CN1037835A

CN1037835A - The compositions of sustained release

Info

Publication number: CN1037835A
Application number: CN89103575.3A
Authority: CN
Inventors: 丹尼尔·巴沙尔罗姆; 图尔·金特一拉森
Original assignee: Buhk Meditec AS
Current assignee: Buhk Meditec AS
Priority date: 1988-03-24
Filing date: 1989-03-23
Publication date: 1989-12-13
Also published as: DK606288D0; JPH0774163B2; JPH03503415A

Abstract

Prepare a kind of method for compositions, said composition by with the substantially invariable erosion rate sustained release active substance on its one or more surfaces to aqueous phase, this method comprises at least a water-soluble basically crystalline polymer, consumption is one or more surfactants of 0～50% of crystalline polymer and surfactant weight, at least a active component and random a kind of filler mix, and form a kind of matrix.Compositions can also prepare by room temperture rubber vulcanization (RTV rubber) is mixed a kind of matrix of formation with super-absorbent polymer particles and at least a active substance.Said composition can by extrude, coextrusion, injection moulding or compression forming prepare.

Description

The compositions of sustained release

The present invention relates to the compositions of a kind of sustained release active substance to aqueous phase.

As everyone knows, the powder of active substance such as pharmaceutically active is put into the matrix that a kind of insoluble matter constitutes, this active substance can therefrom little by little ooze out, and obtains the lasting release of active substance thus.With semi-permeable coating be coated onto a tablet in the heart, water and lysed active substance can pass through this coating penetration, perhaps foraminous undissolved coating is coated onto tablet in the heart, active substance discharges by this coating, can reach the lasting release of the supercentral active substance that is included in tablet thus.In addition, with active material particle with microencapsulated in one or more layers film, also can obtain the release gradually of active substance, this film can have different types as cause the medium type that active substance oozes out or discharges in intestinal.

These conventional methods that active substance continue to be discharged have certain shortcoming, when the form of dosage is when being present in the body, are the constant densities that are difficult to maintenance active substance in whole process with these methods, as the constant density of blood plasma Chinese medicine active substance.Particularly for the medicine that an of short duration half-life is arranged in vivo, this may be a problem.In addition, water may cause the hydrolysis of the unsettled active substance in water-bearing media by the infiltration of permeability coating.

The objective of the invention is to overcome these shortcomings and a kind of compositions is provided, the said composition strict sustained release of energy active substance wherein, and can prevent that active substance can be owing to hydrolysis is degraded before release time.

Therefore, relate to a kind of compositions in a kind of example of the present invention, control the release of active substance to aqueous phase by one or more surfaces of corroding said composition with substantially invariable speed, said composition comprises:

It is a kind of by the water miscible crystalline polymer or the matrix that mixture constituted of water miscible crystalline polymer basically basically,

A kind of surfactant or surfactant mixtures, they measure with the weight of crystalline polymer and surfactant, consumption with 0～50% be dispersed in crystalline polymer mutually in, this surfactant comprises one or more chemical compounds, this chemical compound have at least a and the corresponding to regional structure of crystalline polymer and at least another kind come down to lipophilic regional structure, and has a fusing point that is lower than crystalline polymer

At least a active substance, it can be evenly dispersed in basically crystalline polymer mutually in and/or on how much, be arranged in the mutually univocal zone of crystalline polymer and/or be dispersed in surfactant and any one filler,

This surfactant and/or active substance reduced in the crystalline polymer matrix and the intergranule of crystalline polymer matrix itself and slit in the affinity of water of regional structure, substantially eliminated the infiltration of water in the interface between the polymer crystallization thus, therefore the dissolution of aqueous medium on one or more surfaces of the compositions by being exposed to medium, and corrode effectively.

For fear of being present in active substance in the matrix because the effect of water, be easy to hydrolysis and the situation of the Degradation of active substance takes place, the combination of matrix and active substance and/or surfactant must be can not be penetrated in the liquid of water to go basically, body fluid for example, promptly this body fluid demonstrates and compositions of the present invention can be incorporated into the intravital part of body (as at gastrointestinal tract, comprise rectum, at vagina or subcutaneous) or be incorporated in the body cavity (as the bladder of urinary system through conduit, gallbladder, the uterus, the central nervous system chamber, infectiousness/pernicious/postoperative cavity etc.).Water has been eliminated basically to the osmosis of this active substance in the intravital inclusions of base, therefore makes compositions become stable, to such an extent as to even said composition is exposed among body fluid or other liquid in the given time, it is active that this active substance still keeps.Because liquid can only act on the surface of this class mold base, so discharge or during firm discharging, it just is exposed in the aforesaid liquid from matrix when the active substance of wherein putting into.Because release is what to carry out gradually from the matrix surface that is exposed to aforesaid liquid; so when compositions is present in the water (as body cavity); basically certain type of impermeable water matrix will be guaranteed the active agent stability in the matrix in all stage; when this active substance discharges, and will guarantee the controlled and rate of release that can reproduce of active substance from matrix.

The speed that active substance discharges from matrix is a predetermined speed, the speed that can control in promptly during certain.Each required especially rate of release depends on especially and will exert one's influence with the amount of active substance that predictive role takes place with its release and to it, and the total dosage that depends on the active substance that matrix comprises.According to guaranteeing that active substance discharges one or more principles of needed amount, select to form the material and the distribution of active substance in matrix of matrix.

The advantage of compositions of the present invention is: the dosage of included active substance can be determined in the matrix, therefore is present in the whole process of water in compositions, can obtain the dosage of the suitable constant or pulsation of active substance at aqueous phase; The characteristic of basal body structure, i.e. its water impermeability, even active substance this be unsettled in aqueous medium, also can prevent because water is penetrated into the degraded that active substance hydrolysis in the matrix or other factors etc. are produced.

Owing to can obtain the sustained release of active substance from compositions of the present invention, so in a specific time, can access the constant release rate of the active substance that accords with the needed dosage of above-mentioned disposal or the pulsation of control discharges, therefore to observe strict dosage instructions about how to take medicine, can be as the usage of the medicament of needs according to administration at interval until administration for several times in a day.In addition, in compositions of the present invention, may comprise the active substance that two or more are different, to be suitable for and by different concentration and/or to be released, so to make the instructions about how to take medicine that patient is easy to observe doctor's advice at interval.

Compare with known other sustained release compositionss, the other advantage of compositions of the present invention is: can be by fairly simple, cheap method is produced, as the extrusion method that describes in detail being produced by following, in addition, the active substance of being convenient to make higher concentration according to said composition of the present invention combines with the size of corresponding said composition, this obviously is a very big advantage, particularly especially true when compositions is used to the release of pharmaceutically active substance, because it is convenient to discharge the amount of needed active substance, and it is unnecessarily big to need not the size of compositions.In addition, because this class material is consistent with the lipophilic regional structure of surfactant, therefore minimal amounts of dissolved or undissolved active substance may be easy to be incorporated in the compositions of the present invention, for example compositions of the present invention can be used for the minimal amounts of dissolved that is difficult to take with additive method or the release of undissolved medicated powder.

This matrix does not comprise water-soluble crystalline polymer or these mixture of polymers, and comprise water-insolube and active substance material together, and at least in part near aqueous phase liquid and in the presence of said liquid expansible hydroaropic substance, its result then is near matrix partial fracture and discharge active substance hydroaropic substance.

Therefore, another kind of example of the present invention relates to and controllably discharges the compositions of certain active substance to aqueous phase, and it comprises:

The matrix of a kind of room temperture rubber vulcanization (RTV rubber), wherein the granule of super-absorbent polymer is distributed substantially equably, and these super-absorbent polymer particles approach basically compositions the surface and

At least a active substance, this active substance are evenly dispersed in basically in the matrix and/or on how much and are arranged in the univocal zone of this matrix,

Wherein, aqueous phase liquid can be penetrated into the surface of matrix with conditional speed, consequently this super-absorbent polymer particles expands, and makes near matrix partial fracture expanded granular, with a specific control method it is discharged according to the distribution of active substance in matrix thus.

In first kind of example of the present invention, promptly comprise water miscible basically crystalline polymer or basically during the mixture of water miscible crystalline polymer when the matrix of compositions, surfactant generally will be dispersed in crystalline polymer mutually in.

This surfactant comprises one or more chemical compounds, they have at least a and the corresponding to regional structure of crystalline polymer and at least another kind be lipophilic regional structure basically." consistent " speech that uses in the context of the invention is meant that surfactant as described below can emulsifying in the polymer of fusing.This surfactant partly plays the effect of repairing medium, surfactant has and makes itself and the crystalline polymer hydrophilic region structure of affinity mutually therein, can fill it into thus in the intercrystalline and slit of crystalline polymer matrix, and this surfactant partly plays the effect of surfactant, because their lipophile regional structures have basically reduced water in the intercrystalline of crystalline texture and the affinity on the median surface, slit, eliminated the infiltration of the water on interface between the polymer scale crystal thus basically therein.

Slit in the above-mentioned crystalline polymer matrix and crystal grain are the products in the crystallization forming process.Matrix shrinks and trends towards forming the slit and form the not intact positive zone of intergranule in crystallization process.In order to keep the effect of the reparation medium that surfactant plays, this surfactant should be movably in the matrix polymer material cured and after having formed crystallization.Therefore, the fusing point of surfactant must be lower than the fusing point of crystalline polymer phase.

In order to make surfactant normally play the effect of repairing medium, be necessary to make in the molten polymer before crystallization surfactant to distribute equably basically for the slit and the crystal grain of matrix.Therefore, surfactant must in this molten polymer, become emulsifying surfactant.

Have been found that hydrophobic basically active substance helps to make surfactant to reach more equably and disperses, reduced the erosion rate of compositions thus.And hydrophilic or water-soluble basically active substance has shown and has had opposite effect, and promptly they trend towards causing surfactant to disperse not too uniformly in matrix.

Substantial portion for the surfactant in determined independent, sizable regional structure, resultant composition has sizable regional structure that comprises crystalline polymer and active substance, can improve the erosion rate of compositions thus.In addition, have found that, if the compositions of preparation does not comprise active substance, the size of the regional structure of the surfactant that it comprised will be greater than having the regional structure size that is essentially the prepared compositions of hydrophobic active material, and this compositions that lacks certain active substance will suffer erosion with quickish speed.

Therefore, the degree of scatter of surfactant in matrix is important to the erosion rate of matrix, disperses to cause the regional structure of many and less more surfactant all the more uniformly, and slower erosion rate.

When with not being hydrophobic active substance when preparing compositions in fact, or when activity substance content in the compositions is low, then need to add one or more fillers, with dispersion that improves surfactant and the erosion rate that reduces matrix.It is believed that the effect that adds filler is the viscosity that improves surfactant, thereby surfactant is disperseed in matrix more equably.The example of the filler that is fit to is, dextrin, Sucralfate, calcium hydroxy apetite, calcium phosphate, soap such as magnesium stearate.The amount that filler can add should make the mixing of filler and active substance reach the about 60% of composition weight, typically can reach about 50%.

This surfactant is generally nonionic emulsifier, this emulsifying agent contains one or more fatty acid esters and/or fatty acid ether, for example have by 12～24 carbon atoms, be typically the fatty acid ester and/or the fatty acid ether of 12～20 carbon atom carbochains, as palmitic acid or stearic certain fat and/or ether.Exemplary surfactants can comprise and contains macrogol ester or ether, polyethylene glycol ester or ether, and poly-hydroxy ester or ether and/or sugar ester or ether are as dehydration Pyrusussuriensis (sugar) alcohol ester or ether.Surfactant will suitably have the hydrophile-lipophile balance value (HLB) of an about 4-16.In addition, preferably a kind of emulsifying agent that goes through to be used to the product (being medicine and/or food) of the mankind or animal picked-up of surfactant.Surfactant is a polyethylene glycol mono stearate preferably, particularly the PEG400 monostearate.The lactate of tartaric acid, citric acid, monoglyceride and diglyceride, and the fatty acid ester of glycerol also can be used for surfactant.

Especially working as active substance is polarity chron basically, surfactant mixtures need be incorporated in the matrix and go, so that improve the dispersion and the reduction erosion rate of original surfactant in matrix.

In some cases, active substance itself can play surfactant, be that it will have at least one with the mutually corresponding to regional structure of crystalline polymer with another is essentially hydrophilic regional structure at least, so active substance self will be basically can be disperseed equably in mutually at crystalline polymer, and eliminates the infiltration of water to matrix basically.In this case, the effect of surfactant, promptly its reparation medium of plaing a part and as surfactant will partly or entirely be finished by active substance itself, only need on a small quantity or not to need surfactant.Therefore, when active substance itself has the characteristic of nonionic emulsifier, can not use surfactant in the compositions, or its consumption only limits to about 0～2% of matrix weight in compositions.In the ordinary course of things, it is preferably PEG400 single-hard ester acid ester of surfactant, reach active substance and have the characteristic of nonionic emulsifier, the PEG400 single-hard ester acid ester can partly or entirely be replaced by another kind of non-ionic surface active agent, with the characteristic of compensation active substance.

When active substance does not have the characteristic of surfactant, the content of surfactant measures by crystalline polymer and surfactant weight and generally is approximately 2～60% in the compositions, for example be approximately 5～50%, typically be approximately 10～40%, more typically be approximately 15～35%, as about 20～30%.But, as mentioned above, when active substance has the characteristic of surfactant, then surfactant can use the consumption less than 2%, in addition, according to the character of surfactant, active substance and crystalline polymer, and the release characteristics of needed compositions, the maximum level of surfactant is approximately 60%, repair that this content is required with sufficient to guarantee and Action of Surfactant.

The matrix of crystalline polymer generally comprises a kind of Polyethylene Glycol, promptly with homopolymer and/or the formed Polyethylene Glycol of copolymer.The better polymerization thing is Polyethylene Glycol or the block copolymer be made up of oxirane and propylene oxide.The molecular weight that is suitable for use in the Polyethylene Glycol in the crystalline polymer matrix is approximately 2000～500, and 000 dalton typically is approximately 5000～100,000 dalton, more typically be about 10,000～50,000 dalton, especially typically be approximately 20,000～35,000 dalton.The molecular weight of Polyethylene Glycol is approximately 35,000 dalton preferably.Typical block copolymer is made up of up to 30% polypropylene oxide base block weight, and its molecular weight is approximately more than 5000 dalton, typically is approximately 5000～30,000 dalton, more typically is approximately 8000～15,000 dalton.

This crystalline polymer matrix must have the fusing point that is higher than the aqueous medium temperature, and wherein, compositions of the present invention will be used in this aqueous medium.Therefore, according to how being used of compositions, the fusing point of the polymer that it uses in matrix is approximately 20～120 ℃, typically is approximately 30～100 ℃, more typically is approximately 40～80 ℃.Particularly when compositions of the present invention was used to the release of people or medicine for animals, the suitable fusing point of this matrix was approximately 40～80 ℃.

According to the present invention, the active substance that the thing that is combined discharges can be people or medicine for animals, vitamin or other supplementarys, disinfectant, deodorizer or in aqueous environments other materials of successive administration.

Compositions of the present invention is particularly suitable for the release of active substance, and this active substance is an active medicinal matter, particularly active medicated powder.Active medicinal matter or the material that is included in the present composition can be selected from multiple treatment kind, particularly are selected from those and can adopt oral, rectum, vagina or material subcutaneous or by body cavity (as the back cavity etc. of bladder, gallbladder, uterus, central nervous system's cavity, infectiousness/pernicious/operation) administration easily.These materials are antimicrobial drugs, analgesic, anti-inflammatory agent, the counterirritation medicine, the improvement medicine condenses, diuretic, sympathomimetic drug, anorexigenic, antacid and other gastrointestinal tract medicines, antiparasitic, antidepressant drug, antihypertensive, anticholinergic, analeptic, antihormone, maincenter and respiratory stimulant, Drug Antagonists, the lipid regulator, uricosureic agent, cardiotonic glycoside, electrolyte, Ergota and derivative thereof, expectorant, hypnotic and sedative, the anti-diabetic medicament, the dopaminergic agent, Bendectin, muscle speeds to delay agent, secondary sympathomimetic drug, anticonvulsant, antihistaminic, beta blocker, clean medicine, anti-arrhythmic, the contrast medium material, radiopharmaceuticals, antiallergic agent, the tranquillizer, vasodilation, antiviral agents, have the medicine of anticancer property with antineoplastic agent or cytostatic agent or other, or their combination.Other active substances that are fit to can be selected from contraceptive and vitamin, and trace and macronutrient.

In addition, compositions also is suitable for the release of polypeptide, for example hormone such as growth hormone, enzyme is fat (fat) enzyme, protease, carbohydrase, amylase, lactoferrin, lactoperoxidase, lysozyme, micropartical for example, or the like and antibody.Said composition also can be used for the release of microorganism, this microorganism can be that live, thin and delicate or dead, antibacterial for example, gastrointestinal tract antibacterial such as streptococcic, for example streptococcus faecalis, Bacillus SPP. such as bacillus subtilis and bacillus licheniformis, breast (acid) Bacillus, aspergillus SPP.bifidogenic factors, or adeno-associated virus (AAV) is as originating in virus, enterovirus, phage such as vaccine and fungus such as bakery yeast, beer yeast and (End) Gammaproteobacteria entirely not.Said composition can also be used to be released in the active substance on the specific support, and this carrier can be liposome, cyclodextrin, micropartical, micelle and fat.

One of purposes that the present composition is well suited for is to discharge antimicrobial drug to vagina, this antimicrobial drug is an antifungal agent, for example imidazoles antifungal agent such as clotrimazole, econazole, Ketoconazole and Miconazole, polyene antifungal antibiotics such as nystatin and antiprotozoal such as metronidazole and α-(chloromethyl ester)-2-methyl-5-nitre imidazoles-1-ethanol.

About 0.1 micron～500 microns of the granular size that is suitable for that active medicated powder by compositions administration of the present invention has typically is about 0.5～300 micron, more typically is about 1 micron～200 microns, especially typically is about 5 microns～100 microns.

This active substance consumption that is fit to is to reach 60% of composition weight approximately, typically reaches 50% approximately.60% activity substance content is considered to maximum level, and this maximum level is still considered enough amounts of crystalline polymer matrix and surfactant in the compositions.On the other hand, the activity substance content in the compositions can be less amount, and this will depend on the character and the intensity of above-mentioned active substance.

As mentioned above, surfactant in the crystalline polymer matrix and/or active substance will reduce in the matrix affinity of the water of regional structure in the intercrystalline and slit, substantially eliminated the infiltration of the water on interface between the polymer scale crystal thus, so aqueous medium has influenced erosion significantly to the dissolution on the compositions surface that is exposed to medium.Therefore, water is limited in the surface layer of matrix basically to the infiltration of compositions, and thus, matrix is with the speed of substantial constant and pH value and being etched independently.The zero level basically that has consequently obtained active substance discharges.The meaning of " zero level " speech is meant that when this active substance was evenly distributed basically, the release of active substance was constant with the time basically in matrix.Be arranged under the situation in the univocal zone of matrix on active substance how much, the pulsation of the active component that the result of the constant erosion rate of matrix will be controlled by strictness discharges.

The geometric shape of compositions is important to zero level or the pulsation release that obtains above-mentioned control.Therefore, compositions of the present invention has a kind of geometry preferably in the scheme at one of the present invention, and this shape can make substantially invariable surface portion be in exposed state in the erosion process of matrix.Thereby, this compositions to be shaped as the garden cylindricality that has a kind of coating bar-shaped, this coating is insoluble to and liquid impermeable in the deenergized period of expection basically, as body fluid, and in its one or both ends one opening is arranged.

As the useful polymer of coating preferably those methods that may form with extrusion molding, solution methods or dispersion and the polymer that process.Best is those polymer that are applicable to food stage or pharmaceutical grade performance.This base polymer has cellulose acetate, polyamide, polyethylene, polyethylene terephthalate, polypropylene, polyurethane, polyvinyl acetate, polrvinyl chloride, silicone rubber, latex, multi-hydroxybutyrate, polyhydroxy valerate, politef, polylactic acid or polyglycolic acid and their copolymer, copolymer such as ethene-vinyl acetate copolymer (EVA), s-B-S copolymer (SBS) and styrene-isoprene-styrene copolymer-(SIS).

Coating can further comprise any in the above-mentioned matrix material form, and the erosion rate of this material is slower than remaining part of matrix basically.Therefore, this coating can comprise the matrix of one or more water miscible basically crystalline polymer and certain surfactant, this coating is a kind of in slower than the matrix material that the contains active substance basically coating of the erosion rate of aqueous phase, a kind of thus constant area that is substantially devoid of the matrix of active substance in the erosion process of compositions be exposed and this coating be etched because of the erosion of the matrix that contains active substance again.This type coating will be designed to make its longitudinal erosion speed consistent with the longitudinal erosion speed of matrix basically, and thus, matrix and coating longitudinally corrode towards the core of compositions with substantially the same speed.Therefore, when matrix was corroded fully by aqueous medium, this coating also will be corroded fully.The compositions that has this coating has an outstanding advantage and is: it can be by the release of active substance fully by biodegradation.This coating for example can be the compositions of the PEG400 monostearate of Polyethylene Glycol and considerable quantity.The content of the surfactant in coating (as the PEG400 monostearate) will be determined by the characteristic (as erosion rate and size) of the matrix of the active substance under each particular case.

In addition, this coating may divide or fragmentation after the erosion of matrix.As long as being contained the matrix of active substance, such coating supports, it will stand intact, but after matrix corrodes, it has just lost the ability that remains intact, therefore, it is division or broken just so that matrix fully corrode and release of active agent after, he just can not for example keep arbitrary effective time in the human or animal body.

Also can make the not bar composition with garden cylindricality of band coating, in this case, when active substance is located substantially on compositions outside, can obtain to approach basically the release of the active substance of zero level.

On the other hand, the shape of said composition can be the hollow hemisphere shape of hollow garden cylindricality." the garden cylindrical rod " that the context of the invention is used or " hollow Cylinder " word are understood that not only to comprise the geometry of garden shape cross section, also comprising is other geometries of garden cylindricality basically, for example, flat a little (horizontal stroke) cross section is as being cross section, avette or ellipse garden shape (horizontal stroke) basically.In addition, also can use other geometries, these smaller geometries that only can provide have reduced the surface area of compositions, obtained being evenly distributed on basically the release near zero level of the active substance in the compositions thus, for example had a kind of flat and be the flaky or flat compositions in the cross section of rectangle or ellipse garden shape basically.

The those skilled in the art in present technique field are appreciated that the use for the ease of above-mentioned composition, and the specific shape of making of the present composition can comprise some little improvement.For example, the injury or the discomfort that may cause when introducing said composition in the body, the garden is done in the end that can discharge the garden post clavate compositions of medicated powder.In addition, the hollow interior of the compositions of hollow Cylinder shape can optionally be filled with being easy to dissolved substances, for example use low-molecular-weight Polyethylene Glycol (being about 1500～6000 as molecular weight).

As mentioned above, active substance can be evenly dispersed in the crystalline polymer matrix basically, obtain the situation of the zero level release of active substance basically.On the other hand, comprise that crossbedded compositions of the present invention can obtain the pulsation release of active substance.Therefore, by having above-mentioned garden post clavate and comprising the release that the compositions of some basically staggered transverse layers can obtain pulsing, basic staggered transverse layers comprises one deck crystalline polymer matrix and surfactant and is dispersed in random active component in this matrix and one deck optionally is dispersed in active component in crystalline polymer and the surfactant basically.Equally, the compositions of hollow Cylinder shape can comprise: staggered which floor, should be staggered which floor comprise one deck crystalline polymer matrix and surfactant and comprise that random active component and one deck of being dispersed in basically in this matrix comprise the active component that optionally is dispersed in basically in crystalline polymer and the surfactant.In comprising staggered which floor compositions, these staggered layers can comprise two or more different active substances respectively.

Also can be used in combination these two kinds of releasing patterns (being zero level and pulsation delivery mode), carry out with alternating so that the even release of active substance (as with quite low dosage) is discharged with pulsed identical or another kind of active substance (as with higher dosage) ground.

In another example of the present invention; as mentioned above; can obtain the release that certain active substance enters aqueous phase by a kind of compositions through control; said composition comprises: a kind of room temperature-vulcanized rubber (RTV rubber) matrix; wherein, super-absorbent polymer particles is homodisperse basically, and these super-absorbent polymer particles also are present in the near surface of said composition basically; so that aqueous phase liquid can penetrate in the matrix with limited speed

This just causes this super-absorbent polymer particles to expand and matrix is broken near dilated granule partly, and active substance is discharged.According to embodiments of the invention, water is confined to surface layer basically to the infiltration of compositions, and thus, according to the distribution of this active substance in matrix, active substance is to discharge with specific control mode.

Used RTV rubber typically comprises the RTV silicone elastomer based on one or both components of polydimethylsiloxane.The matrix of RTV rubber contains a kind of catalyst and random a kind of cross-linking agent in addition.The catalyst that is fit to is stannous octoate or is approximately platinum-divinyl tetramethyl disiloxane complex (containing about 3～3.5% platinum) of 0.01～0.1%.The cross-linking agent that is fit to be 0～40% 1,3-divinyl tetramethyl disiloxane, 1,1,3,3-tetramethyl disiloxane or 1,3,5,7-tetramethyl-ring tetrasiloxane.

Super-absorbent polymer particles is more such granules, be that they can be in a kind of semi-solid state by absorbing water or other liquid, and can be absorbed as about 10 times water of himself weight at least, typical about 100 times water that can be absorbed as himself weight at least, special about 200 times water that can be absorbed as himself weight at least.These super-absorbent polymer particles can also absorb body fluids and are in semi-solid state; and can be absorbed as about 5 times body fluid of himself weight at least; typically can be absorbed as about 20 times body fluid of himself weight at least, special about 40 times body fluid that can be absorbed as himself weight at least.The typical super-absorbent polymer that is applicable to example of the present invention is acrylic acid, modified acroleic acid, carboxymethyl cellulose, modified carboxy methyl cellulose and crosslinked polyvinyl pyrrolidone.

The degree of partial fracture will be determined by the rate of release of desirable active substance especially, but under any circumstance, this is enough to make other super-absorbent polymer particles can enter into above-mentioned body fluid, guaranteed thus matrix with basically uniformly speed little by little break from interior surface.Swelliong power and its arrangement mode in matrix according to selected specific super-absorbent polymer, the amount of the super-absorbent polymer that can change in the matrix to be contained, be that benchmark measures its amount that is fit to and is approximately 5～75% with the weight of matrix, typically be approximately 10～50%, more typically be approximately 20～40%.

Included active substance can be above-described arbitrary substance in example of the present invention, promptly be used for people or beastly medicine, vitamin or other supplementary, disinfectant, deodorizer or aqueous environments can successive administration other materials, and the type of listing above and the special pharmaceutically active powder of particle size.The amount of active substance is measured by the weight of compositions and is reached 60% approximately, typically reaches 50% approximately, but it also can be to be present in the compositions with much smaller amount.

Compositions according to example of the present invention also must have a kind of geometry, this geometry can make a kind of substantial constant surface area be in exposed state in the erosion process of matrix, thus, can obtain the zero level release or the pulsation release of needed active substance according to the distribution of active substance in compositions.This particular geometric shapes can be above-mentioned any.

Active substance in example of the present invention can be evenly distributed in the matrix basically, and the zero level that will obtain active substance therein basically discharges.Compositions in this example can also comprise staggered layer, and the pulsation that can obtain active substance therein discharges.Therefore, can obtain having top said garden post clavate and comprise that a kind of pulsation of staggered basically transverse layers discharges according to the compositions in the example of the present invention, should staggered transverse layers be to constitute like this: promptly one deck contains matrix and optionally contains the active component that is evenly dispersed in basically in this matrix, reach one deck and contain active component, this composition optionally is evenly distributed in the matrix material basically.Equally, a kind of compositions of hollow Cylinder shape also comprises staggered longitudinal layer, this layer comprises that one deck contains matrix and optionally contains active component and one deck active component that is evenly distributed in basically in the matrix, and this active component is optionally to be evenly distributed in the matrix material basically.

As mentioned above, staggered layer can comprise two or more different active substances respectively.These two kinds of releasing patterns (zero level and pulsation) equally also can be combined in the compositions of example of the present invention, so that make the even release (as with quite low dosage) of active substance and the carrying out that discharges the ground that alternates pulsedly of of the same race or another kind of active substance (as with higher dosage).

In addition, can be used to prepare the multicomponent pharmaceutical formulation according to the compositions of any one example of the present invention, as form with capsule or tablet.Multiple component drugs composition formula is the prescription that contains multiple independent composition, and these independent compositions are promptly obtained along with the decomposition of prescription in the human or animal's of the above-mentioned prescription of picked-up (being typically capsule or tablet) stomach by this way.So in this case, will be constituted by compositions of the present invention to the small part separate constituent in the above-mentioned multicomponent pharmaceutical formulation, the size of this separate constituent can be introduced into this prescription with them and be as the criterion.

Compositions of the present invention can be made with diverse ways, and these methods are the known methods of medical industry itself, or for example according to employed material in required example and the above-mentioned composition, is employed method in the material preparation on basis at polymer.As mentioned above, one of advantage of the present composition is that it can adopt simple and cheap relatively method to be made.

The compositions of band coating can be by the method for for example extruding, and the method for injection moulding or compression forming makes; And the compositions of coating can be by for example coating and matrix and active substance the coextrusion method, extrude and dip coating injection moulding and dip coating and make, or by extruding or injection moulding and make by spraying or immersion solvent coating.

For preparation contains the compositions of the matrix of crystalline polymer, generally this polymer and surfactant are mixed, are being enough to make under the temperature of polymer melted heating and are stirring, to obtain a kind of mixture uniformly basically.Be included at active substance under the situation of matrix, active substance can be added in the polymer and surfactant mixtures that has melted, or joins before heating in this mixture.The mixture that has melted subsequently is extruded or injection moulding with following method.When preparation was used for the compositions of active substance pulsation release, active substance can be included in the matrix material easily, and the mixture of active substance and matrix material is extruded or is injected into lamella, and this lamella replaces mutually with the lamella that does not contain the matrix of active substance.

The compositions that has the RTV rubber matrix for preparation, the component of matrix, it is the RTV elastomeric material, super-absorbent polymer, with catalyst accelerator and/or cross-linking agent, generally be at room temperature under agitation to mix, this mixture is promptly extruded with following method or injecting method carries out subsequently.According to the characteristic of desired compositions, active substance can join in the mixture before for example extruding or injecting, and perhaps extruded individually or injected.

For example, be the compositions of production garden post rod shape, the matrix material that contains active substance can be injected into a preformed pipe.On the other hand, the compositions of garden post clavate can be made by injecting staggered layer, and this staggered layer comprises matrix material and active substance at least respectively, and they are present in the above-mentioned pipe.Garden post clavate compositions also can make by the method for for example extruding matrix material (active substance disperses wherein), dip coating subsequently, or adopt a) matrix material and the coextrusion and the b that disperse active substance wherein) co-extrusion of coating comes out to make.

Garden post clavate compositions also can make by injection moulding method, comprises coating and the bi-component or the multicomponent injection moulding that contain the matrix of active substance.Injection moulding is particularly suitable for having a kind of compositions of erodable coating or divides or broken coating because of the erosion of matrix, but the method also is applicable to other compositionss, be typically, the first step is for example to examine ferrum nuclear around certain to have made the Cylinder of coating effect, in second step or rapid, inject matrix material after the ferrum nuclear and make matrix by removing with alternative multistep.The advantage of this method is simple, is very suitable for big production.

The compositions of hollow Cylinder shape for example can by extrude, compression forming or injection moulding makes.Compositions with hollow hemisphere shape can make by compression forming or injection moulding.

The special advantage that comprises coextrusion (being used to have garden post clavate preparation of compositions) and extrude the production method of (being used to have hollow Cylinder preparation of compositions) is that they are promptly cheap simply again concerning the big production of compositions of the present invention.Be cut into the suitable less sheet of size by rod or the pipe extruded or the coextrusion method is made, compositions is repaired again, for example the end type of garden post rod or hollow Cylinder can be done the garden.

The matrix material of compositions that with crystalline polymer is basic employed fusing is more faster than the curing based on the matrix of the compositions of RTV rubber.Therefore, included extrusion method usually is more suitable in the manufacturing of the compositions that contains the crystalline polymer matrix, and the compositions that contains the RTV rubber matrix is more suitable in being produced by for example material being injected into the preforming pipe.

Active substance consumption, size and the particular form of the present composition will change according to the purposes of the compositions of the character of above-mentioned active substance and expection certainly.When compositions of the present invention is when being used for compositions that active medicated powder discharges, will depend on patient's year order and health to the special dosage of human or animal's administration, and some factors like this such as the specific condition that will treat.

Hereinafter with reference to accompanying drawing the present invention is described more completely.

Fig. 1 represents a kind of sectional view of garden post clavate compositions of band coating, and said composition is used for the constant release of active substance.Compositions comprises the active substance that is evenly distributed in basically in the matrix 2, and is had the coating 1 of opening to coat by an end.This coating 1 is insoluble in the dispose procedure of expection and liquid impermeable body fluid for example.Therefore, matrix 2 is because of the effect of the aqueous medium of employed compositions, slowly corrode from an end of opening, so that the surface area and the time that make matrix 2 be exposed to water keep constant, active substance can discharge with the speed of constant and the strict control of quilt thus.

The compositions of representing among Fig. 2 is except both ends open, and is identical with the compositions of Fig. 1, and matrix 2 corrodes to core from two openings thus.

Fig. 3 represents the sectional view of the garden post clavate compositions of band coating, and the pulsation that said composition is used for certain active substance discharges.Said composition comprises the horizontal cross-bedding of matrix 2 and certain active substance 3, and is coated by the coating 1 of an end opening.Coating 1 is insoluble to and liquid impermeable such as body fluid in the dispose procedure of expection basically.From then on, this base layer 2 is by the effect of the aqueous medium of employed compositions, slowly corrode from an end of opening, thereby, along with each layer of matrix 2 sequentially is etched, discharge active substance 3 from controlled pulsation.This compositions also can adopt both ends open to prepare.

Fig. 4 represents to be used to discharge the sectional view of the compositions of two kinds of active substances.Steel toe Cuo a kind of scorpion of containing high concentration active substance 3 fastens with a bolt or latch among the handkerchief joke , and wherein another kind of active substance is distributing equably with low concentration again, and said composition coated 1 applies, and coating 1 is water insoluble and liquid impermeable such as body fluid in the dispose procedure of expection.Active substance in matrix 2 is with uniform speed and discharging basically, and the active substance that is included in the layer 3 discharges with pulse mode.

Fig. 5 represents a kind of hollow Cylinder shape compositions, and active substance is evenly distributed in the matrix basically in this compositions.Matrix is etched from the inside and outside of hollow Cylinder, and the surface area that therefore is exposed to aqueous phase liquid is constant with the time, and the zero level that obtains active substance thus discharges.

Fig. 6 represents a kind of hollow hemisphere bodily form compositions, and active substance is evenly distributed in the matrix basically.Matrix is etched from the inside and outside of hollow hemisphere, and therefore, the surface area that is exposed to aqueous phase liquid is constant with the time, thereby the zero level that obtains active substance discharges.

Fig. 7 represents a kind of shape compositions, and this active substance is evenly distributed in the matrix basically.This matrix mainly is to be etched from two big planes, and the surface area and the time that therefore are exposed to aqueous phase liquid are constant, and the zero level that obtains active substance thus discharges.

Fig. 8 represents the sectional view of the garden post clavate compositions of coating 2, and the erosion rate of this coating 2 is lower than the matrix 1 that contains active substance basically.After after a while, matrix 1 corrodes to 4 from each end, corrodes slower coating 2 simultaneously comparatively speaking and corrodes to 3 in liquid.

The present invention is further disclosed in following non-limiting example.

Embodiment 1

Blue Polyethylene Glycol (PEG) 20,000 matrix materials with fusing of patent fully mix.Final matrix contains 25% patent orchid, 75%PEG20,000.Matrix is in 4 millimeters the preforming silicone tube to an internal diameter with a filling apparatus squeeze note while hot the time, makes its cooling subsequently.Then pipe is cut into the sheet of 2 centimeter length, the prescribe medicine form any end leave opening, active substance discharges by opening.Record pipe in during 3 days at synthetic urine (1.94% carbamide, 0.8%MgSO ₄, 0.11CaCl ₂, 97.1% water) in erosion rate be 4 millimeters/24 hours.

Embodiment 2

Adopt and embodiment 1 described identical method, but the matrix material that uses comprises 90%PEG20,000 and the 10%HLB value be 11.5 PEG400 monostearate, the tubulose that makes is cut into slices and is contained 75% matrix material, 25% patent orchid.Recording the erosion rate of cutting into slices in the synthetic urine in 8 day time is steady state value 1.3 millimeters/24 hours.

Amplify 50～125 times at microscopically and can see and contain PEG20,000 continuous crystallisation phase, the PEG400 monostearate is dispersed in wherein, and the PEG400 monostearate has been caught liposoluble blue color, and is therefore easily in sight.Can see that the PEG400 monostearate is distributed in the whole polymer crystals basically equably, filled simultaneously and " reparation " slit and the interface between the crystalline solid.

Embodiment 3

With 10.8 gram PEG35,000 and 3.6 gram PEG400 monostearates mix, and heat until fusing under 60～80 ℃ of temperature simultaneously.9.6 gram micro-crystallization theophylline mixes up to obtaining uniform the distribution mutually with the matrix material of fusing.The matrix of this fusing is got in the preformed polyfluortetraethylene pipe (internal diameter is 6 millimeters) and is cooled.Refrigerative matrix is released from pipe by a piston, and the rod of gained is coated with the polyurethane in 20% acetone (Esfane 5712F30) solution.The rod that is coated with is cut into the sheet of 20 millimeters long subsequently.Dosage form is invaded 100 milliliters of (34 grams per liter) simulated intestinal fluid (Revolyt; Component: 22 millimoles/rise bicarbonate, 15 millimoles/rise potassium, 60 millimoles/rise chloride, 3 millimoles/rise magnesium, 67 millimoles/rise sodium and 3 millimoles/rise sulfate) in, constant vibration 28 hours on the rail mounted vibrator under 37 ℃ of temperature is to measure the theophylline amount that is discharged from the dosage form of gained.Got one time sample in per 2 hours,, measure with Perkin Elmer HPLC device by high efficiency liquid chromatography (HPLC) method.

Record the burst size of following theophylline under these conditions:

Release time (hour) burst size (micromolar/liter)

0-2 1380

2-4 1220

4-6 940

6-22 6520(≈ 815/2 hour)

22-24 1055

24-26 850

26-28 810

Under the same conditions, the erosion rate at the matrix of any end of dosage form is 0.44 millimeter/hour.

Embodiment 4

With 25%PEG35,000,12.5%PEG10,000 and the 12.5%PEG400 monostearate mix, heat under 60～80 ℃ of temperature simultaneously, 49% gentamycin sulfate (powdery) and 1% tartrazines join in the matrix material of fusing, up to the even release that obtains them.The matrix of fusing is squeezed in the preformed polyfluortetraethylene pipe (5 millimeters of internal diameters) and is cooled, and cooled pipe is cut into the sheet of 20 millimeters long.

Except using Beckman DU-R spectrophotometer 430nm measures burst size, measure the gentamycin sulfate that from resulting dosage form, discharges by embodiment 3 described methods.

The gentamycin sulfate burst size that records in during 10 hours is 10～15 milligrams/hour, and the erosion rate of matrix is 1 millimeter/hour.

Embodiment 5

With 36%PEG35,000 and the 24%PEG400 monostearate admixed together, under 60～80 ℃ of temperature, heat simultaneously also.The blue V of 39% gentamycin sulfate (powdery) and 1% patent joins in the matrix material of fusing, distributes equably up to obtaining them.The matrix of fusing is expressed in the preformed polyfluortetraethylene pipe (5 millimeters of internal diameters) and is cooled, and cooled pipe is cut into the sheet of 20 millimeters long.

During 8 hours 638nm measure burst size be the 10-14 milligram/hour, press embodiment 4 described methods mensuration basically, the gentamycin sulfate that from resulting dosage form, discharges.

Embodiment 6

Remove and use PEG35,000 and the PEG400 monostearate as matrix material with use polygynax as outside the active substance, adopt and embodiment 5 described same procedure, prepared tubular piece contains 33.3%PEG35, and 000,33.3%PEG400 monostearate, 32.3% polygynax and 1% tartrazines.

The polygynax that from the dosage form of gained, discharges that records by embodiment 4 described methods be the 8-10 milligram/hour, the erosion rate of the matrix of any end is 2 millimeters/6 hours.

Embodiment 7

The block copolymer (the Synperonic F-88 of ICI) of 8 gram oxirane and propylene oxide and 2 gram PEG400 monostearates mix, under 60～80 ℃ of temperature, heat simultaneously until fusing, 2 blue V of gram patents and the matrix material that has melted mix, this mixture is expressed in the preformed polyfluortetraethylene pipe (4 millimeters of diameters), and is cooled.Cooled pipe is cut into the sheet of 20 millimeters long, and the two ends of sheet are the mouths of opening.Recording the erosion rate of sheet in synthetic urine in during 8 days is steady state value 1.2 millimeters/24 hours.

Embodiment 8

With 0.38 gram D6210(1,3-divinyl tetramethyl silica alkane obtains from PetrarCh) and 4g methyl hydrogen-tetramethylsilane siloxane copolymers (PS123 that obtains from PetrarCh) at room temperature mix.Add the polyacrylic acid of 3 a gram Salsorb 84(modification in mixture, granular size is 90～850 microns, and capacity (in 0.9% NaCl) is 45 gram/grams; Obtain from Allied Golloids Ltd), add 4.72 clarithromycin estolate subsequently again, 0.4 gram catalyst solution (polydimethylsiloxane of 0.03% platinum in 10% cyclic vinyl methylsiloxane and 90% vinyl-dimethyl cardinal extremity base) and 1% patent is blue and fully mixing.Matrix material is expressed in the preformed polyfluortetraethylene pipe (6 millimeters of internal diameters), and at room temperature hardens 4 hours.Pipe is cut into the sheet of 20 millimeters long subsequently.

Except dosage form being immersed in 100 milliliters of simulated gastric fluid (pepsin HCl, PH3) outside in (wherein added the front in the simulated gastric fluid described the simulated intestinal fluid as buffer agent), the erythromycin estolate that discharges from the dosage form of gained press embodiment 3 described methods mensuration basically.

Use the patent orchid as indicator, the 9-10 milligram of the erythromycin estolate that records/hour be released in and drop to about 7 milligrams/hour within 24 hours.Under identical condition, the erosion rate of matrix is 16.5 millimeters/24 hours.

Embodiment 9

With 0.19 gram 1,3-divinylsiloxanes (D 6210 of Petrarch) is at room temperature mixed with 2 gram methyl hydrogen-dimethylsiloxane copolymers (PS123 of Petrarch).In this mixture, add 5 gram carboxymethyl celluloses (A250 of Aqualon), add 5 gram gentamycin sulfate and 0.4 gram catalyst solution (polydimethylsiloxane of 0.03% platinum in 10% cyclic vinyl methylsiloxane and 90% vinyl-dimethyl cardinal extremity base) subsequently.Matrix is expressed in the preformed polyfluortetraethylene pipe (internal diameter is 4 millimeters), and at room temperature sclerosis reaches 2 hours, and this hardened pipe is cut into the sheet of 20 millimeters long then.

The burst size of measuring by the method for embodiment 8 of gentamycin sulfate in simulated gastric fluid is 1.3 milligrams/hour.The erosion rate of matrix is 6 millimeters/24 hours.

Embodiment 10

Comparison example with different components

A) PEG10 by having melted, 000 be expressed into the compositions that contains pure PEG in the preformed polyfluortetraethylene pipe (4 millimeters of diameters) with preparation.After the cooling matrix is released from pipe by a piston, the gained club is coated with the poly-amino solution (Estane5712F30) in acetone with 20%.This coated rod is cut into the sheet of 10 millimeters long subsequently.In simulated intestinal fluid (embodiment 3), the erosion rate of PEG is 4 millimeters/hour.

B) be PEG35 except PEG, beyond 000, compositions and erosion rate by above-mentioned a) the method preparation and measure, erosion rate is 18 millimeters/hour.

C) 95%PEG35,000 and the mixture of 5%PEG400 monostearate be melted the rod that applies by above-mentioned method preparation in a), and to use diameter be 6 millimeters preformed polyfluortetraethylene pipe.The erosion rate that records in simulated intestinal fluid is 1.45 millimeters/hour.

D) 75%PEG35,000 and the mixture of 25%PEG400 monostearate be melted.40% the dextrin that accounts for composition total weight is added in the compositions as filler.Resulting mixture is expressed in the preformed polyfluortetraethylene pipe (10 millimeters of diameters), and presses the rod that method preparation a) applies, and the value of the determination of erosion rate in simulated intestinal fluid is 0.34 millimeter/hour.

E) 75%PEG35,000 and the mixture of 25%PEG400 monostearate be melted, in the mixture that has melted, add as the dextrin of filler with as the mixture of the morphine hydrochloride of active substance,

The amount of dextrin and morphine hydrochloride is 40% of a gross weight.Containing 3.55% the muriatic compositions of morphine is expressed in the preformed polyfluortetraethylene pipe (6 millimeters of diameters).This rod applies and is cut into the sheet of 10 millimeters long according to the method a).The release of morphine hydrochloride in simulated intestinal fluid is measured with high efficiency liquid chromatography (HLPC), in 10 hours is 1 milligram/hour, and erosion rate is 0.43 millimeter/hour.

F) be 9.54% except the content of morphine hydrochloride, prepare compositions by above-mentioned method in a), morphine hydrochloride being released in 10 hours in simulated intestinal fluid that records with the HPLC method is 3 milligrams/hour, and erosion rate is 0.48 millimeter/hour.

G) 75%PEG35,000 and the mixture of 25%PEG400 monostearate be melted, and mix mutually with 3.55% tartrazines.Mixture is expressed in the preformed polyfluortetraethylene pipe (6 millimeters of diameters), applies and be cut into the sheet of 12 millimeters long according to method a).Record in 4 hours, sheet is 1.5 millimeters/hour of steady state values from the erosion rate of every end in simulated intestinal fluid.

H) 10.5 gram PEG35,000 and 3.5 gram PEG400 monostearates are melted and mix.Add 6 gram methotrexate, obtain one and contain 52.2% PEG35, the mixture of 000,17.5% PEG400 monostearate and 30% methotrexate (MTX).It is the rod that applies by the method preparation in a) in 4 millimeters the polyfluortetraethylene pipe that the mixture of this fusing is expressed into diameter.Use the HPLC method, record MTX in during 10 hours and be released to 1.5 milligrams/hour in synthetic urine (embodiment 1), erosion rate is 0.5 millimeter/hour.

I) 5.4 gram PEG35,000 and 1.8 gram PEG400 monostearates are melted and mix with 4.8 gram dextrin/tartrazines (99: 1).It is in 6 millimeters the polyfluortetraethylene pipe that mixture is expressed into diameter, and the method in pressing a) applies, and in 12 hours, when wavelength was 430nm, the erosion that records in simulated intestinal fluid was 0.34 millimeter/hour with spectrophotometer.

J) 1 gram PEG35,000,0.5 gram PEG400 monostearate and 1 gram be single-and the diacetyl tartrate of diglyceride (, Dat-S) be melted in together from Denmark Grindsted product.Add 2.5 gram sucralfate subsequently, mixture is expressed in the preformed polyfluortetraethylene pipe (6 millimeters of diameters).The erosion rate in simulated intestinal fluid that records was 1 millimeter in 8 hours.

K) preparation and j) identical compositions, but do not contain diacetyl tartrate.4 gram PEG35,000 and 2 gram PEG400 monostearates are melted, and add 4 gram Sucralfate in the mixture that has melted.Mixture is expressed in the preformed polyfluortetraethylene pipe (6 millimeters of diameters), and the method in pressing a) applies, and the erosion in simulated intestinal fluid is greater than 2 millimeters in 8 hours.

L) 5 gram PEG35,000 is melted and is expressed in the preformed polyfluortetraethylene pipe (6 millimeters of diameters).One end of pipe be immersed in the fusing that contains 10% tartrazines PEG1500 in.Mixture is taken out from pipe and apply EstaneF30, the end that is impregnated in PEG1500 and the tartrazines mixture is also coated.Compositions is cut into the sheet of 7.5 millimeters long subsequently.Corrode after 4 hours in simulated intestinal fluid, obtain a yellow liquid, it is 1.9 millimeters/hour that this liquid demonstrates its erosion rate.

M) 2.25 gram PEG35,000 and 0.75 gram PEG400 monostearate is melted, and adds 2 gram dextrin (40% dextrin), and mixture is expressed in the preformed polyfluortetraethylene pipe (6 millimeters of diameters).By above-mentioned l) program, make the coated rod that has 3.5 millimeters long of PEG1500+ tartrazines in the end that applies, in simulated intestinal fluid, corrode subsequently.Can see yellow liquid after 8 hours, this yellow liquid demonstrates erosion rate and is about 0.23 millimeter/hour.

Embodiment 11

Have 12 millimeters long except rod is cut into, prepare compositions by embodiment 3 described methods.Resulting rod contains 195 milligrams of PEG35,000,65 milligram of PEG400 monostearate and 170 milligrams of micro-crystallization theophylline.The erosion rate in teat glass that records by embodiment 3 described methods is 1 millimeter/hour, is equivalent to per hour discharge about 15 milligrams of theophylline.The accurate theophylline burst size of being measured by the HPLC method is as follows:

Release time (hour) burst size (micromolar/liter)

0-2 2575

2-4 1740

4-6 1645

6-8 1740

In six patients, measured the release of theophylline from compositions in vivo, 3 male surnames wherein, 3 women surnames, a year order is 18～42 years old (average year makes 30 years old), 63～85 kilograms of body weight (average 66 kilograms), all patients diagnose suffers from the bronchial asthma disease.

Early before the meal (promptly in fasting state) allow patient take dosage for the first time, this dosage is the compositions (340 milligrams of theophylline) and 100 milliliters of liquid of two units.Dosage is after at least 3 days for the second time, give patient at 10 minutes angular vein injection theophylline (Theo-Dur20 mg/ml) in the morning, dosage is 5 milligrams/kilogram of standard body weight), to measure the half-life of theophylline at the intravital serum of single patient.After oral dose, 0,1,2,3,4,6,8,10,12,14,16 and 24 hours venous blood samples samples.At 0,15 minute, 30 minutes, 60 minutes, 90 minutes and 2,3,5,7,9, reach 11 hours and extract the serum blood sample behind the intravenous injection dosage.The serum of blood sample part is freezing under-20 ℃ of temperature immediately, and keeps in this freezing state analyzes after 2 weeks.With the theophylline amount in the HPLC methods analyst serum, degree of accuracy is ± 5%.The serum half-life of the single patient's who records serum content and the theophylline that calculates is shown in following table:

Theophylline amount in patients serum's half serum (micromolar/liter)

Retain the phase

Numbering (hour) 123468 10 12 14 16 24

1 6 21 21 - 22 21 20 17 16 14 11 9

2 9 7 16 24 30 36 32 30 32 30 25 19

3 8 25 38 39 39 39 44 51 50 45 41 30

4 9 11 19 22 26 39 33 29 26 21 19 15

5 7 9 14 19 20 25 21 19 22 16 14 8

6 8 9 21 19 18 20 21 21 22 26 25 18

Embodiment 12

E by embodiment 10) the described detection release of morphine from compositions is in vivo undertaken by two patients, and two patients are healthy male surnames, and year makes 40 years old, and body weight is 85 kilograms (patient 1) and 65 kilograms (patient 2).Early two hours after the meal, the compositions that contains 10 milligrams of morphines that doses a patient with was in the same place with 100 milliliters liquid.By each second hour venous blood samples sample, determine the concentration of morphine in the serum, serum keeps cold state, up to second day serum is isolated and freezing under-20 ℃ of temperature.Morphine concentration three week back in the serum is analyzed with the RIAS method, and this method is with ± 5% the degree of accuracy and the free and conjugated morphine of sensitivity mensuration of the whole morphines of 2ng/milliliter serum.Morphine concentration is listed in the table below in the serum that obtains:

Morphine in the serum (ng/ml)

Hour: 12468 10 12 14 21

Patient 1 18 32 44 46 42 51 76 60 34

Patient 2 35 76 64 44 31 21 27--

Embodiment 13

With 18%PEG20,000,27%PEG35,000 and the 15%PEG400 monostearate mix, and under 65～75 ℃ of temperature, heat, in the matrix material that has melted, add 40% gentamycin sulfate and mix, up to being evenly distributed.The mixture that has melted is expressed in the preformed polyfluortetraethylene pipe (3 millimeters of diameters), and is cooled.Resulting rod is released from pipe by a piston subsequently, and be cut into the piece of 15 or 30 millimeters long, Estane 30 solution impregnation with 20% apply, wherein an end does not apply, press embodiment 3 described methods, in teat glass, record the release of gentamycin, use biological agar hole osmosis chemical examination gentamycin, obtain following result by resultant composition:

Release time (hour) release of gentamycin (micromolar/liter)

0-2 1380

2-4 1220

4-6 940

6-22 6520(930/2 hour)

22-24 1065

24-26 850

26-28 810

The determination of erosion rate of compositions opening one end is 1 millimeter/24 hours, is equivalent to 5 milligrams of gentamycin/24 hour.

Aforesaid compositions is adhered to the top place of the conduit (Ruch, 2F, 5 milliliters, size 12) of urinary system balloon-like.The top tip part diameter is identical with conduit, and the length of compositions is 30 millimeters.

By animal detection release in vivo, use a SPR Danish Landrace X Yorkshire LYY female pigs, body weight is 22 kilograms.This pig is supported at the wire mesh cage that has the stainless steel disc that is used for collecting urine.The bladder that is introduced in pig at conduit uses the Sedaperone(subcutaneous simultaneously) and the Hypnodil(intraperitoneal) make its anesthesia to its injection.Went back injecting atropine (subcutaneous) at that time in case fluid stopping is prolonged.Collected the urine sample of 20 milliliters of equal portions in per 24 hours from tray, gentamicin concentration is measured by using biological agar hole osmosis in the urine, and this method sensitivity is 0.2 microgram gentamycin/milligram urine.The gentamicin concentration that draws is as follows:

Microgram gentamycin/milligram urine

0-24 hour: 1.75

24-48 hour: 1.40

48-72 hour: 1.55

Find that in the 4th day obduction there is hyporrhea the bladder outside, the mucosa and the urethra that observe bladder are normal.

Embodiment 14

Use identical compositions (embodiment 13) as stated above, carry out zooscopy once more with pig.Argyle silicon balloon-like conduit (12ch, 5 milliliters, lot number 027603) is used in experiment this time.Each conduit has the cylindrical compositions of one 15 millimeters long, and conduit top tip part diameter is identical with conduit, and Therapy lasted 7 days is used two pig (body weight is 20 and 21 kilograms), and the gentamicin concentration that draws is as follows:

Insert conduit microgram gentamycin/milliliter urine

After natural law pig 1 pig 2

1 2.9 1.25

2 4.7 0.25

3 4.6 0.95

4 3.4 0.27

5 5.3 0.59

6 / 1.25

7 / 3.40

When conduit when the 7th day takes out, compositions only discharges half, so gentamycin may be just blocked from the 5th day from the release on the device in pig 1 body.

The mucosal tissue of finding pig 1 trigonum in the 8th day obduction has signs of inflammation, and this sign may be because the top tip part of conduit causes in the bladder.Mucous membrane of urinary bladder of pig 2 and mucous membrane of urethra are all normal.

Claims

1, a kind of preparation method for compositions, said composition by with the erosion rate sustained release active substance of the substantial constant on its one or more surfaces to aqueous phase, this method comprises mixes following composition: the mixture of the crystalline polymer that water-soluble basically crystalline polymer or some are water-soluble basically, surfactant or some surfactant mixtures, its consumption is 0.5% of crystalline polymer and a surfactant weight, this surfactant comprises and has at least one regional structure that adapts with crystalline polymer and be a kind of chemical compound or some chemical compounds of lipophilic another regional structure at least basically, this chemical compound has the fusing point that is lower than crystalline polymer, at least a active substance and random a kind of filler; Mix above-mentioned composition and form a kind of matrix, this matrix comprises surfactant or some surfactant mixtures of dispersed crystalline polymer phase, basically be scattered in the active substance that is arranged in the mutually univocal zone of crystalline polymer on crystalline polymer phase and/or the geometry and/or is scattered in surfactant equably, thus, this surfactant and/or active substance reduced in the crystalline polymer matrix and between the granule of crystalline polymer matrix itself and slit in the affinity of water.Therefore therefore, eliminated the infiltration of water on the interface between the polymer crystallization basically, be exposed on one or more surfaces of medium the water real Na cottonrose hibiscus an enclosure for storing grain cooked food of sculling by compositions and cherish the bucktooth enlightening of fainting suddenly and call on  that matter plinth of tool that ticks to coughing

2, according to a kind of method of claim 1, wherein, crystalline polymer and surfactant are mixed, be heated to the temperature that is enough to melt polymer simultaneously and stir, so that obtain uniform basically mixture, active substance is joined in the polymer and surfactant mixtures of fusing, or before heating, join in this mixture, subsequently with the mixture forming and the cooling that make.

3, according to a kind of method of claim 1 or 2, wherein, by extrude, the method for coextrusion, injection moulding or compression forming and with composition molding.

4, according to a kind of method in aforementioned any claim, wherein, crystalline polymer comprises Polyethylene Glycol.

5, according to a kind of method in aforementioned any claim, wherein, crystalline polymer is homopolymer and/or copolymer.

6, according to a kind of method in aforementioned any claim, wherein, crystalline polymer comprises the block copolymer of Polyethylene Glycol and/or oxirane and propylene oxide.

7, according to a kind of method of claim 6, wherein, block copolymer comprises based on the weight of block up to about 30% propylene oxide, and have the above molecular weight of about 5000 dalton, typically be about 5000-30,000 dalton, more typically be about 800-15,000 dalton.

8, according to a kind of method in aforementioned any claim, wherein, the crystalline polymer matrix comprises molecular weight and is about 2000-500,000 daltonian Polyethylene Glycol, typically be about 5000-100,000 dalton more typically is about 10,000-50,000 dalton, especially typically be about 20,000-35,000 dalton.

9, according to a kind of method in aforementioned any claim, wherein, the fusing point of crystalline polymer matrix is about 20-120 ℃, and typically about 30-100 ℃, more about 40-80 ℃.

10, according to a kind of method of aforementioned any claim, wherein, the addition of active substance is approximately up to 60% of composition weight, typically approximately up to 50%.

11, according to a kind of method in aforementioned any claim, wherein, a kind of filler such as dextrin, Sucralfate, calcium hydroxy apetite, calcium phosphate or soap such as magnesium stearate join in crystalline polymer and the surfactant mixtures before heating or after the heating.

12, according to a kind of method in aforementioned any claim, wherein, the addition of filler and active substance is approximately up to 60% of composition weight, typically approximately up to 50%.

13, according to a kind of method in aforementioned any claim, wherein, active substance is medicine, vitamin or other nutritional supplement, antibacterial, the deodorizer of a kind of people of being used for or beast or other material that will be incorporated into aqueous environment continuously.

14, according to a kind of method in aforementioned any claim, wherein, active substance is the pharmaceutically active powder.

15, according to a kind of method of claim 14, wherein, the granular size of powder is about 0.1 micron～500 microns, typically is about 0.5～300 micron, more typically is about 1～200 micron, especially typically is about 5～100 microns.

16, according to a kind of method in aforementioned any claim, wherein, surfactant is the nonionic emulsifier that comprises one or more fatty acid esters and/or fatty acid ether.

17, according to a kind of method in aforementioned any claim, wherein, surfactant comprises and has 12～24 carbon atoms, is typically the fatty acid ester and/or the fatty acid ether of the carbochain of 12～20 carbon atoms.

18, according to a kind of method in aforementioned any claim, wherein, surfactant comprises palmitic acid or stearic ester and/or ether.

19, according to a kind of method in aforementioned any claim, wherein, surfactant comprises macrogol ester or ether, and polyethylene glycol ester or ether, poly-hydroxy ester or ether and/or sugar ester or ether are as dehydration Pyrusussuriensis (sugar) alcohol ester or ether.

20, according to a kind of method in aforementioned any claim, wherein, surfactant comprises polyethylene glycol mono stearate, particularly the PEG400 monostearate.

21, according to a kind of method in aforementioned any claim, wherein, the addition of surfactant is the about 0～60% of crystalline polymer and surfactant weight, for example: about 2-60%, 5-50%, typically about 10-40%, relatively typical more about 15～35,20-30% according to appointment according to appointment.

22, according to a kind of method in aforementioned any claim, wherein, compositions is formed as a kind of geometry, when matrix when aqueous phase is etched, this shape can make the surface area of substantial constant become and be exposed.

23, according to a kind of method of claim 22, wherein, compositions is garden post clavate and has the coating that is insoluble to substantially with liquid impermeable such as body fluid in the deenergized period of expection, this coating at one end or two ends opening is arranged.

24, according to a kind of method of claim 23, wherein, compositions molding by the coextrusion of coating and matrix and active substance, or adopt dip-coating subsequently or by the spraying or the solvent coating of dip-coating with extruding of injection moulding, compression forming or matrix and active substance.

25, according to a kind of method of claim 23 or 24, wherein, coating comprises matrix and the surfactant with one or more water-soluble basically crystalline polymers, this coating is lower than the matrix material that contains active substance basically in the erosive speed of aqueous phase, thus, the area of substantial constant that contains the matrix of active substance is exposed in the erosion process of compositions, and thus, coating corrodes with the erosion of the matrix that contains active substance basically.

26, according to a kind of method of claim 23 or 24, wherein, coating corrodes back decomposition or broken at matrix.

27, according to a kind of method of claim 22, wherein, compositions is formed as the hollow cylinder shape.

28, according to a kind of method of claim 22, wherein, compositions is formed as the hollow hemisphere shape.

29, according to a kind of method of claim 22, wherein, compositions is formed as tablet or slab-like.

30, according to a kind of method in aforementioned any claim, wherein, active substance is scattered in the crystalline polymer matrix basically equably.

31, according to a kind of method of aforementioned any claim, wherein, active substance has regional structure and another lipophilic basically regional structure that at least one and crystalline polymer adapt, active substance be evenly dispersed in basically crystalline polymer mutually in.

32, according to a kind of method of claim 31, wherein, surfactant joins in the matrix material with about 0～2% amount of matrix weight and goes.

33, according to a kind of method of claim 23, wherein, by injection or extrusion molding compositions is formed some staggered basically transverse layers, they are layers that comprise crystalline polymer matrix and surfactant, active ingredient is substantially uniformly dispersed in this matrix, with a layer that comprises active ingredient, this active ingredient is substantially uniformly dispersed in crystalline polymer and surfactant.

34, according to a kind of method of claim 33, wherein, staggered layer comprises two or more different active substances respectively.

35, a kind of preparation is as the method for the multiple-unit pharmaceutical formulation of the active substance of sustained release, and this method comprises the combination according to the multiple individual unit of the compositions of aforementioned any claim preparation of the form that adopts capsule or tablet.

36; a kind of method for compositions for preparing the sustained release active substance to aqueous phase; this method comprises room temperature-vulcanized rubber (RTV rubber) combined with super-absorbent polymer particles and at least a active substance and forms a kind of matrix; in this matrix; super-absorbent polymer particles distributes equably basically and is present in the near surface of compositions; and; active substance disperses and/or is positioned at this matrix to go up univocal zone how much basically equably; thus; aqueous phase liquid can be penetrated into limited speed in the matrix; cause the super-absorbent polymer particles swelling and near the partial fracture of the matrix swelling granule; thus according to the distribution of active substance in matrix, it is discharged with the method for special control.

37, according to a kind of method of claim 36, wherein, catalyst and random a kind of cross-linking agent are added in the matrix material.

38, according to a kind of method of claim 36 or 37, wherein, RTV elastomeric material, super-absorbent polymer and catalytic promoter and/or cross-linking agent at room temperature are mixed together simultaneously and stir, before stirring or among stirring, active substance is joined in this mixture, subsequently with mixture forming.

39, according to any one method of claim 36 to 38, wherein, by extrude, the method for coextrusion, injection moulding or compression forming is composition molding.

40, according to any one method of claim 36 to 39, wherein, RTV rubber comprises the RTV silicone elastomer based on one or two composition of polydimethylsiloxane.

41, according to any one method of claim 36 to 40, wherein, super-absorbent polymer particles can keep semi-solid state when absorbing water or other liquid, and can absorb himself weight at least about 10 times water, typically at least about 100 times water, typical especially about 200 times water.

42, according to any one method of claim 36 to 41, wherein, super-absorbent polymer particles can keep semi-solid state when absorb body fluids, and can absorb at least 5 times body fluid of himself weight, typically at least about 20 times, especially typically at least about 40 times.

43, according to any one method of claim 36 to 42, wherein, super-absorbent polymer comprises polyacrylic acid, modified polyacrylic acid, carboxymethyl cellulose, modified carboxy methyl cellulose and/or cross-linking polyethylene pyrrolidone.

44, according to any one method of claim 36 to 43, wherein, super-absorbent polymer adds with about 5～75% amount of matrix weight, typically about 10-50%, relatively typical about 20～25%.

45, according to any one method of claim 36 to 44, wherein, active substance with composition weight up to about 60% amount and add, typically up to about 50%.

46, according to any one method of claim 36 to 45, wherein, active substance is people or medicine for animals, the material of vitamin or other nutritional supplement, antibacterial, deodorizer or another kind successive administration in water environment.

47, according to any one method of claim 36 to 46, wherein, active substance is the medicinal active powder.

48, according to a kind of method of claim 47, wherein, powder particle is about 0.1～500 micron, typically is about 0.5～300 micron and more typically is about 1～200 micron, especially typically is about 5～100 microns.

49, according to any one method of claim 36-48, wherein, compositions is formed as a kind of geometry, when matrix when aqueous phase is etched, this shape can make the surface area of substantial constant be exposed.

50, according to a kind of method of claim 49, wherein, compositions is formed as the cylinder clavate and has and is insoluble to basically in the deenergized period of expection or the coating of liquid impermeable such as body fluid, this coating at one end or two ends opening is arranged.

51, according to a kind of method of claim 50, wherein, compositions is by the co-extrusion modling of coating and matrix and active substance, or adopts dip-coating subsequently or apply with the solution of spraying or dipping with extruding of injection moulding, compression forming or matrix and active substance.

52, according to a kind of method of claim 49, wherein, compositions is formed as the hollow cylinder shape.

53, according to a kind of method of claim 49, wherein, compositions is formed as hollow hemisphere shape.

54, according to a kind of method of claim 49, wherein, compositions is formed as tablet or slab-like.

55, according to any one method of claim 36 to 54, wherein, active substance becomes and is evenly dispersed in matrix basically and has suffered.

56, according to a kind of method of claim 50, wherein, by injection or extrusion molding compositions is formed some staggered basically transverse layers, they are layers that comprise matrix, active ingredient optionally is substantially uniformly dispersed in this matrix, with a layer that comprises active ingredient, this active ingredient is evenly distributed in the matrix material basically.

57, according to a kind of method of claim 56, wherein, staggered layer comprises two or more different active ingredients respectively.

58, a method for the multiple-unit pharmaceutical formulation of preparation sustained release active substance, this method comprise the combination according to the multiple individual unit of the compositions of any one method preparation in the claim 36 to 57 of the form that adopts capsule or tablet.