CN101014319B - Liquid depot formulation - Google Patents

Abstract

The present invention relates to pre-formulations comprising low viscosity, non-liquid crystalline, mixtures of: a) at least one neutral diacyl lipid and/or at least one tocopherol; b) at least one phospholipid; c) at least one biocompatible, oxygen containing, low viscosity organic solvent; wherein at least one bioactive agent is dissolved or dispersed in the low viscosity mixture and wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid. The preformulations are suitable for generating parenteral, non-parenteral and topical depot compositions for sustained release of active agents. The invention additionally relates to a method of delivery of an active agent comprising administration of a preformulation of the invention, a method of treatment comprising administration of a preformulation of the invention and the use of a preformulation of the invention in a method for the manufacture of a medicament.

Description

Liquid depot formulation

Technical field

The present invention relates to for the preparation precursor (preformulation) that produces in position the controlled release lipid composition.Specifically, the present invention relates to the preformulation of low viscosity mixtures (for example molecular solution) form of amphiphilic component and at least a bioactivator, described preformulation is being exposed to aqueous fluid for example in the body fluid time, experience changes at least one times mutually, thereby forms the randomly controlled release matrix of bioadhesion.

Background technology

Many bioactivators comprise that medicine, nutrient, vitamin etc. all have " function window ".That is to say, when the concentration of these bioactivators surpasses certain limit, can observe it and have biologic activity.When health suitably the concentration in the part (for example, partly or serum-concentration indicated) fall certain level when following, these bioactivators just can not produce useful effect.Similarly, usually have a upper limit concentration, when being higher than this concentration, concentration increases also more can not produce further benefit.In some cases, increasing concentration can cause undesirable or even dangerous effect to specified level.

Some bioactivators have long biological half-life and/or wider function window, therefore can use once in a while and can be in the long time (for example 6 hours to a couple of days) keep functional living being concentration.In other cases, clearance rate is higher and/or the function window is narrower, therefore just needs regular (or even continuous) dosage of a small amount of in order to keep biological concentration in this function window.When non-oral administration (for example parenteral) was carried out in expectation, it was difficult especially reaching above-mentioned requirements.In addition, in some cases, for example in the assembling of implant (for example joint replacement or oral implant), for repeat administration, the position of expectation function possibly can't keep being easy to approach always.In this case, single-dose must make activating agent remain on treatment level in the whole time period of needs activity.

With and proposed the whole bag of tricks and come slow release for bioactivator.These methods comprise for example coated tablet of release oral compositions, and the formulation example that is designed to absorb gradually such as transdermal patch, and slow release implant for example are implanted to " bar (stick) " under the skin.

A kind of method of the gradually release bioactive agent that has proposed is called " storage storehouse (depot) " injection.In the method, bioactivator and carrier is formulated together, so that the gradually release of activating agent to be provided in a few hours or a couple of days.These methods are come release bioactive agent based on the matrix degradation that is dispersed in gradually in the health usually.

Fixed the most frequently used storage storehouse injection is using polymer storage storehouse system.Its typically Biodegradable polymeric for example poly-(lactic acid) (PLA) and/or poly-(lactic acid-altogether-glycolic) (PLGA), its form can be the solution in organic solvent, the prepolymer that mixes with initiator, the polymer beads of sealing or polymer microballoon.This polymer or polymer beads are embedded with activating agent, and by slow diffusion and/or when substrate is absorbed, it is degraded gradually and discharges activating agent.The example of these systems is included in those that describe among US4938763, US5480656 and the US6113943, and it can cause active agent delivery in the time of several months at the most.Yet but there are a lot of limitation in these systems, comprise making complexity and being difficult to sterilization (particularly microsphere).The local excitation that lactic acid and/or glycolic cause in injection site release also is a significant shortcoming.And preparing injected dose from the powder precursor also is a very complicated process.

From the viewpoint of drug delivery, polymer storage storehouse compositions also has following shortcoming: it only can be accepted relatively low drug loading amount and have " burst/lag behind " release profiles.Polymeric matrix, when particularly using as solution or prepolymer, the burst when its character can cause that medicine is initial when using compositions for the first time discharges.Then slowly discharge in following period of time, substrate begins degraded simultaneously, and last rate of release increase reaches desirable protensive features.The bulk concentration that the release profiles of this burst/hysteresis can cause using rear activating agent is higher than suddenly the function window immediately, then falls back to the bottom of function window in the lag period, then just can reach lasting function concentration.Obviously, from function and toxicologic viewpoint, this burst/hysteresis curve is undesirable, and may be dangerous.It also can limiting balance concentration, owing to should prevent in the danger of the ill effect at " peak value " some place.

Storage storehouse system in the past is in order to solve the prominent problem of releasing.Particularly, as described in US6113943 and US6630115, proposed to provide with polylactic acid and the embedding PLEG of hydrolysis the polymer system of " low burst discharges ".These systems provide the curve that improves, but burst/hysteresis effect still arranged, and they do not solve other problem yet, for example use polymer to produce the acid degradation product and the stimulation that causes.

A kind of more definite storage storehouse system based on polymer of as an alternative scheme is proposed by US5807573.It has proposed a kind of system based on liquid, comprises DG, phospholipid and optional water, glycerol, ethylene glycol or propylene glycol, with at reverse micelle " L ₂" mutually in or provide a kind of drug-supplying system in the cube liquid crystalline phase.Because this storage storehouse system is formed by physiological compatibility good DG and phospholipid, and does not produce lactic acid or the glycolic catabolite of polymer system, so this system is less in the tendency that injection site produces inflammation.But liquid crystalline phase viscosity is higher, L ₂Also thickness and be inconvenient to use too mutually.The author of US5807573 does not provide the mensuration of release profiles in any body of said preparation yet, " prominent releasing " feature of therefore can not determine whether it provides.

Now, established relatively maturely the application of non-lamellar phase structure (for example liquid crystalline phase) in sending bioactivator.Form described structure when amphipathic compound is exposed in the solvent, this is that they gather together and have just formed doping region and nonpolar district because amphiphile, amphiphilic molecule has polarity and non-polar group.These zones can be dissolved polarity and non-polar compound effectively.In addition, the many such structure that is formed by amphiphile in polarity and/or non-polar solven has very large polar/non-polar interfacial area, can absorb and stablize other amphiphile on this interface.Also can prepare amphiphile and comprise the interference of enzyme at the biotic environment of being immune against attacks property of prolection agent at least in a way, thereby for the stable of activating agent with discharge favourable control is provided.

The formation of non-layer-like zone is a kind of well-known phenomenon in amphiphile/water, amphiphile/oil and amphiphile/oil/water figure.These comprise mutually liquid crystalline phase for example cube P, cube D, cube G and hexagon mutually, but the latter is liquid at molecular level has demonstrated significantly widely order, and L ₃Phase, it comprises double-deck multiple interconnected co-continuous network, and this double-layer network is unstratified, but lacks the widely order of liquid crystalline phase.According to the curvature of amphiphile layer, these can be described as mutually is normal (average curvature is towards nonpolar district) or reverse (average curvature is towards doping region).

Non-layered liquid crystal phase and L ₃Stable system in theory mutually.That is to say that they are not can separate simply and/or the metastable state of cambium layer, lamellar phase etc. again, but the Thermodynamically stable form of liquid/solvent mixture.

Although the effectiveness of known storage storehouse liquid preparation is very high, their performance still is lower than ideal performance in certain aspects.The character of the cube liquid crystalline phase of particularly, advising is thickness relatively.This also may be harmful to object so that the application standard syringe is had any problem, and so that filtration sterilization becomes impossible, because compositions can not be passed through essential microporous membrane.The result is, compositions must prepare under the height aseptic condition, and this has increased the complexity of preparation.When using L ₂Phase time, the common viscosity of these compositionss is lower, but still can have any problem in application facet, and can only use the very zonule of phasor.Particularly, used solvent is only having limited effect aspect the reduction mixture viscosity in known liquid preparation.For example water can reduce the formation of high viscosity liquid crystalline phase, and the solvent for example viscosity of glycerol and ethylene glycol is very high, can not provide very large benefit aspect the composition viscosity reducing.Ethylene glycol also is poisonous usually, or toleration is relatively poor in the body, can cause stimulation when use the part.

In addition, known low solvent L ₂Fluid composition is mutually supported a lot of bioactivators of relative low concentration only, because they only have limited dissolubility in component of mixture in the situation that lacks water.Yet exist in the situation of water, preparation can hold full-bodied cube liquid crystalline phase.Can low viscosity injection and discharge the bioactivator of desired concn with less storage storehouse compositions volume, such storage storehouse system obviously has superiority.

Known liquid storage storehouse compositions in fact also can only be used some phase structure and combination, can not administration (those mixture that high phospholipid concentration is for example arranged) because other mixture or viscosity are too high, the danger that is separated into two-phase or multiphase is perhaps arranged (for example with the L that balances each other that is rich in phospholipid ₂Phase).Particularly, can't obtain to be higher than 50% phospholipid concentration with known method with from the phasor shown in the US5807573, as if from this phasor, required cube is stable in the situation that is not higher than 40% phospholipid mutually.As a result, in practical operation, can not obtain storage storehouse compositions high phospholipid concentration or that have hexagon liquid crystalline phase structure.

Summary of the invention

The inventor now confirms, comprise specific amphiphilic component, at least a bioactivator and the biological solvent that can tolerate by providing, particularly at the low viscosity preformulation in the molecular solution for example mutually, may produce the preformulation of a lot of shortcomings that overcome aforementioned depot formulation.Particularly, this preformulation is easy to prepare, can carry out aseptic filtration, it has low viscosity (can be easy to and administration that pain is less), can mix the high-caliber bioactivator compositions of small amount (thereby can only use) and/or form non-stratiform storage storehouse compositions in the desired body with controllable " prominent releasing " or " non-prominent releasing " feature.By nontoxic, biology can tolerate also can form described compositions with biodegradable material.In addition, this preformulation is suitable for forming parenteral and parenteral outer (for example local) is administered into the storage storehouse compositions at body cavity and/or body surface or other position.

First aspect, therefore the present invention provides a kind of preformulation that comprises the low viscosity mixtures of following component:

A) at least a neutral diacyl lipid and/or tocopherol;

B) at least a phospholipid;

C) at least a biocompatible (preferably oxygen containing) organic solvent;

Wherein, at least a bioactivator is dissolved in or is scattered in the low viscosity mixtures, and wherein, described preformulation forms when contacting with aqueous fluid and maybe can form at least a liquid crystalline phase structure.

Generally speaking, aqueous fluid is body fluid, for example from fluid, tear, perspiration, saliva, gastro-intestinal Fluid, extravascular Fluid, extracellular fluid, interstitial fluid or the blood plasma of mucomembranous surface, when the aqueous body fluids with body surface, zone or body cavity (for example in the body) contacted, preformulation can form the liquid crystalline phase structure.Preformulation of the present invention did not generally contain the water of any significant quantity before administration.

Second aspect present invention also provides the method that bioactivator is delivered to people or non-human animal's (preferred mammal) health, and the method comprises uses the preformulation that (preferred parenteral administration) comprises the low viscosity mixtures of following component:

A) at least a neutral diacyl lipid and/or tocopherol;

B) at least a phospholipid;

C) at least a biocompatible (preferably oxygen containing) organic solvent;

And at least a bioactivator is dissolved in or is scattered in the low viscosity mixtures, thus after administration by forming at least a liquid crystalline phase structure when aqueous fluid in the body contacts.Preferably, the preformulation of using in the method is preformulation of the present invention as described herein.

The medication that is suitable for above the inventive method will be the method that is fit to institute's disease for the treatment of and the bioactivator that uses.Therefore, to form parenteral storage storehouse by parenteral (for example subcutaneous or intramuscular) administration, and pass through to skin surface, mucosa and/or fingernail, to eye, nose, mouth or inner surface, or to cavity such as nasal cavity, rectal cavity, vaginal canal or oral cavity, periodontal pocket, or extract after natural structure or the implant infrastructure or insert outer (for example local) of parenteral that administration in the cavity that implant (for example joint, support, cosmetic implant, tooth, tooth filling or other implant) forms before can form bioadhesion and store storehouse compositions.

The further aspect of the present invention also provides the method for preparing liquid-crystal composition (especially storing the storehouse compositions), comprises that the preformulation that will comprise the low viscosity mixtures of following component is exposed in the aqueous fluid (especially in the body and/or especially this paper point out body fluid):

A) at least a neutral diacyl lipid and/or tocopherol;

B) at least a phospholipid;

C) at least a biocompatible (preferably oxygen containing) organic solvent;

And be dissolved in or be scattered at least a bioactivator in the low viscosity mixtures.The preferred preformulation of using is described preformulation of the present invention.Being exposed to " body in " fluid obviously can be in vivo or in the body cavity, or can be at body surface, skin surface for example, and this depends on the character of compositions.

The liquid-crystal composition that forms in the method is bioadhesion as described herein preferably.

The present invention further aspect provides the formation method that is suitable for using to (preferred mammal) object the preformulation of bioactivator, and described method comprises the low viscosity mixtures that forms following component:

A) at least a neutral diacyl lipid and/or tocopherol;

B) at least a phospholipid;

C) at least a biocompatible (preferably oxygen containing) organic solvent;

With at least a bioactivator is dissolved in or is scattered in the low viscosity mixtures, or before forming low viscosity mixtures, at least a bioactivator is dissolved in or is scattered in a, b or c component at least a.The preferred preformulation that so forms is preparation of the present invention as herein described.

The present invention further aspect provides the purposes of the low viscosity mixtures of following component:

A) at least a neutral diacyl lipid and/or tocopherol;

B) at least a phospholipid;

C) at least a biocompatible (preferably oxygen containing) organic solvent;

Wherein, at least a bioactivator is dissolved in or is scattered in the low viscosity mixtures, described low viscosity mixtures is used for the preparation of the preformulation that described activating agent continues medication, and wherein, described preformulation can form at least a liquid crystalline phase structure when contacting with aqueous fluid.

When being used for herein, term " low viscosity mixtures " be used for expression can be easily to the mixture of object administration, the especially easy mixture by standard syringe and pricking with needle (needlearrangement) administration.For example, by showing this point from the 1ml disposable syringe by the ability that 22awg (or 23 gauges (gauge)) syringe needle distributes with Manual pressure.In particularly preferred embodiments, low viscosity mixtures is can be by the mixture of standard aseptic filtration film such as 0.22 μ m syringe filter.In other preferred embodiment, the similar functional definition of proper viscosity can be defined as the viscosity of preformulation, and this viscosity can be sprayed with conventional sprayer unit with compressor pump or pressure atomization device.The typical range of proper viscosity is for example at 20 ℃ of lower 0.1～5000mPas, preferred 1～1000mPas.

Observe, can obtain the change of viscosity highly significant by a small amount of low viscosity solvent that adds this paper indication.As shown in Figure 2, for example, only add 5% solvent and just viscosity can be reduced 100 times, add 10% and viscosity can be decreased to many 10000 times.In order to reduce to reach this nonlinear synergy aspect the viscosity, the solvent that adopts suitable low viscosity and suitable polarity is important.Such solvent is included in those that this paper hereinafter describes.

The example of particularly preferred low viscosity mixtures is for example L of molecular solution and/or isotropic phase ₂And/or L ₃Phase.As mentioned above, L ₃Be the non-lamellar phase of interconnection layer, it has certain phase structure, but lacks the widely order of liquid crystalline phase.Unlike liquid crystalline phase, liquid crystalline phase is normally full-bodied, L ₃Phase viscosity is lower.Obviously, L ₃Mutually and molecular solution and/or be suspended in L in a large amount of molecular solution of one or more components ₃The mixture of phase also is suitable.L ₂So-called " reversed micelle " phase or microemulsion mutually.Most preferred low viscosity mixtures is molecular solution, L ₃Phase and composition thereof.More not preferred L ₂Phase is except at following swelling L ₂In the situation of phase.

The invention provides the preformulation that comprises component a, b, c and at least a bioactivator described herein.A significant advantage of preformulation of the present invention is that component a and b can prepare in the ratio in a big way.Particularly, might prepare and use than the phospholipid of the present invention preformulation much bigger with respect to the ratio of neutral diacyl lipid and/or tocopherol in the previous preparation that obtains, and not exist preformulation to be separated and/or unacceptable full-bodied danger.Therefore the weight ratio of component a: b can be any one ratio in 5: 95 to 95: 5.Preferred ratio is generally 90: 10～and 20: 80, more preferably 85: 15～30: 70.In a preferred embodiment of the present invention, the components b ratio more shared than component a is large.That is to say a: the weight ratio of b is less than 50: 50, and for example 48: 52～2: 98, preferred 40: 60～10: 90, more preferably 35: 65～20: 80.

The amount of amount of component b will be enough to provide the low viscosity mixtures (for example molecular solution, referring to more than) of component a, b and c at least in the preformulation of the present invention, and be easy to measure any specific composition of each component with standard method.Phase behavior itself can be analyzed with following technology, for example visualization associating PLM, nuclear magnetic resonance, NMR and low temperature transmission electronic microscope technology (low temperature-TEM), seek solution, L ₂Or L ₃Phase or liquid crystalline phase.Can directly measure viscosity with standard method.As mentioned above, suitable applicable viscosity is can be by effective injection, the especially viscosity of aseptic filtration.As shown herely will be easy to assess viscosity.The maximum of included amount of component b will depend on the correct application of preformulation, but in general, required character is to provide by any amount that forms low viscosity mixtures (for example molecular solution, referring to more than) and/or have abundant low viscous solution.Owing to usually do not wish unnecessarily to use a large amount of solvents to object, therefore the amount of amount of component b will usually be limited in and be no more than 10 times (for example 3 times) that form the required minimum of low viscosity mixtures, preferably be no more than 5 times, be most preferably not exceeding 2 times of this minimum.Yet, but the present composition can comprise than the more quantity of solvent of receiving amount in the rapid release dosage composition.This is to pass through from compositions because the process (for example forming the shell of liquid crystalline phase as herein described) that activating agent slowly discharges also helps to delay solvent.The result is that solvent just discharged through a period of time (for example several minutes or a few hours) longer than instant-free, therefore can be tolerated by health better.

The solvent of higher proportion also can be used for parenteral outer (for example local) to be used, and especially is applied to body surface, on body surface, solvent is by drain evaporation, rather than runs off in the body by being absorbed into.Use for this, can use at the most 100 times the solvent (for example at the most 95% of composition weight of minimum, preferred 80% weight at the most, more preferably 50% weight at the most), especially when wishing last parenteral to store the storehouse outward be very thin layer.

When the present composition is made into (outside the parenteral) aerosol combination when (for example being used for localized delivery of active agents or systemic delivery), said composition also can comprise propellant.Such compositions also can comprise a high proportion of solvent composition c), consider that as above because when compositions spreads out, most of solvent will evaporate.

Suitable propellant is volatile compound, and it can mix with the present composition under the pressure of spraying distributor mechanism, and can not produce full-bodied mixture.Obviously, they have acceptable biocompatibility.Can identify at an easy rate suitable propellant by simple test, the example of suitable propellant comprises hydrocarbon (especially C1～C4 hydrocarbon), carbon dioxide and nitrogen.Volatility hydrogen fluorohydrocarbon for example HFCs 134,134a, 227ea and/or 152a also may be fit to.

Instruct as generality, the weight of amount of component b normally the a-b-c total solution weight about 0.5～50%.This ratio is (especially for injectable storage storehouse) 2～30% preferably, more preferably 5～20% weight.

Component as herein described " a " is the neutral lipid component that comprises polarity " head " group and nonpolar " afterbody " group.Generally speaking, the head of this lipid partly links to each other by ester moiety with afterbody, also can pass through ether, amide, carbon-carbon bond or other connection but should connect.Preferred polar head group is non-ionic, and comprises polyhydric alcohol, for example glycerol, two glycerol and sugar moieties (for example part take inositol and glucosyl group as the basis); With the ester of polyhydric alcohol, for example acetas or succinate.Preferred polar group is glycerol and two glycerol, especially glycerol.

One preferred aspect in, component a is diacyl lipid, because it has two nonpolar " afterbody " groups.Usually preferably use monoacyl (" molten ") fat because these lipids toleration is relatively poor usually in vivo.These two non-polar groups can have the carbon atom of identical or different number, and are saturated or undersaturated independently of one another.The example of non-polar group comprises C6～C32 alkyl and thiazolinyl, and they exist as the form of higher fatty ester usually.Often with reference to the unsaturated number in carbon number and the carbochain these groups are described.Therefore, CX:Z represents to contain the hydrocarbon chain of X carbon atom and Z unsaturated group.Example especially comprises caproyl (C6:0); caprylyl (C8:0); capryl (C10:0); lauroyl (C12:0); myristoyl (C14:0); palmityl (C16:0); phytane acyl group (phytanoly) (C16:0); palmitoleoyl (C16:1); stearyl (C18:0); oleoyl (C18:1); elaidoyl (elaidoyl) (C18:1); inferior oleoyl (linoleoyl) (C18:2); Caulis et Folium Lini acyl group (linolenoyl) (C18:3); arachidonic acyl group (C20:4) behenic acid acyl group (behenoyl) (C22:0) and two myristoyl (C24:9) group.Therefore, typical apolar chain is based on the fatty acid of neutral esters fat, comprise caproic acid, sad, capric acid, lauric acid, myristic acid, Palmic acid, phytanic acid, palmitolic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, arachidonic acid, behenic acid or lignoceric acid, or corresponding alcohol.Preferred apolar chain is Palmic acid, stearic acid, oleic acid and linoleic acid, especially oleic acid.

When as whole component " a " or its part, diacyl lipid can be synthesized, or from natural origin purification and/or chemical modification vegetable oil for example.The mixture of the diacyl lipid of any amount can be used as component a.Most preferably, this component comprises at least a portion DG (DAG), especially glyceryl dioleate (GDO).In a preferred embodiment, component a is comprised of DAG.These DAG can be single DAG or are the mixture of DAG.Particularly preferred example is to comprise at least 50%, preferably at least 80%, even basically comprise the DAG of 100%GDO.

As the as an alternative scheme of whole component a or its part or other particularly preferred classes of compounds be tocopherol.When being used for herein, term " tocopherol " is used for representing that non-ionic lipid tocopherol, these tocopherols are commonly called vitamin E and/or its any suitable salt and/or its analog.Suitable analog is to have phase behavior, does not have toxicity, and with those analog that can change mutually when being exposed to aqueous fluid, it has showed the feature of the present composition.When pure compound was water-soluble, these analog can not form the liquid crystalline phase structure usually.Most preferred tocopherol is tocopherol itself, and it has following structure.Obviously, especially when tocopherol be out the time, can have a small amount of non-tocopherol " pollutant ", but these pollutant to be not enough to change favourable phase behavior or avirulence this point from the natural origin purification.Usually, tocopherol comprises the chemical compound of no more than 10% non-tocopherol anologs, and is preferred no more than 5%, most preferably no more than 2% weight.

Tocopherol

In the further favourable embodiment of the present invention, component a) is comprised of tocopherol basically, especially is comprised of above-mentioned tocopherol.

Component preferred combination of components a) is the mixture of at least a DAG (for example GDO) and at least a tocopherol.Such mixture comprises 2: 98 by weight～98: 2 tocopherol: GDO, for example 10: 90～90: 10 tocopherol: GDO, especially 20: 80～80: 20 described chemical compound.The similar mixture of tocopherol and other DAG also is fit to.

Component of the present invention " b " is at least a phospholipid.A is the same with component, and this component comprises head group and at least a nonpolar tail groups of polarity.Difference between component a and the b mainly is polar group.Therefore, nonpolar part can be suitably from above component a used fatty acid or corresponding alcohol.Common situation is, phospholipid can comprise two non-polar groups, but one or more compositions of this component can have a nonpolar part.When having a more than non-polar group, these groups can be identical or different.

Preferred phospholipid polarity " head " group comprises phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine and phosphatidylinositols.Phosphatidylcholine (PC) most preferably.In preferred embodiments, components b) formed preferred 70%PC at least, most preferably 80%PC at least by 50%PC at least.Components b) can basically be formed by PC.

Phospholipid moiety even more suitable than any diacyl lipid part, it can be from natural origin.Suitable phospholipid source comprises egg, heart (for example Cor Bovis seu Bubali), brain, liver (for example Hepar Bovis seu Bubali) and plant origin, comprises Semen sojae atricolor.These sources can provide one or more compositions of components b, and it can comprise any mixture of phospholipid.

Because preformulation of the present invention is will the control that object be administered for activating agent be discharged, so preferred ingredient a and b are biocompatible.In this, preferably use for example diacyl lipid and phospholipid, rather than monoacyl (molten) chemical compound.Exception is tocopherol especially, as mentioned above.Although it only has an alkyl chain, it is not " molten " lipid on the conventional meaning.Tocopherol is obvious so that it is very suitable aspect the biocompatibility as the character of the good essential vitamin of the compatibility.

In addition most preferably, the lipid of component a and b and phospholipid are natural generation (no matter it are generated by natural origin or synthetic source).The lipid of natural generation tends to the inflammation and the reaction that cause that subject's body is less.This is not only more comfortable for object, and it can prolong the retention time of the storage storehouse compositions of gained, especially for parenteral storage storehouse, because medicine-feeding part has caused less immune system activation.Yet in some cases, may wish in component a and/or b, to comprise the lipid of a part of non-natural generation.This lipid can be for example " ether fat ", and wherein, head is to link to each other rather than link to each other by ester bond by ehter bond with tail groups.The lipid that such non-natural generates is passable, destroys the mechanism that activating agent discharges the position existence by having larger or less dissolubility or vulnerability, is used for for example changing the degradation rate of the storage storehouse compositions of gained.Although all ratios all drop within the scope of the invention, yet in general, component a and b at least 50% will be the lipids of natural generation separately.This ratio preferably at least 75%, and can be at the most basically 100%.

The combination of two kinds of particularly preferred component a and b is GDO and PC, and tocopherol and PC, especially 30～90wt%GDO/ tocopherol, 10～60wt%PC and 1～30% solvent (especially ethanol, NMP and/or isopropyl alcohol).

Except amphiphilic component a and b, preformulation of the present invention can also comprise relatively low-level other amphiphilic component.In one embodiment of the invention, preformulation comprises at the most charged amphiphile, especially anionic amphiphilic thing, for example fatty acid of 10% (by the weighing scale of component a and b).The preferred fatty acid that is used for this purpose comprises caproic acid, sad, capric acid, lauric acid, myristic acid, Palmic acid, phytanic acid, palmitolic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, arachidonic acid, behenic acid or lignoceric acid, or corresponding alcohol.Preferred fatty acid is Palmic acid, stearic acid, oleic acid and linoleic acid, especially oleic acid.Particularly advantageous is that this component is used for and cationic peptide activating agent (referring to following) coupling.We think that the coupling of anion lipid and cationic peptide provides valuable especially slow releasing composition.This part ground is because the more protection of peptide has been avoided the degraded of the enzyme of existence in the body.

The component of preformulation of the present invention " c " is oxygen containing organic solvent.When contacting hydrous fluid, can produce storage storehouse compositions after (for example in the body) because the preformulation administration, therefore wish that this solvent can tolerate object, and can mix with aqueous fluid, and/or diffusion or dissolve preformulation in aqueous fluid.Therefore preferably has at least appropriate water miscible solvent.

Preferably, solvent is added to relatively few amount in the compositions that comprises a and b, namely is lower than 20%, or more preferably less than 10%, just can make larger viscosity reduce one or more orders of magnitude.As described herein, add 10% solvent can make viscosity with respect to not solvent-laden compositions reduce 2,3 or even 4 orders of magnitude, even compositions is solution or not solvent-laden L2 phase, or unaccommodated solvent such as water (special circumstances that belong to following consideration), or glycerol.

The typical solvent that is suitable as amount of component b comprises at least a following solvent that is selected from: alcohol, ketone, ester (comprising lactone), ether, amide and sulfoxide.The example of suitable alcohol comprises ethanol, isopropyl alcohol and glycerol formal (glycerol formal).

Monohydric alcohol (monool) is more more preferred than dihydroxylic alcohols and polyhydric alcohol.When using dihydroxylic alcohols or polyhydric alcohol, preferably with at least monohydric alcohol or other preferred solvent of equivalent are united use.The example of ketone comprises acetone and propylene carbonate.Suitable ether comprises diethyl ether, Tetrahydrofurfuryl polyethylene glycol ether (glycofurol), diethylene glycol monoethyl ether, dimethylisobarbide and Polyethylene Glycol.Suitable ester comprises ethyl acetate and isopropyl acetate, and dimethyl sulphide is suitable sulfide solvent.Suitable amide and sulfoxide comprise dimethyl acetylamide (DMA), n-methyl pyrrolidone (NMP), 2-Pyrrolidone and dimethyl sulfoxide (DMSO).More not preferred solvent comprises Isosorbide dimethyl ether, tetrahydrofurfuryl alcohol, diethylene glycol dimethyl ether and ethyl lactate.

Because preformulation is will be to the live subject administration, it is biocompatible fully therefore needing solvent composition c.This biocompatibility degree will depend on application process, because amount of component b can be any solvent mixture, obviously may have unacceptable a certain amount of solvent when relatively large.In case administration, the solvent or the mixture that form amount of component b necessarily can not cause the unacceptable reaction of object yet in a word.Generally speaking, such solvent is hydrocarbon or preferred oxygen containing hydrocarbon, and the two all randomly has other substituent group, for example nitrogen-containing group.Preferably extremely a small amount of amount of component b comprises and does not comprise halogenated hydrocarbons in halogenated hydrocarbons or the amount of component b, because these halogenated hydrocarbons tend to have lower biocompatibility.When must have a part of halogenated solvent such as dichloromethane or chloroform, generally speaking this ratio will minimize.Compare with the storage storehouse that parenteral uses, the storage storehouse compositions that forms with the outer form of parenteral obviously can be used solvent in a big way.

Amount of component b used herein can be the mixture of single solvent or appropriate solvent, but usually has low viscosity.Because an importance of the present invention provides and has low viscous preformulation, so the Main Function of appropriate solvent is to reduce viscosity.This reduced viscosity is the result of following two kinds of effect associatings, i.e. the effect of low solvent viscosity, and the effect of the interaction of molecules between solvent and the lipid composition.The low viscosity that the inventor's a discovery is oxo solvent as herein described has very large advantage, and and the lipid part of compositions between do not wish the intermolecular interaction that occurs, thereby make the non-linear reduction of viscosity by adding a small amount of solvent.

Under 20 ℃, the viscosity of " low viscosity " solvent composition c (single solvent or mixture) is not more than 18mPas usually.Under 20 ℃, preferably be not more than 15mPas, more preferably no more than 10mPas, most preferably be not more than 7mPas.

Solvent composition c usually loses along with the composition of storage storehouse compositions in vivo at least in part, perhaps suction and being diluted from surrounding air and/or tissue.Therefore, preferred ingredient c is that water is mixable and/or water is dispersible at least to a certain extent, should not repel at least water absorbs water to refusal degree.In this respect, the oxo solvent that preferably has relatively small amount carbon atom (10 carbon atoms at the most for example, preferably at the most 8 carbon atoms).Obviously, when having more polyoxy, solvent can tend to keep water solublity with more substantial carbon atom.Therefore, carbon and hetero atom (for example N, O, preferred oxygen) normally about 1: 1～6: 1 of ratio, preferred 2: 1～4: 1. in the solvent of its ratio of use outside these preferable range, preferably be no more than 75% with the solvent of preferred solvent (for example ethanol) coupling, preferably be no more than 50%.This can be used for for example reducing the ratio that solvent evaporates from preformulation, with the ratio of control liquid crystal storage storehouse formation.

The further advantage of preformulation of the present invention is that the bioactivator of higher level can be incorporated in this system.Especially, by suitable selection component a～c (especially c), high-level activating agent dissolves in or is suspended in the preformulation.Generally speaking, lacking in the situation of water, the dissolubility of lipid composition is relatively relatively poor, but exists in the situation of water, and the phase of formation is too thickness and at an easy rate administration then.By using in suitable solvent can be included in the bioactivator of higher proportion as amount of component b, this level can its original form be dissolved in the compositions of storage storehouse, perhaps can form microdroplet or the crystallite of gradually dissolving and release bioactive agent.In guidance program in this paper, by normal experiment, just can select suitable solvent.

Preformulation of the present invention does not comprise the water of significant quantity usually.Owing to basically can not from fluid composition, remove the water of all traces, think that therefore the water of bottom line trace existence like this can not be removed easily.Such amount normally is lower than 1% weight, preferably is lower than the preformulation of 0.5% weight.One preferred aspect in, preformulation of the present invention does not comprise glycerol, ethylene glycol or propylene glycol, and comprises the water of no more than trace, as described in just now.

Yet there is a certain embodiment in the present invention, wherein can hold the water of higher proportion.This be wherein water as the situation of the other mixable amount of component b of water (single solvent or mixture) of the part of solvent composition associating.In this embodiment, can have the at the most water of 10wt%, condition is also to have at least 3wt%, preferably at least 5%, the more preferably amount of component b of 7wt% at least, wherein, amount of component b is that water is mixable, and the preformulation of gained still keeps not thickness, does not therefore form liquid crystalline phase.Generally speaking, compare with the weight of the water that comprises in the preformulation, have relatively large amount of component b) weight.The most suitable solvent that uses with water comprises ethanol, isopropyl alcohol, NMP, acetoneand ethyl acetate in the present invention is aspect this.

Preformulation of the present invention comprises one or more bioactivators (being described as in this article " activating agent ") of equal valuely.Activating agent can be any chemical compound with required biology or physiological role, for example protein, medicine, antigen, nutrient, cosmetics, aromatic substance, flavoring agent, diagnostic agent, medicine, vitamin or balanced diet agent (dietary agent), and can be formulated into the level of the bulk concentration that is enough to provide functional level (the local concentration that comprises topical composition).In some cases, one or more of component a, b and/or c also can be activating agents, but preferred activating agent is not one of these components.Most preferred activating agent is pharmaceutical agents, comprises medicine, vaccine and diagnostic agent.

Can comprise by the pharmaceutical agents that the present invention sends the medicine that acts on following position: cell and receptor, peripheral nervous, adrenoreceptor, cholinoceptor, skeletal muscle, cardiovascular system, smooth muscle, blood circulation, endocrine and Hormone system, blood circulation, summary position (synoptic sites), the neural effector binding site, immune system, reproductive system, skeletal system, hormonal system, nutrition and Excretory system, histamine system and central nervous system.

The example of the medicine that can send by the present composition includes but not limited to, antibacterial, such as beta-lactam or macro ring peptide antibiotics, antifungal is such as polyenoid class macrolide (for example amphotericin B) or azole antifungal agent, anticarcinogen and/or antiviral agents, such as nucleoside analog, paclitaxel and derivant thereof, anti-inflammatory agent is such as NSAID (non-steroidal anti-inflammatory drug) and corticosteroid, cardiovascular drugs, comprise cholesterol-lowering agent and hypotensive agent, analgesic, psychosis and antidepressants, comprise the 5-hydroxy tryptamine uptake inhibitor, prostaglandin and derivant, vaccine, and bone regulator.Diagnostic agent comprises chemical compound and the contrast agent of radioisotope labeling, comprises the X-ray, ultrasonic and MRI contrast medium.Nutrient comprises vitamin, coenzyme, nutrition enhancer etc.

Specially suitable activating agent comprises because fast cracking or drainage and common those very short activating agents of retention time in vivo, and those low activating agents of oral administration biaavailability.These activating agents comprise the activating agent based on peptide, protein and nucleic acid, natural or the hormone of modified forms and the activating agent of other natural generation.Although have fast clearance rate, by using the activating agent of the storage storehouse composition forms that is formed by preformulation of the present invention, can provide this activating agent a period of time to continue level, can last for days during this period of time, several weeks or even several months.Through a plurality of administration times, providing significant advantage aspect stability and the object compliance every day of same phase.In a preferred embodiment, the biological half life of activating agent (when entering blood flow) preferably less than 12 hours, was more preferably less than 6 hours less than 1 day.In some cases, this half-life can be low to moderate 1～3 hour or lower.Suitable activating agent also is the bioavailability that obtains with respect to injection, and those activating agents that its oral administration biaavailability is poor, the activating agent in the oral formulations also have or alternately have and are lower than 0.1% bioavailability, especially are lower than 0.05%.

Comprise based on the activating agent of peptides and proteins and to be selected from following people's medication or veterinary medicine: thyroliberin (ACTH) and fragment thereof, angiotensin and relevant peptide thereof, antibody and fragment thereof, antigen and fragment thereof, atrial natriuretic peptide, the bioadhesive peptide, Kallidin I and relevant peptide thereof, calcitonin and relevant peptide thereof, the cell surface receptor protein fragment, Chemotactic Peptide, ciclosporin, cytokine, dynorphin and relevant peptide thereof, endorphins and P-lidotropin fragment, enkephalin and associated protein thereof, enzyme inhibitor, immunostimulating peptide and polyamino acid, Fn Fiberonectin fragment and relevant peptide thereof, gastrointestinal peptide, gonadotropin releasing hormone (GnRH) agonist and antagonist, glucagon albumen, growth hormone-releasing peptide, the immunostimulating peptide, insulin and insulin like growth factor, interleukin, luteinizing hormone releasing hormone (LHRH) and relevant peptide thereof, melanotropin and relevant peptide thereof, the peptide that nuclear localization signal is relevant, neurotensin and relevant peptide thereof, the neurotransmitter peptide, opioid peptides, oxytocin, vassopressin and relevant peptide thereof, parathyroid hormone and fragment thereof, protein kinase and relevant peptide thereof, somatostatin and relevant peptide thereof, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 and relevant peptide thereof, transforming growth factor (TGF) and relevant peptide thereof, the tumor necrosis factor fragment, toxin and toxoid and functional peptide are as comprising the anticancer peptide of angiostatin, antihypertensive peptide, anticoagulant peptide, and antimicrobial peptide; Be selected from the protein of following collection, such as immunoglobulin, angiogenesis factor, bone morphogenetic protein, chemokines, colony stimulating factor (CSF), cytokine, somatomedin, interferon (I and II type), interleukin, Leptin, leukaemia inhibitory factor, stem cell factor, transforming growth factor and tumor necrosis factor.

The further significant advantage of storage of the present invention storehouse compositions is that activating agent discharged gradually through the long period, and did not need repeat administration.Therefore said composition is particularly suitable for difficult, the unreliable or very important situation of dosage level of object compliance, for example with the activating agent of mood change, the treatment window of this activating agent is narrow, uses with the reliable inconsistent people of dosage regimen to the child or to life style.Also be used for " life style " activating agent, wherein the inconvenience of repeat administration may surpass the benefit of activating agent.Provide the activating agent of the special kind of special benefit to comprise contraceptive, comprise the hormone of the hormone of practising contraception, and in particular for child's hormone such as growth hormone, anti-addiction agent, additive such as vitamin or mineral additive, antidepressants and anticonvulsant.Cationic peptide is specially adapted to the situation that preformulation wherein partly comprises anionic amphiphilic thing such as fatty acid.In this embodiment, preferred peptide comprises octreotide, Lanreotide, calcitonin, oxytocin, interferon-beta and-γ, IL-4,5,7 and 8, and isoelectric point, IP is higher than pH7, especially is higher than other peptide of pH8.

In aspect one of the present invention is preferred, compositions of the present invention is the I2 phase, or comprise I2 mixed phase mutually, this mixed phase be by be exposed to that aqueous fluid forms and also compositions in comprise the polarity activating agent.Specially suitable polarity activating agent comprises peptide and protein active agent, oligonucleotide, and little water-soluble active agent, comprise row superincumbent those.Interested especially in this respect is peptide octreotide and other somatostatin related peptides, interferon-ALPHA and β, glucagon- like peptide 1 and 2, leuprorelin and other GnRH agonist, 1: PN: WO02056903 PAGE: 25 claimed protein and other GnRH antagonist, interferon-ALPHA and β, zolendronate and ibandronate and other diphosphate (bisphosponate), and the chlorhexidine of polarity activity (for example chlorhexidine gluconate or Chlorhexidine hydrochloride).

When being used for the coupling of proteins/peptides class activating agent, the gathering that special advantage of the present invention is activating agent is suppressed.In a preferred embodiment, the present invention provides storage storehouse precursor thus, storage especially as herein described storehouse compositions, and it comprises at least a peptide (for example antibody) or peptide class activating agent, and wherein, being no more than 5% activating agent is aggregated forms.Preferably be no more than 3% and assemble, being most preferably not exceeding 2% (especially being lower than 2%) is aggregated forms.From the viewpoint of high effect, low side effect and expected absorbent properties, this stability of the protein of not assembling is highly favourable.In addition, wish that more and more the proteins/peptides therapy will have low-level protein aggregation, to obtain the approval of administrative organization.

The amount of the bioactivator of preparing with preformulation of the present invention will depend on function dosage, and form storage storehouse compositions so that the persistent period of slow release to be provided by administration.Usually, the preparation dosage of concrete activating agent approximately is a great deal of that normal daily dose multiply by the natural law of preparation release.Obviously, this amount needs to cooperate any side effect of heavy dose when considering the treatment beginning, therefore, and the maximum that this amount is normally used.The accurate amount that is suitable for any situation will be easy to by suitable measuring out.

In one embodiment, preformulation of the present invention will pass through parenteral.This administration is not method in the blood vessel usually, but the interior or intramuscular of preferred cavus subdermalis.Usually by drug administration by injection, term " injection " is used for any method that expression wherein makes preparation pass skin in this article, for example by syringe needle, conduit or needleless injector.

In the precursor of parenteral (especially subcutaneous) storage storehouse, preferred activating agent is to be suitable for those of whole body administration, comprise that antibacterial (comprises amikacin, single cycline and doxycycline), local anaesthetics and GENERAL ANESTHETICS (comprise bupivacaine, tramadol, fentanyl, morphine, hydromorphone, methadone, oxycodone, codeine, aspirin, acetaminophen), NSAIDS (ibuprofen for example, naproxen, keteprofene, indomethacin, sulindac, tolmetin, salicylic acid such as salicylamide, diflunisal), Cox1 or Cox2 inhibitor (celecoxib for example, rofecoxib, valdecoxib), anticarcinogen (comprises octreotide, Lanreotide, buserelin, leuprorelin, goserelin, triptorelin, avorelin, deslorelin, 1: PN: WO02056903 PAGE: 25 claimed protein, degarelix, fulvestrant, interferon-ALPHA, interferon beta, new erythropoietin α, erythropoietin α, β, δ and paclitaxel), psychosis is (as bromperidol, Risperidal, olanzapine, iloperidone, Paliperidone, pipotiazine and zuclopenthixol), antiviral agents, anticonvulsant (tiagabine for example, topiramate or gabapentin) or nicotine, hormone is (such as testosterone, and Testosterone Undecanoate, medroxyprogesterone, estradiol), growth hormone (class human growth hormone), and somatomedin (class granulocyte macrophage colony stimulating factor).

In an alternative embodiment, preparation of the present invention can form parenteral and store the storehouse outward, and wherein, activating agent slowly discharges at body surface.In this embodiment particularly importantly, preformulation of the present invention and/or form preferably bioadhesion of liquid crystal storage storehouse compositions by it.That is to say that said composition should cover the surface of its application, and/or on its surface that suitably forms, and even when this surface suffers air-flow or liquid stream and/or rubs, said composition also should remain on this surface.Particularly preferably be, formed liquid crystal storage storehouse compositions should keep stable to the flushing of water.For example, can be with a small amount of storage storehouse precursor applications in body surface, and per minute is exposed to the current 500 times of itself volume, totally 5 minutes.After processing like this, if lost bioactivator less than 50%, can think that so said composition is bioadhesion.Preferred this loss level with, when current equal 1000 times, more preferably 10000 times the time, at 5 minutes, per minute flow through the volume of compositions in preferred 10 minutes, mates.

Can absorb from the biological surface of their contacts formation liquid crystalline phase structure required some water or whole water although parenteral of the present invention is store the storehouse compositions outward, yet some other water can absorb from surrounding air also.Particularly, when having formed the thin layer of high surface area, compositions may be enough to form the liquid crystalline phase structure by contacting with airborne water to it for the affinity of water.In this embodiment, this paper preferred " aqueous fluid " is at least part of is the air that comprises some moisture.

The outer storage storehouse compositions of parenteral is normally by being applied topically to body surface with preformulation, or is applied to natural or artificial body cavity and/or is applied to implant surface produce.This application can be by direct using liquid, as by spraying, dipping, flushing, from pad or ball use, intracavitary administration (for example with or without needle injection to open body cavity), smear, drop (especially splashing into eyes) and similar method.Special effective method is aerosol spray or pump spraying, and obviously, this requires the viscosity of preformulation low as much as possible, thereby is very suitable for the present composition.Yet the outer storage storehouse of parenteral can be used for using the whole body medicament, for example through mucous membrane or percutaneous.

The outer storage storehouse of parenteral also may be used on the surface, especially with the implant of health or body part or fluid contact and the surface of material.Therefore, devices such as implant and conduit can for example be processed by dipping or sprinkling preformulation of the present invention, and preformulation of the present invention will form the intervention that firm layer reduces infection.The anti-infection activity agent is particularly suitable for this aspect.

The disease that is particularly suitable for carrying out with local bioadhesion storage of the present invention storehouse compositions etiological treatment or symptomatic treatment comprises: the dermatosis (pain that causes such as any reason, comprise and chap, abrade, and dermatosis, comprise eczema and herpes), oculopathy, genitals pain (comprising because the genitals pain that genital infection such as genital herpes cause), infection and the disease (such as antibacterial or the fungal infection of fingernail, such as tinea unguium or poronychia) of finger and/or toe fingernail.Local type biologic adhesion preparation also can be used for using whole body activating agent (for example medicine), especially by skin absorption, oral cavity, percutaneous or rectum approach.The travel sickness medicine is preferred example, for example nicotine (for example in anti-smoking complementary therapy).When context allowed, mentioned " topical application " of this paper comprised that parenteral is applied to the whole body medicament of health specific region outward.

Periodontal infection is particularly suitable for treating with the present composition.Especially, the known compositions for the treatment of periodontal infection is difficult to use, or usually invalid.The most widely used periodontal disease storage storehouse compositions comprises to be inserted collagen " thin slice " in the periodontal spaces, and the infection medicament discharges from this gap.This thin slice is difficult to insert, and can not form shape and the volume that is complementary with periodontal spaces, and therefore, infecting bag may still not obtain medical treatment.In contrast, the present composition of using with the low viscosity preformulation can be easy to and very promptly be expelled in the periodontal spaces, then can flow to this gap to engage fully, and fill free volume.Then said composition absorbs rapidly water and forms firm gel, and this gel has resistance to aqueous environment in the mouth.The unique known previous trial that this is carried out is pouring-in periodontal treatment, and this therapy depends on relatively full-bodied dispersion, and what this was difficult to use and can not expect to occur is separated.All these shortcomings have all obtained solution now in the present composition as herein described.The most suitable activating agent that is used for periodontal disease therapeutic is anti-infective, especially benzydamine, tramadol and chlorhexidine.

Parenteral is store the storehouse compositions is outward also having remarkable benefit, such as cosmetic active agent, aromatic substance, quintessence oil etc. aspect non-forms of pharmacologically active agents coupling.These non-drug depots will keep the importance of bioadhesive and the slow release of the dressing effect that prolongation is provided, but can use at an easy rate by spraying or wiping.Said composition also can be applicable to not only have cosmetic benefits but also has reagent such as the sunscreen of pharmacy (especially prevention) benefit.Because local storage storehouse compositions provides firm waterproof barrier, and they can dissolution of high-concentration activating agent, therefore they are particularly suitable for and ultraviolet (UV, for example Uva, UVb and/or UVc) absorbent and/or scattering diluent unite for sun-proof and shading, especially when the protection of needs high level.In addition, said composition is highly biocompatible, and is used in and makes skin wet and releiving in the sun exposure process.The present composition that comprises releive agent such as Aloe also is particularly suitable for being exposed to releiving and wetted applications after the daylight, or is suitable for owing to the drying, inflammation or the impaired skin that for example stimulate, burn or wear and tear and cause.

Being particularly suitable for parenteral outer (for example local) storage storehouse administration (comprises in the oral cavity, buccal, nose, eye, skin, the vagina route of delivery) activating agent comprises antifungal such as chlorhexidine, chloromycetin, triclosan, tetracycline, terbinafine, tobramycin, sodium fusidate, butenafine, metronidazole (latter is used in particular for (for example symptomatic) treatment acne erythematosa-adult's acne or some vaginal infection), antiviral agents, comprise acyclovir, anti-infective, such as bibrocathol, ciprofloxacin, levofloxacin, Bangesic, such as benzydamine, lignocaine, prilocaine, Xylocaine, bupivacaine, analgesic, such as tramadol, fentanyl, morphine, hydromorphone, methadone, oxycodone, codeine, aspirin, acetaminophen, NSAIDS, such as ibuprofen, flurbiprofen, naproxen, ketoprofen, fenoprofen, diclofenac sodium, etodolac, diflunisal, oxaprozin, piroxicam, piroxicam, indomethacin, sulindac, tolmetin, salicylic acid, such as salicylamide and diflunisal, Cox1 or Cox2 inhibitor, such as celecoxib, rofecoxib or valdecoxib, corticosteroid, anticarcinogen and immunostimulant (metylaminolevulinat hydrocloride for example, interferon-ALPHA and β), anticonvulsant (for example tiagabine topiramate or gabapentin), hormone (testosterone for example, and Testosterone Undecanoate, medroxyprogesterone, estradiol), growth hormone (as the human growth hormone), and somatomedin (as granulocyte macrophage colony stimulating factor), immunosuppressant (ciclosporin, sirolimus, tacrolimus), nicotine and antiviral agents (for example acyclovir).

Some concrete activating agents that formation the present invention that the inventor finds efficiently stores the storehouse comprise following:

Long-acting injectable storage storehouse product for the hydrophilic active agent:

I. octreotide (or be used for the treatment of other somatostatin analogs that carcoid and VIP generate tumor and acromegaly, such as Lanreotide).Especially form subcutaneous storage storehouse with GDO and PC, it has and surpasses 1 month slow-release time, and in the storage storehouse at water-swellable under 37 ℃ 1 month the degraded of octreotide less than 20%.Observed beat all good stability, and found the octreotide that this stability is better than preparing in microsphere.Storage storehouse in the preformulation product under 4 ℃ through demonstrating the degraded less than 5% 8 weeks.

Ii. human growth hormone.Be used for the treatment of growth disorder and growth hormone deficiency.Especially form subcutaneous storage storehouse with GDO and PC, it had between the slow-release period in 2 weeks of surpassing.

Iii. interferon-ALPHA.Be used for the treatment of cancer and viral infection.Especially form subcutaneous storage storehouse with GDO and PC, it had between 1 month the slow-release period of surpassing.

Iv. leuprorelin acetate.Can form the storage storehouse that (preferably in the treatment window, continues to send) between the lasting delivery period with minimum 1 month.

Long-acting injectable storage storehouse product for lipotropy/amphipathic activating agent:

I. Risperidal

Ii. olanzapine

Iii. Testosterone Undecanoate

Can form between the lasting delivery period with minimum 2 weeks the storage storehouse i of (preferably in the treatment window, continuing to send) to iii.

For the local bioadhesion controlled release product that is used for (comprising buccal and periodontal) administration in the oral cavity:

I. benzydamine (Bangesic, anti-inflammatory agent), or other Bangesic, analgesic, anti-inflammatory agent, antimicrobial drug, antifungal agent or its combination.Said composition mucosa place in the oral cavity provides continuous action, and mucosa place especially impaired, responsive, that infect for example suffers from patient (being caused by for example chemistry and the X-ray therapy) body of oral mucositis.In particular for the treatment oral mucositis.

Ii. tramadol (analgesic).Compositions with lasting whole body analgesic activity is provided.

Iii. chlorhexidine gluconate (antibacterial) is used for the treatment of periodontal disease and local infection.Be used in particular for the long-acting of periodontal pocket.When forming bioadhesive gel in position as liquid, said composition causes storing the storehouse with surpassing 1h, preferably surpasses 6h, and the time that most preferably surpasses 24h discharges chlorhexidine.Observe the surface gel formation time between 1 second and 5 minutes.

The storage storehouse i that can form has mixed high-level activating agent to iii, and flushing is had the height repellence.As the preformulation of the i of spraying or the liquid form used of liquid washing liquid/flushing liquor and ii with form the liquid of the iii of gel, wherein, liquid is applied on the periodontal pocket, for example by injection.

Controlled release product for the nasal-cavity administration of outer (for example part or the whole body) bioadhesion of parenteral:

I. when using as aerosol, fentanyl (analgesic) provides quick acting and lasting analgesia duration.

Ii. diazepam (antianxiety drug) provides parenteral the outer intranasal storage storehouse with general action, its quick acting, and effect continues.As spray delivery.

Local bioadhesion controlled release product for dosing eyes:

I. the diclofenac sodium (NSAID) that has continuous action.Form mutually the liquid administration as former.

Ii. be used for the treatment of glaucomatous pilocarpine (parasympathomimetic agent, cholinergic agonist).

The iii Levocabastine Hydrochloride, ketotifen fumarate provides eye drop, treats allergic conjunctivitis with the long-acting release in long-time interval between reapplication.

Iv is used for the treatment of the pilocarpine hydrochloride of Sjogren syndrome.

V dexamethasone (corticosteroid)

Vi chloromycetin (main antibacterial anti-infective)

Vii indomethacin (NSAID)

Storage storehouse i is mixed with liquid spray or preferably is mixed with drop to vii and is used for being applied directly to ocular surface, and forms in position the storage storehouse, the wearing and tearing that this storage storehouse height opposing is rinsed out by tear and blinks/rub one's eyes and cause.

Other activating agent that is suitable for ophthalmic composition comprises antihistaminic, mast cell stabilizers, nonsteroidal anti-inflammatory drug (NSAIDs), corticosteroid (for example treating allergic conjunctivitis), anti-glaucoma agents, comprise and flow into inhibition/blocker (Beta receptor blockers: timolol, betaxolol, carteolol, levobunolol etc., local carbonic anhydrase inhibitors: dorzolamide, brinzolamide, sympathomimetic: epinephrine, dipivefrine, clonidine, Aplonidine, brimonidine), flow out promoter (parasympathomimetic agent (cholinergic agonist): pilocarpine, prostaglandin analogue and relevant chemical compound: latanoprost (atanoprost), travoprost, bimatoprost, Unoprostone).

For outer (for example part or whole body) the bioadhesion controlled release product of the parenteral that is used for the dermatological administration:

I. acyclovir (antiviral agents).Said composition produces the film-forming products of the bioadhesion of continuous action.Use as spraying or liquid.

Ii. Testosterone Undecanoate (hormonoprivia).The film-forming products of the bioadhesion of continuous action.Can be used as the spraying of aerosol spray or pump or use as liquid.

The particularly suitable application of dermatological preparation is anti-infective dermatological bioadhesion storage storehouse, the environment that this storage storehouse probably contacts for the protection of infective agent (for example people or structive sursery, work in the slaughterhouse, the cleaning of some type etc.).The bioadhesion storage storehouse that produces from the present composition provides strong lasting protection for the wearer.It is aseptic for other people healthy very important situation that the compositions that contains anti-infective also can be used for wearer's wherein skin, for example for repeatedly visiting tour patient's nurse or doctor in hospital, must avoid cross infection.Smear in advance the present composition and can be used for resisting the infection that obtains from a zone, thereby avoid being delivered to another zone.

By being exposed to aqueous fluid, especially the liquid neutralization contacts with body surface in the body, and preformulation of the present invention provides non-layered liquid crystal storage storehouse compositions.When being used for herein, term " non-stratiform " is used for normal or reverse (the normal or reversed) liquid crystalline phase (for example cube or hexagon phase) of expression or L ₃Phase, or its any combination.The term liquid crystal represents all hexagon liquid crystalline phases, all cube liquid crystalline phase and/or its all mixture.Unless stated otherwise, the hexagon that is used for this paper represents " normally " or " oppositely " hexagon (oppositely preferred), " cube " represents any cube liquid crystalline phase.The preformulation of the application of the invention might produce any phase structure that exists in the phasor of component a and b and water.This is because preformulation can produce than the previous wider relative concentration of component of liquid storage storehouse system, and does not have the dangerous or generation injection high viscosity solution that is separated.Particularly, the invention provides with respect to the application of amphiphile total content greater than 50% phospholipid concentration.This be so that can produce the phase that only just can see under high phospholipid concentration, especially the hexagon liquid crystalline phase.

For a lot of combinations of lipid, only have some non-lamellar phase to exist, or exist with any steady statue.Usually there is non-lamellar phase in compositions as herein described, and this is the beat all feature of the present invention, and this lamellar phase does not exist under the associating of a lot of other components.Therefore in a particularly advantageous embodiment, the present invention relates to contain the compositions of associating component, when diluting with aqueous solvent, have I ₂And/or L ₂Phase region.The existence of this phase region whether can be at an easy rate with the simple diluted composition of aqueous solvent, and the phase structure that gets with method institute as herein described and detect any specific combination.

In particularly advantageous embodiment, compositions of the present invention can form I when contacting with water ₂Mutually or comprise I ₂At interior mixed phase.I ₂The reverse cube liquid crystalline phase with discontinuous water aquifer mutually.This is advantageous particularly aspect the release of control activating agent, especially advantageous particularly with polarity activating agent such as water-soluble active agent combined aspects, because discontinuous polar region has stoped the rapid diffusion of activating agent.L ₂In storage storehouse precursor with I ₂The combined aspects of storing mutually storehouse formation is effective especially.This is because L ₂What is called " reversed micelle " phase that around discontinuous polarity nuclear, has continuous hydrophobic region mutually.So L ₂With the hydrophilic active agent similar advantage is arranged.

With transition stage after body fluid contacts, compositions can comprise multiple phase, penetrates storage storehouse kernel because the formation of initial surface phase can delay solvent, especially uses the interior reservoir administration of basic identical size.Be not subject to theory, think that this transitional of surperficial phase, especially liquid crystal surfactant phase forms, acutely reduced " burst/lag behind " curve of the present composition by the exchange velocity between limit combination and the surrounding immediately.Transitional face can comprise (usually according to from the storage outside, storehouse towards the storage center, storehouse order): H _IIOr L _α, I ₂, L ₂And liquid (solution).Highly preferred under physiology's temperature with transition stage after water contacts, the present composition can form simultaneously at least 2 with more preferably at least 3 these mutually.Especially, highly preferably formed, be that one of these phases of forming transiently are the L2 phases at least.

Importantly, preformulation of the present invention has low viscosity.Therefore, these preformulations can not be any a large amount of liquid crystalline phase, because all liquid crystalline phases all have significantly higher viscosity than use the viscosity that can reach with syringe or spray dispenser.Therefore, preformulation of the present invention will be non-mesomorphic state, for example solution, L ₂Or L ₃Phase, especially solution or L ₂This paper is used L in the whole text ₂Preferably comprise mutually " swelling " L more than 10wt% solvent (amount of component b) ₂Phase, described solvent have the low viscous effect of falling.This with do not contain solvent or contain the small amount solvent or contain " concentrated " or " the non-swelling " L that can not reduce the solvent that contains the relevant viscosity of oxygen low viscosity solvent (or mixture) emphasized with this paper ₂Differ widely mutually.

During administration, preformulation experience phase structure of the present invention changes, and is transformed into high viscosity (normally tissue adheres to) storage storehouse compositions from low viscosity mixtures.Generally speaking, this is the L from molecule mixture, swelling ₂And/or L ₃Be transformed into mutually one or more (high viscosity) liquid crystalline phase, for example normal or reverse hexagon or cube liquid crystalline phase or its mixture.As implied above, administration also can occur later on further to change mutually.Obviously, for function of the present invention, it is unnecessary changing mutually completely, but the mixture of using is that surface layer can form liquid crystal structure at least.For the preparation of using be surf zone (this part directly contacts with air, body surface and/or body fluid) at least, generally speaking, this transformation is rapidly.The choosing of this process optimum is through several seconds or several minutes (for example at the most 30 minutes, preferably at the most 10 minutes, more preferably 5 minutes or shorter time).The remainder of compositions can change more lentamente by diffusion and/or as the surface region disperse liquid crystalline phase of coordinating.

Therefore in a preferred embodiment, the invention provides preformulation as herein described, wherein, when contacting with aqueous fluid, at least a portion forms the hexagon liquid crystalline phase.The hexagon that so forms can spread mutually gradually, release bioactive agent, or can be transformed into subsequently the cube liquid crystalline phase, then its successively gradually diffusion.Think that hexagon compares cube phase structure, especially I ₂And L ₂Meeting provides activating agent to discharge faster, especially hydrophilic active agent.Therefore, formed the hexagon phase before the cube phase, the initial release that this can cause activating agent causes concentration to be increased to rapidly valid density, then discharges gradually when cube is degraded mutually " maintenance dose ".Can control release profiles in this way.

Be not subject to theory, when thinking exposure (for example being exposed to body fluid), preformulation of the present invention has lost some or all organic solvents (for example by diffusion and/or evaporation) that are included in wherein, and from physical environment (for example close to the humid air of health, or internal milieu) absorbs aqueous fluid in, so that at least part of preparation produces is unstratified, liquid crystalline phase structure especially.In most of situation, these non-layer structures are highly viscous, and are not easy to be dissolved in or to be distributed in the internal milieu, and are bioadhesions, therefore are not easy to wash away or flush away.In addition, because non-layer structure has larger polarity, nonpolar and boundary zone, therefore at solubilising with stablize very eurypalynous activating agent and protect them to avoid aspect the degraded very effective.When the storage storehouse compositions that is formed by preformulation was degraded gradually through a couple of days, several weeks or several months, activating agent discharged gradually and/or is diffused into outside the compositions.Because the environment in the compositions of storage storehouse is subject to relative protection, preformulation of the present invention is particularly suitable for having the activating agent (referring to above) of low biological half life.

The inventor is surprised to find that this preformulation causes storing the storehouse compositions and have very little " prominent releasing " effect in the activating agent release profiles.This is unexpected, because be expected at when being exposed in the water, and the low viscosity mixtures of this pre-composition (if when especially it is solution) agent that can lose activity rapidly.In fact, preformulation of the present invention has gone out significantly less initial " prominent releasing " than the storage storehouse compositions display based on polymer of previously known.In following examples and appended figure, will describe this point in detail.Therefore in one embodiment, the present invention provides the storage storehouse compositions of injectable preformulation and gained, and wherein, the maximum plasma concentration after the administration is not more than 5 times of mean concentration of administration between 24 hours and 5 days.This ratio preferably is not more than 4 times, most preferably is not more than 3 times of mean concentrations.

The present invention other aspect in, topical composition is used in the situation that does not contain activating agent, provides physical barriers at body surface.Especially, because the very high bioadhesion effect of compositions, " barrier " coating that forms by spraying or using liquid can be formed by the present composition, reducing and the contacting of potential infective agent or stimulus, or the minimizing body exposure.The strong character of said composition and wash fast characteristic provide favourable characteristic for this barrier, and this can use as liquid or by spraying easily.

Description of drawings

Further set forth the present invention referring now to following non-limiting examples and accompanying drawing, wherein:

When Fig. 1 has shown in being expelled to excessive water, the cumulative release of methylene blue (MB) from the depot formulation that comprises PC/GDO/EtOH (45/45/10wt%);

When Fig. 2 has illustrated adding N-Methyl pyrrolidone (NMP) and EtOH, the non-linear reduction of preformulation viscosity;

Fig. 3 has shown that subcutaneous injection comprises after the various PC/GDO/EtOH storages storehouse precursor of 500 μ g sCT/g preparations the plasma concentration of the salmon calcitonin of rat (sCT);

Fig. 4 has shown after the subcutaneous injection that sCT discharges (48 hours at the most) at first in vivo to blood plasma interior (in the rat) from two different depot formulations;

Fig. 5 has shown that subcutaneous injection comprises after the 5mg OCT/g preparation depot formulation that contains PC/GDO/EtOH (36/54/10wt%) of (being equivalent to 0.5% drug loading) plasma concentration (in the rat) of octreotide (OCT);

Fig. 6 has shown that subcutaneous injection comprises after the 30mg OCT/g preparation depot formulation that contains PC/GDO/EtOH (47.5/47.5/5.0wt%) of (being equivalent to 3% drug loading) plasma concentration (in the rat) of octreotide (OCT);

Fig. 7 has shown the release in vitro of the excessive aqueous phase of chlorhexidine from comprise 50mg chlorhexidine/g preparation depot formulation that contains PC/GDO/EtOH (36/54/10wt%) of (being equivalent to 5% drug loading).

The specific embodiment

Embodiment:

Embodiment 1: the effectiveness that obtains different liquid crystalline phases by the Selection and Constitute thing in the storage storehouse

Preparation comprises the phosphatidylcholine (" PC "-Epikuron 200) of different proportion and glyceryl dioleate (GDO) and EtOH and illustrates as the injectable preparation of solvent and can obtain different liquid crystalline phases after storing the storehouse precursor formulation with the excessive water balance.

In vial, take by weighing an amount of PC and EtOH, this mixture is placed on the agitator form supernatant liquid solution until PC dissolves fully.Then add GDO and form injectable homogeneous solution.

To use the excessive water balance in each preparation implantation glass bottle.Range estimation is at the phase behavior between cross polarization light under 25 ℃.The results are shown in Table 1.

Table 1

Preparation	PC(wt％)	GDO(wt％)	EtOH(wt％)	H 2Phase among the O
					A B C D	22.5 28.8 45.0 63.0	67.5 61.2 45.0 27.0	10.0 10.0 10.0 10.0	L 2 I 2 H II H II/L α

L ₂=reversed micelle phase

I ₂=reverse cube liquid crystalline phase

H _II=reverse hexagon liquid crystalline phase

L _α=lamellar phase

Embodiment 2: the release in vitro of water-soluble substances

With water-soluble colorant, methylene blue (MB) is distributed to the concentration that reaches the 11mg/g preparation in the formulation C (referring to embodiment 1).When being injected in the 100ml water, the said preparation of 0.5g formed strong reverse hexagon H _IIPhase.Then within 10 day time, under 664nm, measured the absorbance of the MB that is discharged into water.Under 37 ℃, in the erlenmeyer flask of magnetic agitation, carry out releasing research.

The release profiles of MB (seeing Fig. 1) shows (similar with it) preparation to be promising storage system in the hexagonal phase.And, seeming that said preparation has produced low initial release, release profiles shows that material can discharge several weeks; Discharged afterwards only about 50% MB in 10 days.

Embodiment 3: add the PC/GDO (6: 4) of solvent (EtOH, PG and NMP) or the viscosity of PC/GDO (3: 7)

Method according to embodiment 1 prepares the PC/GDO/EtOH mixture.With Rotary Evaporators (vacuum, 40 ℃, 1h) will own in the mixture, or nearly all EtOH removes, then the solid mixture of weighing gained in vial adds 2,5,10 or 20% solvent (EtOH, propylene glycol (PG) or n-methyl pyrrolidone (NMP)).Using Physica UDS200 hemotachometer under 25 ℃, before the shear rate measurement viscosity with 0.1s-1, to allow sample balance several days.

This embodiment has clearly illustrated the demand of solvent with some storage precursor to obtain injectable preparation (seeing Fig. 2).Increase the ratio of PC, the viscosity of solvent-free PC/GDO mixture increases.The system of low PC/GDO ratio (more GDO) can inject with the solvent of lower concentration.

Embodiment 4: form and external mutually research

The method of describing according to embodiment 1 prepares preparation with the composition of table 2.Effective ingredient (peptide), salmon calcitonin (sCT) are joined the concentration that reaches 500g sCT/g preparation in each preparation.Preparation is designed to even suspension is used for parenteral (needing before use to mix immediately, because medicine is not dissolved in the PC/GDO/EtOH system fully).

Studying mutually in a large amount of rat plasmas under 37 ℃ among this embodiment carried out, with simulated in vivo environment.Table 2 show formed with water in those identical phases (with table 1 relatively).

Table 2

Preparation	PC(wt％)	GDO(wt％)	OA(wt％)	EtOH(wt％)	Phase in the rat blood serum
						E F G H I	18 36 34 54 72	72 54 51 36 18	--5--	1010101010	L 2 I 2 I 2 H II H II/L α

OA=oleic acid

Embodiment 5: the aseptic filtration of the preparation of reduced viscosity

Sometimes need to reduce viscosity to obtain injectable preparation and can be with the syringe administration (seeing embodiment 3) of routine with different solvents.Another important function of falling low viscous solvent is can the aseptic filtration preparation.

Preparation E among the embodiment 4 passes through to use the filter (before the adding effective ingredient) of 0.22 μ m to carry out the aseptic filtration experimental study to I.Success is filtered preparation E to H, but because the too high preparation I failure of viscosity.Therefore said preparation needs aseptic preparation process.

Embodiment 6: discharge in the subcutaneous administration depot formulation research body

Preparation E among the embodiment 4 is used for the drug disposition releasing research to I in rat.(21G, 0.6mm * 30mm), the dosage of sCT is 500 μ g/kg body weight with the subcutaneous administration of these preparations between scapula to use syringe.In 13 days, detect release profiles.Use comes sCT concentration in the analyzing rat blood plasma sample from sandwich type (sandwich-type) immunoassay of the commercial kit of DSLabs.

Fig. 3 has shown result (n=4).Selection based on the pure glycerin acid esters carrier of Oleum Sesami as the lipid reference system.

Embodiment 7: releasing research in the body in the start-up phase

Preparation F among the embodiment 6 and G are used for studying to study initial " burst effect " in the rat body.It seems that from Fig. 4 (n=8) preparation of neither one research has violent burst effect.

Embodiment 8: with different solvents preparation storage storehouse precursor composition.

According to character and the concentration of composition and the effective ingredient of preparation, preferably some solvent.

Method by embodiment 1 is with different solvents; NMP, PG, PEG400, glycerol/EtOH (90/10) preparation storage storehouse precursor formulation (PC/GDO/solvent (36/54/10)).All storage storehouse precursor compositions all are can pass through syringe (23G-is 23 gage needle; 0.6mm * 30mm) the uniform phase solution of injection viscosity.After being expelled to the preparation precursor in the excessive water, form rapidly the liquid crystalline phase of high viscosity integral form with the precursor that comprises NMP and PG.This liquid crystalline phase has reverse cube of micelle (I ₂) structure.Comprise PEG400, glycerol/EtOH (90/10), thickness/solidification process is very slow, and the initial liquid precursor is transformed into a bit soft adhesive tab.The difference of appearance has probably reflected with EtOH, NMP compares PEG400 and glycerol to the slower stripping of excessive water with PG.

Embodiment 9: preparation comprises human growth hormone's (HGH) storage storehouse compositions.

Human growth hormone (hGH) plays pivotal role in stimulating physical growth and growing, be included in the fat of muscle protein product and decomposition.The shortage of growth hormone adversely affects many body processes, for example lipid performance, insulin state, corporal characteristic, bone mineral density and quality of life.The target dose in per 2 weeks is estimated as 0.10 to the 0.24mg/kg body weight.

By 10mg hGH and 360mg PC are mixed into the 2 all depot formulation precursors that form 1ml among the 0.1ml NMP continuously.In mixture, add 540mg GDO acquisition low viscosity depot formulation precursor.The said preparation precursor is expelled to excessive water (syringe 23G; 0.6mm * produce whole liquid crystalline phase (I2 structure) in 30mm).

Embodiment 10: preparation comprises the storage storehouse compositions of microsolubility effective ingredient.

The Risperidal antipsychotic agent belongs to chemical classes benzisoxazole derivant.It is potent dopamine blocker (antagonist); Be that it suppresses the dopamine receptor function, it is water-soluble hardly, log (P)=3.49.

The 95%wt EtOH (99.5%) that effective ingredient is dissolved in 0.7g is in the mixture of 5%wt acetic acid, and preparation comprises the 1g depot formulation of 50mg Risperidal.Subsequently 0.34g PC and 0.51g GDO are dissolved in this solution, then reduce solvent to keep 0.15g solvent (evaporating 0.55g under the vacuum).The final all depot formulation compositionss of even clarification that contain the 50mg Risperidal are PC/GDO/ solvent/Risperidal (32/49/14/5).The said preparation precursor is expelled to excessive water (syringe 23G; 0.6mm * produce whole liquid crystalline phase (I in 30mm) ₂Structure).Namely being exposed to after the aqueous environment amount (5%) of effective ingredient does not change and wholely consists of and phase behavior.

Embodiment 11: comprise the alternative preparation of the storage storehouse compositions of Risperidal.

Can also prepare Risperidal storage storehouse precursor formulation by using the solvent mixture that in 10%wt acetic acid, is formed by 90%wt EtOH (99.5%).

The 50mg Risperidal is dissolved in the solvent mixture of 0.7g, then 0.36g PC and 0.54g GDO is joined in this solution.Under the vacuum 0.60g solvent mixture is evaporated to the depot formulation precursor of all even clarifications that contain 50mg Risperidal (PC/GDO/ solvent/Risperidal (34/51/10/5)).The preparation precursor is expelled to excessive water (syringe 23G; 0.6mm * generate whole liquid crystalline phase (I2 structure) in 30mm).That is, being exposed to after the aqueous environment amount (5%) of effective ingredient does not change and wholely consists of and phase behavior.

Embodiment 12: the temperature stability that comprises the storage storehouse compositions of slightly soluble active substance.

Test implementation example 10 and 11 Risperidal storage storehouse precursor formulation are resisted the stability of crystallization in storage.In 25 ℃ of lower each at least two weeks of preparation stabilization, under+8 ℃, stablize at least one week.

Embodiment 13: preparation comprises the storage storehouse compositions of benzydamine.

Benzydamine is the non-steroidal anti-inflammatory medicine, is widely used as topical remedy in inflammatory disease.

1 description prepares the depot formulation that 1g comprises the 1.5mg benzydamine by effective ingredient being dissolved in PC/GDO/EtOH (36/54/10) mixture such as embodiment.In 25 ℃ of storages, these storage storehouse compositions opposing at least two weeks of crystallization-stable.Produce the whole liquid crystalline phase (I of high viscosity with excessive water balance said preparation precursor ₂Structure).

Embodiment 14: for the stability of the preparation behavior of excipient mass change.

The method of using embodiment 1 is with several different GDO quality (Danisco, Dk provides), table 3, and the storehouse precursor formulation is store in preparation.Final storage storehouse precursor comprises 36%wt PC, 54%wtGDO and 10%wt EtOH.The outward appearance of depot formulation is insensitive to the variation of service property (quality), and integral body forms and has reversed micelle cube phase behavior (I after contacting with excessive water ₂Structure).

The GDO quality of table 3. test.

GDO quality monoglyceride (%wt) diglyceride (%wt) triglyceride (%wt)

A 10.9 87.5 1.6

B 4.8 93.6 1.6

C 1.0 97.3 1.7

D 10.1 80.8 10.1

E 2.9 88.9 8.2

F 0.9 89.0 10.1

Embodiment 15: preparation comprises the storage storehouse compositions of saturated PC (Epikuron 200SH).

Such as embodiment 1, store the storehouse precursor formulation by Epikuron 200SH directly being joined the PC/GDO/EtOH mixture with the not commensurability PC preparation that comprises saturated hydrocarbon chain.These preparations are listed in the table 4.All precursor formulation all are uniform single-phase samples in RT, simultaneously their more thickness that becomes along with the increase of Epikuron 200SH amount.To store the storehouse precursor is expelled in the excessive water to produce and comprises reversed micelle cube (I ₂) integral body of structure.Comprise the integral body that a large amount of Epikuron 200SH samples form and become muddy, perhaps show to be exposed to behind the water Epikuron 200SH with other component separating and to have formed 12 mutually.

Table 4. comprises the storage storehouse compositions of saturated PC

The saturated PC of preparation, Epikuron 200SH (%wt) PC (%wt) GDO (%wt) EtOH (%wt)

G1 3.9 34.6 51.9 9.6

G2 7.0 33.5 50.2 9.3

G3 14.3 30.8 46.3 8.6

Embodiment 16: preparation is as the storage storehouse precursor of peptide salmon calcitonin decentralized photo or solution.

Add 500 μ gsCT/g preparations in PC/GDO/EtOH (36/54/10) solution that obtains to embodiment 1,, formed the dispersion of sCT.

In alternative method, 500 μ g sCT are dissolved among the excessive EtOH, then add PC and GDO.Then solvent strength is reduced (evaporation EtOH) to forming uniformly (active medicine is in solvent) preparation.Can obtain with the technology of back higher medicine carrying capacity.The precursor composition of finally storing the sCT of storehouse precursor composition at least 1500 μ g dissolving corresponding to every gram can obtain by the method.

Embodiment 17: discharge in the depot formulation subcutaneous administration research body.

By subcutaneous injection (between scapula) with rat model in two kinds of sCT compositions donors describing among the embodiment 16.The first storage storehouse precursor that discovery has the sCT of dispersion has produced somewhat unsettled initial plasma concentration, and the second storage storehouse precursor with sCT of dissolving has produced more stable initial blood plasma level (seeing Table 5).

Table 5

Preparation	The coefficient of variation (%CV)
		Disperse: 500 μ g sCT/g PC/GDO/EtOH (36/54/10)	32-127
Dissolving: 500 μ g sCT/g PC/GDO/EtOH (36/54/10)	20-37

Embodiment 18: preparation comprises the storage storehouse compositions of peptide octreotide

Octreotide is the acetate of eight-peptide of synthesizing, is similar to the hormone somatostatin.Octreotide for example can make, and the generation of growth hormone, insulin and glucagon reduces.Be used for the treatment of acromegaly, and be used for reduce by the cancerous tumour (carcinoid syndrome) that shifts or be called flushing and the watery diarrhea that the tumor of vasoactive intestinal peptide tumor (VIPomas) causes.

The octreotide of 24mg or 60mg is dissolved among the EtOH of 0.1g.Then 0.36gPC and 0.54g GDO are dissolved in and have obtained the depot formulation precursor in this solution.The said preparation precursor is expelled to excessive water (syringe 23G; 0.6mm * produce whole liquid crystalline phase (I2 structure) in 30mm).Octreotide (2.4% or 6.0%) does not change whole formation and phase behavior after namely being exposed to aqueous environment.

Test the stability of crystallization in the octreotide storage storehouse precursor formulation opposing storage among this embodiment.4～8 ℃ of lower each preparations can stablize at least two weeks.

Embodiment 19: the interior release of depot formulation subcutaneous administration research body that comprises octreotide.

In the rat model, record the drug release of octreotide in 28 day time in vivo.Use syringe (23G, 0.6mmx25mm) with said preparation subcutaneous administration between scapula.Record the rat plasma octreotide concentration (seeing Fig. 5) of 28 day time.Be 5mg/kg at dosage, the 1ml/kg volume is equivalent to the medicine carrying capacity of 0.5% octreotide in depot formulation precursor (PC/GDO/EtOH (36/54/10)).

Fig. 5 (n=3) demonstration is subjected to test preparation to produce the release profiles that does not substantially comprise the effect that happens suddenly.

Fig. 5 has shown the octreotide blood plasma level that gives the rear rat model of octreotide preparation precursor (0.5%, octreotide).

Embodiment 20: the decomposition of depot formulation in rat

(1,2, storage storehouse precursor 6ml/kg) (36%wt PC, 54%wtGDO and 10%wt EtOH) is injected in the rat, removes after 14 days again with different volumes.Find that still there is subcutaneous rat in later large volume preparation during this period of time, see Table 6.

The average diameter of table 6. storage storehouse integral body

Dosage (ml/kg)	The 3rd day average diameter (mm)	The 14th day average diameter (mm)
			1(n＝3)	15.8	12.5
2(n＝3)	18.5	15.3
			6(n＝3)	23.3	19.3

Embodiment 21: the storage integrally formed in vitro study in storehouse after injecting the depot formulation precursor between bone and the periosteum.

By syringe precursor (such as embodiment 1 preparation 36%wt PC, 54%wt GDO and 10%wt EtOH) is injected between bone and the periosteum.Observe the compositions diffusion and fill the space, form integral body behind the absorption aqueous fluid, this integral body bioadhesion is on bone and periosteum.

Embodiment 22: the bioadhesion aerosol of storage storehouse precursor formulation.

Found that pump formula spray bottle is the convenient approach of topical application said preparation, for example is applied to skin or oral mucosa.

To be sprayed onto on skin or the oral mucosa with pump formula spray bottle such as the storage storehouse precursor formulation (36%wt PC, 54%wt GDO and 10%wt EtOH) of embodiment 1 preparation.Formed immediately the film with Solid Mechanics character after the application.

Embodiment 23: the stability of topical film

Describe such as embodiment 22, will store storehouse precursor formulation (36%wt PC, 54%wt GD O and 10%wt EtOH) and be applied to after the skin, the preparation of using was exposed to flushing water (10L/min) lower 10 minutes.Said preparation demonstrates fabulous bioadhesion character, and anti-impact is washed and can not distinguished that preparation has any loss.

Embodiment 24: formation had the cube phase of solid property after storage storehouse precursor formulation was exposed to air.

To be exposed to such as the storage storehouse precursor formulation (36%wt PC, 54%wtGDO and 10%wt EtOH) that embodiment 1 describes preparation in the air (RT, relative humidity 40%) after at least 3 hours, form solid cube phase.Topical film behind the formation application of this cube phase structure will obtain in a large number non--stratiform storage storehouse character and not need directly to be exposed in the excessive aqueous fluid.

Embodiment 25: the preparation for the treatment of periodontitis or implant Zhou Yan (perimplantitis).

In order to treat periodontitis or implant Zhou Yan, antibiotic preparation is expelled in the periodontal pocket, expectation obtains the effect that said preparation prolongs usually.

Such as the interpolation of embodiment 1 preparation 100 μ L the preparation of antibiotic chlorhexidine (PC/GDO/EtOH/ chlorhexidine (35/53/10/2)), inject the rat periodontal ligament bag by syringe.Observe the compositions of injection by absorbing gingiva liquid from spreading apart at first the low viscosity preparation of filling the space, change the solid piece of formation.Antibiotic storage storehouse system so just is provided.

Remain on clinical effective level (MIC 125 μ g/ml) above the chlorhexidine among the GCF of periodontal pocket after 1 week.Storage storehouse system is degradable and do not need to take out by enzyme in 7 to 10 days.

Embodiment 26: the interchangeable antibiotic preparation for the treatment of periodontitis or implant Zhou Yan.

Describe preparation such as embodiment 1 interchangeable antibiotic preparation is provided, comprise antibiotic detergent Gardol (Gardol) (glycine, N-methyl-N-(l-oxo dodecyl)-, sodium salt) (PC/GDO/EtOH/ Gardol (34/51/10/5)).Said preparation is injected the rat periodontal ligament bag.

Observe and in the time (several days) that prolongs, keep clinical effect level among the GCF of Gardol at periodontal pocket.Storage storehouse system is degradable and do not need to take out by enzyme in 7 to 10 days.

Embodiment 27: preparation is sticked at the high-energy surface.

In order to treat implant Zhou Yan, not only being adhered to biological surface but also being adhered to the high-energy surface is very important on gold or the titanium implant for example.Preparation is adhered to pottery or frosting is also important.

To be applied to such as the preparation (PC/GDO/EtOH (36/54/10)) of embodiment 1 preparation the different surfaces in oral cavity.Said composition with shown that to common dental surface is the same excessive aqueous fluid can not rinse out to pottery, plastics, the fabulous adhesion strength of gold.The storage storehouse that is made by said composition kept 6 hours at the position, oral cavity of its application at least.

Embodiment 28: the sodium fluoride bioadhesion slow releasing preparation that is used for tooth

The chemical compound that comprises fluoride is attacked through being usually used in resisting dental caries, is had as described in Example 1 the bioadhesion preparation precursor of storage storehouse effect by the preparation of PC/GDO/EtOH/ sodium fluoride (35/53/10/2) mixture.Because it is insoluble in the precursor, so said preparation is the dispersion of sodium fluoride.Help said preparation is applied on the tooth with brush.Solidify by absorbing the saliva said preparation, and form the storage storehouse at long-time (several hours) inner slow release that sodium fluoride is provided.

Embodiment 29: mouthspray storage storehouse compositions

In order to be suitable as oral cavity partial storage storehouse system, come the mechanical property of adjustment system by the ratio that reduces PC/GDO.

1 preparation comprises the mixture of PC/GDO/EtOH (27/63/10) according to embodiment.Add the preparation development after a patent blue makes application.Use pump formula spray bottle that the preparation of about 300 μ l is sprayed in the oral cavity.After the application, because it has experienced phase transfer by absorbing aqueous fluid (saliva) and solvent loss (EtOH), so immediately thickness/curing of preparation.For example hard palate and gingiva have fabulous adhesion strength to said preparation to the keritinized surface.Although the mechanical wear of salivation and tongue is arranged, thin film still can continue several hours.And on soft mucomembranous surface, many (some minutes) that the persistent period will lack.

Embodiment 30: mouth cavity liquid storage storehouse compositions

In order to be fit to be applied to the oral cavity with pipette, the curing/thickness of preparation has to prolong with respect to spray agent.This is to allow easily preparation to be scattered in thin film with tongue for after using in the oral cavity.

In the preparation such as embodiment 1 preparation, add propylene glycol (PG) and EtOH, form final composition PC/GDO/EtOH/PG (24/56/10/10).Be applied to expediently in the oral cavity with the preparation of pipette with 300 μ l, in the oral cavity, be scattered in thin film with tongue.Because it has experienced phase transfer by absorbing aqueous fluid (saliva) and solvent loss (EtOH and PG), the thickness of preparation melts the beginning after 20 seconds.After fixing/thickness seemed to finish in 1 minute.For example hard palate and gingiva have fabulous adhesion strength to said preparation to the keritinized surface.Although the mechanical wear of salivation and tongue is arranged, thin film still can continue several hours.And on soft mucomembranous surface, many (some minutes) that the persistent period will lack.

Embodiment 31: the bioadhesion storage storehouse that is used for fingernail

The mixture of embodiment 29 is sprayed onto on the nail matrix of toe.By absorb aqueous fluid (referring to: antiperspirant) said preparation slowly solidifies/thickness.Curing can be accelerated by adding water after the spray applications.Said preparation has fabulous bioadhesion character, continues several hours.

Embodiment 32: the load capacity of bioactivator benzydamine in the preparation precursor.

Use the preparation of method preparation table 7 specified ingredients of embodiment 1.Excessive benzydamine (50mg) is joined in the preparation of 0.5g.Under 15 ℃ vial placed agitator upper 3 day, afterwards solution is filtered to remove insoluble benzydamine crystal by filter (0.45 μ m).Measure the concentration of benzydamine with the UV of reverse gradient HPLC and 306nm, the results are shown in Table 7.

Table 7

Compositions GDO/PC (Lipoid S100)/EtOH	Benzydamine concentration in the preparation
		67.5/22.5/10	3.4％
63/27/10	3.2％
		58.5/31.5/10	3.3％
60/20/20	4.0％
		56/24/20	4.5％
52/28/20	4.3％

Embodiment 33: the compositions that comprises PC and tocopherol

The method of use embodiment 1 prepares the storage storehouse precursor formulation (PC is dissolved among an amount of EtOH first, then adds alpha-tocopherol and obtain clarifying homogeneity solution) of several different PC/ alpha-tocopherol compositionss.

To use the excessive water balance in each preparation implantation glass bottle.25 ℃ of lower phase behaviors of estimating between the cross polarization light.The results are shown in Table 8.

Table 8

α-tocopherol	PC	Ethanol	Excessive H 2Phase among the O
				2.25g	2.25g	0.5g	H II
2.7g	1.8g	0.5g	H II/I 2
				3.15g	1.35g	0.5g	I 2
3.6g	0.9g	0.5g	I 2/L 2

Embodiment 34: the compositions that comprises octreotide

The 60mg octreotide is dissolved among the 0.1g EtOH.Then 0.25g PC and 0.59g alpha-tocopherol are dissolved in this solution acquisition depot formulation precursor.The said preparation precursor is injected into excessive water solution, and (octreotide (6.0%) did not change whole formation and phase behavior after phosphate buffered saline (PBS)-PBS) the middle whole liquid crystalline phase of generation (I2 structure) namely was exposed to aqueous environment.

The brilliant stability of the resistive connection of octreotide storage storehouse precursor formulation in storage in the test present embodiment.Said preparation can stablize at least two weeks under 4～8 ℃.

Embodiment 35: the release in vitro of water soluble fluorescence element disodium

Water-soluble colorant uranine yellow (Fluo) is dissolved in the concentration that reaches 5mg Fluo/g preparation in the preparation that comprises PC/ alpha-tocopherol/ethanol (27/63/10wt%).When being injected in the phosphate buffered saline (PBS) (PBS) of 2ml, the preparation with 0.1g formed reversed micelle (I2) phase.Be discharged into the absorbance of the fluorine of water in 3 days at 490nm place record.Carry out in the 3mL vial that the bottle cap of tearing off with aluminum of this releasing research under 37 ℃ is covered with.This glass tubing places on the vibration table of 150rpm.

Discharge fluorine from PC/ alpha-Tocopherol preparation (seeing Table 9) and show that this (and similar) preparation is promising storage storehouse system.And noteworthy is its effect that do not happen suddenly, and discharges and to show that this material can several thoughtful several months of slow release; Discharged afterwards only about 0.4% fluorine in 3 days.

Table 9

^*Release is lower than the detectable limit of absorbance measurement

Embodiment 36: the preparation of analgesia/antiinflammatory benzydamine

Be mixed with preparation such as embodiment 1 by GDO, PC, ethanol and optional PG/AP mixture with benzydamine and following ratio.

Preparation	BZD	GDO	PC	EtOH	PG	AP
								1	3.0	53.3	28.7	10.0	5.0	0.01
2	3.0	53.3	28.7	15.0	0	0.01
							3	3.0	57.4	24.6	10.0	5.0	0.01
4	3.0	49.2	32.8	10.0	5.0	0.01

Wherein BZD is benzydamine, and EtOH is ethanol, and PC is LIPOID S100 S-PC, and GDO is glyceryl dioleate, and PG is propylene glycol, and AP is ascorbyl palmitate.

All preparations all are low viscosity solutions, and it is Generation Liquid crystalline phase compositions when being exposed to aqueous environment.

Embodiment 37: the fentanyl nasal formulations

As described in example 1 above, be mixed with said preparation by the mixture with GDO, the PC of narcosis analgesic fentanyl and following ratio, ethanol and optional PG.

Preparation	Fentanyl	PC	GDO	EtOH	PG
							1	0.05	34	51	10	5
2	0.05	36	54	10	-
						3	0.05	42	43	10	5
4	0.05	45	45	10	-
						5	0.15	34	51	10	5
6	0.15	36	54	10	-
						7	0.05	30	45	15	10
8	0.15	30	45	15	10

Wherein, EtOH is ethanol, and PC is LIPOID S 100 S-PCs, and GDO is glyceryl dioleate, and PG is propylene glycol.

All preparations all are the low-viscosity (mobile) liquids that is adapted to pass through the nose spray delivery, and it is being exposed to aqueous conditions generation of lower time liquid crystalline phase compositions.

Embodiment 38: the diazepam nasal formulations

As described in previous embodiment, be mixed with said preparation by the mixture with GDO, the PC of Benzodiazepines antianxiety drugs diazepam and following ratio, ethanol and optional PG.

Preparation	Diazepam	PC	GDO	EtOH	PG
							1	5	32	48	10	5
2	5	34	51	10	-
						3	10	37	38	10	5
4	10	40	40	10	-
						5	10	30	45	10	5
6	10	32	48	10	-
						7	10	26	39	15	10
8	10	30	45	15	-

Wherein, EtOH is ethanol, and PC is LIPOID S 100 S-PCs, and GDO is glyceryl dioleate, and PG is propylene glycol.

All preparations all are the low-viscosity (mobile) liquids that is adapted to pass through the nose spray delivery, and it is being exposed to aqueous conditions generation of lower time liquid crystalline phase compositions.

Embodiment 39: Intederon Alpha-2a

Interferon (IFN) is used for the treatment of polytype general cancer, usually with chemotherapy or X-ray therapy associating.Nearest data show that IFN α is the multifunction immunity adjusting cytokine that reaction has remarkable effect (comprising multiple antiinflammatory property) to cytokine cascade.The immunoloregulation function that these are identified recently and anti-inflammatory properties in treatment such as the disease such as chronic viral hepatitis with help to explain that some IFN are extremely important aspect machine-processed.

By PC (360mg) and GDO (540mg) are dissolved in the non-water precursor formulation of EtOH (100mg) formation.With Intederon Alpha-2a (4mg) water-soluble (76mg), after this this solution is added in the precursor formulation of non-water, to form low viscous depot formulation precursor.

This storage storehouse precursor is injected excessive water (syringe 23G; 0.6mm * 30mm), generate whole liquid crystalline phase (I ₂Structure).

Embodiment 40: leuprorelin (leuprorelin acetate)

Leuprorelin acetate (or leuprorelin acetate) is the synthetic nonapeptide analog of the gonadotropin releasing hormone (GnRH or LH-RH) of natural generation, when continuing medication (for example as depot formulation), it suppresses the pituitary gonadotropic hormone secretion and suppresses testis and ovary Steroidgenesis.Leuprorelin is used for the treatment of carrying out property carcinoma of prostate.

In 100mgNMP, form the depot formulation precursor by continuous-dissolution 22.5mg leuprorelin acetate and 360mg PC.540mg GDO is added in the mixture, generates low viscosity molecular solution depot formulation precursor.The said preparation precursor is injected excessive water (syringe 23G; 0.6mm * 30mm), generate whole liquid crystalline phase (I2 structure).

Embodiment 41: alendronate

Diphosphate is the analog of pyrophosphate, and owing to diphosphate has pharmacological activity to skeleton especially to the strong affinity of hydroxyapatite (the main inorganic component of skeleton).This chemical compound is used for the treatment of postmenopausal osteoporosis, malignant tumor and metastatic bone lesions (MBD) hypercalcemia.

By PC (360mg) and GDO (540mg) are dissolved in the non-water precursor formulation of formation among the EtOH (100mg).With alendronate (12mg) water-soluble (80mg), then this solution is added non-water precursor formulation to form low viscous depot formulation precursor.Should store the storehouse precursor and inject excessive water (syringe 23G; 0.6mm * 30mm), generate whole liquid crystalline phase (I ₂Structure).

Embodiment 42: olanzapine

Olanzapine is the low-molecular-weight drug that is used for the treatment of the schizophrenia object.

By 50mg olanzapine, 360mgPC and 100mgEtOH are mixed continuously, form depot formulation.540mgGDO is added in this mixture, generates final depot formulation precursor.

The said preparation precursor is injected excessive water (syringe 23G; 0.6mm * 30mm), generate whole liquid crystalline phase (I ₂Structure).

Embodiment 43: the acne preparation that contains clindamycin

As described in previous embodiment, be mixed with said preparation by the mixture with GDO, PC, ethanol and the PG of semisynthetic antibiotics clindamycin (free alkali or salt) and following ratio (weight).

Preparation	Clindamycin Hydrochloride	PC	GDO	EtOH	PG
							1	1	30	54	10	5
2	2	29	54	10	5
						3	1	34	50	10	5
4	2	33	50	10	5

Preparation	Clindamycin alkali	PC	GDO	EtOH	PG
							5	1	30	54	10	5
6	2	29	54	10	5
						7	1	33	54	2	10
8	2	32	54	2	10

The preformulation of gained is low-viscosity (mobile) liquid, after using, and its opposing water, antiperspirant etc.Said preparation is applied topically on the skin as gel or by spraying, and said preparation is the bioadhesive polymer with good filming character.

Embodiment 44: the another embodiment of the viscosity of PC/GDO mixture when adding cosolvent

According to the method for embodiment 1 and embodiment 3, ratio shown in the according to the form below prepares the mixture of PC/GDO and cosolvent.25 ℃ of lower carrying out with Physica UDS 200 galvanometer before the viscosity measurement, allow sample balance a couple of days.

Sample	PC/GDO (wt/wt)	EtOH/ wt％	Glycerol/wt%	H 2O/ wt％	Viscosity/mPas
						1	50/50	3	-	-	1900
2	50/50	5	-	-	780
						3	50/50	7	-	-	430
4	50/50	8	-	-	300
						5	50/50	10	-	-	210
6	50/50	15	-	-	100
						7	45/55	3	-	-	1350
8	45/55	5	-	-	540
						9	45/55	7	-	-	320
10	45/55	8	-	-	250
						11	45/55	10	-	-	150
12	45/55	15	-	-	85
						13	40/60	3	-	-	740
14	40/60	5	-	-	400
						15	40/60	7	-	-	240
16	40/60	8	-	-	200
						17	40/60	10	-	-	130
18	40/60	15	-	-	57
						19	40/60	-	10	-	8*10 6
20	40/60	-	-	3	2.5*10 8
						21	40/60	-	-	5	4*10 7

This embodiment further illustrates the solvent that need to have reduced viscosity character and obtains injectable formulation.The mixture that comprises glycerol (sample 19) or water (sample 20 and 21) is thickness too, can't inject (comparing with 17 with sample 13,14) under the solvent strength identical with containing the EtOH sample.

Embodiment 45: the octreotide preparation compositions

As described in example 1 above, be mixed with said preparation by the mixture with the GDO (one of several purity level) of peptide activating agent octreotide and following ratio (weight) or tocopherol, PC, ethanol and optional dioleoyl PG.

Preparation	OCT	EtOH	PC	GDO1	GDO2	GDO3	TP	DOPG
									E
	2	10	35.2	-	-	52.8	-	-
									F	2	10	35.2	52.8	-	-	-	-
G	2	10	35.2	-	52.8	-	-	-
									H	2	10	26.4	-	-	-	61.6	-
I	1	10	35.6	53.4	-	-	-	-
									J	2	5	37.2	-	-	55.8	-	-
K	3	5	36.8	-	-	55.2	-	-
									L	6	5	35.6	-	-	53.5	-	-
M	3	5	35.8	-	-	55.2	-	1
									N	3	5	33.8	-	-	55.2	-	3
O	3	5	30.8	-	-	55.2	-	6
									P	3	5	46	-	-	46	-	-
Q	3	10	43.5	-	-	43.5	-	-
									R	6	10	42	-	-	42	-	-
S	3	7	45	-	-	45	-	-
									T	6	7	43.5	-	-	43.5	-	-

Wherein, OCT is octreotide, and EtOH is ethanol, and PC is LIPOID S100 S-PC, and GDO is glyceryl dioleate, and TP is alpha-tocopherol, and DOPG is the dioleoyl phospholipid acylglycerol

GDO quality (according to AC)

	Monoglyceride	Diglyceride	Triglyceride
				GDO1	10.9％	87.5％	1.4％
GDO2	4.2％	92.1％	3.5％
				GDO3	0.5％	95.3％	4.0％

In rat with level (corresponding to the 30mg/kg octreotide) the subcutaneous injection preparation P of the every kg body weight of 1ml preparation (for its combination referring to more than).

After the administration, the blood plasma level of monitoring octreotide 5 days is to check any burst curve.Observe maximum plasma concentration and be lower than 3 times of mean plasma concentration in originally 5 days.

Result of study is presented among Fig. 6.

Embodiment 46: sun-screening agent

As described in example 1 above, by each and GDO, the PC of following ratio (weight) in a plurality of UV absorbent/scattering diluents and the mixture of ethanol are mixed with said preparation.

Preparation	PC	GDO	EtOH	Tioveil CM	Spectraveil FIN	Solaveil CT-100	Tioveil 50 MOTG
								1	38	42	5	-	-	-	15
2	38	42	5	-	-	15	-
								3	37	38	5	15	5	-	-

Wherein, TIOVEIL CM(Uniqema) comprise cyclomethicone (with) titanium dioxide (with) the simethicone copolyol (with) aluminium stearate (with) aluminium oxide, SPECTRAVEIL FIN(Uniqema) comprise zinc oxide (with) C12～15 alkyl benzoates (with) multi-hydroxy stearic acid, SOLAVEILCT-100(Uniqema) comprise C12～15 alkyl benzoates (with) titanium dioxide (with) multi-hydroxy stearic acid (with) aluminium stearate (with) aluminium oxide, and TIOVEIL 50 MOTG(Uniqema) comprise titanium dioxide (with) three caprylic/capric glyceride (with) mineral oil (with) multi-hydroxy stearic acid (with) aluminium stearate (with) aluminium oxide.

The preparation precursor of preparation gained has demonstrated low viscosity, is easy to by the pump spray applications.When contacting with body surface, form the UV protective layer of bounce-back.

Embodiment 47: chlorhexidine periodontal disease storage storehouse

As described in example 1 above, by anti-infective chlorhexidine gluconate and GDO, the PC of following ratio (weight) and the mixture of ethanol are mixed with said preparation.

Table. chlorhexidine gluconate depot formulation compositions

Preparation	Chlorhexidine gluconate	PC	GDO	EtOH
					A
	5	34	51	10
					B	5	36	54	5
C	7	33	50	10
					D	10	32	48	10
E	15	30	45	10

Chlorhexidine storage storehouse preformulation has low viscosity, and is easy to be administered in the periodontal pocket.When with present product as

When comparing, said composition provides active component to spread all over better distribution and the coating of periodontal pocket.

There is the protective effect of antagonism periodontal pocket reinfect in the storage storehouse that forms after using.This storage storehouse also has good bioadhesive, and pastes mucosa, tooth and bone surface.

The research chlorhexidine gluconate is from the release of 250mg preparation A (referring to more than) 0.9%NaCl aqueous solution (500ml).Said preparation is placed in the cylindric metal cup, places it in the teflon container, be placed on standard USP and discharge the bottom of bathing.Preparation and on every side the contact area between the saline solution be 2.4cm ², stir this solution with slurry with 100rpm.

The release profiles that is presented among Fig. 7 has confirmed that through 24 hours chlorhexidine continues and discharges substantially equably from preparation.

Claims (35)

1. the preformulation that comprises the non-liquid crystal compound of low viscosity of following component:

A) at least a DG and/or at least a tocopherol, wherein said DG have two and are independently of one another C ₁₆-C ₂₄The non-polar tail group of alkyl or alkenyl;

B) at least a phosphatidylcholine;

C) at least a biocompatible solvents that is selected from monohydric alcohol, ether, amide and composition thereof, the viscosity of described solvent under 20 ℃ is not more than 18mPas;

Wherein, at least a bioactivator is dissolved in or is scattered in this low viscosity mixtures, wherein, this preformulation forms when contacting with aqueous fluid and maybe can form at least a liquid crystalline phase structure, and wherein, the non-liquid crystal compound of this low viscosity is 20 ℃ of viscosity with 0.1～5000mPas, and component a) and b) weight ratio be 90: 10～20: 80, amount of component b) account for component a)+b)+c) weight 0.5～50%.

2. the preformulation that comprises the non-liquid crystal compound of low viscosity of following component:

A) at least a tocopherol and optional at least a DG, wherein said DG have two and are independently of one another C ₁₆-C ₂₄The non-polar tail group of alkyl or alkenyl;

B) at least a phosphatidylcholine;

C) at least a biocompatible, oxygen containing, the low viscous organic solvent that is selected from alcohol, amide, ether and composition thereof, the viscosity of described solvent under 20 ℃ is not more than 18mPas;

Wherein, at least a bioactivator is dissolved in or is scattered in this low viscosity mixtures, wherein, this preformulation forms when contacting with aqueous fluid and maybe can form at least a liquid crystalline phase structure, and wherein, the non-liquid crystal compound of this low viscosity is 20 ℃ of viscosity with 0.1～5000mPas, and component a) and b) weight ratio be 90: 10～20: 80, amount of component b) account for component a)+b)+c) weight 0.5～50%.

3. preformulation as claimed in claim 1 or 2, wherein, described liquid crystalline phase structure is bioadhesion.

4. preformulation as claimed in claim 1 or 2, wherein, component a) is comprised of DG.

5. preformulation as claimed in claim 4, wherein, described DG is glyceryl dioleate.

6. preformulation as claimed in claim 1 or 2, wherein, component a) is comprised of at least a tocopherol.

7. preformulation as claimed in claim 1 or 2, wherein, component is a) by the compositions of mixtures of glyceryl dioleate and tocopherol.

8. preformulation as claimed in claim 1 or 2, it has molecular solution, L2 and/or L3 phase structure.

9. preformulation as claimed in claim 1 or 2, it comprises the weighing scale by a)+b) in addition, 10% charged amphiphile at the most, described charged amphiphile is the acid of anion fat.

10. preformulation as claimed in claim 1 or 2, wherein, described activating agent is selected from medicine, nutrient, cosmetics, aromatic substance, flavoring agent, diagnostic agent and composition thereof.

11. preformulation as claimed in claim 1 or 2, wherein, described activating agent is selected from antigen, vitamin, nutrition enhancer and composition thereof.

12. preformulation as claimed in claim 10, wherein, described medicine is selected from hydrophilic small molecules medicine, lipotropy small-molecule drug, amphipathic small molecules medicine, protein, oligonucleotide and composition thereof.

13. preformulation as claimed in claim 10, wherein, described medicine is selected from peptide.

14. preformulation as claimed in claim 10, wherein, described medicine is selected from somatostatin related peptides, interferon, glucagon-like peptide 1 and 2, GuRH-A, antagonists of gonadotropin-releasing hormone, diphosphate, chlorhexidine and composition thereof.

15. preformulation as claimed in claim 1 or 2, it can pass through drug administration by injection.

16. preformulation as claimed in claim 1 or 2, it can be by spraying, dipping, flushing, use, smear from pad or ball, the drop administration.

17. preformulation as claimed in claim 1 or 2, it can pass through aerosol spray or pump spray delivery.

18. preformulation as claimed in claim 1 or 2, described preformulation is the injection preformulation.It forms the storage storehouse of the activating agent sustained release that at least two weeks were provided, and wherein, described activating agent comprises at least a following material that is selected from:

I. octreotide

Ii. human growth hormone

Iii. interferon-ALPHA

Iv. leuprorelin acetate.

19. preformulation as claimed in claim 1 or 2, described preformulation is the injection preformulation, and it forms the storage storehouse of the activating agent sustained release that at least two weeks were provided, and wherein, described activating agent comprises at least a following material that is selected from:

I. Risperidal

Ii. olanzapine

Iii. Testosterone Undecanoate.

20. preformulation as claimed in claim 1 or 2, described preformulation is for being used for topical formulations oral administration, that form the controlled release product of bioadhesion, and wherein, described activating agent comprises at least a following material that is selected from:

I. benzydamine

Ii. tramadol.

21. preformulation as claimed in claim 1 or 2, described preformulation is to be suitable for local preformulation oral administration, that be used for the treatment of periodontal disease and local infection, wherein, activating agent is chlorhexidine gluconate, and wherein, this preformulation is used as fluid product, it after using between 1 second to 5 minute in original place formation surface gel.

22. preformulation as claimed in claim 1 or 2, described preformulation is for being used for the parenteral external preparation intranasal spray delivery, that form the controlled release product of bioadhesion, and wherein, described activating agent comprises at least a following material that is selected from:

I. fentanyl

Ii. diazepam.

23. preformulation as claimed in claim 1 or 2, described preformulation is the topical formulations that is suitable for dosing eyes, wherein, described activating agent comprises at least a following material that is selected from: diclofenac sodium, pilocarpine, Levocabastine Hydrochloride, ketotifen fumarate, timolol, betaxolol, carteolol, levobunolol, dorzolamide, brinzolamide, epinephrine, dipivefrine, clonidine, Aplonidine, brimonidine, latanoprost, travoprost, bimatoprost, Unoprostone, pilocarpine hydrochloride, dexamethasone, chloromycetin and indomethacin.

24. preformulation as claimed in claim 1 or 2, described preformulation is for being used for the parenteral external preparation dermatosis administration, that form the controlled release product of bioadhesion, and wherein, described activating agent is selected from:

I. acyclovir

Ii. Testosterone Undecanoate.

25. preformulation as claimed in claim 1 or 2, described preformulation is for being used for the topical formulations dermatosis administration, that form the controlled release product of bioadhesion, wherein, described activating agent is selected from: cosmetic reagent, aromatic substance, flavoring agent, UV absorbent and composition thereof.

26. preformulation as claimed in claim 1 or 2, described preformulation is for being used for the topical formulations dermatosis administration, that form the controlled release product of bioadhesion, and wherein, described activating agent is selected from quintessence oil.

27. one kind prepares the method that is suitable for bioactivator is applied to the preformulation of object, described method comprises the non-liquid crystal low viscosity mixtures that forms following component:

A) at least a neutral DG and/or at least a tocopherol, wherein said DG have two and are independently of one another C ₁₆-C ₂₄The non-polar tail group of alkyl or alkenyl;

B) at least a phosphatidylcholine;

C) at least aly be not more than the biocompatible solvents of 18mPas 20 ℃ of viscosity, be selected from monohydric alcohol, ketone, ester, ether, amide, sulfoxide and composition thereof;

With at least a bioactivator is dissolved in or is scattered in this low viscosity mixtures, or before forming this low viscosity mixtures, at least a bioactivator is dissolved in or is scattered in component a, b or c at least a, the non-liquid crystal compound of wherein said low viscosity is 20 ℃ of viscosity with 0.1～5000mPas, and component a) and b) weight ratio be 90: 10～20: 80, amount of component b) account for component a)+b)+c) weight 0.5～50%.

28. one kind prepares the method that is suitable for bioactivator is applied to the preformulation of object, described method comprises the non-liquid crystal low viscosity mixtures that forms following component:

A) at least a tocopherol and optional at least a DG, described DG have two and are independently of one another C ₁₆-C ₂₄The non-polar tail group of alkyl or alkenyl;

B) at least a phosphatidylcholine;

C) at least a biocompatible, oxygen containing, low viscous organic solvent, the viscosity of described solvent under 20 ℃ is not more than 18mPas;

With at least a bioactivator is dissolved in or is scattered in this low viscosity mixtures, or before forming this low viscosity mixtures, at least a bioactivator is dissolved in or is scattered in component a, b or c at least a, the non-liquid crystal compound of wherein said low viscosity is 20 ℃ of viscosity with 0.1～5000mPas, and component a) and b) weight ratio be 90: 10～20: 80, amount of component b) account for component a)+b)+c) weight 0.5～50%.

29. such as claim 27 or 28 described methods, wherein, described preformulation is the arbitrary described preformulation of claim 1-22.

30. such as the purposes of each described preformulation of claim 1-26 for the preparation of the medicine that continues medication that is used for activating agent.

Be selected from following disease 31. the purposes of claim 30, wherein said activating agent are used for the treatment of: antibacterial infection, fungal infection, skin pain, oculopathy, genitals pain, travel sickness, the addiction that comprises nicotine addiction and hormone are not enough or imbalance.

32. being used for the treatment of, the purposes of claim 30, wherein said activating agent be selected from following disease: infection and disease, periodontal infection, conjunctivitis and the glaucoma of finger and/or toe fingernail.

33. the purposes of claim 30, wherein said activating agent is used for preventing at least a following disease that is selected from: the infection of operation process, sunburn, burned part infection, incision or scratch, oral cavity infection and genital infection.

34. the purposes of claim 30, wherein said activating agent is used for preventing at least a following disease that is selected from: the infection of implantation process.

35. the purposes of claim 30, wherein said activating agent are used for preventing at least a following disease that is selected from: cause being exposed to the activity of infective agent and the infection that causes.

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