CN102210871A - Pharmaceutical carrier of slow-release medicine - Google Patents

Abstract

The invention discloses a pharmaceutical carrier of a slow-release medicine with improved performances. The pharmaceutical carrier comprises: (a) an aliphatic additive, (b) water-soluble, low-viscosity and nonirritating additive particles, (c) a water-swelling hydrophobic acid (or alkaline) polymer, (d) an alkaline (acid) substance, (e) a water-soluble surfactant, and (f) a medicine, wherein in vivo and in vitro melting points of the aliphatic additive are higher than a temperature of 37 DEG C. The pharmaceutical carrier has a better medicine release characteristic, a higher salt-poisoning resisting effect and better medicine release uniformity, and better releases or solves a problem of tail end release; the irritation of a mucous membrane is lower, and biological compatibility is better; and a medication use safety problems of drug fast release, or dose dumping and the like are not easy to occur.

Description

The pharmaceutical carrier of slow release release

Technical field

The present invention relates to a kind of pharmaceutical carrier of slow release release.More particularly, the present invention relates to a kind of pharmaceutical carrier of slow release release of performance improvement, and the inside and outside fusing point of this pharmaceutical carrier occlusion body is greater than the aliphatic additive of 37 ℃ of temperature, water-soluble low viscous additive granules, water-insoluble acidity (or alkalescence) polymer, alkalescence (or alkalescence) material, water soluble surfactant active and the medicine of water-swellable.

Technical background

The present patent application is the patent of invention in first to file: that does on the basis of application number 201010228316.8 (publication number CN102000339A) or application number 201010227255.3 (publication number CN101983723A) applies in the back.

Slow releasing preparation such as slow release suppository, especially with oil material the preparation of main slow-release material, often show so-called " terminal release " problem, it is fast to be that medicine discharges in earlier stage, mid-term is slack-off gradually, and the later stage is slow partially, at last usually in the action time of regulation (or expectation) also a part of medicine remain in the substrate, can not bring into play the effect of expection, show as " rate of releasing drug before fast back slow " in other words and reach problems such as " do not hold release incomplete ".People have been to having done some technological improvements, but usually also have some not satisfied places, need carry out technological improvement.

For example, U.S. Pat 4,344,968 have disclosed a kind of pharmaceutical carrier of making suppository, and this pharmaceutical carrier comprises the fatty glyceride of (a) a kind of fusing point greater than 37 ℃ of temperature; (b) a kind of water soluble, low viscosity, non-irritating organic compound, the particle diameter of described organic compound is less than 28 orders (about 600 microns, Tyler standard), and the viscosity of its solution of 2% is less than 300cps; (c) a kind of particle diameter contacts the organic polymer of swellable with water less than 28 purposes; (d) a kind of water soluble surfactant active.Organic polymer in this pharmaceutical carrier generally is selected from sodium polyacrylate.

This technology has been done certain technological improvement to the problem of technology before it, still has some more serious defectives, and bigger room for improvement is still arranged, as " release first quick and back slow " and " do not hold release incomplete " problem.In addition, also have other than major defect, the pharmaceutical carrier drug release that discloses as this technology still is subjected to the influence of electrolyte solution significantly, though done certain improvement.

It is believed that, produce these gap main causes and be the organic polymer of the work " disintegrating agent " that contacts swellable with water that pharmaceutical carrier that this technology discloses generally selects for use, as sodium polyacrylate etc., " salt poisoning " effect and " gel blockage " effect still easily take place, particularly under artesian condition, (can be subjected to the counteracting force of substrate wall when promptly expanding), " salt poisoning " effect (implication in the below herewith) is meant the organic polymer that contacts swellable with water such as sodium polyacrylate etc. herein, particularly under artesian condition, containing electrolytical aqueous solution such as normal saline, urine, menses, body fluid in the vagina, the phenomenon that the ability of the water absorption and swelling in the body fluid in the rectum reduces greatly with respect to deionized water, " gel blockage " effect (implication in the below herewith) is meant the wetted and particle swelling of the organic polymer particle that contacts swellable with water herein, suppressed fluid to other zone of particle as innerly shift and suppressed particle further swollen phenomenon, the phenomenon of just so-called as forming " not with the dough of opening " will be more serious under artesian condition particularly.After the main cause of generation gel blocking phenomenon was swelling, particularly under artesian condition, gap between particles reduced and viscosity increases.After " salt poisoning " effect and " gel blockage " effect take place in the organic polymer that contacts the work " disintegrating agent " of swellable with water, swelling behavior is given birth to bigger change with secondary, some polymer particles graininesses fail effectively to expand or fully expand, thereby make pharmaceutical carrier fail abundant or complete disintegrate, thereby produce pharmaceutical carrier " release first quick and back slow " and problems such as " do not hold release incomplete ", it is unstable that the drug release behavior also becomes, and is subjected to the influence of electrolyte solution significantly.

In addition, the pharmaceutical carrier that this technology disclosed also shows certain bio-incompatibility, feels partial discomfort (as sensation of pricking) as zest, patient.It is believed that, a major reason is, the organic polymer that contacts swellable with water that this technology is generally selected for use, has quick high-intensity water absorbing capacity as sodium polyacrylate, can make the quick dehydration of mucosa that contact with this pharmaceutical carrier or contiguous with this pharmaceutical carrier, cause local " drying ", thereby cause that zest, patient feel partial discomfort bio-incompatibility problems such as (as sensation of pricking).

It needs to be noted that the prominent dosage drug safety problems such as releasing (dose-dumping) of inclining of releasing in other words of medicine also may appear in pharmaceutical carrier that this technology discloses.When for example pharmaceutical carrier comprises contacting with body fluid of more amount in body cavity just liquefaction or the fatty glyceride that melts (this class fatty glyceride is generally the pure or fatty acid mixed that carbon number is C10～C12; as capric monoglyceride and lauric monoglyceride) or surfactant liquefaction or melt when pharmaceutical carrier will be contacted with body fluid in body cavity, thus cause that the prominent dosage of releasing in other words of medicine inclines and releases (dose-dumping).

Therefore, also need in the reality it is carried out further technological improvement.

Goal of the invention

The present invention is directed to defective and other defectives of above-mentioned technology, it is carried out technological improvement, make its Release Performance can obtain bigger improvement.

Particularly, one of main purpose of the present invention just provides a kind of pharmaceutical carrier of slow release release of performance improvement, the pharmaceutical carrier drug release process is further improved by the influence of electrolyte solution, better Release Performance is arranged, alleviated or solve as problems such as " release first quick and back slow " that show in the pharmaceutical carrier drug release process or " do not hold release incomplete ".

Another main purpose of the present invention just provides a kind of pharmaceutical carrier of slow release release of performance improvement, and the biocompatibility of pharmaceutical carrier is enhanced.

Another main purpose of the present invention just provides a kind of pharmaceutical carrier of slow release release of performance improvement, and pharmaceutical carrier is not prone to the prominent dosage drug safety problems such as releasing (dose-dumping) of inclining of releasing in other words of medicine.

Other purposes are referring to following description.

Summary of the invention

The present invention relates to a kind of external fusing point of performance improvement and the fusing point when contacting with body fluid in body cavity all is higher than the pharmaceutical carrier of the slow release release of 37 ℃ of temperature, the fusing point when this pharmaceutical carrier comprises (a) a kind of pharmaceutically acceptable fusing point and contacts with body fluid greater than 37 ℃ of temperature and in body cavity also is higher than the aliphatic additive of 37 ℃ of temperature; (b) a kind of pharmaceutically acceptable, water-soluble, low viscous additive, its granule largest cross-sectional sized is less than about 600 microns (about 28 orders, Tyler standard), and the viscosity of its solution of 2% is less than 300 centipoises (mPas); (c) a kind of pharmaceutically acceptable, water-swellable and water-insoluble acidic polymer, its pKa is about 2～about 12; (d) a kind of pharmaceutically acceptable alkaline matter, more preferably a kind of pharmaceutically acceptable water-swellable and water-insoluble alkaline polymer; (e) a kind of pharmaceutically acceptable water miscible surfactant; (f) a kind of medicine.

Perhaps, (a) fusing point when a kind of pharmaceutically acceptable fusing point contacts with body fluid greater than 37 ℃ of temperature and in body cavity also is higher than the aliphatic additive of 37 ℃ of temperature; (b) a kind of water soluble, low viscous, pharmaceutically acceptable additive, its granule largest cross-sectional sized is less than about 600 microns (about 28 orders, Tyler standard), and the viscosity of its solution of 2% is less than 300 centipoises (mPas); (c) a kind of pharmaceutically acceptable, water-swellable and water-insoluble alkaline polymer, its pKb is about 2～about 12; (d) a kind of pharmaceutically acceptable acidic materials, more preferably a kind of pharmaceutically acceptable, water-swellable and water-insoluble acidic polymer; (e) a kind of pharmaceutically acceptable water miscible surfactant; (f) a kind of medicine.

The term " slow release release " that the present invention uses is meant that the time of release is a few hours to about 24 hours or longer.

Term " active component ", " bioactive ingredients ", " medical active component ", " active matter ", " activating agent " that the present invention uses reaches " bioactive substance ", " medicine " etc. and is meant that any material has detectable biological effect and comprises any physiological, diagnosis, preventative or pharmacological effect when it bestows live body.This term is intended to include but not limited to material any pharmacy, therapeutic, preventative, the threpsology.

The term that the present invention uses " comprises " and reaches " containing " and be meant and include but not limited to or can also comprise other one-tenth similar implication of grading except this thing.

The term " a kind of " that the present invention uses be meant comprise at least a kind of, can for a kind of, two kinds or more kinds of.

The term " water soluble " that the present invention uses is meant that the dissolubility of material in the 100ml water of 25 ℃ of temperature is not less than 5g, preferably 10～30g.

The term " low viscosity " that the present invention uses is meant that the viscosity in aqueous solution in temperature 25 ℃ following 2.0% (weight/volume) is not higher than 300 centipoises (mPas).

The term " pharmaceutically acceptable " that the present invention uses refers to abiology or the unfavorable material of others, promptly can give individuality with this material, and can not cause any too unfavorable biological effect in individuality, or excessive deleterious interaction can not take place with any component in the compositions that comprises it.

The term " additive " of the present invention's use is meant one or more auxiliary material that can be mixed with each other and not have interaction and can not reduce pharmaceutical carrier stability and/or render a service and be applicable to part or oral administration that pharmaceutical carrier comprises.

But the term " about " that the present invention uses be the excursion of exponential quantity or span in ± 30%, preferably ± 20% in, in ± 10%, best ± 5%, according to appointment 10, then represent 7～13, preferably 8～12, more preferably 9～11, best 9.5～10.5.

Detailed Description Of The Invention

Below the pharmaceutical carrier that the present invention relates to is described in more detail.

The substrate of the pharmaceutical carrier that the present invention relates to and the material of the control drug release fusing point when to be pharmaceutically acceptable fusing point greater than 37 ℃ of temperature and in body cavity contact with body fluid also is higher than the aliphatic additive of 37 ℃ of temperature, it preferably is 40 ℃～90 ℃ aliphatic additive for fusing point, it more preferably is 40 ℃～70 ℃ aliphatic additive, more preferably be 40 ℃～50 ℃ aliphatic additive, described aliphatic additive comprises but is not limited to the vegetable and animals oils lipid that the fusing point of fusing point when contacting with body fluid greater than 37 ℃ of temperature and in body cavity also is higher than 37 ℃ of temperature, semi-synthetic oils and fats, fatty glyceride, the wax class, higher fatty acids, high fatty alcohol, high-grade aliphatic ester, senior aliphatic hydrocarbon and composition thereof.

The fatty glyceride that fusing point when wherein, fusing point contacts with body fluid greater than 37 ℃ of temperature and in body cavity also is higher than 37 ℃ of temperature is for most preferably.Be used for fatty glyceride of the present invention and can be for example fatty acid glycerine one ester, fatty acid diglyceride, fatty acid triglycercide and their mixture, fatty acid described herein is generally the fatty acid mixed that carbon number is C14～C18.The fusing point of these fatty glyceride must be higher than 37 ℃ of temperature, but preferably is not higher than 45 ℃, is not less than 40 ℃, when particularly being applied to suppository.The example that can be used for fatty glyceride of the present invention as CP (37～39 ℃ of fusing points), C, CM, CS2, CS2X, CT (38～40 ℃ of fusing points), D, DM, ND (42～45 ℃ of fusing points) (Gattefosse Co., Ltd makes),

E75, E76 (37～39 ℃ of fusing points), H185 (38～39 ℃ of fusing points), E85 (42～44 ℃ of fusing points) (Dynamic Nobel Chemicals Co.Ltd manufacturing).

Exemplary fusing point comprises greater than the aliphatic additive of 37 ℃ of temperature but is not limited to Synthetic Spermacet (43～47 ℃ of fusing points), hexadecanol (45～50 ℃ of fusing points), cetostearyl alcohol (48～56 ℃ of fusing points), stearic acid (about 54 ℃ of fusing point), ethylene glycol monostearate (54～57 ℃ of fusing points), microwax (54～102 ℃ of fusing points), glycerol tristearate (55 ℃ of fusing points), stearyl alcohol (55～60 ℃ of fusing points), hydrogenated vegetable oil (57～85 ℃ of fusing points), cera alba (61～65 ℃ of fusing points), yellow beeswax (61～65 ℃ of fusing points), tripalmitin (62～68 ℃ of fusing points) behenic acid (80 ℃ of fusing points), Brazil wax (80～88 ℃ of fusing points), Cera Chinensis (81～85 ℃ of fusing points), cholesterol ester stearic acid (82.5 ℃ of fusing points), terpene resin (82～120 ℃ of fusing points), castor oil hydrogenated (85～88 ℃ of fusing points), cholesterol cetylate (90.5 ℃ of fusing points).

The material that is used for the substrate of pharmaceutical carrier of the present invention and control drug release does not just comprise when the fusing point when those contact with body fluid is not higher than contacting with body fluid in other words of 37 ℃ of temperature in body cavity usually can liquefaction, the lipidic matrix of emulsifying or thawing or such lipidic matrix in the quantity not sufficient of pharmaceutical carrier (as to be less than about 5%wt/wt, more preferably be less than about 1%, based on the gross weight of pharmaceutical carrier) make pharmaceutical carrier liquefaction, emulsifying or thawing when it contacts with endoceliac body fluid.These lipidic matrix comprise carbon number for example be the fatty glyceride (as described capric monoglyceride of WO99/17737 and lauric monoglyceride), the fat-soluble surfactant of some self emulsifyings (as anhydrous sorbitol tristearate, propylene glycol monostearate, glycol distearate) of C8～C12 but and contain the lipidic matrix (as self-emulsifying monostearate, cetomacrogol emulsifying wax, emulsifing wax) of the self emulsifying of a certain amount of surfactant.It is believed that this is because pharmaceutical carrier just can liquefaction, emulsifying when contact with body fluid or melted and will cause that the prominent dosage of releasing in other words of medicine inclines and releases (dose-dumping) in body cavity, thus initiation drug safety problem.

The content that fusing point when fusing point contacts with body fluid greater than 37 ℃ of temperature and in body cavity also is higher than the aliphatic additive (a) of 37 ℃ of temperature is generally 40～80%wt/wt, based on the gross weight of pharmaceutical carrier.

Water-soluble, low viscous pharmaceutically acceptable and non-irritating additive in the present invention mainly as filler or diluent, pharmaceutical carrier disintegrate promoter and drug release rate regulator.

Can be used for water-soluble, low viscous pharmaceutically acceptable and non-irritating additive of the present invention, comprise, but be not limited thereto: water-soluble aminoacid, oligopeptide (2～10 peptide), monosaccharide and pharmaceutically acceptable and non-irritating derivant thereof, oligosaccharide (2～6 sugar) and pharmaceutically acceptable and non-irritating derivant thereof, water-soluble, low viscous, pharmaceutically acceptable and non-irritating polymer, and their mixture.

The example that can be used for water-soluble aminoacid of the present invention or oligopeptide as, but be not limited thereto: alanine, glycine, serine, valine, agedoite, lysine, glutamine, methionine, arginine, hydroxyproline, proline, power peptide (L-alanyl-L-glutamine), glutathion.

Available water-soluble monosaccharide and pharmaceutically acceptable and non-irritating derivant thereof comprise, but be not limited to left-handed and/or dextral monosaccharide and sugar alcohol thereof, the example as, but be not limited thereto: triose (as D-glyceraldehyde and dihydroxy acetone), tetrose is (as the D-erythrose, the D-Erythrulose, erythritol), pentose is (as D-ribose, the D-2-deoxyribose, the D-xylose, L-arabinose, pentulose is (as the D-ribulose, the D-xylulose), xylitol), hexose (glucose, galactose, mannitol, mannose, ketohexose is (as fructose, sorbose)), heptose is (as the D-mannoheptulose, the D-sedoheptulose).

The example of available water-soluble oligosaccharide and pharmaceutically acceptable and non-irritating derivant as, but be not limited thereto: disaccharidase (as maltose, lactose, sucrose, cellobiose, gentiobiose, 6-(.alpha.-D-galactosido)-D-glucose., Sargassum disaccharide, hydroxyl isomaltulose, maltose alcohol, lactitol, trehalose), trisaccharide (as Raffinose), tetrose (as stachyose), pentasaccharides (as verbascose, maltopentaose), six sugar (as MALTOHAXAOASE).

Water-soluble, low viscous, pharmaceutically acceptable and non-irritating examples of polymer as, but be not limited thereto: water-soluble pharmaceutically acceptable and non-irritating cyclodextrin and cyclodextrin derivative are (as alpha-cyclodextrin, gamma-cyclodextrin, 2,6 DM-, hydroxypropyl/ethyl-beta-schardinger dextrin-, side chain-beta-schardinger dextrin-, glycosyl-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, water-soluble low-molecular-weight cyclodextrin (as molecular weight 3000～6000)), dextrates (Dextrates), water-soluble low viscous pharmaceutically acceptable and non-irritating oligosaccharide (degree of polymerization 7～20) is (as oligofructose (degree of polymerization 7～20), oligomeric isomaltose (degree of polymerization 7～20)), dextrin, water-soluble glucosan (be as molecular weight 1200～2000 glucosan), water-soluble low viscous carrageenin is (as λ-carrageenin, the carrageenin sodium salt), low viscous Radix Acaciae senegalis, low viscous pulullan polysaccharide (as molecular weight for or be less than 100000), low viscous pectinic acid, low viscous pectic acid, low viscous hydroxyl second methylcellulose, (product following as trade name: WP 02 for low viscous hydroxyethyl-cellulose, WP and QP 09, WP and QP 3, WP and QP 40, WP and QP 300), low viscous hydroxypropyl cellulose (the product following: Klucel JF as trade name, Klucel LF, Klucel EF), low viscous hydroxypropyl methylcellulose (the product following: Methocel K100Premium LVEP as trade name, Methocel F50Premium, Methocel E3 Premium LV, Methocel E5Premium LV, Methocel E6 Premium LV, Methocel E15 Premium LV, Methocel E50Premium LV, low viscosity level Metolose 60SH, low viscosity level Metolose 65SH, low viscosity level Metolose 90SH), low viscosity methylcellulose (the product following: A15-LV) as trade name, low viscous polyvinyl alcohol, low viscous polyvidone (the product following: K-11/14 as trade name, K-16/18, K-24/27, K-28/32, K-85/95).

The granule largest cross-sectional sized of above-mentioned water soluble, low viscous, pharmaceutically acceptable and non-irritating additive is less than about 600 microns (about 28 orders, Tyler standard), preferably less than about 75 microns (about 200 orders, Tyler standard), more preferably less than about 25 microns (about 500 orders, Tyler standard).Based on the gross weight of pharmaceutical carrier, water soluble, low viscous, pharmaceutically acceptable and non-irritating content of additive are generally 10～40%wt/wt.

" pharmaceutically acceptable water-swellable and water-insoluble polymer " used in the present invention is meant so a kind of pharmaceutically acceptable material (polymer), when it is exposed in the excessive water, it is expanded to its balance volume, but is not dissolved in the solution.With regard to definition used herein, if a kind of material is considered to water miscible, it is dissolved in basically in the excessive water and forms solution, loses thus that it is initial, granular shape particularly, and is scattered in the aqueous solution with molecularity in fact.Common criterion is that the water dissolvable material is that no substantial extent is crosslinked, because the crosslinked material that will make has water-insoluble.

The molecular weight ranges that is used for the water-swellable of pharmaceutical carrier of the present invention and insoluble polymer is very wide.High-molecular weight relatively water-swellable and insoluble polymer, normally favourable for the use among the present invention.But be applicable to that molecular weight ranges of the present invention is normally very wide.The weight average molecular weight that is applicable to water-swellable of the present invention and insoluble polymer is usually greater than about 20000, to be good greater than about 100000, is preferably greater than approximately 200000, more preferably greater than about 500000, greater than 1000000 preferably, is up to about 10000000.The method of measuring polymer molecular weight is being known in the art usually.

Sometimes the mode of expressing polymer molecular weight more easily is under 25 ℃, the viscosity of the aqueous solutions of polymers of 1.0 weight %.Being applicable to polymer of the present invention, is that about 200～about 80000 centipoises (mPas) are advisable with 25 ℃ of following its 1.0 weight % viscosity in aqueous solution, is preferably about 500～about 80000 centipoises, and optimum is about 1000～about 80000 centipoises.

The water-swellable and the water-insoluble polymer that are used for pharmaceutical carrier of the present invention are normally crosslinked.Crosslinked amount should be enough to that polymer is kept on the water-insoluble minimum usually, but also should polymer be kept in the water under the enough swollen maximum so that polymer can absorb aequum liquid and and swelling.

Usually the crosslinked of polymer is used for realizing by making of one of two kinds of dissimilar cross-linking agent.First type of crosslinking agent is a polymerizable crosslinking agent.Suitable polymerizable cross-linking agent is to be reactive to the monomer that is used to prepare polymer usually, and therefore contain usually at least two can with the functional group of monomer reaction.The example of suitable polymerizable cross-linking agent comprises vinyl-based unsaturated monomer for radical polymerization, as N, N '-methylene-bisacrylamide comprises polyamines or how pure for polycondensation.

The cross-linking agent of second type is the back cross-linking agent.Back cross-linking agent does not participate in whole polymerization process usually, but the time after when offering suitable crosslinked condition, it can with polymer reaction.Suitable post-treatment condition comprises the use heat treated, is higher than about 60 ℃ as temperature, is exposed to ultraviolet, is exposed to microwave, and steam or high humility are handled, HIGH PRESSURE TREATMENT or handle with organic solvent.

Be applicable to that back of the present invention cross-linking agent is generally water miscible.Suitable back cross-linking agent for have at least two can with the functional group of any carboxyl, carboxylic acid, amino or hydroxyl reaction on the polymer or a kind of organic compound of degree of functionality.The example of suitable back cross-linking agent includes, but is not limited to diamine, polyamines, and dihydroxylic alcohols, how pure, polycarboxylic acid and polyoxide.Another kind of suitable back cross-linking agent contains the metal ion of band more than two positive charges, as Al ³⁺, Fe ²⁺, Ce ³⁺, Ce ⁴⁺, Ti ⁴⁺' Zr ⁴⁺And Cr ³⁺

When polymer was cationic polymer, suitable cross-linking agent was the material of polymer anion, as sodium polyacrylate, and carboxymethyl cellulose, or polyphosphate.

The pharmaceutically acceptable water-swellable and the insoluble polymer that are used for pharmaceutical carrier of the present invention are generally tart and alkaline.Here used " acidity " material is meant the material that can be used as electron acceptor.Usually, acid water swellability and the insoluble polymer that is used for pharmaceutical carrier of the present invention is weakly acidic.Therefore be used for the acid water swellability of pharmaceutical carrier of the present invention and the pKa of water-insoluble polymer is advisable with about 2～about 12, more advantageously be about 2～about 10, be suitably about 3～about 6.Sometimes can measure the monomeric pH value that is used to prepare polymer more easily.Although monomeric pH value is incomplete same with the pH value of the polymer that is made by these monomers, these two pH value should be close basically.Therefore, be used for the acid water swellability and the water-insoluble polymer of pharmaceutical carrier of the present invention, preferably by such monomer preparation, these monomeric pKa be about 2～about 12, more advantageously be about 2～about 10, be suitably about 3～about 6.If polymer is made by two or more monomers, each used monomeric pKa should be about 2～about 12, more advantageously be about 2～about 10, be suitably about 3～about 6, certainly use minute quantity pKa less than about 2 or greater than about 12 monomer, as long as these monomers do not have a negative impact to the desired properties of described water-swellable and insoluble polymer.

Have now found that, use pKa less than about 2, highly acid expansiveness, insoluble polymer, usually will cause not possessing required performance in the pharmaceutical carrier of the present invention, and absorb liquid rate, low Release Performance as low, but also have bigger zest etc.Usually also find, use pKa, will cause not possessing required performance in the pharmaceutical carrier of the present invention usually, as low liquid absorption capacity, low Release Performance greater than about 12, acid too weak expansiveness, insoluble polymer.Its dissociative degree of pKa value representation of acid, in other words, Suan intensity just, so described pKa value should be measured under given conditions, for example measures under the specified temp of water-swellable and insoluble polymer use.

It is more suitable to measure the pKa value down at 25 ℃.Usually, acid is weak more, and its pKa value is high more.The pKa value of many acid under different temperatures is known, and can obtain in any many lists of references that get.

Suitable slightly acidic water swellability and insoluble polymer comprise the functional group that can use as weak acid.These functional groups include but not limited to carboxyl, sulfate groups, inferior sulfate radical group, and phosphate groups.Suitable functional group is a carboxyl.Usually, these functional groups are connected on the crosslinked base polymer.Suitable base polymer comprises polyacrylamide, polyvinyl alcohol, ethenyl maleic anhydride copolymer, polyvingl ether, polyacrylic acid, polyvinyl pyrrolidone, polyvinyl beautiful jade, and their copolymer.Also can use natural polysaccharide polymer, comprise carboxymethyl cellulose, carboxymethyl starch, hydroxypropyl cellulose, alginic acid, alginate, carrageenin, acrylic acid-grafted starch, acrylic acid-grafted cellulose, and their copolymer.Also synthetic polypeptide be can use, (aspartic acid, the example such as poly-aspartate-aspartic acid-lysine acid (4: 2: 1) mixed as gathering as poly-aspartate, polyglutamic acid, poly-mixed acid acidic amino acid; Poly-mixing glutamic acid, the example such as polyglutamic acid-lysine acid (4: 1).Term " poly-mixed acid acidic amino acid " is meant and contains the several amino acids that comprises acidic amino acid in the chain herein, and the molal quantity of acidic amino acid (as aspartic acid, glutamic acid) greater than the molal quantity of basic amino acid (as lysine, arginine) and present tart poly-several amino acids (poly-several amino acids be referring to document: US5247068A).

Preferably be suitable for acid water swellability of the present invention and water-insoluble polymer including but not limited to weight average molecular weight usually greater than about 100000 acrylate copolymer, acrylic acid-acrylate polymer, polyvinyl alcohol-acrylic block copolymers, starch graft acrylic acid polymer, cellulose graft acrylate copolymer, polycarbophil (Polycarbophil polymers), alginic acid, poly-aspartate, polyglutamic acid, poly-ly mix aspartic acid and the poly-glutamic acid that mixes, and their mixture.

Usually, acid water swellability and insoluble polymer are required to be its free acid form.Preferably the form that is neutralized for the part free acid can be brought into play bigger function at pharmaceutical carrier at the release initial stage because of it, can overcome that it is less in release initial stage function.The acidic functionality of wishing the free form of acid water swellability and insoluble polymer usually is about 10～about 95 moles of %, more advantageously is about 30～about 90 moles of %, is suitably about 50～about 90 moles of %, and optimum ground is about 65～about 85 moles of %.In other words, when being used for pharmaceutical carrier of the present invention, acid water swellability and insoluble polymer are preferably partly neutralized.The degree of neutralization of wishing the acidic functionality of acid water swellability and insoluble polymer usually is about 5～about 90 moles of %, more advantageously about 10～about 70 moles of %, about aptly 10～about 50 moles of %, the about 15～about 35 moles of % in optimum ground.

Here used " alkalescence " material is meant the material that can be used as electron donor.Usually, alkaline water swellability and the insoluble polymer that is used for pharmaceutical carrier of the present invention is weakly alkaline.Therefore the pKb that is used for the alkaline water swellability of pharmaceutical carrier of the present invention and water-insoluble polymer be about 2～about 12, more advantageously be about 2～about 10, be suitably about 3～about 6.Sometimes can measure the monomeric pH value that is used to prepare polymer more easily.Although monomeric pH value is incomplete same with the pH value of the polymer that is made by these monomers, these two pH value should be close basically.Therefore, be used for the alkaline water swellability and the water-insoluble polymer of pharmaceutical carrier of the present invention, can be by pKb about 2～about 12, more advantageously be about 2～about 10, be suitably about 3～about 6 monomer preparation.If polymer is made by two or more monomers, then each used monomeric pKb should be about 2～about 12, more advantageously be about 2～about 10, be suitably about 3～about 6, certainly use minute quantity, pKb is less than about 2 or greater than about 12 monomer, as long as these monomers do not have a negative impact to the desired properties of described water-swellable and insoluble polymer.

It is existing that oneself finds, use pKb less than about 2, alkaline water-swellable and insoluble polymer, usually will cause not possessing required performance in the pharmaceutical carrier of the present invention, and absorb liquid rate, low Release Performance as low, but also have bigger zest etc.Usually also find, use pKb greater than about 12, too weak water-swellable and the insoluble polymer of alkalescence, will cause not possessing required performance in the pharmaceutical carrier of the present invention usually, as low liquid absorption capacity, low Release Performance.Its dissociative degree of pKb value representation of alkalescence, in other words, Jian Xing intensity just, the pKb value should be measured under given conditions here, for example measures under the specified temp of water-swellable and insoluble polymer use.

Suit to measure the pKb value down at 25 ℃.Usually, alkali is weak more, and its pKb value is high more.The pKb value of many alkali under different temperatures is known, and can obtain in any many lists of references that get.

Suitable alkalescent water swellability and insoluble polymer comprise the functional group that can use as weak base.These functional groups include, but is not limited to primary, the second month in a season and uncle's amino, imino group, and acylamino-.Suitable functional group is amino.Usually, these functional groups are connected on the crosslinked matrix polymer.Suitable matrix polymer comprises polyamine, polymine, polyacrylamide, and polyquaternary ammonium salt, and their copolymer.Also natural polysaccharide polymer be can use, chitin and chitosan comprised.Also can use synthetic polypeptide, as poly-asparagine, the polyglutamic amide, polylysine, poly arginine, poly-mixed-alkali aminoacid is (as poly-lysine, the example such as the polyglutamic acid-lysine (1: 3) of mixing; Poly-arginine, the example such as the poly-aspartate-arginine (1: 4) of mixing.Term " poly-mixed-alkali aminoacid " is meant and contains the several amino acids that comprises basic amino acid in the chain herein, and the molal quantity of basic amino acid (as lysine, arginine) greater than the molal quantity of acidic amino acid (as aspartic acid, glutamic acid) and present the poly-several amino acids of alkalescence (poly-several amino acids be referring to document: US5247068A).

Preferably be suitable for alkaline water swellability of the present invention and water-insoluble polymer including but not limited to weight average molecular weight usually greater than about 100000 chitin, chitosan, poly-asparagine, the polyglutamic amide, polylysine, poly arginine, poly-lysine and the poly-arginine that mixes of mixing.

Usually, alkaline water swellability and insoluble polymer are required to be its free alkali form.Preferably the form that is neutralized for the part free alkali can be brought into play bigger function at pharmaceutical carrier at the release initial stage because of it, can overcome that it is less in release initial stage function.The basic functionality of wishing the free form of alkaline water swellability and insoluble polymer usually is about 10～about 95 moles of %, more advantageously is about 30～about 90 moles of %, is suitably about 50～about 90 moles of %, and optimum ground is about 65～about 85 moles of %.In other words, when being used for pharmaceutical carrier of the present invention, alkaline water swellability and insoluble polymer are preferably partly neutralized.The degree of neutralization of wishing the basic functionality of alkaline water swellability and insoluble polymer usually is about 5～about 90 moles of %, more advantageously about 10～about 70 moles of %, about aptly 10～about 50 moles of %, the about 15～about 35 moles of % in optimum ground.

Think according to reason or default stripping curve stripping in order to make medicine better, in pharmaceutical carrier of the present invention, use acidity (or alkalescence) water-swellable and the insoluble polymer of two kinds or more kinds of different degree of neutralization, can make pharmaceutical carrier disintegrate on different time like this, drug release presents " stage " or " pulsed ", thereby drug release is release on different time sections, presents release front and back speed unanimity generally.In an embodiment, the degree of neutralization of acidity (or alkalescence) functional group of the acidity of part consumption (or alkalescence) water-swellable and insoluble polymer is about 5～about 40 moles of %, and the degree of neutralization of the acidity of another part consumption (or alkalescence) functional group is about 50～about 90 moles of %; In another embodiment, the degree of neutralization of acidity (or alkalescence) functional group of the acidity of part consumption (or alkalescence) water-swellable and insoluble polymer is about 5～about 30 moles of %, acidity (or alkalescence) about 40～about 60 moles of % of functional group that part is a consumption, the acidity of another part consumption (or alkalescence) functional group is about 70～about 90 moles of %.The amount ratio in pharmaceutical carrier of above-mentioned different degree of neutralization acidity (or alkalescence) water-swellable and insoluble polymer preferably is about 1: 1: 1 ...Above-mentioned different degree of neutralization acidity (or alkalescence) water-swellable and insoluble polymer can be arranged in a kind of release particulate matter, also can lay respectively in the different release particulate matters, the different release particulate matter of this kind is packed in the same drug release carrier as in capsule, the bag agent, perhaps is pressed into simultaneously in the tablet.

Can be used for alkaline matter of the present invention and comprise pharmaceutically acceptable organic base and/or inorganic base.The example of pharmaceutically acceptable organic base as, but be not limited thereto: basic amino acid, meglumine and their mixture.The example of pharmaceutically acceptable inorganic base as, but be not limited thereto: carbonate, bicarbonate, glycine carbonate, the carbonate of L-lysine, arginic carbonate, amino acid whose carbonate contains the carbonate of glycosyl, sulphite, percarbonate is as sodium salt, potassium salt, ammonium salt and their mixture; Wherein, carbonate or bicarbonate and organic base are preferred.

Can be used for acidic materials of the present invention and comprise pharmaceutically acceptable organic acid and/or mineral acid, and their acid salt, the example as, but be not limited thereto: tartaric acid; citric acid, maleic acid, fumaric acid; malic acid, adipic acid, succinic acid; lactic acid, glycolic, taurine; 'alpha '-hydroxy acids, ascorbic acid and acidic amino acid (as glutamic acid, aspartic acid), with and acid salt; dihydric phosphate is as sodium salt, potassium salt, ammonium salt and their mixture.Can be used for alkali of the present invention (or acid) property material and also comprise above-mentioned alkalescence (or acid) water-swellable and insoluble polymer, and be preferred.

Usually above-mentioned acid (or alkali) property water-swellable that uses in pharmaceutical carrier of the present invention and insoluble polymer and above-mentioned alkali (or acid) property material exists preferable with particle form.In an embodiment, above-mentioned acid (or alkali) property water-swellable and insoluble polymer and above-mentioned alkali (or sour) property material can (the two coexists as same granule, is called for short " prefabricated particulate matter ") be scattered in the above-mentioned aliphatic additive substrate after granulation (as grinding or pulverize and mixing or the granulation of adding binding agent).In another embodiment, above-mentioned acid (or alkali) property water-swellable and insoluble polymer and above-mentioned alkali (or acid) property material also can directly disperse or the back of granulating separately (the two is stored in respectively separately in the granule, and the granule of this first mixing redispersion is called for short " premix particulate matter ") redispersion in above-mentioned aliphatic additive substrate.In actual applications, above-mentioned acid (or alkali) property water-swellable and insoluble polymer and above-mentioned alkali (or acid) property material also can be scattered in the above-mentioned aliphatic additive substrate with two kinds of above-mentioned discrete form simultaneously.When requiring release very fast such as a few hours to tens hour mainly or all disperse with first kind of dispersing mode (the two coexists as same granule and is scattered in the above-mentioned aliphatic additive substrate), when requiring release slow in full twenties hours or more long time mainly or all disperse with second kind of dispersing mode (the two is stored in separately granule respectively and is scattered in separately in the above-mentioned aliphatic additive substrate).

In other words, above-mentioned water-swellable and water-insoluble acidity (or alkalescence) polymer is scattered in this pharmaceutical carrier preferable with above-mentioned alkalescence (or acidity) material with particulate matter, the individual particle of this particulate matter contains above-mentioned acidity (or alkalescence) polymer and/or above-mentioned alkalescence (or acid) material, this particulate matter has slow relatively expansible ability, they make disintegrating agent in the present invention, regulate drug release rate.The expansible ability of above-mentioned particulate matter is expressed by the free wxpansion capacity.Combine with embodiment below and provided the assay method of free wxpansion capacity.By the free wxpansion capacity that following algoscopy provides, refer to here in 10 hours, under the load of insignificant about 0.01 pound/square inch (psi), the amount of the absorbable aqueous solution that contains 0.9 weight % sodium chloride in gram of the above-mentioned particulate matter of every gram.Usually, wish that above-mentioned particulate matter is that its initial free wxpansion capacity is at least about 7 gram/grams usually, is preferably about 10～about 100 gram/grams, is suitably about 15～about 70 gram/grams under about 0.01psi in load.Terminology used here " initial free wxpansion capacity " is meant the free wxpansion capacity of measuring in about 1 day after above-mentioned particulate matter prepares that particulate matter had, described particulate matter is to store under environmental condition, under 24 ℃, relative humidity is about 30～60% according to appointment.This free wxpansion capacity should be not lower, common disintegrating property was relatively poor when cause was low, this free wxpansion capacity discomfort is too high, because of too high free wxpansion capacity may cause part " drying ", produces zest then, allows the patient feel partial discomfort (as sensation of pricking).

Expansible speed of above-mentioned particulate matter or speed reach the used time of 60% free wxpansion capacity by it and express.Combine with embodiment below and provided the assay method that reached for 60% used time of free wxpansion capacity, here being meant that above-mentioned particulate matter absorbs reaches the used time of its total absorptive capacity 60%, and total absorptive capacity of particulate matter is expressed as the free wxpansion capacity of particulate matter.Usually wish that the time that above-mentioned particulate matter reaches 60% free wxpansion capacity was at least about 5 minutes, preferably being at least about 10 minutes, advantageously is about 10～about 300 minutes, more advantageously is about 20～about 200 minutes, be suitably about 20～about 120 minutes, be about 20～about 60 minutes preferablyly.The time that reaches 60% free wxpansion capacity usually should be too not short, because of imbibition may cause part " drying " too soon, and then produces zest, allows the patient feel partial discomfort (as sensation of pricking); But also uncomfortable long, not so, drug release is too slow, unless special preface needs are arranged, as time-delay release (as delaying time 2～8 hours) or long period release (as 2 days or 7 days or interior release of longer time).

Because above-mentioned particulate matter is impregnated in the substrate of pharmaceutical carrier as absorbing disintegrating agent, and is wherein in bond, thereby, when it expands, be not conventional free wxpansion, but the expansion under the counteracting force that is subjected to the substrate wall (pressure) is promptly expanded under the pressure-bearing.The common resistance to pressure of using in the former invention technology of absorption disintegrating agent is relatively poor, and " gel blockage " easily takes place under pressure, and the expansion and disintegration performance is subjected to bigger restriction, and the pharmaceutical carrier release may be not exclusively.The conduct that the present invention uses absorb disintegrating agent above-mentioned particulate matter have a withstand voltage preferably effect, under artesian condition, be difficult for " gel blockage " takes place, have expansion and disintegration performance preferably.Above-mentioned particulate matter has absorption liquid and expansible ability under external pressure or pressure-bearing, is called expansion volume under the pressure-bearing here.Combine with embodiment below and provided the assay method of expansion volume under the pressure-bearing.Expansion volume under the pressure-bearing that provides by following mensuration refers in 10 hours here, under the load of about 0.3 pound/square inch (psi), and the amount of the absorbable aqueous solution that contains 0.9 weight % sodium chloride in gram of the above-mentioned particulate matter of every gram.Usually, wish that above-mentioned particulate matter is that expansion volume is at least about 7 gram/grams under its initial pressure-bearing, is preferably about 10～about 70 gram/grams, is suitably about 10～about 40 gram/grams under about 0.3psi in load.Terminology used here " expansion volume under the initial pressure-bearing " is meant expansion volume under the pressure-bearing of measuring in about 1 day after above-mentioned particulate matter prepares that particulate matter had, described particulate matter is to store under environmental condition, under 24 ℃, relative humidity is about 30～60% according to appointment.Expansion volume should be not lower under this pressure-bearing, common disintegrating property was relatively poor when cause was low, expansion volume is also uncomfortable too high under this pressure-bearing, and expansion volume may cause part " drying " under the too high pressure-bearing, produces zest then, allows the patient feel partial discomfort (as sensation of pricking).

Above-mentioned particulate matter is expressed with the time that reaches expansion volume under 60% pressure-bearing relatively slowly absorbing liquid and expansible speed or speed under external pressure or the pressure-bearing.Combine with embodiment below and provided the assay method of used time when reaching expansion volume under 60% pressure-bearing.The time that reaches expansion volume under 60% pressure-bearing that following mensuration provides, here be meant in minute, above-mentioned particulate matter absorbs and always under 60% the pressure-bearing reach this particulate matter to absorb the used time of expansion volume, always under the pressure-bearing of particulate matter absorbs expansion volume under the pressure-bearing that expansion volume is expressed as particulate matter.Usually the time when above-mentioned particulate matter reaches expansion volume under 60% pressure-bearing of wishing was at least about 5 minutes, preferably being at least about 10 minutes, advantageously is about 10～300 minutes, more advantageously is about 20～200 minutes, be suitably about 20～120 minutes, be about 20～60 minutes preferablyly.The time that reaches expansion volume under 60% pressure-bearing usually should be too not short, because of imbibition may cause part " drying " too soon, and then produces zest, allows the patient feel partial discomfort (as sensation of pricking); But also uncomfortable long, not so, drug release is too slow, unless special preface needs are arranged, as time-delay release (as delaying time 2～8 hours) or long period release (as 2 days or 7 days or interior release of longer time).

Think according to reason or default stripping curve stripping in order to make medicine better, in pharmaceutical carrier of the present invention, use the above-mentioned particulate matter of two kinds or expansible speed of more kinds of difference or speed, can make pharmaceutical carrier disintegrate on different time like this, drug release presents " stage " or " pulsed ", thereby drug release is release on different time sections, presents release front and back speed unanimity generally.In an embodiment, the time that reaches expansion volume under 60% pressure-bearing of the above-mentioned particulate matter of part consumption is about 5～about 60 minutes (preferably about 10～about 60 minutes), and the time that reaches expansion volume under 60% pressure-bearing of the above-mentioned particulate matter of another part consumption is about 90～about 300 minutes; In another embodiment, the time that reaches expansion volume under 60% pressure-bearing of the above-mentioned particulate matter of part consumption is about 5～about 60 minutes (preferably about 10～about 60 minutes), the time that reaches expansion volume under 60% pressure-bearing of the above-mentioned particulate matter of a part consumption is about 90～about 300 minutes, and the time that reaches expansion volume under 60% pressure-bearing of the above-mentioned particulate matter of another part consumption is about 180～about 600 minutes.The amount ratio in pharmaceutical carrier of the particulate matter of expansible speed of above-mentioned difference or speed preferably is about 1: 1: 1 ...The particulate matter of expansible speed of above-mentioned difference or speed can be scattered in in a kind of release particulate matter, also can be scattered in the different release particulate matters respectively, the different release particulate matter of this kind is packed in the same drug release carrier as in capsule, the bag agent, perhaps is pressed into simultaneously in the tablet.

When above-mentioned water-swellable and water-insoluble acidity (or alkalescence) polymer and above-mentioned alkalescence (or acidity) when material is scattered in this pharmaceutical carrier with particulate matter, the individual particle of this particulate matter contains above-mentioned acidity (or alkalescence) polymer and/or above-mentioned alkalescence (or acid) material, usually wish that this particulate largest cross-sectional sized is less than about 600 microns (about 28 orders, Tylerstandard), preferably less than about 75 microns (about 200 orders, Tyler standard), more preferably less than about 25 microns (about 500 orders, Tyler standard).

Usually, get the acidity or alkaline water swellability and the insoluble polymer that are essentially its free acid (or free alkali) form respectively, add in the pharmaceutical carrier of the present invention with alkalescence (or acid) material respectively, they separately acidity and the mol ratio of basic functionality should be enough to offer in the pharmaceutical carrier of the present invention with required performance.Preferred acidic (or alkalescence) water-swellable and insoluble polymer are about 10: 1～about 1: 10 with alkalescence (or acid) acidity of material and the mol ratio of basic functionality respectively, be suitably about 4: 1～about 1: 4, be about 2: 1～about 1: 2, optimum ground is about 1: 1 preferablyly.

Gross weight based on pharmaceutical carrier, the total content of above-mentioned acid (or alkali) property water-swellable and insoluble polymer and above-mentioned alkali (or acid) property material (content and) is respectively 0.1～25%wt/wt usually, preferably 0.5～20%wt/wt, more preferably 1～15%wt/wt.

Usually, commercially available water-swellable and insoluble polymer are essentially form or the salt form that is neutralized.But unfortunately, " salt poisoning " effect and " gel blockage " effect easily take place in the water-swellable and the insoluble polymer of salt form, particularly under artesian condition, its disintegration easily is greatly diminished, thereby the release to medicine produces bigger influence, and more neutralization is preceding not high usually in side effect such as its zest, and biocompatibility descends.

Thereby, be used for the form that water-swellable of the present invention and insoluble polymer adopt its free acid or free alkali basically.Yet, the acidity of above-mentioned water-swellable and insoluble polymer and polymer or basic functionality are respectively relative more weak character, when it places liquid separately, as in water or the moisture sodium chloride solution time, these faintly acids or weakly alkaline functional group are not easy disassociation, are difficult to bring into play its performance usually.

Yet, the present invention finds, when mixing use, the pharmaceutical carrier of gained has more performance with alkali (or acid) material (particularly alkalescence (or acid) water-swellable and insoluble polymer) when the above-mentioned acidity that is respectively its free acid (or free alkali) form basically (or alkalescence) water-swellable and insoluble polymer.It mainly shows following several aspect.The first, better drug release feature, higher anti-" salt poisoning " effect can release better in high level salt solution; The second, better release homogeneity is alleviated better or is solved problems such as " release first quick and back slow " and/or " do not hold release incomplete "; The 3rd, better biocompatibility.

When pharmaceutical carrier is placed aqueous solution, basically be respectively acidity (or alkalescence) water-swellable and the insoluble polymer of its free acid (or free alkali) form, with respectively with opposite alkalescence (or acid) substance reaction, and the acidity that this chemical equilibrium helps being respectively its free acid (or free acid) form (or alkalescence) chemical compound changes its salt form into.Water-swellable after the conversion and insoluble polymer will have them and can bring into play the performance roughly suitable with the salt form chemical compound generally.Water-swellable and insoluble polymer water absorption and swelling after the conversion (ionizing) play the disintegrating agent effect, promote the release of medicine thereby the medicine carrier matrix is decomposed break.

Containing dielectric solution, water-swellable and insoluble polymer as above-mentioned acidity in the sodium-chloride water solution (or alkalescence) are transformed to its salt form by its free acid (or free alkali) form respectively, this comes down to containing the desalination that dielectric solution has, relax " salt poisoning " effect thus, thereby improved its performance respectively.

In addition, the inventor also finds the acidity by its free acid (or free alkali) form (or alkalescence) water-swellable and the insoluble polymer of above-mentioned use, mix use as absorbing disintegrating agent with opposite alkalescence (or acid) material, this absorption disintegrating agent has withstand voltage preferably effect, under artesian condition, be difficult for taking place " gel blockage ", thereby the pharmaceutical carrier disintegrate is more abundant or more thorough, and drug release is more abundant or more complete.

It is believed that, just be based on above-mentioned these factors, the pharmaceutical carrier that the present invention relates to has good drug release feature, higher anti-" salt poisoning " effect, can in high level salt solution, release show better release homogeneity, can alleviate or solve problems such as " release first quick and back slow " and/or " do not hold release incomplete " better.

Because water-swellable of acid (or alkalescence) and insoluble polymer are respectively by this conversion of its free acid (or free alkali) form to its salt form, it is the process that a slow relatively disassociation and ions diffusion are gone into polymer, therefore, the slowly performance of the water-swellable of acid (or alkalescence) and the performance of insoluble polymer with continuing, thereby make to contact with this pharmaceutical carrier or be difficult for taking place quick dehydration, cause local " drying ", thereby zest lowers, the patient feels that partial discomfort (as sensation of pricking) sense alleviates with the contiguous mucosa of this pharmaceutical carrier.Especially, when the water-swellable of above-mentioned tart water-swellable and insoluble polymer and alkalescence and insoluble polymer coexist as pharmaceutical carrier, they are transformed to separately salt form by its free acid (or free alkali) form respectively, there are not to introduce a large amount of unnecessary ions, as sodium ion, potassium ion, chloride ion, sulfate ion, thereby when guaranteeing that they can bring into play the performance roughly suitable with the salt form chemical compound generally, and reduce zest widely to mucosa etc.Thereby the biocompatibility of pharmaceutical carrier is enhanced better.

Great special feature of the present invention and conventional art is, by swelliong power and particularly its expansible speed or speed of controlling above-mentioned absorption disintegrating agent, control the body fluid absorbtivity of pharmaceutical carrier in body cavity, particularly delay pharmaceutical carrier body fluid absorption rate in vivo, eliminate or delay part " drying ", lower zest, alleviate the patient and feel partial sense of discomfort (as sensation of pricking).

In the pharmaceutical carrier that the present invention relates to, also to add a kind of pharmaceutically acceptable water-soluble surfactant.Described surfactant is mainly made porogen in the present invention, for acid (or alkalescence) water-swellable and insoluble polymer provide how required medium---aqueous water with alkalescence (or acidity) substance reaction, quicken its reaction, and promote the pharmaceutical carrier release.Can be used for water-soluble surfactant of the present invention, with the neutral surface active agent for better, the example includes but not limited to that castor oil derivatives is (as commodity HCO 60 by name, polyoxyethylene (60) castor oil hydrogenated that Nikko Chemical Co., Ltd produce), Polysorbate (as Tween61, Tween60, Tween80), polyoxyethylene stearic acid ester (as Polyethylene Glycol (40) stearate).The amount of water-soluble surfactant in pharmaceutical carrier should be not enough to make pharmaceutical carrier liquefaction or emulsifying or thawing when it contacts with endoceliac body fluid, and the fusing point when pharmaceutical carrier contacts with body fluid in other words must be higher than 37 ℃ of temperature.This is because pharmaceutical carrier just can liquefy when contact with body fluid in body cavity or melt will be caused that medicine is dashed forward and release in other words dosage and incline and release (dose-dumping), thus initiation drug safety problem.Water-soluble dosage of surfactant is generally 0.1～5%, and preferably 0.5～2%, based on the gross weight of pharmaceutical carrier.

Any medicine or active component may be used to the present invention, especially are fit to the medicine or the active component of sustained-release administration.Suitable to be used for medicine of the present invention be to be selected from, but be not limited to this: adrenocortical hormone, local anesthetic, analgesic/analgesia/antibiotic medicine, antiinflammatory/antipruritic, Wound-healing agent, vitamin, sulfonamides, antibiotic, antifungal, antibacterial, antiviral agents, vasoconstrictor, antihistaminic, anesthetis, astringent, contraceptive, the termination of pregnancy medicine, defecation promoter, the hypnosis tranquilizer, antianxiety drugs, Anti-epileptics, excited inoitantia, antiparkinsonian drug, the central nervous system does medication, analgesics, skeletal muscle relaxant, autonomic drug, spasmolytic, antivertigo drug, antiemetic, cardiac tonic, anti-arrhythmic, diuretic, antihypertensive, the coronary vasodilator vasodilator, peripheral vasodilator, the hyperlipidemia medicine, breathe accelerator, the beta 2 receptor agonist, anti-Meniere's disease medicine, antitumor agent, antidiarrheal/intestinal function regulator, the ulcerative colitis therapeutic agent, the peptic ulcer therapeutic agent, resistance dysfunction medicine, Labor-inducing medicine, anthelmintic, bronchodilator, biological product or peptide class, anti-allergic drug, cathartic, enema, choleretic and the multiple hormone except that adrenocortical hormone.

Can be compounded in the concrete medicine in the pharmaceutical carrier of the present invention, its illustration can be to be selected from one or more following medicines, but is not limited to these:

Adrenocortical hormone, for example prednisone acetate dragon, prednisolone, acetic acid hydrocortisone, hydrocortisone, acetic acid cortisone, cortisone, acetic acid dexamethasone, dexamethasone, acetic acid triamcinolone;

Local anesthetic, lidocaine hydrochloride for example, lignocaine, dibucaine hydrochloride, dibucaine, procaine hydrochloride, procaine, tetracaine hydrochloride, tetracaine, chloroprocaine hydrochloride, chloroprocaine, bupivacaine hydrochloride, bupivacaine, the hydrochloric acid third handkerchief caine (propalacaine), the third handkerchief caine, meprylcaine hydrochloride ((mepurylcaine), meprylcaine, mepivacaine, benzocaine, orthocaine (orsocaine), Mucaine, Ethyl aminobenzoate., hydrochloric acid is to fourth aminobenzoyl diethylaminoethanol, oxidation polyethoxy decane or east flower labor belong to extract;

Analgesic-analgesia-antibiotic medicine, for example aspirin, acetaminophen, mefenamic acid, acetamido benzene, Phenacetin, diclofenac sodium, diclofenac potassium, the delicious suffering of Yin, buprenorphin hydrochloride, ibuprofen, mefenamic acid, aminophenazone, ketoprofen, piroxicam, ibuprofen, (S)-ibuprofen, naproxen, sulfasalazine, mesalazine, ketoprofen, meloxicam, benzydamine hydrochloride, ethenzamide and piroxicam;

Antiinflammatory-antipruritic, for example enoxolone, lisozima, diformazan isopropyl azulene, ichthyol, Camphora, crotamiton, lysozyme chloride, tribenoside, aluminium potassium sulfate, Radix Arnebiae (Radix Lithospermi) extract, rosskastanien extract, Hamamelis virginiana (witch hacel) extract, the cana Brava of processing, refined vitelline lecithin, elgen, d-Camphora, dl-Camphora, Oleum menthae, l-menthol, dl-menthol, Eucalyptus oil;

Vitamin, for example tocopherol acetate, tocopherol, vitamin D2, palmitic retinol, Vitamin A1 acetate, pyridoxine hydrochloride, hydrochloric acid pyridoxamine, phosphopyridoxamine, pyridoxal hydrochloride, pyridoxal 5-phosphate, riboflavin, Riboflavin butyrate, vitamin A oil, vitamin C, vitamin B6, vitamin e acetate, senior liver oil or liver oil;

Sulfonamides, for example sulfadiazine, sulfasomidine, sulfasomidine sodium, high sulfonamide, domian, domian sodium, homosulfamine;

Antibiotic or antifungal, for example cephalosporins such as ceftizoxime sodium, penicillins such as sodium ampicillin, quinolones such as norfloxacin, ofloxacin, ciprofloxacin, ciprofloxacin lactate, pefloxacin mesilate, levofloxacin lactate, Macrolide such as erythromycin, Tetracyclines such as tetracycline, quadracycline, tetramycin hydrochloride, antimycotic such as clotrimazole, miconazole, tinidazole, miconazole nitrate, econazole nitrate, terconazole (triaconazole), ketoconazole, Nitric acid butoconazole, sertaconazole, oxygen health azoles, Fazol (Schering), hachimycin, nysfungin, natamycin, ciclopirox olamine, nifuratel, econazole, econazole nitrate, miconazole, micatin, the chlorine trityl imidazole, bifonazole, terbinafine HCl and butenafine hydrochloride, other antibiotic such as streptomycin sulfate, gentamycin sulfate, lincomycin hydrochloride, clindamycin phosphate, polygynax, amphotericin B, kanamycin sulfate, metronidazole, ornidazole, secnidazole, chloromycetin, nitrofurantoin, fibrauretin, matrine, Sodium Houttuyfonate, pimaricin;

Antibacterial, for example ethacridine, chlorhexidine acetate, poly-aminoethyl glycine Arrcostab, isopropyl cresol, cetyl pyridine chlorine, dequalinium chloride, berberine chloride, benzalkonium chloride, Chlorhexidine hydrochloride, cetab, chlorination decahydronaphthalenes, phenol, resorcin, policresulen, povidone iodine;

Astringent, for example zinc oxide, tannic acid, albumin tannate and aluminum potassium sulfate;

Wound healing promoters, for example allantoin and chlorine hydroxyl aldioxa;

Vasoconstrictor, for example adrenalin hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, meta-synephrine hydrochloride, hydrochloric acid dl-methylephedrine and oxymetazoline hydrochloride;

Antihistaminic, for example diphenhydramine, diphhydramine hydrochloride, diphenhydramine tannate, diphenhydramine lauryl sulfate, chlorphenamine or diphenylpyraline hydrochloride;

Anesthetis, for example morphine hydrochloride, ethylmorphine hydrochloride, morphine sulfate, codeine phosphate, dihydrocodeine phosphate, cocaine hydrochloride or pethidine hydrochloride;

Contraceptive, for example mandelic acid, nonoxynolum;

Termination of pregnancy medicine, for example carboprost methylate, dinoprostone;

Defecation promoter, for example bisacodyl, glycerol;

Peptic ulcer therapeutic agent, for example cuscohygrylis;

Antiemetic, for example domperidone, Ondansetron Hydrochloride;

Progestogens medicine, for example Progesterone;

Resistance dysfunction medicine, for example Alprostadil, phentolamine mesylate;

Anthelmintic, for example Pyrantel Pamoate, levamisole hydrochloride bolt;

Antiviral agents, for example zidovudine;

Progestogens medicine, for example Progesterone;

Alora, for example estriol, estradiol, promestriene;

Labor-inducing medicine, for example PGE2;

Steroid hormone class, for example danazol;

Ulcerative colitis therapeutic agent, for example mesalazine;

Analgesics, for example morphine sulfate, tramadol hydrochloride;

Anti-Meniere's disease medicine, for example sodium bicarbonate;

Antitumor agent, for example 5-fluorouracil and ftorafur;

Beta 2 receptor agonist, for example clenbuterol hydrochloride;

Convulsion, epilepsy medicine, for example valpromide;

Bronchodilator, for example aminophylline;

Biological product class, for example recombinant human interferon alpha-2, recombinant human interferon alpha 2 b, peptide class such as insulin, recombined human granulocyte-macrophage stimulating factors, lactobacillus.

Medicine or the active component content in pharmaceutical carrier is generally 0.1～30%, based on the gross weight of pharmaceutical carrier.

The pharmaceutical carrier that the present invention relates to can also add other additives except above-mentioned matrix components, (as anhydrous silicic acid, starch, crystalline cellulose, zinc oxide and alginic acid, wherein, anhydrous silicic acid is preferred as the fatty glyceride insoluble composition.), antioxidant, antiseptic, coloring agent etc.These additive amount are generally 0.1～10%, based on the gross weight of pharmaceutical carrier, but not limited, decide on actual needs.

The rate of releasing drug of the pharmaceutical carrier that the present invention relates to can be adjusted by adjusting above-mentioned relevant components in proportions, particularly water soluble, low viscosity, non-irritating organic compound and the ratio of water soluble surfactant active in pharmaceutical carrier, and contain the ability of imbibition of particulate matter of above-mentioned acid (or alkali) property water-swellable and insoluble polymer and/or above-mentioned alkali (or acid) property material and speed and the consumption in pharmaceutical carrier thereof and wait and regulate rate of releasing drug.

The fusing point of the pharmaceutical carrier that the present invention relates to must be higher than 37 ℃ of temperature, preferably is higher than 40 ℃, but preferably is not higher than 80 ℃, more preferably is not higher than 60 ℃, is not higher than 50 ℃ best.This ceiling temperature depends on clinical practice, and oral in this way interior with still tract external, normal temperature is suitably good than the lowland during tract external, as 40～50 ℃; This temperature is then good than the highland when oral, as 40～60 ℃, and preferably 50～80 ℃.In addition, fusing point when pharmaceutical carrier contacts with body fluid must be higher than 37 ℃ of temperature, can not liquefaction when guaranteeing that pharmaceutical carrier contact with body fluid in body cavity, emulsifying or thawing, dash forward and release in other words the dosage drug safety problems such as releasing (dose-dumping) of inclining thereby avoid taking place medicine.

The preparation application form of the pharmaceutical carrier that the present invention relates to is the dosage form and the suppository of the oral administration of slow release release best.The dosage form of suitable oral administration of the present invention such as tablet, capsule, granule, pill (containing drop pill).Be fit to be applied to suppository form of the present invention, as be rectally suppository, vagina administration suppository, urethra administration suppository or auditory meatus administration suppository, wherein vagina administration suppository is for more preferably.The profile that is used for suppository of the present invention has no particular limits, have only suitable clinical practice just, the example of the suitable profile that is used for suppository of the present invention such as sheet shape, ball shape, prismatic, pencil shape, sphere, bullet-shaped, top fuller shape, torpedo shape, ovum shape or duck chew shape or the like.

The pharmaceutical carrier that the present invention relates to can also comprise the part that a part of medicine rapid release discharges.

The pharmaceutical carrier that the present invention relates to can be produced by the following method, but is not limited to this, has only suitable production reality just.For example, at first, the fusion of aliphatic additive; Then surfactant, water soluble, low viscosity, non-irritating organic compound particulate matter contain the particulate matter of acidity (or alkalescence) polymer and/or alkalescence (or acid), and medicine and the adding of other additives also are stirred to uniform mixing.The mixture that is generated is loaded into container then, be shaped, or the like, the curing that is cooled of shaping thing; Can also further pulverize after the curing, can further make the form that is fit to oral administration or cavity/canal drug administration after the pulverizing, as tablet, capsule, pill.

The present invention is relatively with technology, has one of following advantage at least:

1), better drug release feature, as higher anti-" salt poisoning " effect, can release better in high level salt solution, better release homogeneity is alleviated better or is solved " release is first quick and back slow " and " do not hold release incomplete " problem;

2), lower mucous membrane irritation, better biocompatibility;

3), be not prone to the prominent dosage drug safety problems such as releasing (dose-dumping) of inclining of releasing in other words of medicine;

4) in the time of, can realizing selecting or stage release.

Described the present invention thus in detail, obviously also various changes can have been arranged within the scope of the invention to those skilled in the art, the present invention is not subjected to the described restriction of description.

Description of drawings:

Fig. 1 embodiment 1 and reference examples 1 drug release test result

Fig. 2 embodiment 2 and reference examples 2 drug release test results

Fig. 3 embodiment 3 and reference examples 3 drug release test results

Fig. 4 embodiment 4 and reference examples 4-1,4-2 drug release test result

Fig. 5 embodiment 5 and reference examples 5-1,5-2 drug release test result

Fig. 6 embodiment 6 and reference examples 6-1,6-2 drug release test result

Fig. 7 measures the device of expansion volume

Embodiment

Below non-selective embodiment further described preferred embodiment in the scope of the invention.Yet should be appreciated that the present invention is not limited only to these embodiment.

Embodiment 1:

Annotate: a1, this granule Specifeca tion speeification sees Table 1;

B1, the particulate preparation method of this sodium polyacrylate: the above-mentioned carbopol gel of this embodiment that is used for is mixed the carbopol gel granule that neutralizes above-mentioned thus with the sodium hydrate aqueous solution of excessive slightly 0.1 weight %.What will obtain before using cleans to (23 ℃ at ambient temperature of neutral expanded gel repeatedly with distilled water, relative humidity 30%) at least after dry 3 day, add an amount of PVP anhydrous alcohol and granulate, cross the granule that 80 orders and 160 mesh sieves get 106～180 microns of particle diameters after the drying.

Embodiment 2:

Annotate: a2, this granule Specifeca tion speeification sees Table 1;

B2, the particulate preparation method of this polylysine citrate: the above-mentioned polylysine gel that is used for this embodiment is mixed the polylysine gel particle that neutralizes above-mentioned thus with the aqueous solution of citric acid of excessive slightly 0.1 weight %.What will obtain before using cleans to (23 ℃ at ambient temperature of neutral expanded gel repeatedly with distilled water, relative humidity 30%) at least after dry 3 day, add an amount of PVP anhydrous alcohol and granulate, cross the granule that 80 orders and 160 mesh sieves get 106～180 microns of particle diameters after the drying.

Embodiment 3:

Annotate: a3, this granule Specifeca tion speeification sees Table 1;

B3, the particulate preparation method of this sodium polyacrylate: the above-mentioned carbopol gel of this embodiment that is used for is mixed the carbopol gel granule that neutralizes above-mentioned thus with the sodium hydrate aqueous solution of excessive slightly 0.1 weight %.What will obtain before using cleans to (23 ℃ at ambient temperature of neutral expanded gel repeatedly with distilled water, relative humidity 30%) at least after dry 3 day, add an amount of PVP anhydrous alcohol and granulate, cross the granule that 80 orders and 160 mesh sieves get 106～180 microns of particle diameters after the drying.

Embodiment 4:

Annotate: a4, this granule Specifeca tion speeification sees Table 1;

B4-1, the particulate preparation method of this sodium polyacrylate: the above-mentioned carbopol gel of this embodiment that is used for is mixed the carbopol gel granule that neutralizes above-mentioned thus with the sodium hydrate aqueous solution of excessive slightly 0.1 weight %.What will obtain before using cleans to (23 ℃ at ambient temperature of neutral expanded gel repeatedly with distilled water, relative humidity 30%) at least after dry 3 day, add an amount of PVP anhydrous alcohol and granulate, dry back cross 60 orders and 90 mesh sieves get 160～250 microns of particle diameters granule.

B4-2, the particulate preparation method of this chitosan salts hydrochlorate: with the above-mentioned combined that is used for the chitosan gel of this embodiment and excessive slightly 0.1 weight %, the chitosan gel granule that neutralizes above-mentioned thus.What will obtain before using cleans to (23 ℃ at ambient temperature of neutral expanded gel repeatedly with distilled water, relative humidity 30%) at least after dry 3 day, add an amount of PVP anhydrous alcohol and granulate, cross the granule that 60 orders and 90 mesh sieves get 160～250 microns of particle diameters after the drying.

Embodiment 5:

Annotate: a5, this granule Specifeca tion speeification sees Table 1;

B5-1, the particulate preparation method of this sodium polyacrylate: above-mentioned sodium polyacrylate (degree of neutralization 20%) gel that is used for this embodiment is mixed the sodium polyacrylate gel particle that neutralizes above-mentioned thus with the sodium hydrate aqueous solution of excessive slightly 0.1 weight %.What will obtain before using cleans to (23 ℃ at ambient temperature of neutral expanded gel repeatedly with distilled water, relative humidity 30%) at least after dry 3 day, add an amount of PVP anhydrous alcohol and granulate, cross the granule that 60 orders and 90 mesh sieves get 160～250 microns of particle diameters after the drying.

B5-2, the particulate preparation method of this chitosan salts hydrochlorate: with the above-mentioned combined that is used for the chitosan gel of this embodiment and excessive slightly 0.1 weight %, the chitosan gel granule that neutralizes above-mentioned thus.What will obtain before using cleans to (23 ℃ at ambient temperature of neutral expanded gel repeatedly with distilled water, relative humidity 30%) at least after dry 3 day, add an amount of PVP anhydrous alcohol and granulate, cross the granule that 60 orders and 90 mesh sieves get 160～250 microns of particle diameters after the drying.

Embodiment 6:

Annotate: a6, this granule Specifeca tion speeification sees Table 1;

B6-1, the particulate preparation method of this sodium acrylate graft starch: the above-mentioned acrylic acid grafted starch gel that is used for this embodiment is mixed the acrylic acid grafted starch gel particle that neutralizes above-mentioned thus with the sodium hydrate aqueous solution of excessive slightly 0.1 weight %.What will obtain before using cleans to (23 ℃ at ambient temperature of neutral expanded gel repeatedly with distilled water, relative humidity 30%) at least after dry 3 day, add an amount of PVP anhydrous alcohol and granulate, cross the granule that 60 orders and 90 mesh sieves get 160～250 microns of particle diameters after the drying.

B6-2, the particulate preparation method of this polylysine hydrochlorate: with the combined of the above-mentioned polylysine gel that is used for this embodiment with excessive slightly 0.1 weight %, the polylysine gel particle that neutralizes above-mentioned thus.What will obtain before using cleans to (23 ℃ at ambient temperature of neutral expanded gel repeatedly with distilled water, relative humidity 30%) at least after dry 3 day, add an amount of PVP anhydrous alcohol and granulate, cross the granule that 60 orders and 90 mesh sieves get 160～250 microns of particle diameters after the drying.

Embodiment and reference examples preparation method:

Get the aliphatic additive (as

H15, E85, glycerol three stearic acid, Brazil wax, stearic acid and tripalmitin, propylene glycol monostearate, hydrogenated vegetable wet goods) heating (to temperature 60-90 ℃) make its fusing, add surfactant (as HCO 60, TWEEN 80, Polyethylene Glycol (40) stearate etc.), mix homogeneously; Adding contains the particulate matter of acidity (or alkalescence) polymer and/or alkalescence (or acid) (as polyacrylic acid-sodium bicarbonate particle, polyacrylic acid (sodium) granule, citric acid-polylysine granule, polylysine citrate granule, (premix) particulate matter of sodium polyacrylate (degree of neutralization 20%) granule and chitosan particle etc.), levigate and cross water soluble compound (as glycine, mannitol, glucose, the sucrose etc.) granule of 100 mesh sieves and levigate and cross the Bleocin Hydrochloride of 200 mesh sieves, mixing repeatedly repeatedly; Under the condition of molten mixture insulation, pour into torpedo shape suppository (the about 10mm of base diameter, high about 16mm) or fusiformis tablet mould (diameter about 4mm in middle part is about 8mm), get final product after the cooling.

Table 1 absorbs the performance parameter of disintegrating agent

Absorb the particulate preparation method of disintegrating agent: embodiment 1～4 and 6, it is levigate and cross 250 mesh sieves repeatedly to get polymeric material and alkaline matter (or acidic materials), behind the mix homogeneously, add an amount of PVP anhydrous alcohol and granulate, 80 orders and 160 orders or 60 orders and 90 mesh sieves are crossed in dry back, and to get the granule of particle diameter 106～180 or 160～250 microns standby; Embodiment 5, and it is levigate and cross 250 mesh sieves repeatedly to get acidity and alkaline polymer material respectively, add an amount of PVP anhydrous alcohol respectively and granulate, and the granule that 60 orders and 90 mesh sieves get 160～250 microns of particle diameters is crossed in dry back, and is standby behind the particulate matter mix homogeneously that makes.

Annotate: §, by Friedrich Helfferich, Ion Exchange, page 84, MaGraw-Hill Book Company, 1962 is that obtain or measured the value that obtains voluntarily by the inventor.

★, represent 25 ℃ under, be dissolved in the viscosity of the chitosan soln of 1% in 1% acetic acid solution.

Attached:

Free wxpansion capacity and the method for testing that reaches the time of 60% free wxpansion capacity

The free wxpansion solid measure be that 1 gram absorbed the disintegrating agent material in 10 hours, at insignificant load or binding force, under for example about 0.01 pound/square inch load, can absorb the gram number of the aqueous solution that contains 0.9% sodium chloride.

Accompanying drawing 7 has been described the method and apparatus of measuring the free wxpansion capacity.The shown perspective view that is to use in the process this device in position.Laboratory has adjustable knob 2 with crane 1, in order to hoistable platform 3.Laboratory is supporting spring 5 with stand 4, and this spring 5 is connected in improved pachometer probe 6, and this probe 6 passes the chamber 7 of the pachometer that is fixedly secured with stand by laboratory.The plastic sample cup 8 that the absorption disintegrating agent material sample that will test is housed has the permeable end of liquid and drops in the culture dish 9, and culture dish contains the saline solution that will absorb.Only under measuring pressure-bearing, during absorption value, absorb (not shown) on the pad disk on the disintegrating agent sample (not shown) top, have a weight 10 to be put on its top.

Specimen cup is made up of plastic cylinder, and this cylindrical internal diameter is 1 inch, and external diameter is 1.25 inches.The 200 order metallic sieves that will have 75 microns perforates be adhered to this cylindrical open-ended on, form the end of specimen cup, this bonding be that screen cloth is heated to more than the fusing point of plastics, and with plastic cylinder press to heat screen cloth screen cloth is connected on the plastic cylinder.

Expansible improved thickness measuring is counted Mitutoyo Digimatic Indicator when being used for working sample absorption saline, IDCSeries 543, Model 543-180, its measuring range is 0～0.5 inch, and precision is 0.00005 inch (Mitutoyo Corporation, 31-19, Shiba 5-chome, Minato-ku, Tokyo 108, Japan).The thickness measuring that is provided by Mitutoyo Corporation is in respect of the spring that is connected in probe, and this probe is in the chamber of pachometer.Remove spring with provide free-falling, downward force be about 27 the gram probes.In addition, also removed the medicated cap on the probe tip that is positioned at the pachometer chamber roof, so that probe is connected in suspended spring S (by McMaster-Carr Supply Co., Chicago, IIinois obtains, Item No.9640K41), this spring is in order to offset the downward force of probe or be decreased to about 1 ± 0.5 gram.The metal wire hook can be connected in the top of probe, so that probe is connected with the spring that is folded down.Probe also provides the pointer (Mitutoyo Corporation, Part No.131279) of extension in the bottom of probe, so that can be inserted in the specimen cup.

For measuring, will absorb disintegrating agent sample 0.160 gram and place specimen cup.Be that about 0.995 inch plastic spacer disk covers with this sample with heavy 4.4 grams, diameter then, the effect of this pad disk be prevent sample in test process by disturbance, and load is put on the sample equably.Then specimen cup and material sample and pad disk are weighed, to obtain its dry weight.Specimen cup is placed culture dish on the platform, and laboratory is raise with crane, contact with the tip of probe until the top margin of plastic spacer disk.Pachometer is returned to zero.In culture dish, add the saline solution (50～100 milliliters) of q.s, begin test.The distance that the plastic spacer disk that is caused by the expansion of probe assay absorption of sample saline solution raises.This distance multiply by the interior sectional area of specimen cup, is sample by absorbing the expanding volume that is caused.In conjunction with the density of saline solution and the weight of sample, be easy to calculate the amount of the saline solution of absorption.The saline solution weight of 10 hours post-absorption, the free wxpansion capacity that reaches with the gram numerical table that is that every gram absorbs that disintegrating agent absorbs.If need, the reading of improved pachometer can be input to continuously in the computer (Mitutoyo Digimatic Miniprocessor DP-2DX), to calculate and to provide the free wxpansion capacity.As cross check, also can determine the free wxpansion capacity by the weight difference of working sample cup before and after test, this weight difference is the solution amount of absorption of sample.

According to the continuous monitoring that provides by computer, be easy to determine to reach the time of 60% free wxpansion capacity to the free wxpansion capacity.

Expansion volume and the assay method that reaches the time of expansion volume under 60% pressure-bearing under the pressure-bearing

The expansion volume test determination is to apply under about 0.3 pound/square inch load or binding force under the pressure-bearing, the gram number of the aqueous solution that contains 0.9% sodium chloride that 1 gram absorption disintegrating agent material was absorbed after 10 hours.It is basic identical with the method for measuring the free wxpansion capacity to measure the method that absorbs disintegrating agent pressure-bearing absorption value, different is the weight of placing 100 grams at the top of plastic spacer disk, applies about 0.3 pound/square inch load thus on the absorption disintegrating agent that absorbs saline solution.

According to the continuous monitoring that provides by computer, be easy to determine to reach the time of 60% pressure-bearing absorptive capacity value to the pressure-bearing absorption value.

According to said method measured some absorb the free wxpansion capacity of disintegrating agents and reach time of 60% free wxpansion capacity and pressure-bearing under expansion volume and reach time of expansion volume under 60% pressure-bearing, see Table 1.

Inspection example 1: the mensuration of drug release rate

Test sample:

The suppository of embodiment 1-6 and reference examples 1-6 is used as test sample.

The method of inspection:

Each test sample is prepared 6 long 17mm and the test tube of 10ml compound sodium chloride injection (ringer's solution) (Chinese Pharmacopoeia 2005 version two ones) is housed.Test tube is inserted in 37 ℃ the temperature chamber and is remained static.Test sample is with gauze parcel and to be dipped in label be that the back is taken out test sample and immersed successively in next test tube compound sodium chloride injection at regular intervals in 1 the invisible spectro compound sodium chloride injection.The medicine that discharges into solution is measured at 292.5nm with spectrophotography.

Result: Fig. 1-6 shows the rate of release of Bleocin Hydrochloride.The suppository of embodiment demonstrates the better medicament release characteristics, as higher salt tolerance and effectively alleviate " release first quick and back slow " and problems such as " do not hold release incomplete ".

Inspection example 2 vaginal mucosa irritation tests

Test sample:

Bolt/the tablet of embodiment 1,2,4 and reference examples 1,2,4 is used as test sample.

The method of inspection:

Get 12 of rabbit (healthy adult new zealand rabbit, body weight 2.5～2.7kg, female), be divided into administration group, matched group at random by body weight, 6 every group.The administration group gives embodiment bolt/sheet, and matched group gives reference examples bolt/sheet, and dosage is only pressed rabbit vagina maximum dosage-feeding 1.0g/, give respectively in administration group and the matched group rabbit vagina, continue 6h, administration continues therebetween rabbit and puts in the fixed bin successive administration 10 days.Behind last administration 24h, put to death animal, dissect and take out the vagina specimen, vertically cut, the perusal mucosa has or not phenomenons such as hyperemia, swelling, carries out mucous membrane irritation reaction scoring by table 2.Simultaneously with every rabbit vagina tissue, more than 10% formalin fixed 24h, choose central part through dehydration, embedding, section and H-E dyeing, carry out histopathological examination at microscopically after the film-making, press every animal pathological reaction scoring of table 3 pathological reaction standards of grading record.The results are shown in (see Table 4, table 5).

The result shows that the mucous membrane irritation of bolt/tablet of embodiment obviously is less than than reference examples.

Table 2 mucous membrane irritation reaction standards of grading

Table 3 mucosal tissue pathological reaction standards of grading

Table 4 embodiment bolt is to rabbit vagina mucosa perusal irritant reaction result

Table 5 bolt is to the pathology microscopy result of rabbit vagina mucous membrane irritation response organization

Annotate: ☆, the scoring of expression epithelial tissue pathology microscopy; ★, the scoring of expression leukocyte infiltration histopathology microscopy; ※: expression (epithelial tissue pathology microscopy scoring sum+leukocyte infiltration histopathology microscopy scoring sum) ÷ 6.

Inspection example 3: mucous membrane of rectum irritation test

Test sample:

Press the prescription and the not blank bolt (/ sheet) agent of pastille of prepared of embodiment 3,5,6 and reference examples 3,5,6.The blank bolt (/ sheet) agent of embodiment 2,6 and reference examples 2,6 is used as test sample.

The method of inspection:

12 rabbit (healthy adult new zealand rabbit, body weight 2.5～2.7kg, male and female half and half) are divided into administration group (anus gives embodiment blank bolt (/ sheet)) and matched group (anus gives reference examples blank bolt (/ sheet)), 6 every group, male and female half and half.With each 1 of grain (heavy 1.0g), 7d inserts the rabbit internal rectum continuously with the blank bolt of embodiment (/ sheet), contacts 6h (1d overnight fasting before the administration, administration in morning next day) at least with it at every turn, observe to tried behind the thing 24,48h overall health of patients and local excitation react.Put to death rabbit on the 7th day, take out rectum, observation has or not phenomenons such as hyperemia, redness, carry out local mucosa irritation reaction grade scale by method in the inspection example 2 and table 2 and mark, and carry out mucosa histopathologic examination and by table 3 result of determination according to the method in the inspection example 2.The results are shown in Table 6,7.

The blank bolt of table 6 is to rabbit mucous membrane of rectum perusal irritant reaction result

The blank bolt of table 7 is to rabbit mucous membrane of rectum irritant reaction histopathology microscopy result

Annotate: ☆: the scoring of expression epithelial tissue pathology microscopy; ★: expression leukocyte infiltration histopathology microscopy scoring; ※: expression (epithelial tissue pathology microscopy scoring sum+leukocyte infiltration histopathology microscopy scoring sum) ÷ 6.

The result shows that the mucous membrane irritation of the blank suppository of embodiment obviously is less than the blank suppository than reference examples.

Synthesis result shows that the overall performance of embodiment is better than reference examples.

Claims (40)

1. the external fusing point of a performance improvement and the fusing point when contacting with body fluid in body cavity all are higher than the pharmaceutical carrier of the slow release release of 37 ℃ of temperature, and this pharmaceutical carrier comprises the aliphatic additive that fusing point that (A) a kind of pharmaceutically acceptable fusing point is higher than 37 ℃ of temperature and when contacting with body fluid also is higher than 37 ℃ of temperature in body cavity; (B) a kind of pharmaceutically acceptable, non-irritating, water-soluble and 25 ℃ of temperature the viscosity of the solution of 2.0% (weight/volume) is less than the additive of 300 centipoises (mPas) down, described additive granules largest cross-sectional sized is less than about 28 orders (Tyler standard); (C) a kind of pharmaceutically acceptable, water-swellable and water-insoluble acidic polymer, this polymer pKa is about 2～about 12; (D) a kind of pharmaceutically acceptable alkaline matter; (E) a kind of pharmaceutically acceptable water miscible surfactant, the use amount of this surfactant is not enough so that this pharmaceutical carrier liquefaction or emulsifying or thawing when it contacts with endoceliac body fluid; (F) a kind of medicine; Perhaps

A kind of external fusing point of performance improvement and the fusing point when contacting with body fluid in body cavity all are higher than the pharmaceutical carrier of the slow release release of 37 ℃ of temperature, and this pharmaceutical carrier comprises the aliphatic additive that fusing point that (A) a kind of pharmaceutically acceptable fusing point is higher than 37 ℃ of temperature and when contacting with body fluid also is higher than 37 ℃ of temperature in body cavity; (B) a kind of pharmaceutically acceptable, non-irritating, water-soluble and 25 ℃ of temperature the viscosity of the solution of 2.0% (weight/volume) is less than the additive of 300 centipoises (mPas) down, described additive granules largest cross-sectional sized is less than about 28 orders (Tyler standard); (C) a kind of pharmaceutically acceptable, water-swellable and water-insoluble alkaline polymer, this polymer pKb is about 2～about 12; (D) a kind of pharmaceutically acceptable acidic materials; (E) a kind of pharmaceutically acceptable water miscible surfactant, the use amount of this surfactant is not enough so that this pharmaceutical carrier liquefaction or emulsifying or thawing when it contacts with endoceliac body fluid; (F) a kind of medicine.

2. according to the pharmaceutical carrier of claim 1, wherein said acidic polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described alkaline matter (D), the individual particle of this particulate matter contains this acidic polymer (C) and/or this alkaline matter (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), the free wxpansion capacity of this particulate matter is at least about 7 gram/grams, and its time that reaches 60% free wxpansion capacity was at least about 5 minutes; Perhaps

Wherein said alkaline polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described acidic materials (D), the individual particle of this particulate matter contains this alkaline polymer (C) and/or this acidic materials (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), the free wxpansion capacity of this particulate matter is at least about 7 gram/grams, and its time that reaches 60% free wxpansion capacity was at least about 5 minutes.

3. according to the pharmaceutical carrier of claim 1 or 2, wherein said acidic polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described alkaline matter (D), the individual particle of this particulate matter contains this acidic polymer (C) and/or this alkaline matter (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), the free wxpansion capacity of this particulate matter is about 10～about 100 gram/grams, and its time that reaches 60% free wxpansion capacity was at least about 10 minutes; Perhaps

Wherein said alkaline polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described acidic materials (D), the individual particle of this particulate matter contains this alkaline polymer (C) and/or this acidic materials (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), the free wxpansion capacity of this particulate matter is about 10～about 100 gram/grams, and its time that reaches 60% free wxpansion capacity was at least about 10 minutes.

4. any one pharmaceutical carrier in the aforementioned claim, wherein said acidic polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described alkaline matter (D), the individual particle of this particulate matter contains this acidic polymer (C) and/or this alkaline matter (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), expansion volume is at least about 7 gram/grams under the pressure-bearing of this particulate matter, and its time that reaches expansion volume under 60% pressure-bearing was at least about 5 minutes; Perhaps

Wherein said alkaline polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described acidic materials (D), the individual particle of this particulate matter contains this alkaline polymer (C) and/or this acidic materials (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), expansion volume is at least about 7 gram/grams under the pressure-bearing of this particulate matter, and its time that reaches expansion volume under 60% pressure-bearing was at least about 5 minutes.

5. any one pharmaceutical carrier in the aforementioned claim, wherein said acidic polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described alkaline matter (D), the individual particle of this particulate matter contains this acidic polymer (C) and/or this alkaline matter (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), expansion volume is about 10～about 70 gram/grams under the pressure-bearing of this particulate matter, and its time that reaches expansion volume under 60% pressure-bearing was at least about 10 minutes; Perhaps

Wherein said alkaline polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described acidic materials (D), the individual particle of this particulate matter contains this alkaline polymer (C) and/or this acidic materials (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), expansion volume is about 10～about 70 gram/grams under the pressure-bearing of this particulate matter, and its time that reaches expansion volume under 60% pressure-bearing was at least about 10 minutes.

6. any one pharmaceutical carrier in the aforementioned claim, wherein said acidic polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described alkaline matter (D), the individual particle of this particulate matter contains this acidic polymer (C) and/or this alkaline matter (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), expansion volume is about 10～about 40 gram/grams under the pressure-bearing of this particulate matter, and its time that reaches expansion volume under 60% pressure-bearing is about 10～300 minutes; Perhaps

Wherein said alkaline polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described acidic materials (D), the individual particle of this particulate matter contains this alkaline polymer (C) and/or this acidic materials (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), expansion volume is about 10～about 40 gram/grams under the pressure-bearing of this particulate matter, and its time that reaches expansion volume under 60% pressure-bearing is about 10～300 minutes.

7. any one pharmaceutical carrier in the aforementioned claim, wherein said acidic polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described alkaline matter (D), the individual particle of this particulate matter contains this acidic polymer (C) and/or this alkaline matter (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), the time that reaches expansion volume under 60% pressure-bearing of the part in this particulate matter is about 10～about 60 minutes, and the time that reaches expansion volume under 60% pressure-bearing of another part is about 90～about 300 minutes; Perhaps

Wherein said alkaline polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described acidic materials (D), the individual particle of this particulate matter contains this alkaline polymer (C) and/or this acidic materials (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), the time that reaches expansion volume under 60% pressure-bearing of a part is about 10～about 60 minutes in this particulate matter, and the time that reaches expansion volume under 60% pressure-bearing of another part is about 90～about 300 minutes.

8. any one pharmaceutical carrier in the aforementioned claim, wherein said acidic polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described alkaline matter (D), the individual particle of this particulate matter contains this acidic polymer (C) and/or this alkaline matter (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), the time that reaches expansion volume under 60% pressure-bearing of the part in this particulate matter is about 10～about 60 minutes, the time of expansion volume under 60% pressure-bearing that a part reaches is about 90～about 300 minutes, and the time that reaches expansion volume under 60% pressure-bearing of another part is about 180～about 600 minutes; Perhaps

Wherein said alkaline polymer (C) is scattered in this pharmaceutical carrier with particulate matter with described acidic materials (D), the individual particle of this particulate matter contains this alkaline polymer (C) and/or this acidic materials (D), this particulate matter largest cross-sectional sized is less than about 28 orders (Tyler standard), the time that reaches expansion volume under 60% pressure-bearing of a part is about 10～about 60 minutes in this particulate matter, the time that reaches expansion volume under 60% pressure-bearing of a part is about 90～about 300 minutes, and the time that reaches expansion volume under 60% pressure-bearing of another part is about 180～about 600 minutes.

9. any one pharmaceutical carrier in the aforementioned claim 2 to 8, the particulate matter largest cross-sectional sized that wherein contains described acidic polymer (C) and/or described alkaline matter (D) is less than about 200 orders (Tyler standard).

10. any one pharmaceutical carrier in the aforementioned claim 2 to 9, the particulate matter largest cross-sectional sized that wherein contains described acidic polymer (C) and/or described alkaline matter (D) is less than about 500 orders (Tyler standard).

11. any one pharmaceutical carrier in the aforementioned claim, the pKa of wherein said acidic polymer (C) is about 2～about 10; Perhaps

The pKb of wherein said alkaline polymer (C) is about 2～about 10.

12. any one pharmaceutical carrier in the aforementioned claim, the pKa of wherein said acidic polymer (C) is about 3～about 6; Perhaps

The pKb of wherein said alkaline polymer (C) is about 3～about 6.

13. any one pharmaceutical carrier in the aforementioned claim, the degree of neutralization of the acidic functionality of wherein said acidic polymer (C) is about 10～about 50 moles of %; Perhaps

The degree of neutralization of the basic functionality of wherein said alkaline polymer (C) is about 10～about 50 moles of %.

14. any one pharmaceutical carrier in the aforementioned claim, the degree of neutralization of the acidic functionality of wherein said acidic polymer (C) is about 15～about 35 moles of %; Perhaps

The degree of neutralization of the basic functionality of wherein said alkaline polymer (C) is about 15～about 35 moles of %.

15. any one pharmaceutical carrier in the aforementioned claim, 25 ℃ of wherein said acidic polymers (C) 1.0 weight % viscosity in aqueous solution down are about 500～about 80000 centipoises; Perhaps

25 ℃ of following 1.0 weight % viscosity in aqueous solution of wherein said alkaline polymer (C) temperature are about 500～about 80000 centipoises.

16. any one pharmaceutical carrier in the aforementioned claim, wherein said acidic polymer (C) weight average molecular weight is usually greater than about 100000; Perhaps

Wherein said alkaline polymer (C) weight average molecular weight is usually greater than about 100000.

17. any one pharmaceutical carrier in the aforementioned claim, wherein said acidic polymer (C) is by the base polymer preparation, and these base polymers are selected from polyacrylamide, polyvinyl alcohol, ethenyl maleic anhydride copolymer, polyvingl ether, polyacrylic acid, polyvinyl pyrrolidone, the polyvinyl beautiful jade, carboxymethyl cellulose, carboxymethyl starch, hydroxypropyl cellulose, alginic acid, alginate, carrageenin, acrylic acid-grafted starch, acrylic acid-grafted cellulose, poly-aspartate, polyglutamic acid, the molal quantity of acidic amino acid is greater than the poly-mixed acid acidic amino acid and their copolymer of the molal quantity of basic amino acid in the chain; Perhaps

Wherein said alkaline polymer (C) is by base polymer preparation, and these base polymers are selected from polyamine, polymine, polyacrylamide, polyquaternary ammonium salt, chitin, chitosan, poly-asparagine, polyglutamic amide, polylysine, poly arginine, the amino acid whose molal quantity of chain neutral and alkali poly-mixed-alkali aminoacid and their copolymer greater than the molal quantity of acidic amino acid.

18. any one pharmaceutical carrier in the aforementioned claim, wherein said acidic polymer (C) are selected from weight average molecular weight usually greater than about 100000 acrylate copolymer, acrylic acid-acrylate polymer, polyvinyl alcohol-acrylic block copolymers, the starch graft acrylic acid polymer, the cellulose graft acrylate copolymer, polycarbophil (Polycarbophil polymers), alginic acid, poly-aspartate, polyglutamic acid, the molal quantity of acidic amino acid that comprises aspartic acid in the chain is greater than the poly-mixing aspartic acid of the molal quantity of basic amino acid, the molal quantity of acidic amino acid that comprises glutamic acid in the chain is greater than the poly-mixing glutamic acid and their mixture of the molal quantity of basic amino acid; Perhaps

Wherein said alkaline polymer (C) be selected from weight average molecular weight usually greater than the molal quantity of the basic amino acid that comprises lysine in about 100000 chitin, chitosan, poly-asparagine, polyglutamic amide, polylysine, poly arginine, the chain greater than the molal quantity of the basic amino acid that comprises arginine in the poly-mixing lysine of the molal quantity of acidic amino acid and the chain poly-mixing arginine and their mixture greater than the molal quantity of acidic amino acid.

19. any one pharmaceutical carrier in the aforementioned claim, wherein said alkaline matter (D) is selected from basic amino acid, meglumine, carbonate, bicarbonate, glycine carbonate, the carbonate of L-lysine, arginic carbonate, amino acid whose carbonate contains the carbonate of glycosyl, sulphite, percarbonate, described salt are selected from sodium salt, potassium salt, ammonium salt and their mixture;

Perhaps wherein said acidic materials (D) are selected from tartaric acid, citric acid, maleic acid; fumaric acid, malic acid, adipic acid; succinic acid, lactic acid, glycolic; taurine, 'alpha '-hydroxy acids, ascorbic acid and acidic amino acid; with and acid salt; dihydric phosphate, described salt are selected from sodium salt, potassium salt, ammonium salt and their mixture.

20. any one pharmaceutical carrier in the aforementioned claim, that wherein said alkaline matter (D) is selected from is pharmaceutically acceptable, water-swellable and water-insoluble alkaline polymer;

That perhaps wherein said acidic materials (D) are selected from is pharmaceutically acceptable, water-swellable and water-insoluble acidic polymer.

21. any one pharmaceutical carrier in the aforementioned claim, that wherein said alkaline matter (D) is selected from is pharmaceutically acceptable, water-swellable and water-insoluble alkaline polymer, and this polymer pKb is about 2～about 12;

That perhaps wherein said acidic materials (D) are selected from is pharmaceutically acceptable, water-swellable and water-insoluble acidic polymer, and this polymer pKa is about 2～about 12.

22. the molal quantity that any one pharmaceutical carrier in the aforementioned claim, wherein said alkaline matter (D) are selected from the basic amino acid that comprises lysine in chitin, chitosan, poly-asparagine, polyglutamic amide, polylysine, poly arginine, the chain is greater than the molal quantity of the basic amino acid that comprises arginine in the poly-mixing lysine of the molal quantity of acidic amino acid and the chain poly-mixing arginine and their mixture greater than the molal quantity of acidic amino acid;

Perhaps wherein said acidic materials (D) are selected from acrylate copolymer, acrylic acid-acrylate polymer, polyvinyl alcohol-acrylic block copolymers, the starch graft acrylic acid polymer, the cellulose graft acrylate copolymer, polycarbophil (Polycarbophil polymers), alginic acid, poly-aspartate, polyglutamic acid, the molal quantity of acidic amino acid that comprises aspartic acid in the chain is greater than the poly-mixing aspartic acid of the molal quantity of basic amino acid, the molal quantity of acidic amino acid that comprises glutamic acid in the chain is greater than the poly-mixing glutamic acid and their mixture of the molal quantity of basic amino acid.

23. any one pharmaceutical carrier in the aforementioned claim, the mol ratio of the basic functionality of the acidic functionality of wherein said acidic polymer (C) and described alkaline matter (D) is about 10: 1～about 1: 10; Perhaps

The mol ratio of the acidic functionality of the basic functionality of wherein said alkaline polymer (C) and described acidic materials (D) is about 10: 1～about 1: 10.

24. any one pharmaceutical carrier in the aforementioned claim, the mol ratio of the basic functionality of the acidic functionality of wherein said acidic polymer (C) and described alkaline matter (D) is about 2: 1～about 1: 2; Perhaps

The mol ratio of the acidic functionality of the basic functionality of wherein said alkaline polymer (C) and described acidic materials (D) is about 2: 1～about 1: 2.

25. the fusing point that any one pharmaceutical carrier in the aforementioned claim, wherein said aliphatic additive (A) are selected from fusing point when contacting with body fluid greater than 37 ℃ of temperature and in body cavity also is higher than the vegetable and animals oils lipid of 37 ℃ of temperature, semi-synthetic oils and fats, fatty glyceride, wax class, higher fatty acids, high fatty alcohol, high-grade aliphatic ester, senior aliphatic hydrocarbon and composition thereof.

26. the fusing point that any one pharmaceutical carrier in the aforementioned claim, wherein said aliphatic additive (A) are selected from fusing point when contacting with body fluid greater than 37 ℃ of temperature and in body cavity also is higher than the fatty glyceride of 37 ℃ of temperature.

27. any one pharmaceutical carrier in the aforementioned claim, wherein said aliphatic additive (A) is selected from Synthetic Spermacet, hexadecanol, cetostearyl alcohol, stearic acid, ethylene glycol monostearate, microwax, glycerol tristearate, stearyl alcohol, hydrogenated vegetable oil, cera alba, yellow beeswax, tripalmitin, behenic acid, Brazil wax, Cera Chinensis, cholesterol ester stearic acid, terpene resin, castor oil hydrogenated, cholesterol cetylate.

28. any one pharmaceutical carrier in the aforementioned claim, wherein said water-soluble additive (B) be selected from water-soluble aminoacid, oligopeptide, monosaccharide, oligosaccharide, sugar alcohol, water-soluble 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than the pharmaceutically acceptable and non-irritating polymer of 300 centipoises (mPas), and their mixture.

29. any one pharmaceutical carrier in the aforementioned claim, wherein said water-soluble additive (B) is selected from alanine, glycine, serine, valine, agedoite, lysine, glutamine, methionine, arginine, hydroxyproline, proline, power peptide (L-alanyl-L-glutamine), glutathion, the D-erythrose, the D-Erythrulose, erythritol, D-ribose, the D-2-deoxyribose, the D-xylose, L-arabinose, the D-ribulose, the D-xylulose, xylitol, glucose, galactose, mannitol, mannose, fructose, sorbose, the D-mannoheptulose, the D-sedoheptulose, maltose, lactose, sucrose, cellobiose, gentiobiose, 6-(.alpha.-D-galactosido)-D-glucose., the Sargassum disaccharide, hydroxyl isomaltulose, maltose alcohol, lactitol, trehalose, Raffinose, stachyose, verbascose, maltopentaose, MALTOHAXAOASE, alpha-cyclodextrin, gamma-cyclodextrin, 2,6 DM-, hydroxypropyl/ethyl-beta-schardinger dextrin-, side chain-beta-schardinger dextrin-, glycosyl-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, water-soluble cyclodextrin of molecular weight 3000～6000, oligofructose (degree of polymerization 7～20), oligomeric isomaltose (degree of polymerization 7～20)), dextrin, molecular weight is 1200～2000 glucosan, 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than λ-carrageenin of 300 centipoises (mPas), 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than the carrageenin sodium salt of 300 centipoises (mPas), 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than the Radix Acaciae senegalis of 300 centipoises (mPas), 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than the blue polysaccharide in the Shandong of 300 centipoises (mPas), 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than the pectinic acid of 300 centipoises (mPas), 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than the pectic acid of 300 centipoises (mPas), 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than the hydroxyl second methylcellulose of 300 centipoises (mPas), 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than the ethyl cellulose of 300 centipoises (mPas), 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than the hydroxypropyl cellulose of 300 centipoises (mPas), 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than the hydroxypropyl methylcellulose of 300 centipoises (mPas), 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than the methylcellulose of 300 centipoises (mPas), 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than the polyvinyl alcohol of 300 centipoises (mPas), 25 ℃ of temperature down the viscosity of the solution of 2.0% (weight/volume) less than the polyvidone of 300 centipoises (mPas).

30. any one pharmaceutical carrier in the aforementioned claim, wherein said water-soluble additive (B) granule largest cross-sectional sized is less than about 200 orders (Tyler standard).

31. any one pharmaceutical carrier in the aforementioned claim, wherein said water-soluble additive (B) granule largest cross-sectional sized is less than about 500 orders (Tyler standard).

32. any one pharmaceutical carrier in the aforementioned claim, wherein said surfactant (E) is selected from the neutral surface active agent.

33. any one pharmaceutical carrier in the aforementioned claim, wherein said surfactant (E) is selected from castor oil derivatives, Polysorbate, polyoxyethylene stearic acid ester.

34. any one pharmaceutical carrier in the aforementioned claim, its Chinese medicine (F) is selected from adrenocortical hormone, local anesthetic, analgesic/analgesia/antibiotic medicine, antiinflammatory/antipruritic, Wound-healing agent, vitamin, sulfonamides, antibiotic, antifungal, antibacterial, antiviral agents, vasoconstrictor, antihistaminic, anesthetis, astringent, contraceptive, the termination of pregnancy medicine, defecation promoter, the hypnosis tranquilizer, antianxiety drugs, Anti-epileptics, excited inoitantia, antiparkinsonian drug, the central nervous system does medication, analgesics, skeletal muscle relaxant, autonomic drug, spasmolytic, antivertigo drug, antiemetic, cardiac tonic, anti-arrhythmic, diuretic, antihypertensive, the coronary vasodilator vasodilator, peripheral vasodilator, the hyperlipidemia medicine, breathe accelerator, the beta 2 receptor agonist, anti-Meniere's disease medicine, antitumor agent, antidiarrheal/intestinal function regulator, the ulcerative colitis therapeutic agent, the peptic ulcer therapeutic agent, resistance dysfunction medicine, Labor-inducing medicine, anthelmintic, bronchodilator, biological product or peptide class, anti-allergic drug, cathartic, enema, choleretic and the multiple hormone except that adrenocortical hormone.

35. any one pharmaceutical carrier in the aforementioned claim, wherein said aliphatic additive (A) content is 40～80% (w/w), the content of described water-soluble additive (B) is 10～40% (w/w), described acidic polymer (C) is 0.1～25% (w/w) with the total content of alkaline matter (D), the content of described surfactant (E) is 0.1～5%wt/wt, with described content of medicines (F) be 0.1～30% (w/w), the content of every kind of composition is that gross weight with pharmaceutical carrier is a basic calculation; Perhaps

Wherein said aliphatic additive (A) content is 40～80% (w/w), the content of described water-soluble additive (B) is 10～40% (w/w), described alkaline polymer (C) is 0.1～25% (w/w) with the total content of described acidic materials (D), the content of described surfactant (E) is 0.1～5%wt/wt, with described content of medicines (F) be 0.1～30% (w/w), the content of every kind of composition is that gross weight with pharmaceutical carrier is a basic calculation.

36. any one pharmaceutical carrier in the aforementioned claim, wherein contain the lipidic matrix that fusing point when contacting with body fluid is not higher than 37 ℃ of temperature, this lipidic matrix use amount is not enough so that this pharmaceutical carrier liquefaction or emulsifying or thawing when it contacts with endoceliac body fluid.

37. any one pharmaceutical carrier in the aforementioned claim, its fusing point is 40～60 ℃ of temperature.

38. any one pharmaceutical carrier in the aforementioned claim, its dosage form is the dosage form of the oral administration of slow release release.

39. any one pharmaceutical carrier in the claim 1 to 37, its dosage form is the suppository of slow release release.

40. any one pharmaceutical carrier in the claim 1 to 37, its dosage form is the vagina administration suppository of slow release release.

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