CN1213733C - Method of preparing stable suspension of insoluble microparticles - Google Patents

Method of preparing stable suspension of insoluble microparticles Download PDF

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CN1213733C
CN1213733C CNB998156442A CN99815644A CN1213733C CN 1213733 C CN1213733 C CN 1213733C CN B998156442 A CNB998156442 A CN B998156442A CN 99815644 A CN99815644 A CN 99815644A CN 1213733 C CN1213733 C CN 1213733C
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surface modifier
phospholipid
micron
preparation
mean particle
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CN1337877A (en
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S·坎
I·帕里克
H·C·洛克雷
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SKEYI PHARMA CANADA Inc
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Abstract

Sub-micron and micron-size stable particles of water-insoluble or poorly soluble drugs or other industrially useful insoluble compounds suspended in an aqueous medium containing at least one surface modifier are prepared by selecting the surface modifier or modifiers such that the hydrophile-lipophile balance (HLB) of the composition, defined as formula (I): is between 4 and 9. This provides a reliable HLB-based selection criteria for selecting the type and amount of surface modifiers used to obtain sub-micron size stable suspensions.

Description

The method for preparing the suspension of stable particulate matter
The present invention relates to produce the compositions and the method for submicron and micron big or small stable particle, this granule is water insoluble or is slightly soluble in medicine or other insoluble compound with industrial application value of water.The present invention provides reliably first based on the choice criteria of HLB, uses this standard can select to be used to obtain kind and the consumption of the surface modifier of submicron stable suspension.
Background of the present invention
People have proposed various schemes, attempt to adopt surface modifier to prepare the insoluble drugs prescription in aqueous solution, and the surface modifier that is adopted is the conjugate such as independent phospholipid or phospholipid and one or more surfactants.Yet, do not deliver the standard of any selection feature and consumption.United States Patent (USP) 5,145,684 have described a kind of microsolubility medicine, and it contains and is adsorbed on its surperficial non-crosslinked surface modifier.The amount of surface modifier is 0.1%-90% (weight), and the gained granular size is less than 400nm.United States Patent (USP) 5,298,262,5,326,552,5,336,507,5,340,564 and 5,470,583 have described the application of cloud point modifier, and microsolubility medicine wherein or diagnostic agent are adsorbed on its surface with cloud point modifier and non-crosslinked ion-type surface modifier.Cloud point modifier it is said the cloud point that can improve surfactant, thereby the growth of granular size can not appear in the gained nano-particle when carrying out heating disinfection for 121 ℃.These patents provide the example of the various specific cloud point modifier that are used in combination with the different surfaces activating agent, and wherein cloud point modification surfactant is optional.
WO 98/07414 has described a kind of microsolubility medicine, and it contains two kinds and is adsorbed on its surperficial surface modifier; With only compare with a kind of modifier, adding second surface modifier makes granular size reduce nearly 50%.
EP 0580690B1 has described with charged phospholipid and water-fast peptide has been carried out coating so that its solubilising, so the weight ratio of medicine and phospholipid is higher than a marginal value.Poloxamer 188 also is used to prepare drug particles when 0.01%-0.5% concentration.People observe, and when the concentration of poloxamer 188 increased, the ζ electromotive force significantly reduced.
United States Patent (USP) 5,091,187 have proposed to prepare injectable water-insoluble drug by the aqueous suspension that forms phospholipid coating microcrystal.Cause that by supersound process or other method of high shear force makes crystalline drug be reduced to 50nm-10 μ m in the presence of phospholipid.Phospholipid is used as unique surface modifier and is described.
United States Patent (USP) 5,858,410 by adopting piston clearance (piston-gap) homogenizer adding surfactant (synthetic or natural) to make the water-insoluble drug solubilising.The gained granule records its size for 10nm-1 through the photon correlation microscopy, 000nm, have account for sum less than its size of granule of 0.1% greater than 5 microns.Equally, surface modifier is chosen wantonly.
The present invention's narration
According to the compositions of the inventive method preparation, except water-insoluble or be slightly soluble in the drug particles and other industrial chemical compound of water, also comprise natural or synthetic phospholipid or the surfactant that uses separately, perhaps their uses that is bonded to each other.According to program of the present invention, with respect to the kind and the consumption of medicament selection surface modifier, so the system of this system hydrophilic-lipophile balance (HLB) value defined is as follows: system
System HLB value is in 4 to 9 scopes.When the HLB value was in this scope, the unit weight mean particle size of resulting product was less than about 1 micron, at each temperature and all show good stable in stress test.Used terminology is meant whole compositions in this description and claims, comprises that medicine, surface modifier, carrier, excipient, diluent and other are present in the component in this based composition usually.
Hydrophilic-lipophile balance (HLB) is the balanced proportions between two kinds of opposite trends that exist in the surfactant: hydrophilic (part that glassware for drinking water is had affinity) is to lipophile (part that oil is had affinity).The hydrophilic surfactant active is many more, and then HLB value high more (surpassing 10) when the HLB of surfactant value is 1-10, then is considered to have lipophile.The HLB value of surface modifier or surface modifier system is preferably between 5 to 35.
Chemical compound water insoluble or that be slightly soluble in water can be selected from various therapeutic agents, comprises antifungal, immunosuppressant or immune activation agent, antiviral agent, antitumor agent, analgesics or antiinflammatory, antibiotic, Anti-epileptics, anesthetis, sleeping pill, tranquilizer, psychosis, psychosis, antidepressant, antianxiety drugs, anticonvulsant, antagonist, neuron blocker, anticholinergic or cholinomimetic, antimuscarinic drug or muscarine medicine, antiadrenergic, antiarrhythmics, antihypertensive, hormone or nutrient.
Used surface modifier is divided into two classes substantially usually: phospholipid and surfactant.Phospholipid can be the phospholipid or the mixture of phospholipids of any natural generation, and sometimes this paper indication is " commerce " phospholipid, and for example lecithin or soybean phospholipid perhaps are used in combination them.Phospholipid can be desalination, hydrogenant or partially hydrogenated, and is perhaps natural, semisynthetic or synthetic.The example of the commercial phospholipid that obtains includes but not limited to lecithin P123 (Pfanstiehl), Lipoid E80 (lipid) and hydrogenated soya phosphatide Phospholipon 90H and 100H (Natterman) and 99% pure lecithin and S-PC (Avanti PolarLipids).The content of phospholipid is 0.01%-50% in the compositions, is preferably 0.05%-20%.
Surfactant is used as the second surface surface modifier sometimes, it comprises: (a) natural surfactant, for example casein, gelatin, tragakanta, wax, intestinal resin (enteric resins), paraffin, acacin, gelatin cholesterol ester and triglyceride; (b) nonionic surfactant, for example polyoxyethylene aliphatic alcohol ester, sorbitan fatty acid esters, polyoxyethylene fatty acid ester, sorbitan ester monostearin (sorbitan esters glycerolmonostearate), Polyethylene Glycol, hexadecanol, cetostearyl alcohol, octadecanol, poloxamer, poloxamines, methylcellulose, hydroxylated cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, amorphous cellulose element, polyvinyl alcohol, polyvinylpyrrolidone and synthetic phospholipid; (c) colloidal clay, for example soap clay, fillite, colloidal silica.People Remington ' s Pharmaceutical Sciences in 1986 and Theory of Practice ofIndustrial Pharmacy such as Lachman are seen in detailed description about these surfactants.
The specific examples of suitable second surface modifier comprises: poloxamer, and as PLuronic TMF68, F108 and F127, they are the oxirane of BASF production and the block copolymer of expoxy propane; Poloxamines is as the Tetronic of BASF production TM908, it is the alkyl aryl polyether sulphonic acid ester Triton that produces by four functional blocks copolymers, Rohm and Haas that continuous adding oxirane and expoxy propane in ethylenediamine obtain TMThe polyoxyethylene sorbitan fatty acid esters polysorbas20 that X-100, ICISpecialty Chemicals produce, 40,60 and 80, the Polyethylene Glycol Carbowax that produces of Union Carbide TM3550 and 934; And HYDROXY PROPYL METHYLCELLULOSE and polyvinylpyrrolidone.
Surface modifier preferably polyoxyethylene sorbitan fatty acid esters, oxirane and expoxy propane block copolymer, Myrj 45, in ethylenediamine, add four functional blocks copolymers, alkyl aryl polyether sulphonic acid ester, Polyethylene Glycol, hydroxypropyl emthylcellulose and the polyvinylpyrrolidone that oxirane and expoxy propane obtain continuously.
Ideal surfactant is the block copolymer of polyoxyethylene sorbitan fatty acid esters, Myrj 45, oxirane and expoxy propane, add four functional blocks copolymers, alkyl aryl polyether sulphonic acid ester, Polyethylene Glycol, hydroxypropyl emthylcellulose and the polyvinylpyrrolidone that oxirane and expoxy propane obtain in ethylenediamine continuously.
Phospholipid can be that be desalted, that be hydrogenated or by partially hydrogenated, and is perhaps natural, semisynthetic, synthetic, preferably phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidylinositols, phosphatidyl glycerol or phosphatidic acid.
The preferred embodiment explanation
In order to further specify and describe selection course of the present invention, carried out following test.In an embodiment, use high pressure equipment under steady temperature and pressure premix to be handled, thereby make preparation be subjected to shear action, cavitation, impact and friction, this carries out in microcosmic fluidized bed plant or homogenizer.Details sees the following form.
Type of preparation Processing machine Total pass under the operating pressure Average pressure (kPsi) Mean temperature (℃)
Cyclosporin A Avestin C-50 homogenizer 200 18 10
Ursodiol Avestin C-5 homogenizer 100 18 13
Benprofibratum Microcosmic fluidized bed plant M110 EH 50 18 5
" all over (pass) " is defined as the circulation of preparation by the machine each several part.Each machine " all over " or circulate as follows: Avestin C-50 homogenizer and Avestin C-5 homogenizer: preparation is placed on the inlet storage, flows to current again,, get back to the inlet storage then next through over-heat-exchanger.It is to make preparation be subjected to shearing force, cavitation, impact and friction by current.M110 EH: at first allow preparation through 20 times bypass circulation, it is defined as: the inlet storage arrives heat exchanger again to the aid in treatment assembly, gets back to the inlet storage then.Allow the gained preparation through loop, mutual chamber (interaction chember loop) again, it is defined as: the inlet storage arrives heat exchanger to the aid in treatment assembly again to mutual chamber (interaction chamber), gets back to the inlet storage then.It is to make preparation be subjected to shearing force, cavitation, impact and friction at mutual intracavity.After above-mentioned processing, each preparation is collected the phial of packing into, clog with rubbery stopper, the reuse aluminium lid covers, to be used for stability test.Acceptable granule is those microscopic particles in the 0.05-10 micrometer range.
Adopted following substances in an embodiment:
The abbreviated list of surface modifier
Full name Abbreviation
Lipid E-80 LipE80
Phosphatidase 11 00H Ph100H
Myrj 52 Myrj52
Tween 80 Tw80
PLuronic F68 (being called poloxamer 188 again) PF68
PLuronic F108 (being called poloxamer 338 again) PF108
PLuronic F127 (being called poloxamer 407 again) PF127
Tetronic 908 T908
Supplier's list
Trade name Supplier/place of production
Cyclosporin A North China drugmaker, China
Ursodiol Tokyo Tanabe, the Tokyo
Benprofibratum Laboratorio Chimico Internazionale s.p.a, Milan, ITA
Lipid E-80 Lipoid GMBH, Ludwigshafen, Germany
Phosphatidase 11 00H American Lecithin Company Natterman Phospholipids, Connecticut, U.S. Oxford
Myrj52 ICI, the Wilmington City, Delaware, USA State
Tween 80 ICI, Delaware, USA become the Er Mingdun city
Tetronic and PLuronic block copolymer BASF, New Jersey Mount Olive
Following five kinds of different tests are used to assess stability of formulation.
Stability test Explanation
4 ℃ Embodiment is stored in 4 ℃ (control temperature)
25 ℃ Embodiment is stored in 25 ℃ (control temperature, 60% relative humiditys)
40 ℃ Embodiment is stored in 40 ℃ (control temperature)
Vibration Under ambient room temperature embodiment is sidelong on the vibration table, hunting speed is 100rpm-110rpm.
Thermal cycle A circular definition is: embodiment stored 1-2 days down at 4 ℃, stored 1-2 days down at 40 ℃ again.
If can satisfy at least two in the following condition, then said preparation is considered to stable:
(1) during 4 ℃ of following 4 weeks, mean particle size is less than 1.5 μ m.
(2) during 25 ℃ of following 4 weeks, mean particle size is less than 1.5 μ m.
(3) during 40 ℃ of following 1 weeks, mean particle size is less than 2.5 μ m.
(4) through after the vibration in 7 days, mean particle size is less than 1.5 μ m.
(5) through after 3 thermal cycles, mean particle size is less than 1.5 μ m.
Embodiment A
In this embodiment, assessed of the influence of system HLB value to the granular size and the stability of Cyclosporin A microgranule.We find to make system HLB value greater than 9 o'clock, gained preparation instability when phospholipid is used in combination with a kind of surface modifier.Yet when selecting system HLB value less than the combination of 9 (but greater than 0) for use, the gained preparation is a sub-micron, is stable.There is not the controlled trial of surface modifier to be used as with reference to having comprised yet.
Table 1.1 Cyclosporin A 5%w/w
Embodiment No. 1, surface modifier No. 2, surface modifier Size (μ m) Pass System HLB
Kind ％w/w HLB Kind ％w/w HLB
1 - - 0 - - 0 8.33 138 0
2 LipE-80 10 7 - - - 2.86 187 14
3 LipE-80 9 7 PF68 1 29 1.77 177 18.4
4 Ph 100H 2 6 Tw80 2 15 1.04 180 8.4
Above-mentioned preparation be with the amounts of 200 grams separately in batches in Avestin C-50 18, the 000psi operating pressure down preparation and.Before homogenize, the NaOH that adds 5.5%w/w mannitol and 1N is adjusted in pH value between the 7-8.Granular size is the average volume density of being measured by Malvern Mastersizer.The mean particle size of embodiment 1 during homogenize is 7 μ m-9 μ m.Even showing through granule after 180 times, the data extrapolation still remains in this scope.
The stable embodiment 4 of table 1.2-Cyclosporin A microgranule
Through the preparation after the 211 times processing; Final size is 1.00 μ m
Temperature (℃) the final size of initial size (micron) (micron) natural law
4 1.00 0.81 56
25 1.00 0.80 82
From the above-mentioned data of the embodiment 2 of table 1.2 and embodiment 3 as can be known, Lipoid E-80 is used in combination with Pluronic F68, the total w/w% that makes surface modifier can not obtain stable submicron preparation at 10% o'clock, and the gained system HLB value of these preparations is greater than 9.Embodiment 4 has illustrated and has adopted the appropriate combination of phospholipid and surface modifier that system HLB value is reduced to 8.4 that this just can obtain the stabilization formulations of sub-micron.
Embodiment B
Next studied of the influence of system HLB value to the granular size and the stability of ursodiol microgranule.These experiments (by the prepared in batches of 50 grams with 5.5%w/w mannitol) show when phospholipid is used in combination with one or more surface modifiers, make system HLB value greater than 9 or less than 4 o'clock, gained preparation instability.Yet when the combination of selecting for use system HLB value between 4-9, the gained preparation is a sub-micron, is stable.There is not the controlled trial of surface modifier to be used as with reference to being included yet.
Table 2.1-URSODIOL 10%w/w+2 surface modifier
Embodiment No. 1, surface modifier Surface modifier number Whether stable
Kind ％w/w HLB Kind ％w/w HLB Size (μ m) Pass System HLB
1 - - 0 - - 0 12.61 0 * 0 No
2 Lip E80 2.4 7 - - - 1.40 105 1.7 No
3 Lip E80 6 7 - - - 0.99 104 4.2 Be
4 Lip E80 6 7 PF68 2 29 1.31 107 10 No
5 Lip E80 3.8 7 PF68 2 29 0.99 106 8.5 Be
6 Lip E80 1.6 7 T908 0.8 31 1.15 107 3.6 No
Ursodiol 10%w/w+3 surface modifier
Embodiment Surface modifier 1 Surface modifier 2 Surface modifier 3
Kind, %w/w HLB Kind, %w/w HLB Kind, %w/w HLB Size (μ m) Pass System HLB Whether stable
7 Lip E80，6.1 7 Myrj 52，2 16.9 PF68，1.1 29 1.35 102 11.6 No
*When not having surface modifier, mixed phase produces too much foam when difficulty, and preparation can't be processed.
The stability of table 2.2-IDD-PTMUrsodiol
Implement 4 ℃ 22 ℃ 40 ℃ of sizes 7 days 3 times
Example (micron) stability stability stability vibration thermal cycle
Natural law size natural law size natural law size
3 0.99 28 1.03 28 1.05 7 1.07 1.05 1.07
5 0.99 28 1.02 28 1.03 7 1.06 1.04 1.09
Can draw following important conclusion from the result of table 2.1 and table 2.2:
The embodiment of table 2.1 1,2 and 3 has illustrated that thereby phospholipid concentration is increased to 2.4%, 6% system HLB value from 0% is increased to 1.7,4.2 result from 0 respectively.Under the situation of embodiment 1, there is not surface modifier, be difficult with medicine and water mixing, and preparation can't be by homogenize.The preparation that has greater than 4 system HLB value is a sub-micron and stable, and other preparation then is not like this.
Embodiment 3 and 4 illustrated when phospholipid concentration and has been fixed on 6%, the concentration of PF 68 is increased to 2% from 0%, thereby system HLB value is respectively 4.2 and 10 result.Preparation with system HLB value of 4-9 is a sub-micron and stable, and other preparation then is not like this.
Embodiment 4 and 5 has illustrated concentration fixed as PF 68 2%, content of phospholipid is reduced to 3.8% from 6%, thereby system HLB value is respectively 10 and 8.5 result.Preparation with system HLB value of 4-9 is a sub-micron and stable, and other preparation then is not like this.
Embodiment 6 and 7 has illustrated the result when system HLB value is outside the 3.9-9 scope: granular size is greater than 1 micron, and the preparation instability.Particularly the system HLB value of embodiment 5 is less than 3.9, and the system HLB value of embodiment 6 is greater than 9.
Embodiment C
Present embodiment has been studied the influence of system HLB value to the granular size and the stability of Benprofibratum.These experiments show when phospholipid is used in combination with one or more surface modifiers, make system HLB value less than 4 o'clock, gained preparation instability.Yet when the combination of selecting for use system HLB value between 4-9, the gained preparation is a sub-micron and stable.There is not the controlled trial of surface modifier to be used as with reference to being included yet.
Table 3.1-Benprofibratum 10%w/w (+5.5%w/w mannitol)
Embodiment No. 1, surface modifier No. 2, surface modifier Whether stable
Kind ％w/w HLB Kind ％w/w HLB Size (μ m) Pass System HLB
1 - - 0 - - 0 65 0 * 0 No
2 Lip E80 3 7 - - 0 1.06 70 2.1 No
3 Lip E80 4 7 - - 0 0.95 70 2.8 No
4 Lip E80 3 7 PF127 1 29 0.86 70 5.0 Be
5 ** Ph10OH 0.83 6 PF108 1.67 29 0.85 84 5.3 Be
6 ** Ph100H 1.33 6 PF108 0.67 29 0.83 70 2.7 No
Benprofibratum 5%w/w (+5.5%w/w mannitol)
7 LipE-80 2 7 PF127 0.5 29 88 70 5.7 Be
8 LipE-80 2.3 7 PF127 0.2 29 0.91 70 4.4 Be
*When not having surface modifier, mixed phase is when difficulty, and pharmaceutical suspension and can't process preparation on water.
*There is not mannitol to exist.
In the table 3.1 given preparation be with the amounts of 200 grams separately in batches in M110 EH 18, the 000psi operating pressure down preparation and.Before homogenize, the NaOH that adds 1N is adjusted in pH value between the 6-8.Granular size is the average volume density of being measured by Malvern Mastersizer.
The stability of table 3.2-Benprofibratum microgranule
Embodiment Size (micron) 4 ℃ of stability 22 ℃ of stability 40 ℃ of stability Vibration in 7 days
Natural law Size Natural law Size Natural law Size
4 0.86 33 1.10 29 1.32 8 2.31 1.27
5 0.91 26 1.1 26 1.29 7 1.68 1.16
7 0.88 29 1.01 29 1.18 12 2.47 1.09
8 0.91 35 1.12 35 1.25 7 1.4 1.04
The embodiment of table 3.1 2 and 4 has illustrated that thereby PF 127 concentration are increased to 1%w/w system HLB value from 0% is respectively 2.1 and the result that produced at 5 o'clock.The preparation that has greater than 4 system HLB value is a sub-micron and stable, and other preparation then is not like this.Thereby embodiment 3 and 4 has illustrated the result that the total surface modification agent content of relative quantity that changes Lip E80 and PF 127 is produced when being 4%w/w.The preparation (embodiment 4) that has greater than 4 system HLB value is stable, and system HLB value is then unstable less than 4 preparation (embodiment 3).
The result that embodiment 5 and 6 has been produced when the relative quantity that changes phosphatidase 11 00H and PF 108 has been described: system HLB value is stable greater than 4 preparation (embodiment 5), and system HLB value is then unstable less than 4 preparation (embodiment 6).
Embodiment 7 and 8 is stable sub-micron preparations, and the total content of its surface modifier is 2.5%w/w, and the system HLB value of each preparation is between 4-9.In two kinds of preparations, used the various combination of Lip E80 and PF 127.
Embodiment 3 and 7 illustrated when the weight ratio of Lip E80 remains on 4, and PF 127 is increased to the result who was produced with respect to the weight ratio of medicine at 1 o'clock from 0.System HLB value is respectively 2.8 and 5.7.System HLB value is a sub-micron greater than 4 preparation, is stable, and other preparation is then unstable.
Embodiment D
In the table 4.1 preparation of listed present embodiment be with the amounts of 200 grams separately in batches (22 ℃ following 120 times) in M110 EH under the 18kpsi operating pressure preparation and.Granular size is the average volume density of being measured by Malvern Mastersizer.
Table 4.1-VEX 5%
Embodiment Surface modifier #1 Surface modifier #2 Whether stable
Kind ％w/w HLB Kind ％w/w HLB Size (μ m) Pass System HLB
1 Lip E80 0.5 7 PF 108 1.0 29 0.34 120 6.5 Be
Through after 4 weeks, granular size is 0.34 micron, and is identical with initial size under 25 ℃, and this granule is stable thus.
Embodiment in the last table 4.1 has the system HLB value between the 4-9, at room temperature (25 ℃ of following 4 weeks) show good stable.Medicine after the lyophilization (containing the 5%w/w polyvinylpyrrolidone) reconstitutes 0.37 micron, and is identical with initial size basically.In addition, this preparation demonstrates significant bioavailability for Canis familiaris L. and mouse.The bioavailability of Canis familiaris L. is 27%, and the bioavailability of mouse is 33%.

Claims (13)

1. the method for the consumption of a surface modifier of selecting phospholipid surface modifier and one or more surfactants, the medicine that this method is used for obtaining the water insoluble of stable granular size or being slightly soluble in water is at a kind of micron of steady suspension or the stabilising system of sub-micron microgranule, described suspension is prepared by water-bearing media, this method comprises the consumption of selection with respect to the surface modifier of the consumption of the phospholipid surface modifier of drug dose and one or more surfactants, the consumption of the surface modifier of described phospholipid surface modifier and one or more surfactants is defined as " surface modifier j " together, so that the hydrophilic of described system-lipophile equilibrium valve is between 4 to 9, wherein said system hydrophilic-lipophile balance is defined as:
Figure C998156440002C1
And wherein said system places phial and when sealing, if satisfy in the following condition at least two, then it is stable:
(1) during 4 ℃ of following 4 weeks, the unit weight mean particle size is less than 1.5 μ m;
(2) during 25 ℃ of following 4 weeks, the unit weight mean particle size is less than 1.5 μ m;
(3) during 40 ℃ of following 1 weeks, the unit weight mean particle size is less than 2.5 μ m;
(4) through after the vibration in 7 days, the unit weight mean particle size is less than 1.5 μ m, and wherein phial is put on the vibration table at the ambient room temperature downside, and hunting speed is 100rpm-110rpm; Or
(5) through after 3 thermal cycles, the unit weight mean particle size is less than 1.5 μ m, and one of them circulation is stored down at 40 ℃ and formed in 1-2 days by storing 1-2 days down at 4 ℃.
2. the process of claim 1 wherein that the lipophile equilibrium valve of surface modifier of described surfactant is between 5 to 35.
3. the process of claim 1 wherein that described phospholipid surface modifier is selected from lecithin, soybean phospholipid and combination thereof.
4. the process of claim 1 wherein that described phospholipid surface modifier is desalination, hydrogenant or partially hydrogenated.
5. the process of claim 1 wherein that described phospholipid surface modifier is selected from phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidylinositols, phosphatidyl glycerol, phosphatidic acid, lysophosphatide, and combination.
6. the process of claim 1 wherein that the surface modifier of described surfactant is selected from the block copolymer of polyoxyethylene sorbitan fatty acid esters, oxirane and expoxy propane, Myrj 45, adds four-functional group block copolymer, alkyl aryl polyether sulphonic acid ester, Polyethylene Glycol, hydroxypropyl emthylcellulose, polyvinylpyrrolidone and the polyvinyl alcohol that oxirane and expoxy propane obtain in proper order in ethylenediamine.
7. the process of claim 1 wherein that described medicine water insoluble or that be slightly soluble in water is antifungal, immunosuppressant or immune activation agent, antiviral agent, antitumor agent, analgesics or antiinflammatory, antibiotic, Anti-epileptics, anesthetis, hypnotic, tranquilizer, psychosis, psychosis, antidepressant, antianxiety drugs, anticonvulsant, antagonist, neuron blocker, anticholinergic or cholinergic agent, antimuscarinic drug or muscarine medicine, antiadrenergic, antiarrhythmics, antihypertensive, hormone or nutrient.
8. the process of claim 1 wherein that the lipophile equilibrium valve of surface modifier of described surfactant is between 5 to 35.
9. the process of claim 1 wherein that described phospholipid surface modifier is selected from lecithin, soybean phospholipid and combination thereof.
10. the process of claim 1 wherein that described phospholipid surface modifier is desalination, hydrogenant or partially hydrogenated.
11. the process of claim 1 wherein that described phospholipid surface modifier is selected from phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidylinositols, phosphatidyl glycerol, phosphatidic acid, lysophosphatide, and combination.
12. the process of claim 1 wherein that the surface modifier of described surfactant is selected from the block copolymer of polyoxyethylene sorbitan fatty acid esters, oxirane and expoxy propane, Myrj 45, adds four-functional group block copolymer, alkyl aryl polyether sulphonic acid ester, Polyethylene Glycol, hydroxypropyl emthylcellulose, polyvinylpyrrolidone and the polyvinyl alcohol that oxirane and expoxy propane obtain in proper order in ethylenediamine.
13. the process of claim 1 wherein that described medicine water insoluble or that be slightly soluble in water is antifungal, immunosuppressant or immune activation agent, antiviral agent, antitumor agent, analgesics or antiinflammatory, antibiotic, Anti-epileptics, anesthetis, hypnotic, tranquilizer, psychosis, psychosis, antidepressant, antianxiety drugs, anticonvulsant, antagonist, neuron blocker, anticholinergic or cholinergic agent, antimuscarinic drug or muscarine medicine, antiadrenergic, antiarrhythmics, antihypertensive, hormone or nutrient.
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