containing .

Fig. 6 has shown the contrast dissolution study of sample indapamide in the phosphate buffer of pH6.8 as far as containing .

Fig. 7 has shown the contrast dissolution study of sample pimobendan in the phosphate buffer of pH6.8 as far as containing

.

Fig. 8 has shown the compositions wettability relatively that only comprises the pharmaceutical composition of hyper branched polymer and active pharmaceutical ingredient and also comprise carrier.

Fig. 9 has shown the scanning electron microscope image of medicament composition granule, its size, shape and growth.

Figure 10 has shown the dosage form wettability relatively that only comprises the pharmaceutical dosage forms of hyper branched polymer and active pharmaceutical ingredient and also comprise carrier.

Figure 11 has shown respectively and has only comprised hyper branched polymer and active constituents of medicine, comprises hyper branched polymer, active constituents of medicine and crystallization carrier (200 order lactose) and comprise the wettability of the pharmaceutical composition of hyper branched polymer, active constituents of medicine and amorphous carrier (spray-dried lactose).

Figure 12 has shown the ATR spectrum (being respectively the spectrum at top and middle part) of glimepiride and Hybrane HA1690.The difference spectrum that the spectrum representative of bottom obtains through deduction goes out with arrow labeled owing to the change that forms the H-key between glimepiride and the hyper branched polymer.

Figure 13 A has shown the X-ray powder diffraction pattern of solid dispersion of glimepiride and the PEG 6000 (middle part curve) or the Gelucire 50/13 (upper curve) of original glimepiride material (bottom curve) and 5/95%w/w weight ratio.

Figure 13 B has shown the solid dispersion of the glimepiride that contains 2/98 (A), 5/95 (B) and 20/80 (C) w/w weight ratio and hyper branched polymer Hybrane S1200 and the X-ray powder diffraction pattern of pure hyper branched polymer Hybrane S1200 (D).

Figure 13 C has shown the X-ray powder diffraction pattern of the solid dispersion of the glimepiride that contains 7/93 (A), 10/90 (B) and 12/88 (C) weight ratio and hyper branched polymer Hybrane S1200.

Embodiment

Comparative example 1 – 8 (referring to Figure 1A and Figure 1B)

The comparative example 1: the simple Hun He Wu – 9%w/w of glimepiride and Texapon (sodium laurylsulfate)

The comparative example 2: the simple Hun He Wu – 9%w/w of glimepiride and Polysorbate

The comparative example 3: comprise the granule through glimepiride, Polysorbate and the lactose (4/1/95%w/w) that grinds

The comparative example 4: comprise the granule without glimepiride, Polysorbate and the lactose (4/1/95%w/w) that grind

Comparative example 5:Duetact 30/4*

* the glimepiride joint product with the pioglitazone hydrochloride associating that is called Duetact (military field) with name is at present sold.Originator company has improved low solubility through surfactant being mixed goods (polyoxyethylene sorbitan monoleate).

The comparative example 6: glimepiride and linear polymer polyethylene glycol 6000 (PEG6000; Average molar mass is 6000 – 7500g/mol) weight ratio be the solid dispersion of 5/95%w/w.Glimepiride and PEG6000 are dissolved in ethanol, obtain settled solution.Stir this solution.Remove through vacuum evaporation at 40 ℃ then and desolvate.Then with exsiccant solid dispersion hand lapping powdered, the sieve through 250 μ m holes sieves.

The comparative example 7: (Gelucire 50/13 for linear polymer stearic acid polyethyleneglycol glyceride (stearyl macroglyceride); Fusing point Tm=50 ℃, average molar mass is 300 – 4000g/mol) weight ratio be the solid dispersion of 5/95%w/w.As comparative example 6, make solid dispersion.

The comparative example 8: through the glimepiride of the amorphous form that glimepiride is dissolved in ethanol, makes with postlyophilization (Lio5P, 5Pascal, Italy).

Because the low aqueous solubility and the pH dependency of glimepiride are tested some pharmaceutically acceptable surfactants, non-active ingredient, linear polymer and amorphous form to increase the dissolubility of glimepiride.The result provides in Figure 1A and Figure 1B.Result by Figure 1A and Figure 1B can find out: none provides gratifying result to used non-active ingredient significantly improving aspect the dissolubility.The active component (4mg) of test dissolving about 50% after 60 minutes under following condition: 37 ℃, in USP dissolution test appearance Apparatus II (oar method), adopt 900ml phosphate buffer (pH6.8) as dissolution medium, under the rotating speed of 75rpm.

In following experiment, use available from the high branched polyamide ester

of DSM used be:

and

The characteristic of polymer:

representes polyesteramide; Wherein construction unit is hexahydrophthalic acid anhydride, diisopropanolamine (DIPA) and N; N-pair-(3-dimethylamino-propyl) amine, and wherein mean molecule quantity is 1.600.The feature description of said polymer is in following open source literature:

1.Froehling?P.:Development?of?DSM’s?

hyperbranched?polyesteramides.J?Polym?Sci?A?1.42.2004.3110–3115.

2.Froehling?P.，Brackman?J.:Properties?and?applications?of?poly(propylene?imine)dendrimers?and?poly(esteramide)hyperbranched?polymer.Macromol?Symp.151.2000.581–589.

3.Dritsas people such as G.S.: Investigation of thermodynamic properties of hyperbranched poly (ester amide) by inverse gas chromatography.Journal of Polymer science.Part B:Plymer physics.2008.46:2166-2172.

Unexpectedly find: if having the high branched polyamide ester of tertiary amine group, preferred

is used as hyper branched polymer, then the dissolubility of API can obtain increasing especially.Observe identical result if use

.

Embodiment 9 – 19 (referring to Fig. 3 A, Fig. 3 B and Fig. 4)

Hyper branched polymer is to the effect of active pharmaceutical ingredient dissolubility in the time of in being incorporated in powder or granule

As follows with glimepiride and hyper branched polymer intimate: at first prepare physical mixture, in room temperature glimepiride and said polymer are dissolved in the mutual solvent isopropyl alcohol then, use magnetic stirring apparatus continuous stirring (100rpm) 1 hour simultaneously.Prepared solution is transparent.Remove then desolvate (so-called solvent method).In the situation that obtains semisolid or fluid product, use granulation.Polymer and medicine (being API) are dissolved in the mutual solvent, then solution are applied on the crystallization lactose granule.In mortar with solution with thin spray applications on the inertia crystalline particle of lactose, the mixture that forms is mixed to guarantee uniformity.Technically, this can also for example realize with fluidized bed granulation or high-shear mixer.Dry moist agglomerate in vacuum drying oven then.Guarantee that the required temperature of isopropyl alcohol evaporation is 40 ℃.After 3 days, from vacuum drying oven, take out sample, obtain the solid finished product,, sieve through sieve with 250 μ m holes then with its hand lapping powdered.Repeat the compositions of this technology with preparation various polymerization thing/active component weight ratio.

The composition of sample is as shown in the table.

* hyper branched polymer:

The sample (Fig. 3 A and Fig. 3 B) that contains

:

Composition:	Glimepiride [mg]	Polymer [mg]	Lactose [mg]
				Embodiment 9	2	98	/
Embodiment 10	2	98	400
				Embodiment 11	5	95	/
Embodiment 12	5	95	400
				Embodiment 13	20	80	400
Embodiment 14	7	93	/
				Embodiment 15	10	90	/
Embodiment 16	12	88	/

The sample (Fig. 4) that contains

:

Composition:	Glimepiride [mg]	Polymer [mg]	Lactose [mg]
				Embodiment 17	2	98	400
Embodiment 18	5	95	400
				Embodiment 19	20	80	400

External stripping research:

In 37 ℃ through USP dissolution test appearance, Apparatus II (oar method), with the rotating speed of 75rpm, adopt 900ml phosphate buffer (pH6.8) to estimate the stripping of glimepiride as dissolution medium.Specimen is directly added in the buffer with the correct amount that reaches 4.4 μ g/ml glimepiride final concentrations (equaling to be dissolved in the therapeutic dose of 900ml).Draw the aliquot of each 2ml from dissolution medium at 5,15,30,60 minutes intervals.Sample is drawn through syringe, filters through the Millipore filter, adopts the HPLC method to analyze glimepiride content.

The HPLC algoscopy is measured:

Through reversed-phase HPLC (Waters Alliance), with binary mode, the amount of glimepiride of stripping of having used photodiode array detector and communication bus module estimation.With the C18 that maintains 30 ℃ (column ovens); 150x 4.6mm; 3.5 μ m post, use the mobile phase A of sending with flow velocity and the following gradient of 1.5ml/min (phosphate buffer, pH=2.5: acetonitrile=72:28) and Mobile phase B (phosphate buffer, pH=2.5: acetonitrile=30:70) analyze:

Time (min)	%A
		0	100
6	0
		6.5	100
7.5	100

The retention time of medicine is about 4min.

In 37 ℃ studied medicine and hyper branched polymer mix (can be characterized by non-covalent association or compound) effect to the dissolubility of glimepiride in PBS.By Fig. 3 and 4 obvious: when use hyper branched polymer/active constituents of medicine of the present invention specific than the time, the dissolubility of glimepiride significantly increases.

According to the result that external stripping is measured, measured in solid dispersion load capacity (seeing table) with the compound glimepiride of specific HB polymer.The glimepiride ultimate load of Hybrane S1200 or Hybrane HA 1690 polymer is about 5%w/w, this means HB polymer that different chemical forms, is that Hybrane S1200 or Hybrane HA1690 do not demonstrate any significant difference.Contain more than 2%, preferred 2%w/w to 12%w/w, more preferably 2%w/w to 10%w/w, the solid dispersion of 20%w/w API demonstrates the load capacity of improvement at the most.

Table: with the amount of calculation (load capacity) of the compound glimepiride of specific hyper branched polymer

Embodiment 20 (referring to Fig. 5 and Fig. 6)

Sample like embodiment 9 to 16 preparation indapamides.In 37 ℃ through USP dissolution test appearance, Apparatus II (oar method), adopt 900ml phosphate buffer (pH6.8) to estimate the stripping of indapamide as dissolution medium, with the rotating speed of 75rpm.Specimen is directly added in the buffer with the amount that reaches 15 μ g/ml indapamide final concentrations.Draw the aliquot of each 2ml from dissolution medium at 5,15,30,60 minutes intervals.Sample is drawn through syringe, filters through the Millipore filter, adopts the UV spectrophotography to analyze indapamide in 287nm.

Obvious by Fig. 5, the polyesteramide hyper branched polymer has significantly improved the dissolubility of indapamide.

Embodiment 21 (referring to Fig. 7)

Sample like embodiment 9 to 16 preparation pimobendans.In 37 ℃ through USP dissolution test appearance, Apparatus II (oar method), with the rotating speed of 75rpm, adopt 900ml phosphate buffer (pH6.8) to estimate the stripping of pimobendan as dissolution medium.Specimen is directly added in the buffer with the correct amount that reaches 5.5 μ g/ml pimobendan final concentrations (equaling to be dissolved in the therapeutic dose of 900ml).Draw the aliquot of each 2ml from dissolution medium at 5,15,30,60 minutes intervals.Sample is drawn through syringe, filters to separate undissolved sample through the Millipore filter, adopts HPLC methods analyst pimobendan.

Have been found that: when with pimobendan (2% and 5% active constituents of medicine) when mixing, polyesteramide

has significantly increased the dissolubility of active component.

Embodiment 22

Estimate the effect of the combination of active component and hyper branched polymer: tadanafil, atovaquone, indapamide to the dissolubility of following chemical compound.Prepare sample according to embodiment 9 described methods, they show that the dissolubility of each active component increases.Increase respectively 55-doubly, 100-doubly and 140-doubly.The maxima solubility of sample in the phosphate buffer of pH=6.8 that contains 5%w/w

Embodiment 23 (referring to Fig. 8 and Figure 11)

The wettability of the sample of given compositions in the test implementation example 9,11,12 and 18.When contacting 75% relative humidity for 25 ℃, measuring water absorption.By the saturated nacl aqueous solution conservation condition that remains on 25 ℃.Measuring relative weight after 3 and 24 hours increases.The weight that the weight increase that only contains the sample of hyper branched polymer and active pharmaceutical ingredient is significantly higher than the sample that contains hyper branched polymer, active pharmaceutical ingredient and hydrophilic carrier lactose increases.The water that only contains adsorption/absorption in the sample of hyper branched polymer and active pharmaceutical ingredient causes sample liquefaction, promptly from the solid-state liquid state that changes into.The high-hygroscopicity of sample makes operating difficulties.Observe method of granulating and significantly improved operation.Hygroscopicity is owing to mixing of carrier reduced.After 75% relative humidity is assigned 24 hours, observe weight increase only 3%.Granule remains solid form, and can easily operate.The result is as shown in Figure 8.And observe:, then compare hygroscopicity and mainly reduce with amorphous carrier (for example spray-dried lactose) if use crystallization carrier (for example 200 order lactose).The result is shown in figure 11.

Embodiment 24 (referring to Fig. 9)

Use scanning electronic microscope examination that the sample among the embodiment 23 is studied.Granularity, shape, gathering, growth and liquefaction have been estimated.Observe and also comprise lactose and remain clear and discrete particle form as the sample of carrier; Do not have granularity increase, alteration of form and general liquefaction, and only comprise hyper branched polymer and tend to constitute aggregation, particle size growth and alteration of form as the sample of the glimepiride of active component.Therefore, Fig. 9 shows: the pharmaceutical composition that used carrier material such as lactose stabilized and allow in storage process, to keep the primary characteristic of pharmaceutical composition.

Embodiment 25 (referring to Figure 10)

To only contain sample (sample of the compositions shown in embodiment 11) the compacting written treaty 100mg tablet among the embodiment 23 of hyper branched polymer and active pharmaceutical ingredient through the hydraulic press that adopts 10000N, the sample that also contains the hydrophilic carrier lactose (sample of the compositions shown in embodiment 12) will be suppressed written treaty 500mg tablet.

Make tablet as in Example 23 in the relative humidity of 25 ℃ of contacts 75% then.Measuring relative weight after 3 and 24 hours increases.The weight increase that only contains the tablet of hyper branched polymer and medicine is significantly higher than the weight increase of the tablet that also contains lactose.As in powder sample, being seen in the past, only contain adsorbed in the sample of hyper branched polymer and active pharmaceutical ingredient/water of absorbing and cause tablet to liquefy.The result is shown in figure 10.

Embodiment 26

Mensuration contains the chemical stability and the particulate chemical stability of the 500mg tablet of hyper branched polymer, active pharmaceutical ingredient and lactose.Make the stressed condition of sample contact elevated temperature (50 ℃) reach 3 days.Because non-active ingredient is responsive to elevated temperature, so there is not to use higher temperature.

When the heterogeneity in the hybrid medicine preparation, there is each composition probability interact with each other.In addition, every kind of composition can have different degradation characteristics.This can cause the problem brought by the chemical stability of the active pharmaceutical ingredient in the dosage form subsequently.

Use is equipped with and maintains 30 ℃ of C18 in the column oven, 5 μ m, and the Waters system of 150X 4.6mm post carries out HPLC and analyzes.Mobile phase is made up of the phosphate buffer of pH=2.5 and the mixture of acetonitrile (50:50V/V).Flow velocity is 1ml/min, and the detection wavelength is 228nm.All impurity of eluting are represented the total amount of glimepiride impurity in 15 minutes.

Following table has provided the contrast stability study of sample:

Can find out from The above results, significant degraded after 50 ℃ elevated temperatures reach 3 days, not occur.Glimepiride as active pharmaceutical ingredient is stable, and compatible with selected composition.

Embodiment 27 (referring to Figure 12)

The IR-spectrographic method

On Perkin Elmer System 2000 spectrogrphs, write down infrared spectrum.Usually, 256 scanning is averaged, with 2cm ^-1Nominal resolution use trigonometric function to cut toe (apodized).Measured spectrum in room temperature with ATR and transmission means, in the later case, carried out with the KBr sheet form of compacting.With record ATR spectrum in the Specac Golden Gate ATR pond that is equipped with diamond crystal.The ATR spectrum is not carried out extra processing as using owing to the penetration depth of frequency dependence or the unusual correction of spectrum due to the reflection.

The ATR spectrum also has the characteristic due to the reflection except that having absorption information.The influence of so-called anomalous dispersion is interference band shape and bands of a spectrum frequency significantly.These interference depend between the refraction index that is loaded with crystallization and sample and the ratio between the angle of incidence.The bands of a spectrum that intensity is lower more are not vulnerable to the influence of anomalous dispersion, and this is able to confirm (seeing table) through the bands of a spectrum frequency of relatively being recovered by transmission and ATR spectrum.

Table: with the frequency ratio of the bands of a spectrum of intensity maximum in transmission and the glimepiride of ATR mode record, Hybrane HA1690 and the Hybrane S1200 spectrum

Make and attempt explaining the interaction between API and the hyper branched polymer.Notice the little frequency difference between transmission and the ATR spectrum, used it for API – hyper branched polymer interaction in the whole original ATR spectrum of research.As far as full-fledged research sample light penetration depth is very nearly the same, and therefore, the ATR spectrum is preferably for the application of spectral difference subtracts.And, ATR spectrum do not have extra for through employing KBr (owing to the OH bands of a spectrum of aquation KBr sheet) or nujol as typical bands of a spectrum for the spectrum of the solid sample of carrier recording.

The ATR spectrum (being respectively top and middle part spectrum) shown in figure 12 of glimepiride and Hybrane HA1690.The ATR spectrum of the hyper branched polymer that deduction is pure from the spectrum of the solid dispersion of the glimepiride that contains the 5/95%w/w weight ratio and hyper branched polymer.The difference spectrum of Hybrane HA1690 (bottom spectrum) shown in figure 12.

Because of interact the significantly change of the infrared spectrum that produces of Hybrane HA1690 and glimepiride is at ~ 2450cm ^-1The center occur wide absorption and ν (O)-C=O with (N)-C=O bands of a spectrum red shift (Figure 12).At 1725cm ^-1Negative band appears and at 1691cm ^-1The appearance These positive bands is the result that the frequency of Hybrane HA1690 (O)-C=O tension belt (stretching band) moves down.Similar frequency displacement is observed in stretching for (N)-C=O, and it is from 1636cm ^-1Move to 1598cm ^-1This frequency displacement is the characteristic that the hydrogen band forms.Compound other evidence that causes the hydrogen band to form is at 2450cm between medicine and the hyper branched polymer ^-1Near the wide absorption of NH tension belt.NH stretching Zhang Xianzhu broadening and be displaced to lower wave number (~ 2450cm ^-1) the strong relatively hydrogen band of existence in glimepiride/Hybrane HA1690 complex is described.

Pure spectrum through deduction Hybrane S1200 from the complex of Hybrane S1200 and glimepiride obtains similar difference spectrum.(O)-C=O with (N)-red shift of C=O tension belt and also be present in such difference spectrum because of the appearance of the wide absorption due to the NH group of hydrogen bonding.In zone, do not observe remarkable change to the hydroxyl vibration performance property of Hybrane S1200 functional group.Therefore, the expectation hydroxyl is not participated in the H-bonding.

Viewed change means between ester carbonyl group (the O)-C=O of the NH of glimepiride group and Hybrane polymer and amide (N)-C=O group and has hydrogen bond in infrared difference spectrum.The type that hydrogen bond between medicine and hyper branched polymer forms is similar in two kinds of Hybrane polymer.From shown in the result we can draw as drawing a conclusion: the proton that hyper branched polymer is mainly set up hydrogen bond with it as the NH group of API is accepted the source of group.

Embodiment 28

X-ray powder diffraction research (XRD)

Adopt X ' Pert PRO MPD powder diffraction meter to obtain the X-roenthenograph.Make the CuK alpha ray of 2 ° of < 2 θ>40 ° of scopes of sample contact.Be 50 seconds the time of integration in per step.

Carrying out XRD analysis changes with the polymorphic of analyzing glimepiride in the solid dispersion.

The x-ray diffraction pattern of original glimepiride (Figure 13 A, lower curve) show its crystal formation for the point strong peak shown in.The characteristic peak of glimepiride also is present in (Figure 13 A in the solid dispersion with PEG 6000 or Gelucire 50/13; Be respectively middle part and upper curve), show glimepiride with the solid dispersion of general linear polymer (being PEG 6000 or Gelucire 50/13) in remain isomorphism mutually.Viewed glimepiride peak intensity in the solid dispersion sample (top and middle part curve) is than glimepiride peak intensity (lower curve) height of pure medicine, and this is result's (compare conventional determining that pure drug sample carries out long 40 times) of long minute.

Figure 13 B has shown the x-ray diffraction pattern of the solid dispersion of prepared glimepiride that contains the Different Weight ratio and hyper branched polymer Hybrane S1200.Medicament contg is 2 to demonstrate the image of representing amorphous polymer with the solid dispersion of 5%w/w.Only in the image that shows the 20%w/w glimepiride, observe the characteristic peak of glimepiride.

According to same way as, prepared have hyper branched polymer Hybrane S1200 and 7,10 and the solid dispersion of 12%w/w API, their x-ray diffraction pattern is respectively shown in curve A, B and the C of Figure 13 C.

Only in the x-ray diffraction pattern of the solid dispersion that contains the 12%w/w glimepiride, clearly observe peak (Figure 13 C, curve C) corresponding to the crystallization glimepiride.

With regard to the granule that contains API, Hybrane HA1690 and lactose, in their x-ray diffraction pattern, only observe peak, and do not detect the peak of glimepiride owing to nonactive lactose constituent.

Claims

1. pharmaceutical composition comprises:

A) at least a hyper branched polymer; With

B) at least aly in the aqueous medium of pH6.8 and 37 ℃, demonstrate active constituents of medicine less than the dissolubility of 1mg/ml; And

Wherein said at least a hyper branched polymer: the weight ratio of described at least a active pharmaceutical ingredient is 99:1w/w to 11:1w/w; Perhaps the wherein wt ratio is 99:1w/w to 4:1w/w; Condition is that active pharmaceutical ingredient is selected from phosphodiesterase inhibitor, non-thiazine sulfonamide medicine, sulfonyl urea derivates and hydroxyl-1,4-naphthoquinone derivatives; Perhaps the wherein wt ratio is 99:1w/w to 4:1w/w, and condition is that high branched polyamide ester is used as hyper branched polymer.

2. the pharmaceutical composition of claim 1, wherein said hyper branched polymer and described at least a ingredient form solid dispersion, optional at least a water-dispersible or the water solublity pharmaceutically suitable carrier of also comprising of said solid dispersion.

3. claim 1 or 2 pharmaceutical composition; Wherein said at least a active constituents of medicine is selected from glimepiride, gliclazide, glipizide, glibenclamide, pimobendan, tadanafil, atovaquone and indapamide; Preferred glimepiride, pimobendan, tadanafil, atovaquone and indapamide, more preferably active constituents of medicine is a glimepiride.

4. aforesaid right requires each pharmaceutical composition, is powder or the particle form that also comprises hydrophilic or hydrophobic carrier.

5. pharmaceutical dosage forms comprises each pharmaceutical composition of claim 1 to 4, wherein pharmaceutical dosage forms solid dosage form preferably.

6. aforesaid right requires each pharmaceutical composition or pharmaceutical dosage forms, and wherein pharmaceutical composition or pharmaceutical dosage forms do not contain surfactant.

7. preparation of drug combination method, this method comprises the following steps:

A) at least a hyper branched polymer and at least aly in the aqueous medium of pH6.8 and 37 ℃, demonstrate the active pharmaceutical ingredient less than the dissolubility of 1mg/ml is provided; Its weight ratio is 99:1w/w to 11:1w/w; Perhaps wherein wt is than being 99:1w/w to 4:1w/w; Condition is that active pharmaceutical ingredient is selected from phosphodiesterase inhibitor, non-thiazine sulfonamide medicine, sulfonyl urea derivates and hydroxyl-1; The 4-naphthoquinone derivatives, perhaps wherein wt is than for 99:1w/w to 4:1w/w, and the high branched polyamide ester that condition is high branched polyamide ester, preferably have a tertiary amine group is used as hyper branched polymer;

C) remove organic solvent.

8. the method for claim 7, wherein the drug prepared compositions is powder or particle form, this method also is included in step b) or the step c) mixture and hydrophilic or hydrophobic carrier, preferred crystallization carrier is merged and preparation powder or granule.

9. claim 7 or 8 method, wherein organic solvent is selected from C ₂-C ₄Alkanol, for example ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutanol; Aliphatic series or alicyclic ethers, for example ether, Di Iso Propyl Ether, methyl tertiary butyl ether(MTBE), two

10. the method for claim 7 to 9, wherein step c) is carried out through adopting high shear mixing, spray drying or fluidized bed granulation.

11. the crystallization carrier comprises the purposes in the pharmaceutical composition of hyper branched polymer and active constituents of medicine in preparation.

12. the polyesteramide hyper branched polymer comprises the purposes in the pharmaceutical composition of at least a active pharmaceutical ingredient in preparation; The weight ratio of wherein said hyper branched polymer and described at least a active pharmaceutical ingredient is 99:1w/w to 11:1w/w; Perhaps wherein wt compares even can be 99:1w/w to 4:1w/w, and condition is that active pharmaceutical ingredient is selected from phosphodiesterase inhibitor, preferably phosphoric acid diesterase III inhibitor or Phosphodiesterase V inhibitors; Non-thiazine sulfonamide medicine; Sulfonyl urea derivates; And hydroxyl-1, the 4-naphthoquinone derivatives.

13. hydrophilic or the hydrophobic carrier purposes in pharmaceutical compositions; Said pharmaceutical composition comprises and blended phosphodiesterase inhibitor, non-thiazine sulfonamide medicine, sulfonyl urea derivates and hydroxyl-1, the active constituents of medicine of 4-naphthoquinone derivatives of being selected from of at least a hyper branched polymer.

14. be selected from phosphodiesterase inhibitor, non-thiazine sulfonamide medicine, sulfonyl urea derivates and hydroxyl-1; The active pharmaceutical ingredient of 4-naphthoquinone derivatives comprises the purposes in the pharmaceutical composition of at least a hyper branched polymer in preparation; Wherein said at least a active constituents of medicine demonstrates the dissolubility less than 1mg/ml in the aqueous medium of pH6.8 and 37 ℃, and the weight ratio of wherein said at least a hyper branched polymer and described at least a active pharmaceutical ingredient is 99:1w/w to 4:1w/w.

15. the purposes of claim 14, wherein ingredient is selected from pimobendan, tadanafil, indapamide, glimepiride and atovaquone.