CN101831067A - Polyethylene glycol ester conjugate and application thereof in medicine preparation - Google Patents

Abstract

The invention discloses a polyethylene glycol ester conjugate, comprising a central architecture formed by glycerol molecules, an ester group covalently conjugated with the glycerol central architecture, and a polyethylene glycol (PEG) chain covalently conjugated with the glycerol central architecture, wherein, the molecular weight of the PEG chain is 200-1200 daltons, and more than 75% of PEG in the chain has the same molecular weight. The conjugate of the invention can be applied to medicinal preparation, is beneficial to improving the water solubility and pharmacological property of a medicine, can be widely applied to a clinical human or animal medicinal preparation, and is of great significance for development and innovation of a medicine preparation technology.

Description

Polyethylene glycol ester conjugate and the application in the preparation medicine thereof

Technical field

The invention belongs to field of medicine and chemical technology, relate to polyethylene glycol ester conjugate, especially relate to highly purified Macrogol Ester compounds and contain dispersity single (mondisperse) or the polyglycol chain of range of molecular weight distributions single (narrow distribution) and Macrogol Ester compounds and the application in the preparation medicine thereof.

Background technology

During as drug delivery vehicle, the Macrogol Ester compounds has the ability that promotes pharmacology feature and lipophilic drugs solubility.In addition, it also has other potential advantages, for example reduces the side effect and the toxicity that are caused by medicine in the clinical treatment to greatest extent.The narrow range of molecular weight distributions of drug delivery polymer is most important for its application at biomedicine field, during especially for intravenous injection.For example: polyoxyethylene glycol-8 caprylic/capric glyceryl ester (PEG-8Caprylic/Capric Glycerides) is the mixture of monoglyceride, diester and three esters and polyoxyethylene glycol monoesters and diester, and the averagemolecular wt amount is between 200 dalton and 400 dalton.Because it can cause the animal anaphylaxis, for many water-fast medicines, the application of polyoxyethylene glycol-8 caprylic/capric glyceryl ester is restricted, thereby in the clinical oral administration pharmaceutical preparation, the dose limit of polyoxyethylene glycol-8 caprylic/capric glyceryl ester is about about 6%.

Its molecular weight of the polyglycol chain of being made by Raolical polymerizable is at 200-1200 dalton or above polyglycol chain, and the distribution of its molecular weight can not be subjected to very strict control.Generally, with reaching target molecular weight in the polymerisate of a collection of product well below 50%.Narrow range of molecular weight distributions can be realized by gel exclusion chromatography or molecular sieve chromatography, yet realize that the single distribution of the polyoxyethylene glycol of purifying is very difficult.The high purity polyoxyethylene glycol with about 12 ethylene glycol that the merchant sells is extremely expensive and need extra synthesis step just can be applied in medicine or the cosmetic formulations.

The length that United States Patent (USP) 6610322 points out to change PEG chain and acyl chain can influence the accumulation parameter of conjugate, otherwise it determines again whether polyethylene glycol ester combination of compounds composition can form liposome.When preparation had the pharmaceutical preparation of Macrogol Ester compounds, the selection of lipoid substance and PEG size also might produce obviously influence to pharmacokinetics and stability thereof except meeting influences the physical structure of drug molecule.Therefore, have specific and relatively single PEG chain length dispersity in the same high molecular polymer and the conjugate that constitutes often to be much better than those have the uneven PEG of chain length dispersity and constitute conjugate.

Summary of the invention

The object of the present invention is to provide a kind of Macrogol Ester compounds that to have a class glycerol molecule be the center framework, this class center framework links to each other with covalent linkage with one or two highly purified polyglycol chain and a fat group.These compounds are significant to the water solubility and the pharmacological characteristics of medicine.

Another object of the present invention is to realize the application of this compounds in the preparation medicine.

Chemical name that the present invention uses and abbreviation contrast are as follows:

DAG-PEGs: triglyceride-polyoxyethylene glycol (Diacylglycerol-polyethyleneglycols)

DMAP:4-dimethylamino pyridine (N, N-dimethylamino pyridine)

MPEG: poly glycol monomethyl ether (monomethox polyethylene glycol ether)

PEG-12: polyoxyethylene glycol-12 (polyethyleneglycols 600)

PEG 23: polyoxyethylene glycol-23 (polyethyleneglycols 1000)

PEG 27: polyoxyethylene glycol-27 (polyethyleneglycols 1200)

GDM-12:1,2-two mnyristoyls-racemize-glycerine-3-polyoxyethylene glycol-12 (1,2-dimyristoyl-rac-glycerol-3-dodecaethylene glycol)

GDO-12:1,2-two oily tin glycerine-racemize-glycerine-3-polyoxyethylene glycol-12 (1,2-dioleoyl-rac-glycerol-3-dodecaethylene glycol)

GDC-12:1,2-two oily tin glycerine-racemization-glycerine-3-polyoxyethylene glycol-12 (1,2-dicholoyl-rac-glycerol-3-dodecaethylene glycol)

GDO-600:1,3-dioleoyl-glycerine-2-polyoxyethylene glycol-12 (1,3-dioleoyl-glycerol-2-dodecaethylene glycol)

GDC-600:1,3-two oily tin glycerine-glycerine-2-polyoxyethylene glycol-12 (1,3-dicholoyl-glycerol-2-dodecaethylene glycol)

GDS-12:1,2-distearyl acyl group-racemization-glycerine-3-polyoxyethylene glycol-12 (1,2-distearoyl-rac-glycerol-3-dodecaethylene glycol)

GOB-12:1,2-two (polyoxyethylene glycol-12) glycerine-3-oleic acid ester (1,2-bis (dodecaethyleneglycol) glycerol-3-oleate)

GMB-12:1,2-two (polyoxyethylene glycol-12) glycerine-3-myristinate (1,2-bis (dodecaethylene glycol) glycerol-3-myristate)

DSB-12:1,2-two (polyoxyethylene glycol-12) glycerine-3-stearic acid (1,2-bis (dodecaethyleneglycol) glycerol-3-stearate)

GOBH:1,2-two (six ethylene glycol) glycerine-3-oleic acid ester (1,2-bis (hexaethyle glycol) glycerol-3-oleate)

GMBH:1,2-two (six ethylene glycol) glycerine-3-myristinate (1,2-bis (hexaethyle glycol) glycerol-3-myri state)

GCBH:1,2-two (six ethylene glycol) glycerine-3-cholate (1,2-bis (hexaethyle glycol) glycerol 3-cholate)

GCLBH:1,2-two (six ethylene glycol) glycerine-3-cholesterol (1,2-bis (hexaethyle glycol) glycerol 3-cholesterol)

GPBH:1,2-two (six ethylene glycol) glycerine-3-palmitinic acid (1,2-bis (hexaethyle glycol) glycerol-3-palmitate)

GDO-23:1, and 2-dioleoyl-racemization-glycerine-3--polyoxyethylene glycol-23 (1,2-dioleoyl-rac-glycerol-3-polyethylene (1000) glycol, n=23)

GDO-27:1, and 2-dioleoyl-racemization-glycerine-3--polyoxyethylene glycol-27 (1,2-dioleoyl-rac-glycerol-3-polyethylene (1200) glycol, n=27)

GDM-23:1, and 2-two myristinates-racemization-glycerine-3-polyoxyethylene glycol-23 (1,2-dimyristoyl-rac-glycerol-3-polyethylene (1000) glycol, n=23)

GDM-27:1, and 2-two myristinates-racemization-glycerine-3-polyoxyethylene glycol-27 (1,2-dimyristoyl-rac-glycerol-3-polyethylene (1200) glycol, n=27)

GDS-23:1, and 2-distearyl acyl group-racemization-glycerine-3-polyoxyethylene glycol-23 (1,2-distearoyl-rac-glycerol-3-polyethylene (1000) glycol, n=23)

TPGS-VE: VE-succinate-polyoxyethylene glycol (d-alpha-tocopheryl polyethyleneglycol-1000succinate)

For finishing goal of the invention, the present invention adopts has the high purity Macrogol Ester compounds of more single PEG chain length dispersity comprising various fat matrix such as saturated/unsaturated fatty acids or bile acides.This PE-lipoid substance can be used for medicine to be sent, and is specially adapted to the intravenous injection of the medicament of poorly water-soluble.All PEG-lipoid substances that design among the present invention or describe and adopt are all entrusted U.S. EquaChem (California, USA Pittsburg city) to process synthetic and are provided.

General thought of the present invention is design and the combination that comprises the synthesizing polyethylene glycol lipoid substance, this compound is that the center framework is formed by the class glycerol molecule, covalently bound one or two single polyoxyethylene glycol of PEG chain length dispersity and one or two lipid groups on this center framework directly or by linking group are linked between center framework and PEG chain or the lipid groups.

If with the glycerol molecule is the center framework, its isomer will comprise with two lipid groups and the single glyceride ester of PEG chain length dispersity (two kinds of isomer), with the glyceryl ester (two kinds of isomer) of a lipid groups and two single polyoxyethylene glycol of PEG chain length dispersity, and, may be multiple compound or group wherein at the 3rd locational compound of center framework with the glyceryl ester (all isomer) of a lipid groups and a single polyoxyethylene glycol of PEG chain length dispersity.

The present invention only uses pure 1,2 or 1,3 glycerine dibasic acid esters isomer. can buy on the market 1,2 glycerin fatty dibasic acid esters perhaps can be used to synthetic multiple compound, but 1,2 glycerine dibasic acid esters can the occurrence positions transfer can generate 1,3 more stable glycerine isomer in storage process, its content can be up to about 30%.In the present invention, use 1,2 or 1,3 pure glycerine isomer even more ideal.Though similar on the function of 1,2 or 1,3 isomer, being chosen in of isomer has different meanings in the different delivery process, for example send in the cell of lipophilic molecules and in medicinal application as carrier.For instance, in dissolving and storage process, each isomer there are differences aspect the ability of stable compound.

If need make the conjugate of two PEG chains among the present invention, then can use the glycerol derivative shown in chemical structural formula 3 or 4.In these structures, R represents a blocking group (can be replaced) or a kind of acyl group lipid compounds (may be contained in final structure).For ramose PEG conjugate, two PEG and chain length unanimity are with particularly suitable.

Except that single non-oxygen base, the present invention adopts other multiple linking groups to be incorporated between glycerine center framework and PEG chain simultaneously.For example, introduce unsettled sulfydryl key linking group may command carrier compound survival time in vivo.Some other useful linking group table 3 list and the present invention in will set forth further.Just synthesizing at the class glycerol molecule is the conjugate that alternative linking group is arranged between center framework and the PEG chain; it is center framework (shown in chemical structural formula 3) that linking group at first is connected to shielded class glycerol molecule; then first reaction PEG oligopolymer is connected to the free end of linking group, and PEG can prolong as required.Perhaps, before linking group was connected on the framework of center, first reaction PEG oligopolymer can be connected with linking group.When reacting with linking group, there are functional groups such as hydroxyl, amino, carboxyl, isocyanic ester, sulfydryl, carbonate in the preferred PEG-reagent, particularly used preferred PEG-reagent comprises the PEG-Phenylsulfonic acid, PEG-methylsulfonic acid and succinyl--PEG in the inventive method implementation process.Also identical linking group can be incorporated between glycerine center framework and the lipid groups.For obtaining this kind conjugate, before being connected on the framework of center, linking group can be connected with lipid groups, or before lipid groups is connected to linking group linking group is connected on the framework of center.

Above-mentioned method has been described the PEG chain has been connected to by on the center framework of a removable blocking group protection, and after PEG was in place, one or more lipid groups were connected on the framework of center.Yet, before being connected to the PEG chain on the framework of center, also can be with one or two lipid groups as the blocking group on the framework of center.This alternative method is specially adapted to not have the alkyl chain of active group, and active group needs protected in PEG connection and overtime.But when the solid sour lipoid substance of needs preparations class, this way is not very effective just, because the bile acids has many hydroxyls, these side groups can go wrong when PEG connects and extend.

Above-mentioned PEG-lipoid substance can be used for preparing the chemical compound lot among the present invention, also can be used for preparing the compound that contains other alternative group.For example, contain 27 unitary conjugates of PEG, can be earlier strand PEG be received glycerine center framework after synthetic again if preparation contains a bile acide and two.Using the same method also to make multiple compound of the present invention, comprises the compound that contains littler PEG chain length.

Conjugate among the present invention comprises and has the monoester group being connected on the framework of glycerine center and the conjugate of a PEG chain, and wherein the 3rd position on the framework of center substituted by the another one group, and this group can be hydroxyl or strong solvent.It should be noted that, when 1, when occurrence positions shifts in the 2 triglyceride storage processs (1, contain above-mentioned free hydroxyl group in 2 triglycerides), if the PEG chain is also longer than six methylene radical, for the conjugate with a monoester group and a PEG chain (being connected on the glycerine center framework that has a free hydroxyl group), it resets probability can be littler, needs very big energy (because steric effect, molecular size and polarity all are different from lipid) because move a PEG chain.In addition, generally speaking, 1,3 isomer is more stable than 1,2 isomer.

Be suitable for preparing the PEG-lipoid substance required lipid compounds comprise bile acide (steroid acid) and alkyl chain.Therefore, present invention includes the multiple PEG-lipoid substance for preparing by existing liquid phase synthesizing method.Steroid acid-PEG conjugate can be introduced in the liposome and as the target group fat base medicine to be delivered to specific cells or as self-emulsifying drug delivery system (self-emulsifying drug delivery systems).

Bile acide (steroid acid) quasi-molecule comprises multiple compound, and it is that a carboxylic acid group forms by four lopps sterol structures, five or eight carbon side chains and tail end, and has the oh group of different numbers.Four rings from left to right are denoted as A, B, C, D, wherein the few carbon of other three rings of D chain rate.The example bile acide is shown in chemical structure 5.All bile acides all have side chain.When a carboxylic group connects v taurine or glycine by acid amides, the nuclear oh group can with glucuronide or vitriol esterification, this is extremely important for bilichol being made water-soluble biliary salts.

It is few in number that present physico-chemical property according to biliary salts carries out structural improved research.Wherein a patent (WO 02083147) discloses the biliary salts fatty acid conjugates, wherein bile acide or biliary salts in the position 24 (carboxyls) put together undersaturated C=C key and one or two fatty acid-based puting together of containing 14-22 carbon atom with suitable amino acid.This conjugate is used as a kind of cholesterol that reduces in the blood, the pharmaceutical composition of treatment fatty liver, hyperglycemia and diabetes.(patent No.: 2003212051) disclose acyclovir-bile acide precursor medicine, wherein linking group can be used between bile acide and the drug molecule another United States Patent (USP).

PEG-lipoid substance among the present invention can be expressed with following general formula: the difference of two kinds of isomer is the relative position of polymkeric substance and the lipid chain on the framework of glycerine center.

Structural formula 1

Several interchangeable embodiments are arranged in the structural formula 1.In wherein a kind of isomer, R1 and R2 can be identical or different, optional in listed saturated of table 1 or table 2 and or unsaturated alkyl; X for-O-C (O)-,-O-,-S-,-NH-C (O)-or select in table 3 and the listed linking group of table 4; P is the PEG chain.Connect the base except listing these standard amino acids in the table 4, the present invention also comprises non-standard amino acid for example beta (beta) amino acid, seleno-cysteine (selenocysteine), L-lanthionine (lanthionine), 2-aminoisobutyric acid (2-aminoisobutyricacid), dehydrogenation-L-Ala (dehydroalanine) and gamma aminobutanoic acid (gamma-aminobutyric acid).

In the changed structure of structural formula 1, one of them may be alkyl for R1 and R2, and another is H.In the specific embodiments of structural formula 1, have at least one to be that the saturated of 6-22 carbon atom or unsaturated alkyl group are arranged among R1 or the R2.In a preferred embodiment, R1 is identical with the R2 group, comprises 6-22 carbon atom, if it is then better to comprise 12-18 carbon atom.Wherein " alkyl " comprises saturated or unsaturated fatty acids.

The present invention also provides general formula 2 expressed following PEG-lipoid substance:

Structural formula 2

Equally, structural formula 2 also has several interchangeable embodiments.In wherein a kind of isomer, R is table 1 or the listed alkyl group of table 2; X for-O-C (O)-,-O-,-S-,-NH-C (O)-or select in table 3 and the listed linking group of table 4; P1 is identical PEG chain with P2.By two PEG of branch chains are provided, the conjugate shown in the structural formula 2 is better than the PEG conjugate with single long-chain.

Table 1: saturated resin acid used in the present invention

Popular name	Chemical name	Chemical structure	Abbreviation	Fusing point (℃)
					Butyric acid	Butyric acid	??CH 3(CH 2) 2COOH	??C4:0	??-8
Caproic acid	Caproic acid	??CH 3(CH 2) 4COOH	??C6:0	??-3
					Sad	Sad	??CH 3(CH 2) 6COOH	??C8:0	??16-17
Capric acid	Capric acid	??CH 3(CH 2) 8COOH	??C10:0	??31
					Lauric acid	Laurostearic acid	??CH 3(CH 2) 10COOH	??C12:0	??44-46
Semen Myristicae	TETRADECONIC ACID	??CH 3(CH 2) 12COOH	??C14:0	??58.8
					Palmitinic acid	Palmitic acid	??CH 3(CH 2) 14COOH	??C16:0	??63-64
Stearic acid	Stearic acid	??CH 3(CH 2) 16COOH	??C18:0	??69.9
					Eicosanoic acid	20 acid	??CH 3(CH 2) 18COOH	??C20:0	??75.5
Behenic acid	Behenic acid	??CH 3(CH 2) 20COOH	??C22:0	??74-78

Table 2: unsaturated fatty acid used in the present invention

Title	Chemical structure	??Δ xThe position of two keys	# singly-bound and two key ratios
				Semen Myristicae oleic acid	??CH 3(CH 2) 3CH＝CH(CH 2) 7COOH	??cis-Δ 9	??14∶1
Zoomeric acid	??CH 3(CH 2) 5CH＝CH(CH 2) 7COOH	??cis-Δ 9	??16∶1
				Oleic acid	??CH 3(CH 2) 7CH＝CH(CH 2) 7COOH	??cis-Δ 9	??18∶1
Linolic acid	??CH 3(CH 2) 4CH＝CHCH 2CH＝CH(CH 2) 7C??OOH	??cis，cis-Δ 9，??Δ 12	??18∶2
				α-linolic acid	??CH 3CH 2CH＝CHCH 2CH＝CHCH 2CH＝CH(??CH 2) 7COOH	??cis，cis，cis-??Δ 9，Δ 12，Δ 15	??18∶3
Arachidonic acid	??CH 3(CH 2) 4CH＝CHCH 2CH＝CHCH 2CH＝??CHCH 2CH＝CH(CH 2) 3COOH NIST	??cis，cis，cis，??cis-Δ 5Δ 8，Δ?? 11，Δ 14	??20∶4
				Sinapinic acid	??CH 3(CH 2) 7CH＝CH(CH 2) 11COOH	??cis-Δ 13	??22∶1

Table 3: used in the present invention other contains the alkyl linking group

Table 4: amino acid linking group used in the present invention

??No	Amino acid	Side chain can be electrically charged at pH7.4 a
			??1	L-Ala	Neutral
??2	Arginine	Positive charge
			??3	L-asparagine	Neutral
??4	Aspartic acid	Negative charge
			??5	Aminothiopropionic acid	Neutral
??6	L-glutamic acid	Negative charge
			??7	Glutamine	Neutral
??8	Glycine	Neutral
			??9	Histidine	Positive charge/neutral l (1/9)
??10	Different bright amino acid	Neutral
			??11	White amino acid	Neutral
??12	Rely amino acid	Positive charge
			??13	Methionine(Met)	Neutral
??14	Phenylpropylamine acid	Neutral
			??15	Proline(Pro)	Neutral
??16	The silk amino acid	Neutral
			??17	Soviet Union's amino acid	Neutral
??18	Tryptophane	Neutral
			??19	Tyrosine	Neutral
??20	The figured silk fabrics amino acid	Neutral

PEG lipoid substance among the present invention also comprises the compound that those lipid groups parts are made up of one or two bile acide.These conjugates (compound) have the same structure shown in structural formula 1 or 2, except alkyl is replaced by bile acide.For the bile acide conjugate, its isomer is identical with PEG-alkyl conjugate with preferred embodiment.Because bile acide has similar lipophilicity to alkyl, the bile acide conjugate is also similar to PEG-alkyl conjugate physical properties, so it also has and the identical purposes of PEG-alkyl conjugate.

Shown in the chemical structure 6 is two kinds of bile acide conjugate isomer among the present invention, and it is shown as and has connected a single PEG chain and two bile acides on the framework of glycerine center.

Chemical structural formula 6

In chemical structure 6, Y1 and Y2 can be identical or different, and it is OH, H, CH ₃Or select a kind of in the bile acide that table 4 is listed.Similarly, the bile acide (as shown in table 5) that has different side groups can be puted together and is connected on the framework of glycerine center.Table 4 has been listed and can be used for bile acide of the present invention and derivative thereof.

Table 5: bile acide used in the present invention (steroid acid) and derivative thereof

The present invention also comprises the isomer that another possibility changes in the compound shown in structural formula I and II, bile acide among its R1 or the R2, and another is an alkyl group.The isomer example of this lipid polymer is shown in following chemical structure 7.

Chemical structural formula 7

In chemical structure 7, Y1 and Y2 can be identical or different, and it is OH, H, CH ₃Or select a kind of in the listed bile acide of table 5.Equally, the side chain of bile acide also can be by structural changes shown in the table 5.R is saturated and or the unsaturated alkyl group shown in table 1 and the table 2.

Another preferred embodiment to compound among structural formula I and the II is the EG-bile acide conjugate shown in chemical structure 8.

Chemical structural formula 8

In chemical structural formula 8, Y1 and Y2 are OH, H, CH ₃Or select a kind of in the listed bile acide of table 5.Equally, the side group of bile acide can be according to structural changes shown in the table 5.

Another kind of preferred embodiment to structural formula I and II formula II is the conjugate of PEG-cholesterol, shown in chemical structure 9:

Chemical structural formula 9

To a kind of preferred using method of PEG-lipid of the present invention is that the preparation liposome contains the preparation of lipid with other.According to the present invention, can comprise one or more genophores, antisense molecule (antisense molecules), protein, polypeptide, biological activity lipid or medicine in the pharmaceutical preparation prescription.For example, can comprise one or more medicines (as one or more cancer therapy drugs or other carcinostatic agent) in the activeconstituents of medicament.Hydrophilic active principle generally can directly be applied in the prescription, and hydrophobic activeconstituents can be mixed with other composition after the dissolving of PEG-lipid compounds earlier again.

The active constituents of medicine that is suitable in the thing pharmaceutical formulation of the present invention comprises one or more genophores, antisense molecule, protein, polypeptide, biological activity lipid or medicine, as mentioned above.High purity PEG-lipid compounds among the present invention is used for clinical administration, and is especially when intravenously administrable, safer than other lipid compounds that contain PEG mixing chain length.

Preferred active constituents of medicine according to the invention comprises the medicament that acts on peripheral nerve, adrenoceptor, cholinergic receptor, skeletal muscle, cardiovascular systems, unstriated muscle, blood circulation, cynapse site, neural effector point of interface, internal secretion and hormone system, immunity system, reproductive system, Skeletal system, digestive tube and Excretory system, histamine system and central nervous system.Suitable pharmaceutical cpd can be selected materials such as protein, enzyme, hormone, Nucleotide, polynucleotide, nucleoprotein, polysaccharide, glycoprotein, lipoprotein, polypeptide, steroid, terpenoid, retinoid, antiulcer agent bisfentidine, anti-ulcer medicament, low blood calcium agent, wetting Agent for Printing Inks, makeup.Active medicine can be an anodyne, narcotic, antiarrhythmic drug, microbiotic, anti-allergic agent, anti-mycotic agent, anticarcinogen is (as mitoxantrone, Taxan, taxol, camptothecine, camptothecine and derivative thereof (as S-38), gemcitabine, anthracycline drug, antisense oligonucleotide, antibody, cytokine, immunotoxin etc.), antihypertensive drug is (as dihydropyridines, thymoleptic, the cox-2 inhibitor), anti-coagulant, thymoleptic, antidiabetic medicine, antiepileptic drug, antiphlogistic corticoid, treatment senile dementia or Parkinson's disease medicament, antiulcer agents, anti-protozoon agent, anxiolytic, the Tiroidina medication, antithyroid drug, antiviral drug, appetite suppressant, diphosphonate, the heart inotropic agent, the cardiovascular medicine of using, alclometasone diproionate, diuretic(s), the Dopamine HCL agent, medicine for digestive system, hemostatic agent, the hypercholesterolemia agent, antihypertensive drug, immunosuppressor, the antigout agent, antimalarial drug, antimigraine, urinary incontinence agent, anti-inflammatory agent, as be used for the treatment of rheumatosis, sacroiliitis, psoriasis, inflammatory bowel and Crohn disease, or be used for the treatment of demyelinating disease, as multiple sclerosis and ophthalmological; Vaccine is (as resisiting influenza virus; pneumonia; hepatitis A; hepatitis B; third liver; b subunit of cholera toxin; typhoid fever; plasmodium falciparum; diphtheria; tetanus; hsv; pulmonary tuberculosis; HIV; Whooping cough; measles; parotitis; rubella; bacterial toxoid; immunity virus; adenovirus; SARS virus; canary bird virus; bacille Calmette-Guerin vaccine; vaccines such as Cray uncle pneumonia); histamine receptor antagonists; soporific; the kidney protective material; lipid regulating agent; the muscle agent of releiving; antipsychotic drug; neurotrophic agents; opiate receptor excitomotor and antagonist; parasympathetic inhibitor; proteinase inhibitor; prostaglandin(PG); tranquilizer; sexual hormoue is (as male sex hormone; oestrogenic hormon etc.); stimulant; sympathetic inhibitor; vasodilator; the synthetics of xenthophylls and these kinds.These medicines can be harmful to kidney (as ciclosporin and amphotericin B) or heart (as amphotericin B and taxol).The functional deriv of etoposide, cytokine, ribozyme, Interferon, rabbit, oligonucleotide, siRNAs, RNAis and above-mentioned substance.

The inventive method is suitable for chemotherapeutics very much.The PEG-lipid formulations that contains chemotherapeutics among the present invention can be injected directly in the tumor tissues, as carrier chemotherapeutics is acted on the cancer cells to guarantee it.In some cases, especially behind tumor resection, Liposomal formulation can directly be implanted cavity or be applied in as protective layer in the tissue of other reservation.

PEG-lipid chemical combination among the present invention can be used for preparing various formulations, comprises tablet, capsule, pill, granule, suppository, solution, suspension and emulsion, ointment, ointment, gel, breast frost, lotion, eye drop, pulvis and sprays and suitable and all kinds of water-soluble or shared preparation of water soluble adjuvant not.

PEG-lipoid substance among the present invention can be used to active drug delivery target cell in the body.Said composition is sent by directly oral, injection (as intravenous injection, subcutaneous injection, intramuscular injection, the outer injection of intestines, intraperitoneal injection, be injected directly into cancer cells and need the position of treatment), suction, mucous membrane, part and/or rectum or by other method existing or exploitation.The prescription that contains PEG phosphatide also can be at topical, as emulsifiable paste, barrier cream, xerosis cutis softening agent, moisturizing emulsion etc.

With regard to clinical use, the invention provides drug formulation process and can comprise the suitable disease treatment of one or more active medicines.The invention provides a kind of method of pharmaceutical preparation, it contains one or more active medicines, can be used to treat certain disease.Generally speaking, this disease is present in the middle of the human and animal.For example in a preferred embodiment, this disease is a cancer, and said preparation comprises one or more carcinostatic agents as active medicine.According to the present invention, this pharmaceutical preparation can independently use or be used for treating the cancer that appears at head, neck, brain, blood, breast, lung, pancreas, bone, spleen, bladder, prostate gland, testis, colon, kidney, ovary and skin etc. as the adjuvant therapy of other therapeutic modality (chemotherapy or radiotherapy).The preparation that contains one or more cancer therapy drugs among the present invention is fit to be used for treating leukemia very much, as acute leukemia (acute lymphoblastic leukemia or acute myelocytic leukemia).Composition among the present invention and method also can be used for treating Kaposi sarcoma (Kaposi ' s sarcoma).

It is following that the structure diagram can the invention will be further described.

Chemical structural formula 10

In chemical structural formula 10, " X " is linking group, comprise oxygen base, sulfydryl, amino ,-COO-,-OCOO-, succinyl-, halogenide and table 3 and table 4 in listed group; " n " expression repeating unit number.On behalf of the PEG with a chain length dispersity single (monodisperse), these structures be connected to intermediate on the framework of glycerine center, and therefore " n " is generally between 5-23.The PEG chain is expanded by continuous etherificate, at first from less chain such as triglycol or Tetraglycol 99 (these chains directly are connected on the glycerine on the framework of center by linking group).The terminal group of PEG chain (r) can be, but be not limited to methyl.

Chemical structural formula 11

In chemical structural formula 11, " X " is linking group, comprise oxygen base, sulfydryl, amino ,-COO-,-OCOO-, succinyl-, halogenide and table 3 and table 4 in listed group." n " represents number of repeat unit.These structures represent that the PEG chain with two chain length dispersity single (monodisperse) is connected to last step on the framework of glycerine center." R " is an alkyl group, as saturated (seeing Table 1) or unsaturated fatty acids (seeing Table 2), courage acyl group and derivative (seeing Table 5) thereof.PEG end group (r) can be methyl etc.

Chemical structural formula 12

In chemical structural formula 12, " X " is linking group, comprise oxygen base, sulfydryl, amino ,-COO-,-OCOO-, succinyl-, halogen halogenide and table 3 and table 4 in listed group." n " expression repeating unit number.These structures represent that the PEG chain with two chain length dispersity single (monodi sperse) is connected to last step on the framework of glycerine center.Equally, the PEG chain is expanded by continuous etherificate, at first from less chains (these chains directly are connected on the framework of glycerine center by linking group) such as triglycol or Tetraglycol 99s." R " is an alkyl group, as saturated (seeing Table 1) or unsaturated fatty acids (seeing Table 2), courage acyl group and derivative (seeing Table 5) thereof.PEG end group (r) can be methyl etc.

Chemical structural formula 13

In chemical structural formula 13, " X " and " L " is identical or different linking group, comprise oxygen base, sulfydryl, amino ,-COO-,-OCOO-, succinyl-, halogenide and table 3 and table 4 in listed group." n " represents number of repeat unit.These structures represent that the PEG chain with two chain length dispersity single (monodisperse) is connected to last step on the framework of glycerine center.Therefore " n " is generally between 5-12." R " is an alkyl group, as saturated (seeing Table 1) or unsaturated fatty acids (seeing Table 2), courage acyl group and derivative (seeing Table 5) thereof.The PEG terminal group can be methyl etc.

Embodiment of the present invention have been described the preparation of medicament and combination herein, and said preparation contains purifying Macrogol Ester compounds with the solubleness that increases active medicine and improve its transmission capacity.Good reagent combination has been done introduction herein substantially with being combined in, and different medicines can have different optimum formulas certainly.

For parenteral solutions, preferred drug level between 0.1%-30%, 0.5%-10% more preferably, 0.5%-5% is then most preferably.(medicine: be 1 to 20,1 to 10 for more preferably the PEG-lipoid substance), 1 to 5 for most preferably for the preferred proportion of PEG-lipoid substance of the present invention and medicine.

For oral liquid, preferred drug level between 1%-40%, 2.5%-30% more preferably, 5%-30% is then most preferably.(medicine: be 0.5 to 20,1 to 5 for more preferably the PEG-lipoid substance), 1 to 3 for most preferably for the preferred proportion of PEG-lipoid substance of the present invention and medicine.

As ophthalmic preparation, preferred drug level between 0.01%-5%, 0.05%-2% more preferably, 0.1%-2% is then most preferably.

(medicine: be 1 to 20,1 to 3 for more preferably the PEG-lipoid substance), 1 to 2 for most preferably for the preferred proportion of PEG-lipoid substance of the present invention and medicine.

As externally used solution, preferred drug level between 0.05%-5%, 0.1%-5% more preferably, 0.1-2% is then most preferably.(medicine: be 1 to 20,1 to 3 for more preferably the PEG-lipoid substance), 1 to 2 for most preferably for the preferred proportion of PEG-lipoid substance of the present invention and medicine.

For oral capsule, preferred medicament contg between 10mg-250mg, 25mg-200mg more preferably, 25mg-100mg is then most preferably.(medicine: be 1 to 10,1 to 5 for more preferably the PEG-lipoid substance), 2 to 5 for most preferably for the preferred proportion of PEG-lipoid substance of the present invention and medicine.

As external preparation, preferred drug level between 0.05%-5%, 0.1%-5% more preferably, 0.5-2% is then most preferably.(medicine: be 1 to 50,1 to 10 for more preferably the PEG-lipoid substance), 1 to 2 for most preferably for the preferred proportion of PEG-lipoid substance of the present invention and medicine.

Except polymeric lipoid substance illustrational as how glycerine PEG chain that is a center framework and a purifying.The present invention comprises that simultaneously other can form or as the compound molecule of the center framework of such PEG-fat based compound, comprising 3-amino-1,2-propylene glycol (3-amino-1,2-propanediol), 3-bromo-1,2-propylene glycol (3-bromo-1,2-propanediol), 3-chloro-1,2-propylene glycol (3-chloro-1,2-propanediol), 3-fluoro-1,2-propylene glycol (3-fluoro-1,2-propanediol), DL-R-Glyceric acid (DL-glyceric acid), two hydroxymethyl propionic acids (2-Bis (hydroxymethyl) propionic Acid) and 1,2, the 4-trihydroxybutane (1,2,4-butanetriol) reach multiple amino acids and comprised aspartic acid, L-glutamic acid all can be used as the center framework and synthesizes the PEG-lipoid substance similar to glycerine being the center framework.Every amino acid contains the center framework that two carboxyls or dihydroxyl or diamino especially are suitable as such PEG-fat based compound, preferred amino acids is aspartic acid (Aspartic Acid), L-glutamic acid (Glutamic Acid), glutamine (Glutamine), l-asparagine (Asparagine), aminocarbonyl L-Ala, Serine (Serine) and Threonine (Threonine), preferred amino acid is aspartic acid, L-glutamic acid, Serine and Threonine, and most preferred amino acid is aspartic acid, L-glutamic acid and Serine.

Chemical structural formula 14 is to use aspartic acid as a kind of conjugate of center framework synthetic among the present invention.The starting raw material of synthetic this conjugate is oleyl alcohol but not oleic acid, because existing two carboxyls exist in the amino acid.PEG is connected on the framework of center by the succsinic acid linking group.The variation of any center framework, PEG chain (or alternative polymer chain) all are chain length dispersity single (monodisperse) molecules.

Chemical structural formula 14 1,4-two oleoyls-2-(mPEG-12-succinyl-amino acid) aspartic acid

In the table 6 for several similarly be the example of center framework or link group with amino acid.

Table 6: amino acid used herein is the example of center framework or link group

Propylene glycol and methylene glycol oligopolymer can be used for substituting the monomer of ethylene glycol polymer, and it also can generate the multipolymer or the segmented copolymer of basic boom.

For example, the PEG reagent that uses in the inventive method can be any PEG derivative, its can with hydroxyl on the glycerine of center or amino reaction, also can with 3-amino-1, the functional group reaction on 2-propylene glycol group or other linking group.

The invention provides the framework of the lipoid substance of a kind of PEG of comprising, the PEG lipoid substance is made up of following material: a glycerine center framework; One or two covalently bound lipid groups on the framework of glycerine center; One or two covalently bound PEG chain on the framework of glycerine center, wherein the PEG chain molecular weight is between 200-1200 dalton.The contained PEG chain of PEG lipoid substance molecule of the present invention has following feature: 75% PEG molecule has identical molecular weight in its PEG chain, even may have the same molecular amount more than 90%.The molecular weight of PEG chain may be 500 dalton or more than 500 dalton.Lipid may be an alkyl, and this alkyl may be to select in listed saturated alkyl of table 1 and the listed unsaturation alkyl of table 2.Said composition also may also comprise another covalently bound lipid on the framework of glycerine center.Lipid may be a bile acide, and this bile acide may be to select that it also comprises cholesterol in the listed bile acide of table 5.This lipid may be an alkyl and a bile acide simultaneously also.

In addition, this PEG lipoid substance also may comprise a linking group (between glycerine center framework and PEG chain), this linking group may be selected from by-S-,-O-,-N-,-member of the group that OCOO-and the listed linking group of table 3 are formed.In addition, said composition also may comprise another covalently bound PEG chain on the framework of glycerine center, linking group between glycerine center framework and this PEG chain may be selected from the list-O-C (O) that is situated between-,-O-,-S-,-NH-C (O)-wait group or select group listed in table 3 and table 4.

On the other hand, the present invention also comprises foregoing PEG lipoid substance, wherein glycerine center framework is replaced by other center framework, as 3-amino-1,2-propylene glycol (3-amino-1,2-propanediol), 3-bromo-1,2-propylene glycol (3-bromo-1,2-propanediol), 3-chloro-1,2-propylene glycol (3-chloro-1,2-propanediol), 3-fluoro-1,2-propylene glycol (3-fluoro-1,2-propanediol), DL-R-Glyceric acid (DL-glyceric acid), two hydroxymethyl propionic acids (2-Bis (hydroxymethyl) propionic Acid) and 1,2, the 4-trihydroxybutane (1,2,4-butanetriol) and multiple amino acids comprise aspartic acid (Aspartic Acid), L-glutamic acid (Glutamic Acid), glutamine (Glutamine), l-asparagine (Asparagine), the aminocarbonyl L-Ala, Serine (Serine) and Threonine (Threonine).

Another aspect, invention is declared foregoing PEG lipoid substance simultaneously and is also comprised high molecular polymer or polymerization such as polymethylene glycol polymethylene glycol, the polypropylene glycol polypropylene glycol of other kinds and comprise the multipolymer of being made of (Co-polymer) first glycol (methylene glycol), propylene glycol (propyleneglycol) or ethylene glycol (ethylene glycol) for monomer mixes.

On the other hand, bioavailability and/or the water solubility that utilizes advantage of the present invention to comprise to improve active medicine. PEG lipoid substance of the present invention can be prepared the preparation that contains one or more medicines, and to be used for animal or human's class clinical.

On the other hand, the present invention comprises the compound with following general formula:

Structural formula 3

Wherein the value of n is between 3-23; R is the lipid group; X is a linking group, X can be selected from oxygen base, sulfydryl, amino ,-COO-,-OCOO-, succinyl-, halogenide or table 3 and the listed linking group of table 4, its molecular weight is between 14-620 dalton.The value of n can be between 4-12, between the 7-12 then more preferably.The molecular weight of PEG last-in-chain(LIC) end group is between 15-210 dalton, and it can be a hydroxyl, methyl or amino acid etc.R may be for selecting the alkyl group in table 1 or table 2.R may be for selecting the bile acide in table 5.R also may be cholesterol.

The present invention also comprises the compound with following general formula simultaneously:

Structural formula 4

The n value is between 3-23; R is the lipid group; X is a linking group, and X is identical or different linking groups, X can be selected from oxygen base, sulfydryl, amino ,-COO-,-OCOO-, succinyl-, halogenide or table 3 and the listed linking group of table 4, its molecular weight is between 14-620 dalton.The value of n can be between 4-12, between the 7-23 then more preferably.The molecular weight of PEG last-in-chain(LIC) end group is between 15-210 dalton, and it can be a hydroxyl, methyl or amino acid etc.R may be for selecting the alkyl group in table 1 or table 2.R may be for selecting the bile acide in table 5.R also may be cholesterol.

The present invention further comprises the compound with following general formula:

Structural formula 5

The n value is between 3-23; R is the lipid group; L and X are linking group, the linking group that L can be identical or different with X, L can be selected from oxygen base, sulfydryl, amino ,-COO-,-OCOO-, succinyl-, halogenide or table 3 and the listed linking group of table 4, its molecular weight is between 14-620 dalton.The value of n can be between 4-12, between the 7-23 then more preferably.The molecular weight of PEG chain end group is between 15-210 dalton, and it can be hydroxyl or methyl.R may be for selecting the alkyl group in table 1 or table 2.R may be for selecting the bile acide in table 5.R also may be cholesterol.X can be selected from oxygen base, sulfydryl, amino ,-COO-,-OCOO-, succinyl-(succinyl), halogenide or table 3 and the listed linking group of table 4.

Polyethylene glycol ester conjugate provided by the present invention helps to improve the water solubility and the pharmacological characteristics of medicine, can be widely used in the clinical mankind or animal pharmaceuticals preparation, and the development and the innovation of drug preparation technique is significant.

Description of drawings

Fig. 1 has described the 3-dimension structure of the two dehydrogenation courage acyl glycyl glyceryl ester of PEG-12-

Fig. 2 has described the itraconazole parenteral solutions at the intravital medicine of mouse (metabolism) dynamic characteristic

Fig. 3 has described the itraconazole oral liquid at the intravital medicine of mouse (metabolism) dynamic characteristic.

Embodiment

Embodiment 1: solid preparation

Earlier in a stainless steel vessel that has a helical mixing blade, add liquid macrogol (PEG) lipoid substance, add bulk drug thereafter and be warmed to 55 ℃-65 ℃ and be stirred to this medicine with lasting weighbridge speed and disperse fully to dissolve in Macrogol Ester.In another independent container, heat solid Macrogol Ester compounds (fusing point is higher than 30 ℃) makes its fusing or is dissolved in then to incorporate in the ethanol in the container that contains bulk drug and continues weighbridge speed and be stirred to it and become complete homogeneous solution state.Available in case of necessity vacuumizing removed ethanol.While hot it is incapsulated in the packaging vessel (mould) of shell or design in advance.The capsule or the mould that are filled are put in the 2-8 ℃ of refrigerating chamber, and its milky mixt will be formed solid after a few hours.The prescription example sees Table 7.

Table 7 solid preparation prescription

Composition	??％
		Bulk drug	??15
The liquid macrogol lipoid substance	??40
		The solid polyethylene glycol lipoid substance	??45
Ethanol	??＜1

Liquid PEG-ester conjugate can be GDM-12, GDO-12, GDC-12, GDM-600, GDO-600, GDC-600, GOB-12, GMB-12, GOBH, GMBH, GCBH, GCBH or GPBH in this example.The solid fat compounds is GDS-12, DSB-12, GDO-23, GDO-27, GDM-23, GDM-27 or GDS-23.Medicine can be dutasteride (Dutasteride), modafinil (modafinil), nifedipine (nifedipine), esomeprazole (esomeprazole), Wyeth-Ayerst Laboratories (rapamycin), triazole or other antibiotic or antibiotic medicine.

Embodiment 2: solid preparation

Earlier in a stainless steel vessel that has a helical mixing blade, add liquid macrogol (PEG) lipoid substance, add bulk drug thereafter and be warmed to 55 ℃-65 ℃ and be stirred to this medicine with lasting weighbridge speed and disperse fully to dissolve in Macrogol Ester.In another independent container, heat solid VE-succinate-polyoxyethylene glycol (TPGS-VE) compound (fusing point is higher than 55 ℃) makes its fusing or is dissolved in then to incorporate in the ethanol in the container that contains bulk drug and continues weighbridge speed and be stirred to it and become complete homogeneous solution state.Available in case of necessity vacuumizing removed ethanol.While hot it is incapsulated in the packaging vessel (mould) of shell or design in advance.The capsule or the mould that are filled are put in the 2-8 ℃ of refrigerating chamber, and its milky mixt will be formed solid after a few hours.The prescription example sees Table 8.

Table 8TPGS-VE solid preparation prescription

Composition	??％
		Bulk drug (active)	??15
The liquid macrogol lipoid substance	??40
		VE-succinate-polyoxyethylene glycol	??45
Ethanol	??＜1

The liquid conjugate is GDM-12, GDO-12, GDC-12, GDM-600, GDO-600, GDC-600, GOB-12, GMB-12, GOBH, GMBH, GCBH, GCBH or GPBH.Medicine can be dutasteride (Dutasteride), modafinil (modafinil), nifedipine (nifedipine), esomeprazole (esomeprazole), Wyeth-Ayerst Laboratories (rapamycin), triazole (triazoles) or other antibiotic or antibiotic medicine.

Embodiment 3: the oral liquid preparation

Earlier in a stainless steel vessel that has a helical mixing blade, add liquid macrogol (PEG) lipoid substance, add bulk drug thereafter and be warmed to 55 ℃-65 ℃ and be stirred to this medicine with lasting weighbridge speed and disperse fully to dissolve in Macrogol Ester.Under stirring fully, in container, slowly add dissolved pharmaceutical excipient then, continue to stir until reaching a kind of complete homogeneous solution state.The prescription example sees Table 9.

Table 9 oral liquid pharmaceutical formulation

Composition	Mg/ml
		Bulk drug (active)	??30.0
Macrogol Ester	??100
		Lactic acid	??50
Sodium hydroxide	See below
		Hydrochloric acid	See below
The sour sodium of benzene (first)	??2.0
		Synthetic flavour	??5.0
Purified water	Equivalent to 1 milliliter

The liquid conjugate is GDM-12, GDO-12, GDC-12, GDM-600, GDO-600, GDC-600, GOB-12, GMB-12, GOBH, GMBH, GCBH, GCBH or GPBH.Medicine can be dutasteride (Dutasteride), modafinil (modafinil), nifedipine (nifedipine), esomeprazole (esomeprazole), Wyeth-Ayerst Laboratories (rapamycin), triazole (triazoles) or other antibiotic or antibiotic medicine.If need, hydrochloric acid or sodium hydroxide can be used for regulating the pH value, and target pH value is between 4.0-7.0.

Embodiment 4: the ciclosporin ophthalmic preparation

In a container that has a spiral stirrer, add Macrogol Ester, ceaselessly stir, continue to stir and be dispersed in the fat until this medicine while add the ciclosporin medicine.Under stirring fully, slowly add dissolved pharmaceutical excipient and sterile purified water then, continue to stir until reaching a kind of complete homogeneous solution state.The prescription example sees Table 10.

Table 10 ciclosporin ophthalmic preparation prescription

Composition	Milligram/100 milliliters
		Ciclosporin	??50
Macrogol Ester	??500
		Sodium hydroxide	See below
Hydrochloric acid	See below
		Sodium-chlor	??900
Through the disinfectant purified water	Equivalent to 100 milliliter

Liquid conjugate (Macrogol Ester) is GDM-12, GDO-12, GDC-12, GDM-600, GDO-600, GDC-600, GOB-12, GMB-12, GOBH, GMBH, GCBH, GCBH or GPBH.Medicine can be dutasteride (Dutasteride), modafinil (modafinil), nifedipine (nifedipine), esomeprazole (esomeprazole), Wyeth-Ayerst Laboratories (rapamycin), triazole (triazoles) or other antibiotic or antibiotic medicine.If need, hydrochloric acid or sodium hydroxide can be used for regulating the pH value, and target pH value is between 6.0-7.4.

Embodiment 5: injection formulation

Except that the pH value is between 6.0-8.0, also require sterilization and sterile packed usually, injection formulation can prepare by example 3 methods.The prescription example sees Table 11.

Table 11 injection formulation prescription

Composition	Milligram/100 milliliters
		Bulk drug (active)	??10.0
Macrogol Ester	??100
		Sodium hydroxide	See below
Hydrochloric acid	See below
		Purified water	Equivalent to 1 milliliter

Liquid conjugate (Macrogol Ester) is GDM-12, GDO-12, GDC-12, GDM-600, GDO-600, GDC-600, GOB-12, GMB-12, GOBH, GMBH, GCBH, GCBH or GPBH.If need, hydrochloric acid or sodium hydroxide can be used for regulating the pH value, and target pH value is between 6.5-7.4. medicine can be triazole (triazoles) such as posaconazole (posaconazole), voriconazole (voriconazole), Itraconazole (itraconazole) or rapamycin (rapamycin) or cyclosporine (cyclosporines) or tacrolimus (tacrolimus) or nifedipine (nifedipine) or taxol (paclitaxel) or docetaxel (docetaxel) or Gefitinib (gefitinib) or propofol (propofol) or rifampin (rifampin) or stable (diazepam) or nelfinavir (nelfinavir) or other triazole or other antibiotic or antibiotic activity agent.

Embodiment 6: medicine (metabolism) dynamic characteristic and the bioavailability of itraconazole prescription

This research is adopted by three male mice (cohorts that (B6D2F1) forms, behind the itraconazole intravenous injection 0 hour, 0.08 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 16 hours and 24 hours, or the itraconazole mouth was raised back 0 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 16 hours and the serum sample of the heparinization mouse of acquisition in 24 hours, the medicine that carries out sample analysis and obtain being correlated with (metabolism) kinetic parameter.In order to determine every kind of drug level, at first use acetonitrile that sample pretreatment is divided medicine and blood plasma and leave away except that behind the protein in the sample use high performance liquid chromatography-mass spectrum/mass spectroscopy (HPLC-MS/MS) quantitative analysis and the drug level that obtains being correlated with.For computer software (WinNonlin) program (5.2 editions) medicine (metabolism) dynamics data is carried out the compartment model analysis by the pharmacology medicine then.

Shown among Fig. 2 that the itraconazole preparation is at the intravital medicine of mouse (metabolism) dynamic characteristic, wherein (1) is that the phosphate buffered saline buffer (pH value is 7.4) with 10 milli Mores (mM) is that medium and GDO-12 are the preparation (ratio of medicine and PEG-lipoid substance is 1: 10) of carrier, (2) be with 10 in the least Mores' (mM) phosphate buffered saline buffer (the pH value is 7.4) be the polyoxyethylenated castor oil (Cremophor) of medium and 10%)-5% methyl alcohol is the preparation of carrier.Use intravenous administration, injected dose is 20mg/kg.DAG-PEG (1) is the polyoxyethylenated castor oil (Cremophor) of the preparation of carrier and 10%)-5% methyl alcohol is that area under curve (AUC) value of the preparation (2) of carrier is respectively 5441 μ ghr/mL and 986 μ ghr/mL.

Shown among Fig. 3 that the itraconazole preparation is at the intravital medicine of mouse (metabolism) dynamic characteristic, wherein (1) is that the phosphate buffered saline buffer (pH value is 7.4) with 10 milli Mores (mM) is that medium and GDO-12 are the preparation (ratio of medicine and PEG-lipoid substance is 1: 10) of carrier, (2) be with 10 in the least Mores' (mM) phosphate buffered saline buffer (the pH value is 7.4) be the polyoxyethylenated castor oil (Cremophor) of medium and 10%)-5% methyl alcohol is the preparation of carrier.Use oral administration, injected dose is 20mg/kg.DAG-PEG (1) is the polyoxyethylenated castor oil (Cremophor) of the preparation of carrier and 10%)-5% methyl alcohol is that the relative bioavailability of preparation (2) of carrier is (based on AUC _{0-24 hour}) be respectively 63% and 45%.

Embodiment 7: the external application cream formulation

Earlier in a stainless steel vessel that has a helical mixing blade, add liquid macrogol (PEG) lipoid substance, add bulk drug thereafter and be warmed to 60 ℃-65 ℃ and be stirred to this medicine with lasting weighbridge speed and disperse fully to dissolve in Macrogol Ester.Continue to stir and add organic acid, cholesterol and glycerine, and then add ethanol and ethoxydiglycol, add carboxyvinyl polymer ETD 2020, purified water and triethylamine at last.Continue to stir until reaching a kind of complete homogeneous solution state.The prescription example sees Table 12.

Table 12 external application cream formulation prescription

Composition	??％
		Bulk drug (active)	??1.0
Macrogol Ester	??5.0
		Carboxyvinyl polymer ETD 2020	??0.5
Ethoxydiglycol	??1.0
		Ethanol	??5.0
Glycerine	??1.0
		Cholesterol	??0.4
Triethylamine	??0.20
		Organic acid	??10
Sodium hydroxide	Equaconazole sees below

Composition	??％
		Purified water	Equivalent to 100

Liquid conjugate (Macrogol Ester) is GDM-12, GDO-12, GDC-12, GDM-600, GDO-600, GDC-600, GOB-12, GMB-12, GOBH, GMBH, GCBH, GCBH or GPBH.If need, hydrochloric acid or sodium hydroxide can be used for regulating the pH value, and target pH value is between 6.5-7.4.Lipid can be GDM-12, GDO-12, GDC-12, GDM-600, GDO-600, GDC-600, GOB-12, GMB-12, GOBH, GMBH, GCBH, GCBH, GPBH, GDS-12, or its arbitrary combination.Organic acid can be lactic acid, pyruvic acid or oxyacetic acid.Target pH value is between 3.5-7.0.As needs, the available hydrogen sodium oxide is regulated the pH value.Medicine can be an itraconazole, posaconazole, voriconazole, such tie up health azoles (Equaconazole), Terbinafine (Terbinafine), amorolfine (Amorolfine), naftifungin (Naftifine), cloth is for naphthalene (Butenafine), phenylformic acid (Benzoic acid), ciclopirox (Ciclopirox), Tonoftal (Tolnaftate), undecylenic acid (Undecylenic acid), flucytosine (Flucytosine), grisovin (Griseofulvin), haloprogin (Haloprogin), sodium bicarbonate (Sodiumbicarbonate), fluocinolone acetonide (Fluocinolone acetonide) or other antibiotic or antibiotic medicine.

Embodiment 8: the externally used solution preparation

Externally used solution group preparation can be according to preparation shown in the example 7, and the prescription example sees Table 13.

Table 13 externally used solution pharmaceutical formulation

Composition	??％
		Bulk drug (active)	??1.0
Macrogol Ester	??5.0
		Alpha-tocopherol	??0.5
Organic acid	??10.0
		Ethanol	??5.0
Sodium Benzoate	??0.2
		Sodium hydroxide	See below
Purified water	Equivalent to 100

Liquid conjugate (Macrogol Ester) is GDM-12, GDO-12, GDC-12, GDM-600, GDO-600, GDC-600, GOB-12, GMB-12, GOBH, GMBH, GCBH, GCBH or GPBH or its arbitrary combination.Organic acid can be lactic acid, pyruvic acid or oxyacetic acid.Target pH value is between 3.5-7.0.As needs, the available hydrogen sodium oxide is regulated the pH value.Medicine can be an itraconazole, posaconazole, voriconazole, such tie up health azoles (Equaconazole), Terbinafine (Terbinafine), amorolfine (Amorolfine), naftifungin (Naftifine), cloth is for naphthalene (Butenafine), phenylformic acid (Benzoic acid), ciclopirox (Ciclopirox), Tonoftal (Tolnaftate), undecylenic acid (Undecylenic acid), flucytosine (Flucytosine), grisovin (Griseofulvin), haloprogin (Haloprogin), sodium bicarbonate (Sodium bicarbonate), fluocinolone acetonide (Fluocinolone acetonide) or other antibiotic or antibiotic medicine.

Embodiment 9: Azythromycin (Azithromycin) eye medicinal preparation

Earlier in a stainless steel vessel that has a helical mixing blade, add liquid macrogol (PEG) lipoid substance, add thereafter and constantly stir down adding Azythromycin bulk drug and lasting weighbridge speed and be stirred to this medicine and disperse fully to dissolve in Macrogol Ester.Under fully stirring, slowly add the auxiliary material and the axenic purification water of predissolve then, continue to stir until reaching a kind of complete homogeneous solution state.The prescription example sees Table 14.

Table 14 Azythromycin eye medicinal preparation prescription

Composition	Mg/ml
		Azythromycin	??15
Macrogol Ester	??150
		Oxyhydroxide	See below
Hydrochloric acid	See below
		Sodium-chlor	??9
Axenic purification water	Equivalent to 1 milliliter

Liquid conjugate (Macrogol Ester) is GDM-12, GDO-12, GDC-12, GDM-600, GDO-600, GDC-600, GOB-12, GMB-12, GOBH, GMBH, GCBH, GCBH or GPBH or its arbitrary combination.Organic acid can be lactic acid, pyruvic acid or oxyacetic acid.Target pH value is between 7.05-7.8.As needs, available hydrochloric acid or sodium hydroxide are regulated the pH value.

The preferred concentration of Azythromycin is between 0.5-3%, and 0.5-2% is for better, and 1-2% then is best.The preferred ratio of Macrogol Ester and the medicine ratio of ciclosporin (Macrogol Ester with) is 1: 20, and 1: 3 ratio is for better, and 1: 2 ratio then is the best.

Claims (22)

1. polyethylene glycol ester conjugate, its structure comprises:

(a) center framework that forms by glycerol molecule;

(b) lipid group covalently bound with glycerine center framework;

(c) polyoxyethylene glycol (PEG) chain covalently bound with glycerine center framework, the molecular weight of this PEG chain is between 200-1200 dalton, and the PEG more than 75% has identical molecular weight in the chain.

2. polyethylene glycol ester conjugate as claimed in claim 1 is characterized in that: in the described PEG chain, the PEG more than 90% has identical molecular weight.

3. polyethylene glycol ester conjugate as claimed in claim 2 is characterized in that: the molecular weight of PEG chain is greater than 300 dalton.

4. polyethylene glycol ester conjugate as claimed in claim 1 is characterized in that: described lipid group is an alkyl.

5. polyethylene glycol ester conjugate as claimed in claim 4 is characterized in that: described alkyl is selected from the following alkyl group: CH ₃(CH ₂) ₂COOH, CH ₃(CH ₂) ₄COOH, CH ₃(CH ₂) ₆COOH, CH ₃(CH ₂) ₈COOH, CH ₃(CH ₂) ₁₀COOH, CH ₃(CH ₂) ₁₂COOH, CH ₃(CH ₂) ₁₄COOH, CH ₃(CH ₂) ₁₆COOH, CH ₃(CH ₂) ₁₈COOH, CH ₃(CH ₂) ₂₀COOH, CH ₃(CH ₂) ₃CH=CH (CH ₂) ₇COOH, CH ₃(CH ₂) ₅CH=CH (CH ₂) ₇COOH, CH ₃(CH ₂) ₇CH=CH (CH ₂) ₇COOH, CH ₃(CH ₂) ₄CH=CHCH ₂CH=CH (CH ₂) ₇COOH, CH ₃CH ₂CH=CHCH ₂CH=CHCH ₂CH=CH (CH ₂) ₇COOH, CH ₃(CH ₂) ₄CH=CHCH ₂CH=CHCH ₂CH=CHCH ₂CH=CH (CH ₂) ₃COOH ^NIST , CH ₃(CH ₂) ₇CH=CH (CH ₂) ₁₁COOH.

6. polyethylene glycol ester conjugate as claimed in claim 1 is characterized in that: it also has second a lipid group covalently bound with glycerine center framework.

7. polyethylene glycol ester conjugate as claimed in claim 6 is characterized in that: this second lipid group is an alkyl group, is selected from the following alkyl group: CH ₃(CH ₂) ₂COOH, CH ₃(CH ₂) ₄COOH, CH ₃(CH ₂) ₆COOH, CH ₃(CH ₂) ₈COOH, CH ₃(CH ₂) ₁₀COOH, CH ₃(CH ₂) ₁₂COOH, CH ₃(CH ₂) ₁₄COOH, CH ₃(CH ₂) ₁₆COOH, CH ₃(CH ₂) ₁₈COOH, CH ₃(CH ₂) ₂₀COOH, CH ₃(CH ₂) ₃CH=CH (CH ₂) ₇COOH, CH ₃(CH ₂) ₅CH=CH (CH ₂) ₇COOH, CH ₃(CH ₂) ₇CH=CH (CH ₂) ₇COOH, CH ₃(CH ₂) ₄CH=CHCH ₂CH=CH (CH ₂) ₇COOH, CH ₃CH ₂CH=CHCH ₂CH=CHCH ₂CH=CH (CH ₂) ₇COOH, CH ₃(CH ₂) ₄CH=CHCH ₂CH=CHCH ₂CH=CHCH ₂CH=CH (CH ₂) ₃COOH ^NIST , CH ₃(CH ₂) ₇CH=CH (CH ₂) ₁₁COOH.

8. polyethylene glycol ester conjugate as claimed in claim 6, it is characterized in that: the described second lipid group is a bile acide, be selected from following bile acide: cholic acid (Cholic acid), Septochol (Desoxycholic acid), 3 beta-hydroxies-D5-cholenic acid (5-Cholenic acid-3 beta-ol), dehydrocholic acid (Dehydrocholic acid), glycocholic acid (Glycocholic acid), glycodesoxycholic acid (Glycodeoxycholic acid), Chenodiol (Chenodeoxycholicacid), glycochenodeoxycholate (Glycochenodeoxycholic acid), ursodesoxycholic acid (Ursodeoxycholic acid), cholelith acid (Lithocholic acid), Hyodeoxycholic Acid (Hyodeoxycholic acid), 3,7-diketone-D5-ursodeoxycholic acid (5 β-Cholanicacid-3,7-dione).

9. polyethylene glycol ester conjugate as claimed in claim 6 is characterized in that: the described second lipid group is a cholesterol.

10. polyethylene glycol ester conjugate as claimed in claim 1 is characterized in that: also comprise two a PEG chain covalently bound with glycerine center framework.

11. polyethylene glycol ester conjugate as claimed in claim 10 is characterized in that: also comprise the linking group between glycerine center framework and the PEG chain.

12. polyethylene glycol ester conjugate as claimed in claim 11 is characterized in that: described linking group is selected from the following groups :-S-,-O-,-N-,-OCOO-, carbamyl-carboxylic acid, n-amino-alkyl-amide, n-hydroxyl-alkyl-acid amides, alkyl-diamide, diamino monocarboxylic acid, n-amino-alcohol, diamino, n-amino-alkyl-carboxylamine, n-amino (methyl sulfo-) _nPropionic acid amide, n-mercaptan carboxylic acid, n-sulfydryl-alpha-amino carboxylic acid, n-sulfydryl-alkyl-carboxylamine, n-sulfydryl-propyl group-sulphur-carboxylic acid, amineothiot, n-mercaptoethanol, dimercapto, n-amino (methyl sulfo-) _nPropionic acid, n-hydroxyl-carboxylic acid, n-amino-carboxylic acid, two-carboxylic acid, glycol, hydroxyl-alkyl-carboxylamine n-hydroxyl (methyl sulfo-) _nPropionic acid, L-Ala, arginine, l-asparagine, aspartic acid, aminothiopropionic acid, L-glutamic acid, glutamine, glycine, histidine, different bright amino acid, white amino acid, bad amino acid, methionine(Met), phenylpropylamine acid, proline(Pro), silk amino acid, Soviet Union's amino acid, tryptophane, Tyrosine, figured silk fabrics amino acid.

13. polyethylene glycol ester conjugate as claimed in claim 11, it is characterized in that: described linking group is selected from the following groups: beta (beta) amino acid, seleno-cysteine (selenocysteine), L-lanthionine (lanthionine), 2-aminoisobutyric acid (2-aminoisobutyricacid), dehydrogenation-L-Ala (dehydroalanine) and gamma aminobutanoic acid (gamma-aminobutyricacid).

14. polyethylene glycol ester conjugate as claimed in claim 1, it is characterized in that: its glycerine center framework can be substituted by other center framework, these center frameworks are selected from: 3-amino-1,2-propylene glycol (3-amino-1,2-propanediol), 3-bromo-1,2-propylene glycol (3-bromo-1,2-propanediol), 3-chloro-1,2-propylene glycol (3-chloro-1,2-propanediol), 3-fluoro-1,2-propylene glycol (3-fluoro-1,2-propanediol), DL-R-Glyceric acid (DL-glyceric acid), two hydroxymethyl propionic acids (2-Bis (hydroxymethyl) propionicAcid) and 1,2,4-trihydroxybutane (1,2,4-butanetriol) and multiple amino acids contain two carboxyls or dihydroxyl or diamino and comprise aspartic acid (Aspartic Acid), L-glutamic acid (Glutamic Acid), glutamine (Glutamine), l-asparagine (Asparagine), the aminocarbonyl L-Ala, Serine (Serine) and Threonine (Threonine).

15. polyethylene glycol ester conjugate as claimed in claim 1, it is characterized in that: wherein the PEG chain can be substituted by other polymkeric substance, and these polymkeric substance comprise: polymethylene glycol polymethylene glycol, polypropylene glycol polypropylene glycol and comprise the multipolymer of being made of (Co-polymer) first glycol (methylene glycol), propylene glycol (propylene glycol) or ethylene glycol (ethylene glycol) for monomer mixes.

16. polyethylene glycol ester conjugate as claimed in claim 1 is characterized in that: the molecular weight of PEG last-in-chain(LIC) end group is between 15-210 dalton.

17. polyethylene glycol ester conjugate as claimed in claim 10 is characterized in that: its structural formula is selected from a kind of in the following structural formula:

In the said structure formula, the n value of rPEG is between 4-27; R is the lipid group; X, L are identical or different linking groups.

18. polyethylene glycol ester conjugate as claimed in claim 17 is characterized in that: the molecular weight of X or L is between 14-620 dalton.

19. polyethylene glycol ester conjugate as claimed in claim 17 is characterized in that: X or L are selected from the following groups: oxygen base, sulfydryl, amino ,-COO-,-OCOO-, succinyl-, halogenide, carbamyl-carboxylic acid, n-amino-alkyl-amide, n-hydroxyl-alkyl-acid amides, alkyl-diamide, diamino monocarboxylic acid, n-amino-alcohol, diamino, n-amino-alkyl-carboxylamine, n-amino (methyl sulfo-) _nPropionic acid amide, n-mercaptan carboxylic acid, n-sulfydryl-alpha-amino carboxylic acid, n-sulfydryl-alkyl-carboxylamine, n-sulfydryl-propyl group-sulphur-carboxylic acid, amineothiot, n-mercaptoethanol, dimercapto, n-amino (methyl sulfo-) _nPropionic acid, n-hydroxyl-carboxylic acid, n-amino-carboxylic acid, two-carboxylic acid, glycol, hydroxyl-alkyl-carboxylamine n-hydroxyl (methyl sulfo-) _nPropionic acid, L-Ala, arginine, l-asparagine, aspartic acid, aminothiopropionic acid, L-glutamic acid, glutamine, glycine, histidine, different bright amino acid, white amino acid, bad amino acid, methionine(Met), phenylpropylamine acid, proline(Pro), silk amino acid, Soviet Union's amino acid, tryptophane, Tyrosine, figured silk fabrics amino acid.

20. polyethylene glycol ester conjugate as claimed in claim 1 is characterized in that: the molecular weight of PEG terminal group (r) is between 15-210 dalton.

21. as each described polyethylene glycol ester conjugate of claim 1-20, it is characterized in that: described lipid group is selected from the following groups: CH ₃(CH ₂) ₂COOH, CH ₃(CH ₂) ₄COOH, CH ₃(CH ₂) ₆COOH, CH ₃(CH ₂) ₈COOH, CH ₃(CH ₂) ₁₀COOH, CH ₃(CH ₂) ₁₂COOH, CH ₃(CH ₂) ₁₄COOH, CH ₃(CH ₂) ₁₆COOH, CH ₃(CH ₂) ₁₈COOH, CH ₃(CH ₂) ₂₀COOH, CH ₃(CH ₂) ₃CH=CH (CH ₂) ₇COOH, CH ₃(CH ₂) ₅CH=CH (CH ₂) ₇COOH, CH ₃(CH ₂) ₇CH=CH (CH ₂) ₇COOH, CH ₃(CH ₂) ₄CH=CHCH ₂CH=CH (CH ₂) ₇COOH, CH ₃CH ₂CH=CHCH ₂CH=CHCH ₂CH=CH (CH ₂) ₇COOH, CH ₃(CH ₂) ₄CH=CHCH ₂CH=CHCH ₂CH=CHCH ₂CH=CH (CH ₂) ₃COOH ^NIST , CH ₃(CH ₂) ₇CH=CH (CH ₂) ₁₁COOH; Or cholic acid (Cholic acid), Septochol (Desoxycholic acid), 3 beta-hydroxies-D5-cholenic acid (5-Cholenic acid-3 beta-ol), dehydrocholic acid (Dehydrocholic acid), glycocholic acid (Glycocholic acid), glycodesoxycholic acid (Glycodeoxycholic acid), Chenodiol (Chenodeoxycholic acid), glycochenodeoxycholate (Glycochenodeoxycholic acid), ursodesoxycholic acid (Ursodeoxycholic acid), cholelith acid (Lithocholic acid), Hyodeoxycholic Acid (Hyodeoxycholic acid), 3,7-diketone-D5-ursodeoxycholic acid (5 β-Cholanic acid-3,7-dione); Or cholesterol.

22. the application of any described compound in the preparation medicine among the claim 1-21.

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