CN102000339A - Drug carrier capable of realizing sustained release of drug - Google Patents
Drug carrier capable of realizing sustained release of drug Download PDFInfo
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- CN102000339A CN102000339A CN2010102283168A CN201010228316A CN102000339A CN 102000339 A CN102000339 A CN 102000339A CN 2010102283168 A CN2010102283168 A CN 2010102283168A CN 201010228316 A CN201010228316 A CN 201010228316A CN 102000339 A CN102000339 A CN 102000339A
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Abstract
The invention discloses a drug carrier capable of realizing sustained release of a drug, which improves the performances and contains (a) an aliphatic additive, wherein the in vivo melting point and the in vitro melting point are higher than the temperature of 37 DEG C; (b) water-soluble additive particles with low viscosity and no irritation; (c) a water-insoluble acidic (or alkaline) polymer with water swelling property; (d) an alkaline (or acidic) surfactant; and (e) the drug. The drug carrier has better drug release property, higher resistance to salt poisoning, lower mucosa irritation, better biocompatibility and better drug release uniformity, can better ease or solve the problem of end release, and is difficult to cause initial burst release of the drug or dose dumping and other drug safety problems.
Description
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 temperature 37, water-soluble low viscous additive granules, water-insoluble acidic polymer, basic surface activating agent and the medicine of water-swellable.
Technical background
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 " drug release rate 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.One is selected from sodium polyacrylate organic polymer in this pharmaceutical carrier.
This technology has been done certain technological improvement to the problem of technology before it, still has bigger room for improvement, as " release first quick and back slow " and " do not hold release incomplete " problem.
In addition, also have some than 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, this is because the organic polymer of one work of selecting for use " disintegrating agent " that contacts swellable with water of pharmaceutical carrier of this technology, as sodium polyacrylate etc., " salt poisoning " effect and " gel blockage " effect still easily take place, " salt poisoning " effect (implication in the below herewith) is meant that the organic polymer that contacts swellable with water such as sodium polyacrylate etc. are containing electrolytical aqueous solution such as normal saline herein, 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 " not with the dough of opening " as forming.The main cause that produces the gel blocking phenomenon is that the gap between particles after the swelling reduces 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, bigger change takes place with its influence that is subjected in swelling behavior, it is unstable that performance becomes, it is unstable that thereby the disintegrating property that makes pharmaceutical carrier becomes, thereby the behavior of pharmaceutical carrier drug release also can become unstable, and each individuality will show bigger difference.
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, one organic polymer that contacts swellable with water of selecting for use of this technology, 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, and " release first quick and back slow " that shows in the pharmaceutical carrier drug release process alleviated with " do not hold release incomplete " problem or solved.
Another main purpose of the present invention just provides a kind of pharmaceutical carrier of slow release release of performance improvement, and the pharmaceutical carrier drug release process is further improved by the influence of electrolyte solution, and better Release Performance is arranged.
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 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, water-insoluble acidic polymer, its pKa is about 2-about 12; (d) a kind of pharmaceutically acceptable basic surface activating agent; (e) 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, water-insoluble alkaline polymer, its pKb is about 2-about 12; (d) a kind of pharmaceutically acceptable acid surface active agent; (e) 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 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.
The term " surfactant " that the present invention uses thus be meant and can reduce any material that oil water interfacial tension reduces newly-increased interface institute energy requirement, but do not comprise " emulsifying agent " of following definition.Term " emulsifying agent " is meant any material that comprises following feature herein: have hydrophilic group and lipophilic group but be insoluble to or be dissolved in petroleum hydrocarbon and water hardly, can combine closely with oil-water interfaces, can cover the surface of little oil droplet or little water droplet basically, basically can keep isolating little oil droplet or little water droplet and stop it to merge, thereby can form the oil-in-water type or the water-in-oil emulsion of stability basically.
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% in, according to appointment 10, then represent 7-13, preferably 8-12, more preferably 9-11,9.5-10.5 best.
Detailed Description Of The Invention
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 (fusing point 37-39 ℃), C, CM, CS2, CS2X, CT (fusing point 38-40 ℃), D, DM, ND (fusing point 42-45 ℃) (Gattefosse Co., Ltd makes),
E75, E76 (fusing point 37-39 ℃), H185 (fusing point 38-39 ℃), E85 (fusing point 42-44 ℃) (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) just can liquefaction when pharmaceutical carrier is contacted with body fluid in body cavity, emulsifying or thawing.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 aliphatic additive Another important function that fusing point when pharmaceutically acceptable fusing point contacts with body fluid greater than 37 ℃ of temperature and in body cavity also is higher than 37 ℃ of temperature is: the product after acid or alkaline water-swellable, insoluble polymer and the surface active agent ionization is played buffer action, prevent or delay their direct interactions.
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 (is the glucosan of 1200-2000 as molecular weight), 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 QP300), 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 E3Premium LV, Methocel E5Premium LV, Methocel E6Premium 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, 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 of water-swellable, insoluble polymer that is used for pharmaceutical carrier of the present invention is very wide.High-molecular weight relatively water-swellable, 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, 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, serves as that about 80000 centipoises of about 200-(mPas) are advisable with 25 ℃ of following its 1.0 weight % viscosity in aqueous solution, is preferably about 80000 centipoises of about 500-, and optimum is about 80000 centipoises of about 1000-.
Be used for the water-swellable of pharmaceutical carrier of the present invention, water-insoluble polymer is 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.
Be used for the pharmaceutically acceptable water-swellable, insoluble polymer of pharmaceutical carrier of the present invention or, perhaps be alkaline for tart.Here used " acidity " material is meant the material that can be used as electron acceptor.Usually, acid water swellability, the insoluble polymer that is used for pharmaceutical carrier of the present invention is weakly acidic.Therefore the pKa that is used for the acid water swellability of pharmaceutical carrier of the present invention, water-insoluble polymer is advisable with about 2-about 12, more advantageously is that about 2-is about 10, is 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 of pharmaceutical carrier of the present invention, water-insoluble polymer, preferably by such monomer preparation, these monomeric pKa are about 12 for about 2-, more advantageously are that about 2-is about 10, are 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, insoluble polymer.
Have now found that, use pKa, will cause not possessing required performance in the pharmaceutical carrier of the present invention usually, absorb liquid rate as low, but also have bigger zest etc. less than about 2, highly acid expansiveness, insoluble polymer.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 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 that water-swellable, 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, insoluble polymer comprises 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 ginseng religion document: US5247068A).
Preferably be suitable for acid water swellability of the present invention, 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, 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, insoluble polymer usually is the about 95 moles of % of about 10-, more advantageously is to be suitably the about 90 moles of % of about 50-by the about 90 moles of % of about 30-, and optimum ground is the about 85 moles of % of about 65-.In other words, when being used for pharmaceutical carrier of the present invention, acid water swellability, insoluble polymer are preferably partly neutralized.The degree of neutralization of wishing the acidic functionality of acid water swellability, insoluble polymer usually is the about 90 moles of % of about 5-, the about 70 moles of % of more advantageously about 10-, the about 50 moles of % of about aptly 10-, the about 35 moles of % of the about 15-in optimum ground.
Think according to reason or default stripping curve stripping in order to make medicine better, alleviate as far as possible or solve " release first quick and back slow " that show in the pharmaceutical carrier drug release process and " do not hold release incomplete " problem, in pharmaceutical carrier of the present invention, use acid water swellability, the insoluble polymer of two kinds or more kinds of different degree of neutralization, can make the disintegrate on different time of medicine body 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 the acid water swellability of a part of consumption, the acidic functionality of insoluble polymer is the about 40 moles of % of about 5-, and the degree of neutralization of the acidic functionality of another part consumption is the about 90 moles of % of about 50-; In another embodiment, the degree of neutralization of the acid water swellability of part consumption, the acidic functionality of insoluble polymer is the about 30 moles of % of about 5-, the degree of neutralization of the acidic functionality of a part consumption is the about 60 moles of % of about 40-, and the degree of neutralization of the acidic functionality of another part consumption is the about 90 moles of % of about 70-.Above-mentioned different degree of neutralization acid water swellability, 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.
Here used " alkalescence " material is meant the material that can be used as electron donor.Usually, alkaline water swellability, 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, water-insoluble polymer is about 12 for about 2-, more advantageously is that about 2-is about 10, is 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, being used for the alkaline water swellability of pharmaceutical carrier of the present invention, water-insoluble polymer, can be that about 2-is about 12 by pKb, and more advantageously about 10 for about 2-, the monomer that is suitably about 3-about 6 prepares.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, insoluble polymer.
Have now found that, use pKb less than about 2, alkaline water-swellable, insoluble polymer, will cause not possessing required performance in the pharmaceutical carrier of the present invention usually, absorb liquid rate as low, but also have bigger zest etc.Usually also find, use pKb, will cause not possessing required performance in the pharmaceutical carrier of the present invention usually, as low liquid absorption capacity greater than about 12, alkaline too weak water-swellable, insoluble polymer.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, 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, insoluble polymer comprises 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 poly-several amino acids (the poly-several amino acids ginseng religion document: US5247068A) of alkalescence.
Preferably be suitable for alkaline water swellability of the present invention, 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, 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, insoluble polymer usually is the about 95 moles of % of about 10-, more advantageously is to be suitably the about 90 moles of % of about 50-by the about 90 moles of % of about 30-, and optimum ground is the about 85 moles of % of about 65-.In other words, when being used for pharmaceutical carrier of the present invention, alkaline water swellability, insoluble polymer are preferably partly neutralized.The degree of neutralization of wishing the basic functionality of alkaline water swellability, insoluble polymer usually is the about 90 moles of % of about 5-, the about 70 moles of % of more advantageously about 10-, the about 50 moles of % of about aptly 10-, the about 35 moles of % of the about 15-in optimum ground.
Think according to reason or default stripping curve stripping in order to make medicine better, alleviate as far as possible or solve " release first quick and back slow " that show in the pharmaceutical carrier drug release process and " do not hold release incomplete " problem, in pharmaceutical carrier of the present invention, use alkaline water swellability, the insoluble polymer of two kinds or more kinds of different degree of neutralization, can make the disintegrate on different time of medicine body 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 the alkaline water swellability of a part of consumption, the basic functionality of insoluble polymer is the about 40 moles of % of about 5-, and the degree of neutralization of the basic functionality of another part consumption is the about 90 moles of % of about 50-; In another embodiment, the degree of neutralization of the alkaline water swellability of part consumption, the basic functionality of insoluble polymer is the about 30 moles of % of about 5-, the about 60 moles of % of the about 40-of basic functionality that part is a consumption, the basic functionality of another part consumption is the about 90 moles of % of about 70-.The amount ratio of above-mentioned different degree of neutralization alkaline water swellability, insoluble polymer preferably is similar to or is about 1: 1: 1 substantially ...Above-mentioned different degree of neutralization alkaline water swellability, 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.
Usually acidity of using in pharmaceutical carrier of the present invention or alkaline water swellability, insoluble polymer are good with particle form.When with particle form, the largest cross-sectional sized of wishing particle usually is less than about 600 microns, aptly less than about 75 microns, preferablyly less than about 25 microns.Based on the gross weight of pharmaceutical carrier, the content of acidity or alkaline water swellability, insoluble polymer is generally 0.1-20%wt/wt, preferably 0.5-10%wt/wt, more preferably 1-5%wt/wt.
In pharmaceutical carrier of the present invention, also must use just opposite surfaces activating agent of the acidity of a kind of acidity or alkalescence and water-swellable, insoluble polymer or alkalescence.Particularly, when in pharmaceutical carrier of the present invention, having used tart water-swellable, insoluble polymer then must use a kind of surfactant of alkalescence; When in pharmaceutical carrier of the present invention, having used alkaline water-swellable, insoluble polymer then must use a kind of tart surfactant.The implication of term " acidity " or " alkalescence " is identical with the acid or alkaline implication of water-swellable, insoluble polymer herein.Promptly " acidity " surfactant is meant the surfactant that can be used as electron acceptor; " alkalescence " surfactant is meant the surfactant that can be used as electron donor.The pKa of acid or alkaline surfactant or pKb are preferably about 12 for about 2-, and it is about 10 to be more preferably about 2-, is about 3-about 6 best.
Can be used for pharmaceutically acceptable basic surface activating agent of the present invention and include but not limited to N-senior alkyl acyl group basic amino acid C1-C6 alkane esters, N-senior alkyl Gemini class basic amino acid surfactant (wherein; n among-NH-(CH2) n-NH-is 1-12; 3-12 preferably; more preferably; 3-9), N-C1-C12 (C1-C8 preferably; C1-C3 more preferably) alkyl acyl-basic amino acid senior alkyl glyceride type surfactant, alkaline senior alkyl acyl-two-six peptide condensation substance, contain the alkaline glycosyl sphingolipid of senior alkyl and their mixture.Described basic amino acid includes but not limited to lysine, arginine, histidine, preferred lysine, arginine, more preferably arginine.Term " senior alkyl " is meant carbon number C8-C24 herein, C8-C18 preferably, the straight or branched of C10-C14, saturated or unsaturated alkyl (following do not indicate especially that implication all herewith) best, because of the lower surfactant of carbon number has higher relatively hydration and dissociation, help the performance of the effect of surfactant.Usually contain 1 or 2 senior alkyl in each surfactant molecule, this helps surfactant stripping from lipidic matrix.
In the above-mentioned basic surface activating agent; N-senior alkyl Gemini class basic amino acid surfactant (wherein; n among-NH-(CH2) n-NH-is 1-12; 3-12 preferably; more preferably, 3-9), N-C1-C12 (preferably C1-C8, more preferably C1-C3) alkyl acyl-basic amino acid senior alkyl glyceride type surfactant is for more preferably; N-C1-C12 (preferably C1-C8, more preferably C1-C3) alkyl acyl-basic amino acid senior alkyl glyceride type surfactant is for most preferably.This is because it has better biocompatibility, biological degradability, hydrophilic preferably and/or lower critical micelle concentration.(basic amino acid surfactant relevant references: L P é rez, M R Infante, R Pons et al.Colloids Surf.B, 2004,35:235-242; C Mor á n, I M R nfante, P Clpa é s.J.Chem.Soc.Perkin Trans.1,2001,2063-2070; Ding Zhaoyun, Hao Aiyou, the synthetic and performance of arginine class surfactant, 2006 the 69th volumes of chemistry circular.)
N-senior alkyl acyl basic amino acid available example of C1-C6 alkane esters such as N
α-ten/12/myristoyl arginine methyl/ethyl ester, N
α-ten/12/myristoyl lysine methyl/ethyl ester, N-ten/12/myristoyl arginine methyl/ethyl ester, N-ten/12/myristoyl arginine methyl/ethyl ester, N-ten/12/myristoyl arginine methyl/ethyl ester.
Contain the N-senior alkyl Gemini class basic amino acid surfactant (wherein, the n among-NH-(CH2) n-NH-is 1-12,3-12 preferably, more preferably, 3-9) available example such as N
1, N
3-two (N-ten/12/myristoyl arginine)-1,3-propane diamine, N
1, N
3-two (N-ten/12/myristoyl arginine)-1,3-propane diamine, N
1, N
6-two (N-ten/12/myristoyl arginine)-1,6-hexamethylene diamine, N
1, N
9-two (N-ten/12/myristoyl arginine)-1,9-nonamethylene diamine, N
1, N
6-two (N-ten/12/myristoyl arginine)-1, the 6-hexamethylene diamine.
N-C1-C12 (C1-C8 preferably; C1-C3 more preferably) alkyl acyl-available example of basic amino acid alkyl glycerol esters surface active agent is as 1; 2-two (ten/12/myristoyl)-3-(N-acetyl group arginyl) glycerol, 1,2-two (ten/12/myristoyl)-3-(N-acetyl group arginyl) glycerol.
The available example of alkaline alkyl acyl-two-six peptide condensation substance such as N-Cortex cocois radicis acyl arginine-ethyl ester of lysine, N-Cortex cocois radicis acyl arginine-HIS-ALA-threonine-lysine).
The alkaline glycosyl sphingolipid (available example includes but not limited to sphingosine, ceramide, sphingomyelins) that contains senior alkyl.
Can be used for pharmaceutically acceptable acid surface active agent of the present invention and include but not limited to the acid of senior alkyl phosphoglyceride; the senior alkyl Phosphatidylserine; at least contain a carboxylic acid group (polyprotic acid senior alkyl glyceride COOH); at least contain a carboxylic acid group (senior alkyl acyl group polybasic ester COOH); at least contain a carboxylic acid group (senior alkyl acyl propylene glycol polybasic ester COOH); senior alkyl acyl group lactic acid; N-senior alkyl acyl group neutrality or acidic amino acid; N-senior alkyl acylsarcosine; acid senior alkyl acyl-two-six peptide condensation substance; sulfonic group is for succinic acid two higher alkyl esters, and their mixture.Term " senior alkyl " is meant carbon number C8-C24 herein, C8-C18 preferably, the straight or branched of C10-C14, saturated or unsaturated alkyl (following do not indicate especially that implication all herewith) best, because of the lower surfactant of carbon number has higher relatively hydration and dissociation, help the performance of the effect of surfactant.Usually contain 1 or 2 senior alkyl in each surfactant molecule, this helps surfactant stripping from lipidic matrix.
Wherein, the acid of senior alkyl phosphoglyceride, senior alkyl Phosphatidylserine, (polyprotic acid senior alkyl glyceride COOH) is for more preferably to contain a carboxylic acid group at least, at least (polyprotic acid senior alkyl glyceride COOH) is for most preferably to contain a carboxylic acid group, because of it not only has more preferably biocompatibility, also has better biological degradability, hydrophilic preferably and/or acidity preferably.
The available example of senior alkyl phosphoglyceride acid as, but be not limited thereto: the acid of just long aliphatic chain phosphoglyceride for example just-ether-glycerol-phosphatidic acid, specifically is lauroyl glycerol-phosphatidic acid, oleoyl glycerol-phosphatidic acid, n-tetradecane base-glycerol-phosphatidic acid.
The available example of senior alkyl Phosphatidylserine as, but be not limited thereto: positive long-chain phosphoserine, specifically be lauroyl-, myristoyl-, oleoyl-or palmityl-phosphoserine, n-tetradecane base phosphoserine, octadecylene-phosphoserine.
Can be used for a water-soluble carboxylic acid group (following C8-C18 of containing of example of polyprotic acid senior alkyl glyceride COOH) that contains at least of the present invention, preferred C8-C14, the more preferably chemical compound of C10-C14 alkyl, but be not limited thereto: list/diacetyl tartarate list/double glyceride, mix acetic acid and tartaric acid list/double glyceride, citric acid glycerol list/two acid esters, oxalyl tartaric acid glycerol list/two acid esters, acetic acid tartaric acid mixing glycerol one/two acid esters, succinic acid glycerol list/two acid esters, tartaric acid glycerol one/two acid esters, octadecanol citric acid glyceryl monoacetate, Fructus Citri Limoniae glycerol list/two acid esters, succinic acid glycerol list/two acid esters, tartaric acid glycerol one/two acid esters, octadecanol citric acid glyceryl monoacetate.
Water-soluble contain at least a carboxylic acid group (the available example of senior alkyl acyl group polybasic ester COOH) as, but be not limited thereto: single stearoyl citrate, single lauroyl tartrate, tartaric acid list stearoyl fat.
Water-soluble contain at least a carboxylic acid group (the available preferred embodiment of senior alkyl acyl propylene glycol polybasic ester COOH) as, but be not limited thereto: stearoyl propylene glycol succinate.
The available example of senior alkyl acyl group lactic acid as, but be not limited thereto: decoyl lactic acid, lauroyl lactic acid, tetradecylic acid lactic acid, hexadecylic acid lactic acid, stearoyl lactic acid, isostearoyl lactic acid, oleoyl lactic acid, cocos nucifera oil acyl lactic acid, 12-hydroxyl stearoyl lactic acid, stearoyl-2-lactic acid, Semen Ricini oleoyl lactic acid and docosane acyl group lactic acid.
Can be used for N-senior alkyl acyl group neutrality of the present invention or acidic amino acid and include but not limited to this: N-alkyl acyl glycine, N-alkyl acyl alanine, N-alkyl acyl valine, N-alkyl acyl glutamic acid, N-alkyl acyl aspartic acid, N-alkyl acyl-N-methyl-Beta-alanine.Preferred N-alkyl acyl acidic amino acid is as N-alkyl acyl glutamic acid, N-alkyl acyl aspartic acid.Acyl group neutrality or acidic amino acid can with example as, but be not limited thereto: two-TEA-palmityl aspartic acid; Capryl/caprin glutamic acid, oleoyl glutamic acid, lauroyl glutamic acid; Oleoyl flesh glycine, stearoyl glycine; The lauroyl alanine.
Can be used for N-senior alkyl acylsarcosine of the present invention and include but not limited to this: myristoyl sarcosine, TEA lauroyl sarcosine, Hamposyl S, Hamposyl L, Hamposyl C, N-Oleoylsarcosine, palmitoyl sarcosine.
Acid senior alkyl acyl-two-six peptide condensation substance can with example as, but be not limited thereto: alkyl acyl glycyl is for propylhomoserin (as, oleoyl glycyl for propylhomoserin, lauroyl acyl glycyl for propylhomoserin, stearoyl glycyl for propylhomoserin).
Can be used for sulfonic group of the present invention for the available preferred embodiment of succinic acid two higher alkyl esters as, but be not limited thereto: sulfonic group is for dioctyl succinate.
Based on the gross weight of pharmaceutical carrier, the content of alkalescence or acid surface active agent is generally 0.1-20%wt/wt, preferably 0.5-10%wt/wt, preferably 1-5%wt/wt.
Usually, get the acidity that is essentially its free acid or free alkali form or alkaline water swellability, insoluble polymer respectively, add in the pharmaceutical carrier of the present invention with alkalescence or acid surface active agent 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 alkaline water swellability, insoluble polymer are about 10 with the acidity of alkalescence or acid surface active agent and the mol ratio of basic functionality respectively: about 1: 10 of 1-, be suitably about 4: about 1: 4 of 1-, be about 2: about 1: 2 of 1-, optimum ground is about 1: 1 preferablyly.
Acid or alkaline water-swellable, insoluble polymer in the present invention mainly as disintegrating agent and promote acidity or the basic surface activating agent from fat-soluble substrate stripping." disintegrating agent " is meant that herein a kind of pharmaceutical carrier that makes little by little decomposes disruptive matrix components, to promote the release of medicine.
Acidity or basic surface activating agent mainly rise in the present invention regulates drug release rate (promptly making porogen), the effects such as performance that improve or improve water-swellable, insoluble polymer.
Usually, commercially available water-swellable, insoluble polymer and ionic surfactant form or salt form for being neutralized basically.But unfortunately, " salt poisoning " effect and " gel blockage " effect easily take place in water-swellable, the insoluble polymer of salt form, and its effect easily is greatly diminished, and more neutralization is preceding not high usually in side effect such as its zest, and biocompatibility descends; " salt poisoning " also can take place in high level salt solution ionic surfactant thereby the effect performance descends, and more neutralization is preceding not high yet usually in side effect such as zest, and biocompatibility descends.
Thereby, be used for water-swellable of the present invention, insoluble polymer and surfactant and go up the form that adopts its free acid or free alkali substantially.Yet, the acidity of above-mentioned water-swellable, insoluble polymer and surfactant 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 the above-mentioned acidity that is respectively its free acid or free alkali form basically or alkaline water swellability, insoluble polymer, respectively with alkalescence or acid surface active agent mix when using, the pharmaceutical carrier of gained has more performance.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 biocompatibility; The 3rd, better release homogeneity is alleviated better or is solved " release first quick and back slow " and " do not hold release incomplete " problem.
Containing dielectric solution, transform to separately salt form by its free acid or free alkali form respectively as water-swellable, insoluble polymer and the surfactant of above-mentioned acidity in the sodium-chloride water solution or alkalescence, this comes down to containing the desalination that dielectric solution has, relax " salt poisoning " effect thus, thereby improved performance separately respectively.It is believed that just to be based on these factors, the pharmaceutical carrier that the present invention relates to has good drug release feature, and higher anti-" salt poisoning " effect can release better in high level salt solution.
When pharmaceutical carrier is placed aqueous solution, basically be respectively the acidity of its free acid or free alkali form or alkaline water swellability, insoluble polymer, to react with alkalescence or acid surface active agent respectively, and this chemical equilibrium helps and will be respectively the acidity or the alkali compounds of its free acid or free acid form, changes its salt form separately into.Water-swellable after the conversion, insoluble polymer and surfactant will have them and can bring into play the performance roughly suitable with the salt form chemical compound generally.Water-swellable, insoluble polymer water absorption and swelling after the conversion (ionizing) play the disintegrating agent effect, make pharmaceutical carrier little by little decompose the matrix components that breaks, to promote the release of medicine.Surfactant after the conversion (ionizing) works the drug release rate effect of regulating as porogen stripping from substrate.Because acid or alkaline water-swellable, insoluble polymer and surfactant are respectively by this conversion to separately salt form of its free acid or free alkali form, be the process that a slow relatively disassociation and ions diffusion are gone into polymer, the slowly performance of therefore acid or alkaline water-swellable, insoluble polymer and surfactant performance separately with continuing.Exactly because it is believed that slowly performance of this porogen effect and disintegrating agent effect with continuing, just in time alleviate or offset " terminal discharge " effect.
It is believed that, water-swellable, insoluble polymer and the surfactant of above-mentioned acidity or alkalescence 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 guarantee that they can bring into play the performance roughly suitable with the salt form chemical compound generally, and can reduce zest greatly mucosa etc.The more important thing is, acid or alkaline water-swellable, the performance of insoluble polymer and surfactant is gently brought into play, and, acid or the alkaline water-swellable of (or " finishing its mission ") after the performance performance separately, insoluble polymer and surfactant (are the disintegrate of swelling messenger drug thing carrier, polymer interface and Ionized water-swellable after fat-soluble matrix interface is separated, insoluble polymer, and (instead) Ionized surfactant after the fat-soluble substrate stripping of pharmaceutical carrier) polymerization precipitates mutually, water in the ion hydration layer in them is compressed again to be discharged, contact or the mucosa difficult generation quick dehydration contiguous thereby make with this pharmaceutical carrier with this pharmaceutical carrier, cause local " drying ", thereby zest lowers, the patient feels that partial discomfort (as sensation of pricking) sense alleviates.In addition, acid or alkaline water-swellable, insoluble polymer and the surfactant of " finishing its mission " and post precipitation loses its original effect, also makes its original ill effect reduce to minimum or elimination simultaneously.In addition, " finish its mission " and the surfactant of post precipitation can not remove emulsifying oil phase (being fatty glyceride) yet, just can liquefy when pharmaceutical carrier is contacted with body fluid in body cavity or melt will cause that medicine is dashed forward and release in other words dosage and incline and release (dose-dumping).Thereby the biocompatibility and the drug safety of pharmaceutical carrier are enhanced.
In the pharmaceutical carrier that the present invention relates to, preferably add a kind of pharmaceutically acceptable water-soluble neutral surface active agent, when the lipophilic group of particularly above-mentioned acidity or basic surface activating agent is the straight or branched of carbon number C16-C18 or C16-C24, saturated or unsaturated higher alkane base.Described neutral surface active agent mainly makes auxiliary porogen in the present invention, for acidity or alkaline water swellability, insoluble polymer and alkalescence or acid surface active agent early reaction provide how required medium---aqueous water, to quicken early reaction, promote the early stage release of pharmaceutical carrier.The example that can be used for water-soluble neutral surface active agent of the present invention includes but not limited to that castor oil derivatives is (as commodity HCO 60 by name, polyoxyethylene (60) castor oil hydrogenated that NikkoChemical Co., Ltd produce), Polysorbate (as Tween61, Tween60, Tween80), polyoxyethylene stearic acid ester (as Polyethylene Glycol (40) stearate).Just can liquefy or emulsifying when the amount of water-soluble neutral surface active agent in pharmaceutical carrier should be not enough to make pharmaceutical carrier to contact with body fluid in body cavity, 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.It is about 5% that water-soluble neutral surface active agent's consumption is generally 0.1-, and preferably 0.5-is about 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;
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.), nonionic surfactant, 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, acidity/alkaline polymer and the ratio of alkalescence/acid surface active agent in pharmaceutical carrier.
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.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.At first, the fatty glyceride fusion; Follow surfactant, water soluble, low viscosity, non-irritating organic compound, water-swellable, insoluble polymer, 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, higher anti-" salt poisoning " effect can release better in high level salt solution;
2), lower mucous membrane irritation, better biocompatibility;
3), better release homogeneity, alleviate better or solve " release is first quick and back slow " and " do not hold release incomplete " problem;
4), be not prone to the prominent dosage drug safety problems such as releasing (dose-dumping) of inclining of releasing in other words of medicine.
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 drug release test results
Fig. 5 embodiment 5 and reference examples 5 drug release test results
Fig. 6 embodiment 6 and reference examples 6 drug release test results
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:
Illustrate: #, the sodium acrylate graft starch of two kinds of different degree of neutralization is by neutralize the two homology with a kind of acrylic acid grafted starch.
Embodiment 2:
Illustrate: ※, cellulose graft acrylic acid (sodium) polymer of two kinds of different degree of neutralization is by neutralize the two homology with a kind of cellulose graft acrylate copolymer.
Embodiment 3:
Illustrate: ☆, the polylysine hydrochlorate of two kinds of different degree of neutralization by with a kind of polylysine through hcl acidifying, the two homology.
Embodiment 4:
Illustrate: ★: under 25 ℃, be dissolved in the viscosity of the chitosan soln of 1% in 1% acetic acid solution.
Embodiment 5:
Illustrate: §, polyglutamic acid-lysine hydrochloride by above-mentioned polyglutamic acid-lysine through hcl acidifying, the two homology.
Embodiment 6:
: ﹠amp is described; , the polyacrylic acid of two kinds of different degree of neutralization (sodium) is by neutralize the two homology with a kind of polyacrylic acid.
Embodiment and reference examples preparation method:
Get liposoluble constituent (as propylene glycol monostearate, hydrogenated vegetable oil, glycerol three stearic acid, Brazil wax,
H15,
E85, stearic acid and tripalmitin) heating (to temperature 50-80 ℃) makes its fusing, adds surfactant (as N
1, N
6-two (N-dodecanoyl arginine)-1,6-hexamethylene diamine, HCO 60,1,2-two (12 carbonic acyl radical)-3-(N-acetyl group arginyl) glycerol or its hydrochlorate, diacetyl tartarate glyceryl monolaurate, TWEEN 80, N-Hamposyl L or its sodium salt, TWEEN 61, myristoyl phosphoserine, N-ten alkanoyl arginine methyl esters etc.), mix homogeneously; Add levigate and cross the polymer (as acrylic acid (sodium) graft starch, cellulose graft acrylic acid (sodium) polymer, polylysine or its hydrochlorate chitosan, polyglutamic acid-lysine or its hydrochlorate, polyacrylic acid (sodium) etc.), levigate and cross 100 purpose water soluble compounds (as glycine, hydroxypropyl cellulose Klucel EF, mannitol, glucose, alanine etc.) granule and levigate and cross the Bleocin Hydrochloride of 200 mesh sieves, mixing repeatedly repeatedly of 200 mesh sieves 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.Be crushed to 8-12 purpose granule after the cooling of embodiment 4 molten mixtures, ground product incapsulates and gets final product.
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.It is 7.0 double distilled water that compound sodium chloride injection in the test tube (ringer's solution) is changed into pH value, does with reference to experiment according to last method again.
The result:
Fig. 1-6 shows the rate of release of Bleocin Hydrochloride.The suppository of embodiment demonstrates the better medicament release characteristics, as effective alleviation of higher salt tolerance and " release first quick and back slow " and " do not hold release incomplete " problem etc.
Inspection example 2 vaginal mucosa irritation tests
Test sample:
Bolt/the tablet of embodiment 2,3 and reference examples 2,3 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 1.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 2 pathological reaction standards of grading record.The results are shown in (see Table 3, table 4).
The result shows that the mucous membrane irritation of bolt/tablet of embodiment obviously is less than than reference examples.
Table 1 mucous membrane irritation reaction standards of grading
Table 2 mucosal tissue pathological reaction standards of grading
Table 3 embodiment bolt is to rabbit vagina mucosa perusal irritant reaction result
Table 4 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 not blank suppository of pastille of the prescription of embodiment 5,6 and reference examples 5,6 and prepared.The blank suppository 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) and matched group (anus gives reference examples blank bolt), 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, 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 1 and mark, and carry out mucosa histopathologic examination and by table 2 result of determination according to the method in the inspection example 2.The results are shown in Table 5,6.
The blank bolt of table 5 is to rabbit mucous membrane of rectum perusal irritant reaction result
The blank bolt of table 6 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 (43)
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 pharmaceutically acceptable aliphatic additive that fusing point that (A) a kind of 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 water-soluble, the viscosity of the solution of 2.0% (weight/volume) is less than 300 centipoises (mPas), pharmaceutically acceptable and non-irritating additive down 25 ℃ of temperature, described additive granules largest cross-sectional sized is less than about 28 orders (Tyler standard); (C) a kind of pharmaceutically acceptable, water-swellable, water-insoluble acidic polymer, this polymer pKa is about 2-about 12; (D) a kind of pharmaceutically acceptable basic surface activating agent; (E) 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 pharmaceutically acceptable aliphatic additive that fusing point that (A) a kind of 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 water-soluble, the viscosity of the solution of 2.0% (weight/volume) is less than 300 centipoises (mPas), pharmaceutically acceptable and non-irritating additive down 25 ℃ of temperature, described additive granules largest cross-sectional sized is less than about 28 orders (Tyler standard); (C) a kind of pharmaceutically acceptable, water-swellable, water-insoluble alkaline polymer, this polymer pKb is about 2-about 12; (D) a kind of pharmaceutically acceptable acid surface active agent; (E) a kind of medicine.
2. according to the pharmaceutical carrier of claim 1, wherein said aliphatic additive (A) content is 40-80% (w/w), the content of described water-soluble additive (B) is 10-40% (w/w), the content of described acidic polymer (C) is 0.1-20% (w/w), the content of described basic surface activating agent (D) is 0.1-20% (w/w), with described content of medicines (E) 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), the content of described alkaline polymer (C) is 0.1-20% (w/w), the content of described acid surface active agent (D) is 0.1-20% (w/w), with described content of medicines (E) be 0.1-30% (w/w), the content of every kind of composition is that gross weight with pharmaceutical carrier is a basic calculation.
3. 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.
4. 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.
5. any one pharmaceutical carrier in the aforementioned claim, the degree of neutralization of the acidic functionality of wherein said acidic polymer (C) is the about 90 moles of % of about 5-; Perhaps
The degree of neutralization of the basic functionality of wherein said alkaline polymer (C) is the about 90 moles of % of about 5-.
6. any one pharmaceutical carrier in the aforementioned claim, the degree of neutralization of the acidic functionality of wherein said acidic polymer (C) is the about 50 moles of % of about 10-; Perhaps
The degree of neutralization of the basic functionality of wherein said alkaline polymer (C) is the about 50 moles of % of about 10-.
7. any one pharmaceutical carrier in the aforementioned claim, the degree of neutralization of the acidic functionality of wherein said acidic polymer (C) is the about 35 moles of % of about 15-; Perhaps
The degree of neutralization of the basic functionality of wherein said alkaline polymer (C) is the about 35 moles of % of about 15-.
8. any one pharmaceutical carrier in the claim 1 to 4, the degree of neutralization of the acidic functionality of a part of consumption in the wherein said acidic polymer (C) is the about 40 moles of % of about 5-, and the degree of neutralization of the acidic functionality of another part consumption is the about 90 moles of % of about 50-; Perhaps
The degree of neutralization of the basic functionality of a part of consumption in the wherein said alkaline polymer (C) is the about 40 moles of % of about 5-, and the degree of neutralization of the basic functionality of another part consumption is the about 90 moles of % of about 50-.
9. any one pharmaceutical carrier in the claim 1 to 4, the degree of neutralization of the acidic functionality of a part of consumption in the wherein said acidic polymer (C) is the about 30 moles of % of about 5-, the degree of neutralization of the acidic functionality of a part consumption is the about 60 moles of % of about 40-, and the degree of neutralization of the acidic functionality of another part consumption is the about 90 moles of % of about 70-; Perhaps
The degree of neutralization of the basic functionality of a part of consumption in the wherein said alkaline polymer (C) is the about 30 moles of % of about 5-, the degree of neutralization of the basic functionality of a part consumption is the about 60 moles of % of about 40-, and the degree of neutralization of the basic functionality of another part consumption is the about 90 moles of % of about 70-.
10. any one pharmaceutical carrier in the aforementioned claim, 25 ℃ of following 1.0 weight % viscosity in aqueous solution of wherein said acidic polymer (C) are about 80000 centipoises of about 500-; Perhaps
25 ℃ of following 1.0 weight % viscosity in aqueous solution of wherein said alkaline polymer (C) temperature are about 80000 centipoises of about 500-.
11. 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.
12. any one pharmaceutical carrier in the aforementioned claim, wherein said acidic polymer (C) be following be connected in by acidic functionality crosslinked in the preparation of following base polymer, wherein, above-mentioned base polymer is 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, and above-mentioned acidic functionality is selected from carboxyl, sulfate groups, inferior sulfate radical group and phosphate groups; Perhaps
Wherein said alkaline polymer (C) is connected in crosslinked in following base polymer base polymer preparation by following basic functionality, wherein, above-mentioned base polymer is selected from poly-mixed-alkali aminoacid and their copolymer of the molal quantity of polyamine, polymine, polyacrylamide, polyquaternary ammonium salt, chitin, chitosan, poly-asparagine, polyglutamic amide, polylysine, poly arginine, basic amino acid greater than the molal quantity of acidic amino acid, above-mentioned basic functionality is selected from primary, the second month in a season and uncle's amino, imino group and acylamino-.
13. 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 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 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 the molal quantity of basic amino acid that weight average molecular weight gathers, comprises lysine greater than about 100000 chitin, chitosan, poly-asparagine, polyglutamic amide, polylysine, poly arginine usually greater than the poly-mixing lysine of the molal quantity of acidic amino acid and the molal quantity of basic amino acid that comprises arginine greater than the poly-mixing arginine and their mixture of the molal quantity of acidic amino acid.
14. any one pharmaceutical carrier in the aforementioned claim, the pKb of wherein said basic surface activating agent (D) is about 2-about 12; Perhaps
The pKa of wherein said acid surface active agent (D) is about 2-about 12.
15. any one pharmaceutical carrier in the aforementioned claim, the pKb of wherein said basic surface activating agent (D) is about 2-about 10; Perhaps
The pKa of wherein said acid surface active agent (D) is about 2-about 10.
16. any one pharmaceutical carrier in the aforementioned claim, the pKb of wherein said basic surface activating agent (D) is about 3-about 6; Perhaps
The pKa of wherein said acid surface active agent (D) is about 3-about 6.
17. any one pharmaceutical carrier in the aforementioned claim, wherein said basic surface activating agent (D) is selected from senior alkyl acyl group basic amino acid C1-C6 alkane esters, N-senior alkyl Gemini class basic amino acid surfactant, N-C1-C8 alkyl acyl-basic amino acid senior alkyl glyceride type surfactant, alkaline senior alkyl acyl-two-six peptide condensation substance, contains the alkaline glycosyl sphingolipid of senior alkyl, and their mixture, the carbon number of wherein above-mentioned senior alkyl is C8-C18; Perhaps
Wherein said acid surface active agent (D) is selected from the acid of senior alkyl phosphoglyceride; the senior alkyl Phosphatidylserine; at least contain a carboxylic acid group (polyprotic acid senior alkyl glyceride COOH); at least contain a carboxylic acid group (senior alkyl acyl group polybasic ester COOH); at least contain a carboxylic acid group (senior alkyl acyl propylene glycol polybasic ester COOH); senior alkyl acyl group lactic acid; N-senior alkyl acyl group neutrality or acidic amino acid; N-senior alkyl acylsarcosine; acid senior alkyl acyl-two-six peptide condensation substance; sulfonic group is for succinic acid two higher alkyl esters; and their mixture, the carbon number of wherein above-mentioned senior alkyl is C8-C18.
18. any one pharmaceutical carrier in the aforementioned claim, wherein said basic surface activating agent (D) is selected from senior alkyl acyl group basic amino acid C1-C6 alkane esters, N-senior alkyl Gemini class basic amino acid surfactant, N-C1-C8 alkyl acyl-basic amino acid senior alkyl glyceride type surfactant and their mixture, and the carbon number of wherein above-mentioned senior alkyl is C8-C18; Perhaps
Wherein said acid surface active agent (D) is selected from the acid of senior alkyl phosphoglyceride, senior alkyl Phosphatidylserine, (polyprotic acid senior alkyl glyceride COOH), the carbon number of wherein above-mentioned senior alkyl is C8-C18 to contain a carboxylic acid group at least.
19. any one pharmaceutical carrier in the aforementioned claim, wherein said acid surface active agent (D) choosing contain and contain a carboxylic acid group at least (polyprotic acid senior alkyl glyceride COOH), wherein, the carbon number of above-mentioned senior alkyl is C8-C18.
20. any one pharmaceutical carrier in the aforementioned claim, wherein said acid surface active agent (D) is selected to contain and contains a carboxylic acid group (following polyprotic acid senior alkyl glyceride COOH) at least, wherein, above-mentioned polyprotic acid senior alkyl glyceride comprises list/diacetyl tartarate list/double glyceride, mix acetic acid and tartaric acid list/double glyceride, citric acid glycerol list/two acid esters, oxalyl tartaric acid glycerol list/two acid esters, acetic acid tartaric acid mixing glycerol one/two acid esters, succinic acid glycerol list/two acid esters, tartaric acid glycerol one/two acid esters, octadecanol citric acid glyceryl monoacetate, Fructus Citri Limoniae glycerol list/two acid esters, succinic acid glycerol list/two acid esters, tartaric acid glycerol one/two acid esters, octadecanol citric acid glyceryl monoacetate, the carbon number of above-mentioned senior alkyl are C10-C14.
21. the pharmaceutical carrier of claim 17 or 18, wherein said basic amino acid is selected from lysine, arginine.
22. the pharmaceutical carrier of claim 17 or 18, wherein said basic amino acid is selected from arginine.
23. any one pharmaceutical carrier in the claim 17 to 22, the carbon number of wherein said senior alkyl is C10-C14.
24. any one pharmaceutical carrier in the claim 1 to 18, wherein said basic surface activating agent (D) is selected from N
α-ten/12/myristoyl arginine methyl/ethyl ester, N
α-ten/12/myristoyl lysine methyl/ethyl ester, N-ten/12/myristoyl arginine methyl/ethyl ester, N-ten/12/myristoyl arginine methyl/ethyl ester, N-ten/12/myristoyl arginine methyl/ethyl ester, N
1, N
3-two (N-ten/12/myristoyl arginine)-1,3-propane diamine, N
1, N
3-two (N-ten/12/myristoyl arginine)-1,3-propane diamine, N
1, N
6-two (N-ten/12/myristoyl arginine)-1,6-hexamethylene diamine, N
1, N
9-two (N-ten/12/myristoyl arginine)-1,9-nonamethylene diamine, N
1, N
6-two (N-ten/12/myristoyl arginine)-1; 6-hexamethylene diamine, 1; 2-two (ten/12/myristoyl)-3-(N-acetyl group arginyl) glycerol, 1,2-two (ten/12/myristoyl)-3-(N-acetyl group arginyl) glycerol, and their mixture.
25. 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 basic surface activating agent (D) is about 4: about 1: 4 of 1-; Perhaps
The mol ratio of the acidic functionality of the basic functionality of wherein said alkaline polymer (C) and described acid surface active agent (D) is about 4: about 1: 4 of 1-.
26. 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 basic surface activating agent (D) is about 2: about 1: 2 of 1-; Perhaps
The mol ratio of the acidic functionality of the basic functionality of wherein said alkaline polymer (C) and described acid surface active agent (D) is about 2: about 1: 2 of 1-.
27. 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 basic surface activating agent (D) is about 1: 1; Perhaps
The mol ratio of the acidic functionality of the basic functionality of wherein said alkaline polymer (C) and described acid surface active agent (D) is about 1: 1.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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 the glucosan of 1200-2000,25 ℃ 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).
33. any one pharmaceutical carrier in the aforementioned claim, about 200 orders of wherein said water-soluble additive (B) granule largest cross-sectional sized (Tyler standard).
34. any one pharmaceutical carrier in the aforementioned claim, about 500 orders of wherein said water-soluble additive (B) granule largest cross-sectional sized (Tyler standard).
35. any one pharmaceutical carrier in the aforementioned claim, the content that the fusing point when wherein contacting with body fluid is not higher than the lipidic matrix of 37 ℃ of temperature is less than about 5%wt/wt, based on the gross weight of pharmaceutical carrier.
36. any one pharmaceutical carrier in the aforementioned claim, its Chinese medicine (E) 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.
37. any one pharmaceutical carrier in the aforementioned claim also further contains a kind of pharmaceutically acceptable water-soluble neutral surface active agent (F), this neutral surface active agent's content is less than about 5%wt/wt, based on the gross weight of pharmaceutical carrier.
38. the pharmaceutical carrier of claim 37, wherein neutral surface active agent (F) is selected from castor oil derivatives, Polysorbate, polyoxyethylene stearic acid ester.
39. any one pharmaceutical carrier in the aforementioned claim, its fusing point is temperature 40-60 ℃.
40. any one pharmaceutical carrier in the aforementioned claim, its fusing point is temperature 40-50 ℃.
41. any one pharmaceutical carrier in the aforementioned claim, its dosage form is the dosage form of the oral administration of slow release release.
42. any one pharmaceutical carrier in the claim 1 to 40, its dosage form is the suppository of slow release release.
43. any one pharmaceutical carrier in the claim 1 to 40, its dosage form is the vagina administration suppository of slow release release.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102283168A CN102000339A (en) | 2010-07-16 | 2010-07-16 | Drug carrier capable of realizing sustained release of drug |
| CN 201110141924 CN102210871A (en) | 2010-07-16 | 2011-05-30 | Pharmaceutical carrier of slow-release medicine |
| CN 201110194167 CN102258785B (en) | 2010-07-16 | 2011-07-12 | Slow-release drug carrier |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102283168A CN102000339A (en) | 2010-07-16 | 2010-07-16 | Drug carrier capable of realizing sustained release of drug |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102000339A true CN102000339A (en) | 2011-04-06 |
Family
ID=43808207
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102283168A Pending CN102000339A (en) | 2010-07-16 | 2010-07-16 | Drug carrier capable of realizing sustained release of drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102000339A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102125043A (en) * | 2011-04-08 | 2011-07-20 | 天津绿动植物营养技术开发有限公司 | Wound healing agent for plants |
| CN102210871A (en) * | 2010-07-16 | 2011-10-12 | 钟术光 | Pharmaceutical carrier of slow-release medicine |
| CN105854022A (en) * | 2011-05-30 | 2016-08-17 | 钟术光 | Drug carrier capable of slowly releasing drug |
| CN106074417A (en) * | 2011-05-30 | 2016-11-09 | 钟术光 | The pharmaceutical carrier of slow-release |
| CN108471791A (en) * | 2015-12-18 | 2018-08-31 | 雀巢产品技术援助有限公司 | For inducing the alimentation composition and infant formula containing relative high levels oligofructose close to the intestinal microbiota pattern of the intestinal microbiota pattern of the baby of human milk feeding |
| CN109180840A (en) * | 2018-09-18 | 2019-01-11 | 昆明理工大学 | A kind of acid-sensitive type ring dextrin and preparation method thereof |
-
2010
- 2010-07-16 CN CN2010102283168A patent/CN102000339A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102210871A (en) * | 2010-07-16 | 2011-10-12 | 钟术光 | Pharmaceutical carrier of slow-release medicine |
| CN102125043A (en) * | 2011-04-08 | 2011-07-20 | 天津绿动植物营养技术开发有限公司 | Wound healing agent for plants |
| CN105854022A (en) * | 2011-05-30 | 2016-08-17 | 钟术光 | Drug carrier capable of slowly releasing drug |
| CN106074417A (en) * | 2011-05-30 | 2016-11-09 | 钟术光 | The pharmaceutical carrier of slow-release |
| CN106139155A (en) * | 2011-05-30 | 2016-11-23 | 钟术光 | The pharmaceutical carrier of slow-release |
| CN108471791A (en) * | 2015-12-18 | 2018-08-31 | 雀巢产品技术援助有限公司 | For inducing the alimentation composition and infant formula containing relative high levels oligofructose close to the intestinal microbiota pattern of the intestinal microbiota pattern of the baby of human milk feeding |
| CN109180840A (en) * | 2018-09-18 | 2019-01-11 | 昆明理工大学 | A kind of acid-sensitive type ring dextrin and preparation method thereof |
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Open date: 20110406 |