CN107929747A - The composition of hydrophilic polymer - Google Patents

The composition of hydrophilic polymer Download PDF

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Publication number
CN107929747A
CN107929747A CN201610888909.4A CN201610888909A CN107929747A CN 107929747 A CN107929747 A CN 107929747A CN 201610888909 A CN201610888909 A CN 201610888909A CN 107929747 A CN107929747 A CN 107929747A
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reference examples
polymer
hydrophilic polymer
aap
values
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CN201610888909.4A
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钟术光
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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Abstract

A kind of composition of the hydrogel-forming polymer improved present invention is disclosed disintegrating property, said composition include one hydrophilic polymers I and AAP values (containing) 1.25 times of hydrophilic polymer II higher than hydrophilic polymer I.In addition, further disclose a kind of (Release Performance (stability)) improvement) (particularly, hydrophilic slow (/ control) release formulation) preparation, said preparation includes one medicines, the composition of above-mentioned hydrogel-forming polymer and optional pharmaceutically acceptable formula agent.Above-mentioned preparation, the detrimental effect that the ionic strength (salinity) of dissolution medium discharges wherein medicine (particularly slow (/ control) release) from said preparation is cancelled, in the ionic strength of change or in the dissolution medium of higher salinity, under the conditions of particularly in fasting and on the feed, dumped along the dosage from said preparation of whole intestines and stomach or dosage is not discharged and is prevented from substantially.

Description

The composition of hydrophilic polymer
Technical field
The present invention relates to a kind of composition of hydrophilic polymer.It particularly relates to a kind of disintegration (or swelling) performance changes The composition of kind hydrophilic polymer.
Technical background
Medicinal hydrophilic polymer can make disintegrant or retarding agent in pharmacy, reach for accelerating or delaying insoluble drug release Expected purpose.Its principle absorbs water to form dilatant to achieve the goal by medicinal hydrophilic polymer.
However, these contact the hydrophilic polymer of swellable work " disintegrant " or " retarding agent " with water, easily occur " in salt Poison " effect and " gel blockage " effect, (can be subject to other peripheral stroma materials particularly under artesian condition when expanding The reaction force of " four walls ")." salt poisoning " effect (implication in lower section is herewith) refers to contact with water swellable hydrophilic herein Polymer, particularly under artesian condition, in the aqueous solution such as physiological saline, urine, menses, vagina containing electrolyte (salt) Body fluid, the phenomenon that is substantially reduced relative to deionized water of the ability of water absorption and swelling in the body fluid in rectum；" gel hinders herein It is wetted and be swollen, suppression that plug " effect (implication in lower section is herewith) refers to contact swellable hydrophilic polymer particles with water Fluid has been made to other regions such as interior shifting of particle and the phenomenon for inhibiting particle to be further swollen, it is so-called just as being formed The phenomenon of " not and open dough ", will be more serious particularly under artesian condition.The main reason for producing gel blocking phenomenon It is that particularly under artesian condition, the gap between particle is reduced and viscosity increase after swelling.
The hydrophilic polymer that swellable work " disintegrant " or " retarding agent " are contacted with water occurs " salt poisoning " effect and " coagulates After glue obstruction " effect, for swelling behavior with after larger change occurs, some polymer particles graininesses fail effectively expansion or fully swollen It is swollen, so that pharmaceutical preparation fails substantially or completely to be disintegrated, thus pharmaceutical preparation drug release rate can be caused to slow down even substantially not The problems such as drug release.
Particularly in slow (/ control) release formulation, because hydrophilic polymer graininess fails effectively expansion or fully expansion, the system Agent, which is also possible that, even to be there is the release of medicine rapid abnormal by faster drug release dosage inclines and releases (dose-dumping) in other words Deng drug safety problem.
Thus, the insoluble drug release behavior of the pharmaceutical preparation containing these hydrophilic polymers will likely become unstable, such as release The possible substantial deviation of medicine speed is expected, too fast or excessively slow, or even is not released the drug or inclined suddenly substantially and release；In addition, insoluble drug release behavior Unstable to further include front and rear drug release rate non-constant, inconsistent, and early period, drug release was fast, partially slow (the same ionic strength of later stage drug release Under (salinity) or under same drug release medium).
This implies that the pharmaceutical preparation containing these hydrophilic polymers preferably has to provide stable drug release pattern, special It is not to have to avoid rate of releasing drug excessive variation in the medium of the ionic strength (salinity) of change, because gastrointestinal cavity content The ion-intensity values (salinity) of change are presented in the different region of intestines and stomach.The ion-intensity values (salinity) run into the gastrointestinal tract Not only with the regional change of intestines and stomach, but also change with the intake of food, said medicine preparation preferably also has to provide stabilization Drug release pattern and especially have to avoid no matter patient is under fasting or fed condition from providing stable insoluble drug release Pattern.The ionic strength of gastrointestinal fluid can between about 0.01 to about 0.2 (Johnson etc., 1993, Int.J.Pharm., 151-159)。
Ionic strength, in most cases by symbol μ (being sometimes I) represent, for solution characteristic and be defined as：
Wherein ciFor the molar concentration of i-th of ion, ZiFor its electric charge, and the summation includes all ions in solution (Martin, A., 1993,134-135 pages of Physical Pharmacy, Williams＆wilkins, the), reflects solution Salinity.On the ion that known electrolyte specific in by solution produces, the foundation of ionic strength can be measured well by solution All ions influence imperfection.
There is the ionic strength (salinity) that surrounding medium is described in document to the pharmaceutical preparation containing these hydrophilic polymers Calving disaggregation, the influence in gelatification and viscosity.
Mitchell etc. (insoluble drug release of pharmaceutical technology control, volume 2, Wells, J.I., Rubinstein, M.H. (editor), Ellis Horwood Limited, the 23-33 pages, 1991) open electrolyte is to hydroxypropyl methyl cellulose (HPMC) calving disaggregation of K15M substrate tablets and the influence of gelatification.Under the low ionic strength of surrounding medium, HPMC matrix is not By Influence of Electrolyte and the complete gel layer of aquation generation occurs.However, under moderate ionic strength, matrix loses shape And integrality, and their rapid fragmentations.Tablet stopping is used as slow (/ control) to release matrix and works, because in surrounding medium is increased Solute concentration in the case of, gelatification is hindered by the reduction of aquation.Accordingly, there exist the electricity in surrounding medium Solution matter can improve medicine from the release mode in HPMC matrix.Medicine can also influence aquation and therefore influence in itself The gelatification of HPMC.Therefore, medicine can have a positive effect in the release of themselves is measured (Mitchell etc., Int.J.Pharm., 1993,100,165-173).So medicine, which is admixed in HPMC matrix, can lead to not expected disintegration Therefore pattern simultaneously causes the unexpected therapeutic effect of formulation.
In Int.J.Pharm., chlorine of the xanthan gum matrix tablet in different ionic strength described in 1995,120,63-72 Change the swelling behavior in sodium solution.In the range of physiological ionic strength, the swelling of xanthan gum tablet is shown and salinity phase Mutual correlation.
The detrimental effect of insoluble drug release behavior of the above-mentioned ionic strength to the pharmaceutical preparation containing these hydrophilic polymers, can It is attributed to the change of the aquation of the hydrophilic polymer of viscosity.The hydrophilic polymer have to composition dissolution medium from The solute of sub- intensity competes hydrate water.So polymer can not be hydrated such degree to ensure to have and can connect to disintegration The matrix of the sufficiently complete for the resistance received is formed.The hydration (disintegration) (effect) of the matrix polymer can be great or even complete It is complete to be suppressed that almost fragmentation immediately triggers to incline suddenly and releases so that slow (/ control) release formulation is in dissolution medium mesostroma, or make general Disintegrant in logical tablet loses calving disaggregation completely and can not release the drug or prolonged disintegration makes drug release slack-off.
Therefore, also need to improve in reality or improve purposes of the above-mentioned hydrophilic polymer in pharmacy.
Following patent provides as reference.
Chinese patent CN1079698C (or US5714156) is disclosed has different AAP values by mixing two classes The hydrogel of (Absorption Against Pressure values, sucting wet gel material absorb the important parameter of the ability of liquid) Type particle, can obtain cooperative effect, and the wherein AAP values of mixture are predicted than the weight percent of the component based on mixture Value is high.There is the aquogel type particle of different TCC values and identical AAP values to make the AAP values of mixture unexpectedly by mixing two classes Increase.But the patent does not refer to that adding above-mentioned aquogel type particle makes what disintegration (drug release) performance (stability) of preparation improved Using.
Chinese patent CN1345233A (or EP0691133B1) discloses pregelatinized starch and is used to prevent the ion in change Dosage from hydrophilic slow (/ control) release formulation in the dissolution medium of intensity dumps the purposes of (dose-dumping).The patent is not Refer to AAP value relevant issues.The patent does not refer to part pregelatinization (/ change) starch yet, is mentioned that drum-type is done in embodiment Dry waxy corn starch.By be made from drum-type seasoning full pregelatinization (/ change) starch (referring to《Pharmaceutic adjuvant handbook》(in Translation, original work the 4th edition, Zheng Jun democracy is translated, Chemical Industry Press) 2005 years the 1st edition page 700：13 preparation method Part II). Wax-like (matter) cornstarch is a kind of starch of almost full side chain.Full pregelatinization (/ change) starch is water-soluble preferably, dissolves in cold Water, is dispersed among normal-temperature water, warm water, its AAP values measured value and other water-soluble preferable polymer are substantially suitable, as HPMC, HPC, MC, PVP etc., hence it is evident that less than the AAP values of part pregelatinization (/ change) starch, also significantly lower than the polymerization of other water-insolubles The AAP values of thing, such as CMC-Na, sodium carboxymethyl starch, HPS, L-HPC, commissure PVP, Sodium Polyacrylate, sodium alginate.
The content of the invention
The present invention relates to a kind of (particularly, in the ionic strength of change or in the dissolution medium of higher salinity) disintegration The composition for the hydrogel-forming polymer that (or swelling) performance (stability) improves, said composition include one parents (i.e. Absorption Against Pressure values, or pressure-bearing expansion (swelling) value, the value are anti-for aqueous polymer I and AAP values The disintegration Swelling Capacity under polymer renitency is reflected, similarly hereinafter) 1.25 times of (containing) higher than hydrophilic polymer I (it is preferred that the AAP Value also dries 1.25 times of wax-like (matter) cornstarch high (containing) than drum-type) one water-insoluble (including usually anticipate " slightly molten ", " slightly soluble ", " almost insoluble " or " fairly insoluble " in justice etc. look like, and " water-insoluble " implication is herewith below) Hydrophilic polymer II.
The present invention relates to above-mentioned composition as the additive for playing disintegration (or swelling) performance in pharmaceutical preparation Purposes.
It is used as the addition that insoluble drug release retardation is played in hydrophilic slow (/ control) release formulation the present invention relates to above-mentioned composition The purposes of agent.
The present invention relates to a kind of purposes of the composition of hydrogel-forming polymer, the composition bag of the hydrogel-forming polymer Preferably, containing 1.25 times of one (or more) kinds of hydrophilic polymers I and AAP values (containing) higher than hydrophilic polymer I, (which also compares Drum-type dries 1.25 times of wax-like (matter) cornstarch high (containing)) one water-insoluble hydrophilic polymers II, this The composition of hydrogel-forming polymer is used to improve the combination comprising one medicines and above-mentioned hydrogel-forming polymer (particularly, hydrophilic slow (/ control) release formulation) preparation (particularly, the ionic strength in change or release in higher salinity of thing In medium) Release Performance (stability) purposes, in other words, the composition of the hydrogel-forming polymer, which is used to offset, to be discharged The ionic strength (salinity) of medium discharges medicine the use of the detrimental effect of (particularly slow (/ control) release) from said preparation On the way, particularly, for prevent in fasting and on the feed under the conditions of, along the drug dose from said preparation of whole intestines and stomach Dump or purposes that drug dose does not discharge substantially).
The present invention relates to a kind of ((particularly, in the ionic strength of change or in the dissolution medium of higher salinity) disintegration (or swelling) performance (stability) (or Release Performance (stability)) improves) preparation (particularly, release by hydrophilic slow (/ control) Preparation), said preparation includes one medicines, a kind of composition of hydrogel-forming polymer (and optionally can pharmaceutically connect The formula agent received), the composition of the hydrogel-forming polymer includes one hydrophilic polymers I and AAP values than hydrophilic Preferably, 1.25 times of polymer I high (containing) (which also dries 1.25 times of wax-like (matter) cornstarch high (containing) than drum-type) One water-insoluble hydrophilic polymers II.Above-mentioned preparation, the ionic strength (salinity) of dissolution medium is to its Chinese medicine Thing discharges (particularly slow (/ control) release from said preparation) detrimental effect be cancelled, change ionic strength or compared with In the dissolution medium of high salinity, particularly in fasting and on the feed under the conditions of, along whole intestines and stomach from said preparation Dosage is dumped or dosage is not discharged and is prevented from substantially.In addition, above-mentioned hydrophilic slow (/ control) release formulation has considerably longer slow (/ control) The time of drug release thing, delays (/ control) release formulation than conventional hydrophilic.
It is preferred that the AAP values of above-mentioned hydrophilic polymer II (particle) are at least the AAP of above-mentioned hydrophilic polymer I (particle) Value 1.5 (preferably 2, more preferably 3, more preferably 5, more preferably 10, most preferably 15) times.
It is preferred that above-mentioned hydrophilic polymer I (particle) is AAP relative to the absorption value of a pressure1, above-mentioned hydrophilic polymer II (particle) is AAP relative to the absorption value of a pressure2, the absorption value relative to a pressure of the two mixture is AAP1,2, AAP1,2/(w·AAP1+p·AAP2) ＞ 1 (more preferably >=1.25), wherein, w accounts for above-mentioned parent for above-mentioned hydrophilic polymer I (particle) The percentage of aqueous polymer I and above-mentioned hydrophilic polymer II (particle) gross weight, p account for for above-mentioned hydrophilic polymer II (particle) State hydrophilic polymer I and the percentage of above-mentioned hydrophilic polymer II (particle) gross weight, and p+w=1, it is above-mentioned relative to pressure Absorption value AAP be between 21.1g/cm2 (0.3psi) and 70.3g/cm2 (1psi), preferably in 35.2g/cm2 (0.5psi) and (the explanation measured under pressure between 56.2g/cm2 (0.8psi)：The measure of all absorption value AAP to compare is herein Carried out under identical conditions (pressure)).
It is preferred that the TCC values of above-mentioned hydrophilic polymer II (particle) are higher than the TCC values of above-mentioned hydrophilic polymer I (particle), The AAP values of the mixture of the two are higher than any of above-mentioned hydrophilic polymer I (particle) and above-mentioned hydrophilic polymer II (particle) AAP values, wherein the absorption value relative to pressure be between 21.1g/cm2 (0.3psi) and 70.3g/cm2 (1psi), It is preferred that measured under pressure between 35.2g/cm2 (0.5psi) and 56.2g/cm2 (0.8psi).
It is preferred that the weight of above-mentioned hydrophilic polymer I (particle) accounts for above-mentioned hydrophilic polymer I and above-mentioned hydrophilic polymer II At least the 10% of (particle) gross weight.
It is preferred that half mass particle size of above-mentioned I particle of hydrophilic polymer is substantially not less than above-mentioned hydrophilic polymer Half mass particle size of II particle.
It is preferred that the AAP values of above-mentioned hydrophilic polymer II and above-mentioned hydrophilic polymer I difference at least 2 (preferably 5, more preferably 10, more preferably 20, most preferably 40) gram gram.
It is preferred that under the pressure of 49.2g/cm2 (0.7psi), the AAP values of above-mentioned hydrophilic polymer II (particle) is extremely Few 8 (preferably 15, more preferably 25) gram gram.
It is preferred that the TCC values of above-mentioned II material of hydrophilic polymer be at least 10 (preferably 20, more preferably 40) gram gram.
It is preferred that it is preferred that the content of above-mentioned hydrophilic polymer I (particle) is in above-mentioned hydrophilic polymer I and above-mentioned hydrophilic 10% and 97% (preferably 20% and 90%, more preferably 20% and 85%, more preferably 30% He of II material gross weight of polymer 75%, most preferably 30% and 65%) between.
It is preferred that half mass particle size of above-mentioned II particle of hydrophilic polymer is between 10 microns and 250 microns, it is above-mentioned Half mass particle size of I particle of hydrophilic polymer is between 20 microns and 400 microns.
In the term " (stability) of disintegration (or swelling) performance improves " used above or below or " Release Performance (stability) improves " refer to ionic strength (or salinity) in dissolution medium in (such as from 0.01 to about 0.2 model by a relatively large margin In enclosing, in the range of more preferably such as from 0.01 to about 0.4) under change, the medicine " disintegration (or swelling) performance " of preparation or " release the drug Performance ", can discharge the ability of medicine from preparation in other words, be basically unchanged or amplitude of variation substantially reduces；Or/and refer to system When agent dissolution medium ionic strength (salinity) is basically unchanged (in same dissolution medium), front and rear phase drug release rate is basically unchanged (substantially constant, basically identical), or substantially reduced with later stage drug release rate intensity of variation early period.
Include the liquid medium of all kinds in the term " dissolution medium " used above or below, wherein can occur Medicine is from the release in preparation, i.e., for example in vitro in dissolving medium, particularly in body fluid, more particularly in gastrointestinal fluid Release.Above-mentioned dissolution medium, especially refers in the dissolution medium with increased ionic strength, particularly refers to having Have scope at most up in the dissolution medium of 0.4 ion-intensity values, even more particularly relate to run into physiological conditions from In the dissolution medium of sub- intensity level, i.e., along whole intestines and stomach in fasting and on the feed under the conditions of, and most particularly about In the dissolution medium of ion-intensity values in the range of 0.01 to about 0.2.
Term " slow (/ control) is released " refer to medicine in time from preparation slowly gradually release, sustained release, extend release the drug, Sustained release or extended release.Especially, it is that the medicine of 50-80% or more does not release immediately in preparation after referring to being administered orally And preparation reduces administration number of times, according to American Pharmacopeia 24 edition page 2059, the definition for the release that is delayed can be exchanged with control release. Discharged herein with extension effect, sustained release or delay the synonymous controlled release dosage form used be described as making administration number of times reduce to Few twice or the more apparent increase trouble compared with regular dosage form (for example, as solution or conventional solid dosage forms of promotion insoluble drug release) The compliance of person or the formulation of therapeutic effect.
Term " dosage " is dumped " know for those skilled in the art and be defined as being intended as the system of control delivery formulations The active ingredient blended in agent largely or entirely discharges suddenly.Instead of the release during time lengthening, all dosage or at least Release in its most of short time.Depending on active ingredient and effect, this can cause serious side effect or even dead.
During " TTC values " (Teabag Centrifuge Capacity) and " AAP values " define and assay method sees below Testing experiment method part.
Have found higher (it is preferred that half mass particle size is also smaller) by the inhomogeneity AAP values for adding sub-fraction Aquogel type particle (hydrophilic polymer II), be particularly conducive to improve low AAP values aquogel type material (hydrophilic polymer I) AAP values.Do not wish to be bound by any theory restrictions, it is believed that the particle for having higher AAP values absorb it is more relatively low than AAP values during liquid " compared with It is soft " ability of particle deformation resistant is big.In the mixture, smaller, " harder " particle keep open architecture and prevent " softer ", compared with Impermeability barrier is formed during big particle expansion.
Based on this, it has unexpectedly been found that, add the hydrophilic polymer II of higher AAP values can offset dissolution medium ion it is strong Spend the infringement or even broken of disintegration (or swelling) performance of (salinity) to low AAP values aquogel type material (hydrophilic polymer I) Bad effect, improves the stability of its disintegration (or swelling) performance, and then improves (hydrophilic poly- comprising low AAP values aquogel type material Compound I) preparation the ionic strength of change or in the dissolution medium of higher salinity Release Performance stability.Such as to In the time interval of 15min or longer after medicine, the hydrophilic polymer II by making higher AAP values is admixed in preparation, preparation Release Performance performance is basically unchanged or amplitude of variation is greatly decreased, particularly in the dissolution medium with increased ionic strength In, more particularly in the dissolution medium of the ion-intensity values with scope at most reachable 0.4, or even more particularly in physiology bar In the dissolution medium of the ion-intensity values run under part, i.e., along whole intestines and stomach in fasting and on the feed under the conditions of, and most The Release Performance performance of preparation in the dissolution medium of the ion-intensity values particularly changed in the range of about 0.01 to about 0.2 It is basically unchanged or amplitude of variation is greatly decreased.
Embodiment
Hydrophilic polymer I
(above-mentioned) hydrophilic polymer I for the present invention, which is generally, pharmaceutically acceptable contacts swellable " collapse with water The hydrophilic polymer of solution ".They can make " disintegrant " in ordinary preparation such as conventional tablet makes it be disintegrated drug release rapidly.They Can make " retarding agent " --- gradual, slow, continuous discharge active component in slow (/ control) release formulation, they be administered after with aqueous stream Body contact swelling, generates viscosity, adjusting insoluble drug release gel layer.
Viscosity for (above-mentioned) hydrophilic polymer I of the invention is preferably 150 to 100,000mPa.s (at 20 DEG C Under, the apparent viscosity of 2% aqueous solution) between.The example of such polymer is：
Polysaccharide, cellulose derivative (slow (/ control) is released) material：
- alkylcellulose, such as methylcellulose；
- hydroxy alkyl cellulose, such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose (including low-substituted hydroxypropyl Cellulose) and hydroxybutyl cellulose；
- hydroxyalkylalkylcellulose, such as hydroxyethylmethylcellulose and hydroxypropyl methyl cellulose；
- carboxyl alkyl cellulose, such as carboxymethyl cellulose；
The alkali metal salt of the alkali metal salt of-carboxyl alkyl cellulose, crosslinked carboxyl alkyl cellulose, such as carboxymethyl cellulose Sodium, Ac-Di-Sol；
- carboxyalkyl alkylcellulose, such as carboxymethylethylcellulose；
- carboxyl alkyl cellulose ester；
- other natural, semi-synthetic or synthesis polysaccharide, such as alginic acid and its alkali metal salt and ammonium salt, Irish moss Glycan, galactomannans, bassora gum, agar, Arabic gum, guar gum, xanthans, starch, hydroxypropul starch, pectin, knot Cold glue, sodium carboxymethyl starch or acrylic acid branch (branch) connect sodium starch, chitin derivative such as chitosan, poly fruit Sugar, inuloid.
Crylic acid resin (slow (/ control) is released) material：
- polyacrylic acid and their salt；
- polymethylacrylic acid and their salt, methacrylate copolymer.
Polyethylene kind (slow (/ control) is released) material：
- polyvinyl alcohol；Polyvinyl acetate；Carbopol (carbopol)；Polyoxyethylene；
The copolymerization of-polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polyvinylpyrrolidone and vinyl acetate Thing；
The composition of-polyvinyl alcohol and polyvinylpyrrolidone；
- polyalkylene oxide class such as polyethylene oxide and polypropylene oxide and the copolymer of ethylene oxide and propylene oxide, such as Poloxamer (F127).
Preferable hydrophilic polymer is polysaccharide, is more particularly cellulose derivative and most specifically for cellulose ether derivative.
Most preferred cellulose ether derivative is hydroxypropyl methyl cellulose and hydroxypropyl cellulose.
The hydroxypropyl cellulose and hydroxypropyl methyl cellulose of different viscosities rank are available on the market.
In the present invention preferably using hydroxypropyl methyl cellulose have in about 3,500mPa.s to about 100, Viscosity grade between 000mPa.s, particularly in about 4,000mPa.s between about 20,000mPa.s, and most particularly Viscosity grade between about 6,500mPa.s to about 15,000mPa.s (at 20 DEG C, the apparent viscosity of 2% aqueous solution) Not, such as hypromellose 2208 (DOW, Antwerp, Belgium).
It is less than the hydroxypropyl cellulose of 1,500mPa.s (at 20 DEG C, the apparent viscosity of 2% aqueous solution) with viscosity It is preferred that particularly about 150 to the viscosity between about 700mPa.s hydroxypropyl cellulose, preferably 200 to Between 600mPa.s, such as Klucel EF (Hercules, Wilminton, USA).
The sticky hydrophilic polymer of composition matrix mainly provides the control pharmacokinetics release mode of preparation.According to making Depending on having the amount of polymer in agent, release mode can be varied.The amount of sticky hydrophilic polymer in invention formulation It is preferred that between about 0.01 to about 80% (w/w).In addition, when using the composition of polymer, the ratio of the polymer Example also influences the release mode of preparation.For example, when using one or more hydrophilic polymer, derive preferably using cellulose Thing, particularly using hydroxypropyl cellulose and hydroxypropyl methyl cellulose, the percentage by weight (%w/ of hydroxypropyl methyl cellulose W) preferably between 0 to about 16%；The percentage by weight of hydroxypropyl cellulose is preferably between about 25% to about 62%. The ratio of hydroxypropyl cellulose and hydroxypropyl methyl cellulose is preferably between 1: 5 to 5: 1, more preferably between 1: 1 to 5: 1, And most preferably between 3: 1 to 5: 1.
The composition of different polymer, which provides, makes the possibility that different mechanism combines, and is released by these mechanism from matrix Put active ingredient.Such combination contributes to the pharmacokinetics release mode of any control preparation.As mentioned above Like that, there are three kinds of main mechanism, by these mechanism can from hydrophilic matrix discharge active component：Dissolution, corrosion And diffusion.When it is dispersed in the matrix network of soluble polymer, active ingredient will be discharged by dissolution mechanism. The mesh will be gradually dissolved in intestines and stomach, thus gradually discharge its load.Matrix polymer also can be gradually from matrix table Face corrosion, same timely discharge active component.When active ingredient is handled in the matrix that insoluble polymer forms, it will be through Dispersal events：Gastrointestinal fluid is penetrated into insoluble, spongioid matrix and concomitant drugs depart from load and diffuse out.
By the releasing mechanism of a set of combination, one or more active ingredients are from including hydroxypropyl cellulose and hydroxypropyl first Discharged in the matrix of base cellulose.Since hydroxypropyl methyl cellulose has higher dissolving compared with hydroxypropyl cellulose Property, the former will gradually dissolving and corrosion from matrix, and the latter is worked as cavernous transformation matrix, the former mainly passes through Dispersal events active ingredient.
Hydrophilic polymer II
It is a kind of " pharmaceutically acceptable water-swellable and water base in (above-mentioned) hydrophilic polymer II used in the present invention Upper insoluble polymer ", they refer to a kind of such pharmaceutically acceptable material (polymer), when it is exposed to excessive Water in when, it is expanded to its equilibrium volume, but is substantially insoluble in solution.This polymeric material is also commonly referred to as " hydrocolloid " or " superabsorbent " material.For definition used herein, if a kind of material is considered water miscible, its base Be dissolved in sheet in excessive water and form solution, thus lose that it is initial, particularly granular shape, and substantially with point Sub- state is scattered in aqueous solution.Common criterion is that water dissolvable material is that no substantial extent is crosslinked, because crosslinking will make Material has water-insoluble.
(above-mentioned) hydrophilic polymer II for the present invention is typically crosslinked.Crosslinked amount usually should be enough to make to gather Compound is kept on the substantially insoluble minimum of water, but also should in polymer is kept water the maximum that be swollen enough it Under, so that polymer can absorb the desired amount of liquid and and be swollen.
The crosslinking of usual polymer is realized by the use of one of two distinct types of crosslinking agent.First type Crosslinking agent is polymerizable crosslinking agent.Suitable polymerizable crosslinking agent is usually in reactivity to the monomer for being used to prepare polymer , and therefore usually contain at least two can be with the functional group of monomer reaction.The example of suitable polymerizable crosslinking agent, for Include vinyl-based unsaturated monomer for radical polymerization, such as N, N '-methylene-bisacrylamide, include for polycondensation Polyamines or polyol.
The crosslinking agent of Second Type is rear crosslinking agents.Rear crosslinking agents are usually not involved in whole polymerization process, but after relatively Time, it can be with polymer reaction when being supplied to appropriate cross linking conditions.Suitable post-treatment condition includes the use of heating Processing, as temperature is greater than about 60 DEG C, exposed to ultraviolet, exposed to microwave, steam or high humility processing, HIGH PRESSURE TREATMENT or with having Solvent processing.
It is usually water miscible to be suitable for the invention rear crosslinking agents.Suitable rear crosslinking agents be at least have two can be with Any carboxyl, carboxylic acid, the functional group of amino or hydroxyl reaction or a kind of organic compound of degree of functionality on polymer.Suitable The example of rear crosslinking agents includes but is not limited to diamine, polyamines, dihydric alcohol, polyol, polycarboxylic acid and polyoxide.Another kind is suitable Suitable rear crosslinking agents contain the metal ion with more than two positive charge, such as Al3+, Fe2+, Ce3+, Ce4+, Ti4+, Zr4+ and Cr3+。
When polymer is cationic polymer, suitable crosslinking agent be polymer anion material, such as polyacrylic acid Sodium, carboxymethyl cellulose, or polyphosphate.
(above-mentioned) hydrophilic polymer II preferably (in molecular structure) for the present invention contains a variety of anionic functional groups, Such as sulfonic group, and the more typically such as polymer of carboxyl.Include suitable for the example of this polymer from polymerizable, unsaturated , acidiferous monomer prepare those polymer.Therefore, this monomer includes the olefinic containing at least one carbon-to-carbon olefinic double bond not Saturated acid and acid anhydride.More specifically, these monomers may be selected from ethylenically unsaturated carboxylic acids and acid anhydrides, olefinic unsaturated sulfonic acid and its mixing Thing.
In above-mentioned hydrophilic polymer II is prepared, it may also comprise some usually with less amount of non-acid monomers.It is this non- Acid monomers may include the water solubility of such as acidiferous monomer or the dispersible ester of water, and without carboxylic acid or sulfonic monomer.Cause This optional non-acid monomers may include the monomer containing such as lower class functional group：Carboxylic acid or sulphonic acid ester, hydroxyl, amide groups, amino, nitrile Base and quaternary ammonium salt base.These non-acid monomers are known material, are described in more detail in such as on 2 28th, 1978 U.S. issued In the United States Patent (USP) 4,062,817 (Westerman) that patent 4,076,663 (Masuda etc.) and on December 13rd, 1977 issue, The two is incorporated by reference.
Ethylenically unsaturated carboxylic acids and carboxylic acid anhydride monomer include acrylic compounds, typically acrylic acid in itself, methacrylic acid, Ethylacrylic acid, chloroacrylic acid, alpha-cyanoacrylate, methacrylic acid (crotonic acid), phenylacrylic acid, acryloxy propionic (- acryloxypropionic acid), sorbic acid, chlorine sorbic acid, angelic acid, cinnamic acid, to chloro-cinnamic acid ,- Sterylacrylic acid, itaconic acid, citraconic acid, mesaconic acid, glutaconate, aconitic acid, maleic acid, fumaric acid, tricarboxylic second Alkene and maleic anhydride.
Olefinic unsaturated sulfonic acid monomer includes aliphatic series or aromatic vinyl sulfonic acids such as vinyl sulfonic acid, allyl sulphonic acid, second Alkenyl toluenesulfonic acid and styrene sulfonic acid；Acrylic acid and methacrylic sulfonic acids such as sulfoethyl acrylate, methacrylic acid sulphur second Ester, acrylic acid sulphur propyl ester, methacrylic acid sulphur propyl ester, 2- hydroxy-3-methyl acryloxypropyl sulfonic acid and 2- acrylamides -2- Methyl propane sulfonic acid.
More preferably be preferred for that during the above-mentioned hydrophilic polymer II of the present invention is usually and/or part neutralizes it is weakly acidic (or It is weakly alkaline) water-swellable and insoluble polymer.The pKa (or pKb) of these polymer is advisable with about 2~about 12, more has It is about 2~about 10 sharply, conveniently about 3~about 6.
It has been found that it is less than about 2 or the expansiveness, the water that use pKa (or pKb) to be greater than about 12 using pKa (or pKb) Insoluble polymer, usually will appear from the unwanted performance of the present invention, such as low absorption liquid rate, low Release Performance, and And it there may also be larger irritation etc.
Above-mentioned suitable slightly acidic water swellability and insoluble polymer (in molecular structure), which include, can be used as weak acid Functional group.These functional groups include but not limited to carboxyl, sulfate groups, inferior sulfate radical group, and phosphate groups.Suitable Functional group is carboxyl.In general, these functional groups are connected on crosslinked base polymer.Suitable base polymer includes poly- third Acrylamide, polyvinyl alcohol, ethylene maleic acid anhydride copolymer, polyvingl ether, polyacrylic acid, poly- carbon number are C1~C4 alkyl Acrylic acid, poly- hydroxyl carbon atom number are C1~C4 alkyl acrylics, polyvinylpyrrolidone, polyvinyl beautiful jade, and they Copolymer.Natural polysaccharide polymer, including carboxymethyl cellulose can also be used, carboxymethyl starch, hydroxypropyl or ethyl are fine Dimension element, alginic acid, alginate, humic acid, carrageenan, acrylic acid-grafted starch, acrylic acid-grafted cellulose, and it Copolymer.The polypeptide of synthesis can also be used, as poly-aspartate, polyglutamic acid, poly- mixing acidic amino acid are (such as poly- mixed Aspartic acid is closed, for example poly-aspartate-aspartic acid-lysine is sour (4: 2: 1) in fact；Poly- mixing glutamic acid, in fact for example Polyglutamic acid-lysine is sour (4: 1).Term " poly- mixing acidic amino acid " refers to exist containing including acidic amino acid in chain herein Interior a variety of amino acid, and the molal quantity of acidic amino acid (such as aspartic acid, glutamic acid) is more than basic amino acid (as relied ammonia Acid, arginine) it is molal quantity and acid poly- a variety of amino acid are presented (poly- a variety of amino acid are referring to document： US5247068A).It is preferred that it is suitable for the above-mentioned slightly acidic water swellability of the present invention and the example bag of the polymer of water-insoluble Contain but be not limited to (in and/or part neutralize) weight average molecular weight and be generally greater than about 100000 acrylate copolymer, poly- carbon atom Number is C1~C4 alkyl acrylics, poly- hydroxyl carbon atom number be C1~C4 alkyl acrylics, acrylic acid-acrylic ester polymer, Polyvinyl alcohol-acrylic block copolymers, starch graft acrylic acid polymer, cellulose graft acrylate copolymer, humic acid, Polycarbophil (Polycarbophil polymers), alginic acid, poly-aspartate, polyglutamic acid, poly- mixing aspartic acid and Poly- mixing glutamic acid, and their mixture.
Above-mentioned suitable alkalescent water swellability and insoluble polymer (in molecular structure), which include, can be used as weak base Functional group.These functional groups include but is not limited to primary, secondary and tertiary amino, imino group, and acylamino-.Suitable functional group is ammonia Base.In general, these functional groups are connected on crosslinked matrix polymer.Suitable matrix polymer includes polyamine or polyimides, Polyethyleneimine, polyethylenepolyamine, polyacrylamide, polypropylene amine, polypropylene carbon number are C1~C4 alkylamines, and poly- carbon is former Subnumber is C1~C4 alkyl amine, and poly- carbon number is that C1~C4 alkyl carbon numbers are C1~C4 alkylamines, poly- hydroxyl Base carbon number is C1~C4 alkyl amine, and poly- hydroxyl carbon atom number is that C1~C4 alkyl carbon numbers are C1~C4 alkane Base amine, and polyquaternium, and their copolymer.It can also use natural polysaccharide polymer, including chitin and deacetylated Chitin and other glycosaminoglycans.The polypeptide of synthesis can also be used, such as poly-asparagine, polyglutamine, polylysine, gathers Arginine, poly- mixed-alkali amino acid (mix lysine, in fact such as polyglutamic acid-lysine (1: 3) as poly-；Poly- mixing essence Propylhomoserin, in fact such as poly-aspartate-arginine (1: 4).Term " poly- mixed-alkali amino acid " refers in chain containing bag herein A variety of amino acid including basic amino acid are included, and the molal quantity of basic amino acid (such as lysine, arginine) is more than acid ammonia Poly- a variety of amino acid molal quantity and that alkalescence is presented of base acid (such as aspartic acid, glutamic acid) (gather a variety of amino acid referring to text Offer：US5247068A).It is preferred that it is suitable for the above-mentioned alkalescent water swellability of the present invention and the example of the polymer of water-insoluble 100000 polyamine or polyimides, polyethylene are generally greater than about including but not limited to (in and/or part neutralize) weight average molecular weight Imines, polypropylene amine, polyethylenepolyamine, polypropylene carbon number are C1~C4 alkylamines, poly- carbon number is C1~C4 alkyl Allylamine, poly- carbon number be C1~C4 alkyl carbon numbers be C1~C4 alkylamines, poly- hydroxyl carbon atom number be C1~ C4 alkyls amine, poly- hydroxyl carbon atom number be C1~C4 alkyl atomicities be C1~C4 alkylamines, it is chitin, deacetylated Chitin, other glycosaminoglycans, poly-asparagine, polyglutamine, polylysine, poly arginine, gathers mixing lysine and gathers Mix arginine, and their mixture.
The above-mentioned hydrophilic polymer II for being more preferably preferred for the present invention is selected from (in molecular structure) containing the water-soluble of carboxyl Swollen property and insoluble polymer.The example of these polymer includes hydrolyzed starch-acrylonitrile graft copolymer, part neutralizes Starch-Acrylontirile Graft Copolymer, starch-acrylate graft copolymer, part neutralize starch-acrylate graft copolymer, Sapond vinyl acetate-acrylate copolymer, the acrylonitrile or acrylamide copolymer, any of the above described copolymer of hydrolysis The crosslinked polymer of microgrid shape, part neutralize polyacrylic acid and part neutralize polyacrylic acid the crosslinked polymerization of microgrid shape Thing, the partially pregelatinized starch (explanation of pregelatinated 20-80%：After starch pregelatinated, its AAP value on pregelatinated degree with rising from Now first rise to maximum and then decline, AAP values are very low after complete pregelatinated, and hardly possible AAP values are to survey in cold water and normal-temperature water Fixed or indeterminacy), and their mixture.These polymer can be used alone or the mixing with two or more different polymer The form of thing uses.The example of these polymeric materials is disclosed in United States Patent (USP) 3,661,875, United States Patent (USP) 4,076,663, U.S. In state's patent 4,093,776, United States Patent (USP) 4,666,983 and United States Patent (USP) 4,734,478.
Most preferably it is preferred for preparing micro- cross-linked network of the above-mentioned hydrophilic polymer II for (part neutralizes) polyacrylic acid Polymer and its starch derivatives.
The neutralization of weak acid (or alkali) property functional group in above-mentioned weak acid (or alkali) property water-swellable and insoluble polymer Degree is about 5~about 100 moles of %, more advantageously about 30~about 95 moles of %, suitably about 50~about 90 moles of %, optimally About 70~about 80 moles of %.
Molecular weight ranges for (above-mentioned) hydrophilic polymer II in the present invention are very wide.Relatively high molecular weight it is water-soluble Swollen property and insoluble polymer, are typically favourable for the use in the present invention.Be suitable for the invention water-swellable and The weight average molecular weight of insoluble polymer is generally greater than about 20000, is preferred with being greater than about 100000, is preferably greater than about 200000, more preferably greater than about 500000, it is preferably more than 1000000, up to about 10000000.Measure polymer molecular weight Method be usually well known in the art.
Sometimes more easily expressing the mode of polymer molecular weight is at 25 DEG C, the aqueous solutions of polymers of 1.0 weight % Viscosity.Polymer is suitable for the invention, the viscosity of its 1.0 weight % aqueous solution is about 200~about 80000 centipoise using at 25 DEG C (mPas) it is advisable, preferably about 500~about 80000 centipoises, optimum is about 1000~about 80000 centipoises.
Currently preferred (above-mentioned) hydrophilic polymer II is that have higher absorption ability or Teabag Centrifuge Capacity values.Absorbability or Teabag Centrifuge Capacity mean given polymer in non-swelling condition The lower ability for absorbing liquid in contact.TCC can be with contact of the property and liquid of absorbed liquid with polymeric material The difference of mode and significantly change.
Medicine
Invention formulation is suitable for giving one or more medicines.
Medicine is generally selected from the medicine with following properties in slow (/ control) release formulation：
(a) there is short half-life period, with 4 to 8 when small or shorter rank, it is had to whole when being given with conventional formulation Natural gift several times take by dosage；Or
(b) there is narrow therapeutic index；Or
(c) there is enough absorptions through whole intestines and stomach；Or
(d) there is relatively small treatment effective dose.
Suitable medicine is the material of performance local physiological effect after those oral administrations and those performance general actions Material.The example of their (being particularly used to delay (/ control) release formulation) is：
- anodyne and anti-inflammatory agent (NSAIDs, fentanyl, Indomethacin, brufen, Ketoprofen, Nabumetone, to acetyl Amino phenols, piroxicam, tramadol, cox 2 inhibitor such as celecoxib (celecoxib) and rofecoxib (rofecoxib))；
- antiarrhymic (procainamide, quinindium, Verapamil)；
- antibacterial and antiprotozoal (Amoxicillin, ampicillin, tardocillin, penicillin, Cefaclor, cephalo Amoxycillin, Cefprozil, cefuroxime axetil, cefalexin, chloramphenicol, chloroquine, Ciprofloxacin, clarithromycin, carat dimension Acid, clindamycin, Doxycycline, erythromycin, flucloxacillin sodium, halofantrine, isoniazid, kanamycin sulfate, lincomycin, first Fluorine quinoline, minocycline, sodium nafcillin, acidum nalidixicum, neomycin, Norfloxacin, Ofloxacin, oxacillin, ospeneff, Pyrimethamine-Sulfadoxine, streptomysin)；
- anticoagulation (warfarin)；
- antidepressants are (amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dosulepin, Prozac, auspicious Bo Xiting, amineptine, selegiline, Gepirone, imipramine, lithium carbonate, Mianserin, Milnacipran, nortriptyline, pa Luo Xiting, Sertraline, 3- [2- [3,4- Dihydrobenzofuranes simultaneously [3,2-c] pyridine -2 (1H)-yl] ethyl] -2- methyl -4H- pyrroles Pyridine simultaneously [1,2-a] pyrimidin-4-one)；
- antidiabetic (glibenclamide, melbine)；
- antiepileptic (carbamazepine, Clonazepam, ethymal, Gabapentin, Lamotrigine, Levetiracetam, benzene bar Than appropriate, phenytoinum naticum, Primidone, Tiagabine, Topiramate, valpromide, sabril)；
- antifungal (amphotericin B, clotrimazole, econazole, Fluconazole, Flucytosine, griseofulvin, Itraconazole, Ketoconazole, miconazole nitrate, nystatin, Terbinafine, voriconazole)；
- antihistamine (astemizole, cinnarizine, cyproheptadine, de- ethoxycarbonyl Loratadine, fexofenadine, fluorine osmanthus profit Piperazine, levocabastine, Loratadine, norastemizole, Oxatomide, fenazil, RMI 9918)；
- antihypertensive (captopril, enalapril, ketanserin, lisinopril, minoxidil, prazosin, Lei meter Pu Profit, Reserpine, Terazosin)；
- antimuscarinic drug (atropine sulfate, hyoscine)；
- antineoplastic and antimetabolite (platinum compounds such as cis-platinum, carboplatin；Taxanes such as taxol, taxotere (docetaxel)；For health class (tecans) such as camptothecine, Irinotecan, topotecan (topotecan)；Vinca alkaloids Such as vincaleukoblastinum, eldisine, vincristine, vinorelbine；Nucleoside derivates and antifol such as 5 FU 5 fluorouracil, add His shore (capecitabine), gemcitabine, mercaptopurine, thioguanine, Cladribine, methotrexate (MTX) of west；Alkylating agent such as nitrogen Mustard class, such as endoxan, Chlorambucil, mustargen, ifosfamide, melphalan or nitrosoureas, such as Carmustine, Lomustine or other alkylating agents, such as busulfan, Dacarbazine, procarbazine, phosphinothioylidynetrisaziridine；Antibiotics are for example soft Erythromycin, Doxorubicin, idarubicin, epirubicin, bleomycin, actinomycin D, mitomycin；2 antibody of HER, such as trastuzumab；Podophyllotoxin derivative, for example, Etoposide, for promise moor glycosides；Farnesyl tranfering enzyme inhibitor；Anthraquinone-derivative Thing, such as mitoxantrone)；
- antimigraine (alniditan, naratriptan, sumatriptan)；
- antiparkinsonism drugs (bromocriptine methanesulfonate, levodopa, selegiline)；
- mental inhibitor, hypnotic and sedative (alprazolam, buspirone, chlorine nitrogen, chlorpromazine, Clozapine, Di Xi Dissolve, Flupentixol, fluphenazinum, Flurazepam, paliperidone, Lorazepam, mazapertine, Olanzapine, Ao Shaxi Dissolve, Pimozide, Pipamperone, Piracetam, promazine, Risperidone, Selfotel, seroquel, Sertindole, Sulpiride, for horse West is dissolved, thiothixene, triazolam, Trifluperidol, zopiclone (ziprasidone), zolpidem)；
- Aggrenox (Lubeluzole, Lubeluzole oxide, Riluzole, aptiganel, Eliprodil, remacemide)；
- antitussive (dextromethorphan, laevodropropizine)；
- antiviral agent (acyclovir, Ganciclovir, Loviride, tivirapine, Zidovudine, Lamivudine, Qi Duo Husband is fixed+Lamivudine, Didanosine, zalcitabine, stavudine (stavudine), Abacavir (abacavir), Lopinavir, anpunave (amprenavir), nevirapine, efavirenz, Delavirdine (delavirdine), Ying Di That Wei (indinavir), Nai Feinawei (nelfinavir), Ritonavir (ritonavir), inverase, adefovir, hydroxyl Base urea)；
- receptor,β blocking agent (atenolol, Carvedilol, metoprolol, Nebivolol, Propranolol (propanolol))；
- cardiotonic drug (Amrinone, foxalin, digoxin, milrinone)；
- corticosteroid (beclomethasone dipropionate, betamethasone, budesonide, dexamethasone, hydrocortisone, first Prednisolone, prednisolone, metacortandracin, fluoxyprednisolone)；
- disinfectant (Chlorhexidine)；
- diuretics (acetazolamide, frusemide, Hydrochioro, isobide)；
- enzyme；
- essential oil is (anethole, fennel oil, cardamom, cassia oil, cineole, cinnamon oil, cloves oil, coriander oil, thin Lotus oil, dill oil, eucalyptus oil, eugenol, ginger, lemon oil, mustard oil, bitter orange flower oil, mace oil, orange oil, peppermint, Red sage, peppermint, terpinol, thyme)；
- gastrointestinal drug (Cimetidine, Cisapride, clebopride, diphenoxylate, domperidone, famotidine, orchid Rope draw azoles, Loperamide, Loperamide oxide, mesalazine, Metoclopramide, Mosapride, nizatidine, Norcisapride, Olsalazine, Omeprazole, Pantoprazole, pyrrole draw azoles (perprazole), prucalopride, thunder shellfish Draw azoles, ranitidine, Ridogrel, sulfasalazine)；
- hemostatic (aminocaproic acid)；
(Atorvastatin (atorvastatin), Lovastatin, Pravastatin, probucol, pungent cut down him to-Lipid Modulating Drugs Spit of fland)；
- local anesthetic (benzocainum, lidocaine)；
- opium kind analgesics (examine by buprenorphine, codeine, dextromoramide, Dihydrocodeine, dihydrocodeinone, hydroxyl Ketone, morphine)；
- parasympathomimetics and anti-dull-witted medicine (AIT-082, according to the bright of this, galanthamine, Bilarcil, Milameline, neostigmine, eserine, Tacrine, donepezil, rivastigmine, sabcomeline, Talsaclidine, xanomeline, Memantine, Lazabemide)；
- peptide and protein (antibody, becaplermin, cyclosporin, erythropoietin(EPO), immunoglobulin, pancreas islet Element)；
- sex hormone (estrogen：With reference to estrogen, ethinyloestradiol, mestranol, estradiol, estriol, oestrone, progestational hormone：Vinegar Sour chlormadinone, cyproterone acetate, 17- deacetyl norgestimates, Desogestrel, Dienogest, Dydrogesterone, two acetic acid alkynes Promise alcohol, gestodene, 3-keto-desogestrel, Levonorgestrel, lynestrenol, medroxyprogesterone acetate, megestrol acetate, norethindrone (norethindrone), norethindrone acetate, norethindrone (norethisterone), norethindrone acetate, norethynodrel, norgestimate, Norgestrel, Norgestrienone, progesterone, quingestanol acetate)；
- excitant (silaenafil (sildenafil))；
- vasodilator (Amlodipine, buflomedil, isoamyl nitrite, your sulphur, Dipyridamole, nitroglycerin, Isosorbide Nitrate, Lidoflazine, molsidomine, nicardipine, nifedipine, pentoxifylline, pentaerythrityl tetranitrate)；Their N- Oxide, their pharmaceutically acceptable acid or base addition salts and their form of three-dimensional chemical isomer.
Pharmaceutically acceptable acid-addition salts include it through the alkali shape with suitable organic and mineral acid treatment active ingredient The acid addition salt form thereof that formula can facilitate.
By using suitable organic and inorganic alkali process, the active ingredient containing acid proton can be converted into the non-of them Toxic metal or amine addition salt form.
Term addition salts also include the hydrate and solvent addition forms that active ingredient can be formed.So example of form For such as hydrate, alcoholates.
The N- oxide forms of active ingredient are oxidized to so-called N- oxides including those wherein one or several nitrogen-atoms Active ingredient.
Term " form of three-dimensional chemical isomer " is defined as all possible alloisomerism bodily form that active ingredient can have Formula.More particularly, Stereocenter can have a R- or S- configurations, and the active ingredient comprising one or more double bonds can have E- or Z- configurations.
One group of important active ingredient is the component that those are such as described above, and condition is not include salbutamol, 5- Ismo 20, dihydroergotamine, vitamin B12, with reference to estrogen, acetylsalicylic acid, fluoride, Miconazole and song Anxi dragon.
Another group of important active ingredient is the component that those are such as described above, and condition is not include and diphenhydramine The salbutamol of combination, 5-ISMN, dihydroergotamine, vitamin B12, with reference to estrogen, acetylsalicylic acid, Fluoride, Miconazole, fluoxyprednisolone, acyclovir, Lamotrigine and paracetamol.
In view of the presence of one or more active ingredients, the present invention also relates to be used as medicine as described hereinabove Hydrophilic control delivery formulations.
Pharmaceutically acceptable formula agent
In addition to active ingredient, hydrophilic polymer and pregelatinized starch, invention formulation also can be optionally comprising pharmaceutically Acceptable formula agent, to promote the preparation of preparation, compressibility, appearance and the sense of taste.These formula agents include for example diluent or Filler, glidant, adhesive, granulating agent, anti-caking agent, lubricant, flavouring, dyestuff and preservative.
Filler may be selected from soluble filler, for example, sucrose, lactose, trehalose, maltose, mannitol, sorb Alcohol, inuloid, and insoluble bulking agent is may be selected from, for example, Dicalcium Phosphate or tricalcium phosphate, talcum powder.Important filling Agent is lactose, particularly lactose monohydrate.The lactose of different stage can be used.Being preferred for a kind of lactose of the invention is 200 mesh of lactose monohydrate (DMV, Veghel, Holland).Also can preferably using another lactose monohydrate, DCL11 types Lactose monohydrate (DMV, Veghel, Holland).Symbol DCL is referred to " direct pressing lactose ".Numbering 11 is the ginseng of manufacturer Examine number.This type lactose is characterized in that the particle of 98% (w/w) has the diameter less than 250 μm, 30% to 60% (w/ W) particle has 100 μm of diameter, and the particle of most 15% (w/w) has the diameter less than 45 μm.
The percentage by weight of filler is between about 6% to about 54% (w/w).
There is such as polyvinylpyrrolidone in addition can be included in that the optional formula agent in matrix formulations can be mentioned (polyvidone), starch, Arabic gum, gelatin, algin derivative such as alginic acid, mosanom and calcium alginate, cellulose derivative Such as ethyl cellulose, hydroxypropyl methyl cellulose, they have useful bonding and granulating properties, glidant such as colloidal silica Silicon, starch or talcum powder, lubricant such as magnesium stearate and/or magnesium palmitate, calcium stearate, stearic acid, polyethylene glycol, liquid stone Wax, lauryl sodium sulfate or Stepanol MG, antitack agent such as talcum powder and cornstarch.
Embodiment
Lower non-limiting examples further describe the preferred embodiment in the scope of the invention.Within the scope of the invention These embodiments can also have many changes.
Determination test method
AAP values (relative to the absorption value of pressure) determination test
The test measurement superabsorbent is relative to external pressure between 21.1g/cm (0.3psi) and 70.3g/cm (1psi) Absorbability, is represented with superabsorbent relative to the single shaft swelling of the pressure.To the aquogel type of two or more types The sucting wet gel material mixture of grain, observation Absorption AgainstPressure change with the percentage composition of component of mixture The curve of change, depends primarily upon pressure condition.Adequately reflect use condition, measure the pressure of AAP values in 21.1g/cm Between (0.3psi) and 70.3g/cm (1psi).AAP values reflect the gel hardness of hygroscopic material.Grain structure is kept during wetting The moisture absorption particle of (keeping gap) is acted on good liquid absorption is shown without collapsing to impermeability blob of viscose.AAP values Low aquogel type material will tend to be formed to the permeability of liquid is relatively low and collapses under stress Weak Gels.
It is " Zero " (ceramic filter bought from Schott by the ceramic filter plate of 120 millimeters of diameter and porosity Duran) it is placed in 150 millimeters of diameter, high 30 millimeters of Petri dish (Petridsh).By 0.9% in distilled water The sodium-chloride water solution of (weight) adds Petri dish so that filter plate is capped.By 125 millimeters of circular filter paper of diameter (Schwarzband 589 bought from Schleicher and Schull) is placed on filter plate, and is chlorinated sodium solution completely Wetting.
Internal diameter 60+/- 0.1 millimeter and high 50 millimeters of plexiglass cylinder bottom aperture are 36 microns (400 mesh) Sieving cloth seals.0.9000+/- 0.0005 gram superabsorbent is carefully sprinkling upon to clean and dry heat-resisting organic glass On the screen of glass cylinder.Superabsorbent must be made to be uniformly distributed on sieve.
The outside diameter of one cover board is 59+/- 0.1 millimeter, internal diameter is 51 millimeters and 25 millimeters a height of, and has a diameter of 50 millimeters With a height of 34 millimeters of additional load, the weight of cover board and the interior pre- level pressure of the scope between 21.1g/cm and 70.3g/cm Power is corresponding, and the pressure is usually default to be set to 49.2g/cm2(0.7psi).Cover board and load are placed in cylinder, and whole cylinder device exists Weigh on balance, be accurate to 0.01 gram.Then whole cylinder device is placed on the filter paper of the moistening in Petri dish, makes it Absorb 1 it is small when.Then the equipment is removed from filter plate, be re-weighed.
Cylinder device and filter plate should be cleaned thoroughly between measurements, and measuring afterchlorinate sodium solution and filter paper every time should replace.
AAP values are calculated as below (relative to the absorption value of pressure)：
AAP values=[(weight of cylinder device after absorption)-(weight of cylinder device when dry)]：(superabsorbent it is initial Weight).
TTC values (Teabag Cetrifuge Capacity) determination test
Teabag Centrifuge Capacity test measurement Teabag Centrifuge Capacity values, it is pair Retain the measurement of liquid under static pressure in gel rubber material.
Superabsorbent is placed in " tea bag ", immerses in the sodium chloride solution of 0.9% (weight) 20 minutes, is then centrifuged for 3 minutes.Retain the absorbability that the ratio between the weight of liquid and the initial weight of dry superabsorbent are superabsorbent.
Sodium chloride solution injection size by 2 liters of 0.9% (weight) in distilled water is 5 lis of 24 cm x, 30 cm x In the disk of rice.Liquid packed height should be about 3 centimetres.
The size of tea bag bag is 6.5 centimetres of 6.5 cm x, can be public from Teekanne in Dusseldorf, Germany Department obtains.This bag is with the plastic bag sealing device for kitchen use of standard (such as from Krups, VACUPACK PLUS that Germany is bought) Heat seal.
Tea bag is opened by carefully partial cut, is then weighed.The superabsorbent of 0.200+/- 0.005 gram is tried Sample is put into tea bag.Then sealed with heat sealer.Referred to as sample tea bag.
Tea bag has been sealed as blank test.
Then make each tea bag holding horizontal, vibration sample tea bag is so that superabsorbent is evenly distributed in whole bag In.Then sample tea bag and blank tea bag are placed on the surface of salt solution, with a flat spoon make tea bag submerge 5 seconds so that its Moistening completely (tea bag will float over salt solution surface but moisten completely).Immediately begin to timing.
After twenty minutes, sample tea bag and blank tea bag are removed from salt solution for dipping, and are put into Bauknecht In WS130, Bosch 772NZK 096 or the centrifuge (230 millimeters of diameter) of equivalence, so that each Bao Jun is adhered to centrifuge On the outer wall of roller.The lid of centrifuge is covered, starts centrifuge, and speed is increased to rapidly to 1400 revs/min.Centrifuge is 1400 After stablizing under rev/min, timing is immediately begun to.After 3 minutes, centrifuge is closed.
Sample tea bag and blank tea bag are taken out, is weighed respectively.
The Teabag Centrifuge Capacity (TCC values) of aquogel type superabsorbent sample are calculated as below：
TCC values=[(weight of sample tea bag after centrifugation)-(weight of blank tea bag after centrifugation)-(dry into hydrogel The weight of superabsorbent)] ÷ (weight of dry superabsorbent).
Half mass particle size determines
By the way that the sample of known weight is put into Retsch mechanical sifters, and vibration one is specific under qualifications Time cycle, determine the particle size distribution of superabsorbent.Weigh and be retained in sample parts on each sieve and chassis Weight, and it is recorded as the percentage of original sample weight.
Specimen mounting is added after the dry superabsorbent polymeric material in 100+/- 0.5 gram is weighed, then lives specimen mounting with the cover.
Four sieves are stacked as follows from bottom to up：Stainless steel bottom plate, No. 325, No. 100, No. 50 and No. 20；These For the screen size (ASTM-E-11-61) in the U.S..Sample is sent to the most top flat of the sieve series, powder is evenly distributed on sieve. Stainless steel cover is placed on No. 20 sieve.
Stacked sieve is placed on to the Retsch testing sieve shaker Vibotronic of timer Appropriate location on TypeVE1.Ensure that top of the Retsch lids as far as possible with vibrator is fitted close.Timer is located at 10 minutes, start to test.When vibrator has stopped, bushing screen is removed from vibrator.
Then, such as by different measurements, the retained screening of each sieve is weighed, is accurate to 0.01 gram.
It is important that rapid operation absorbs moisture to avoid superabsorbent in this test.
Half mass particle size of given aquogel type absorbent polymer particle sample is defined as being divided sample according to quality Into the particle size of half, i.e., half sample will have the particle size for being less than half mass size by weight, and half sample will have More than the particle size of half mass size.When 50% mass value does not correspond to U.S.A.Standard Testing Sieve (U.S.s National standard testing sieve) size perforate when, lead to working standard particle size method for drafting (wherein on graph paper draw retain The accumulating weight percentage of particle sample on given sieve size perforate or by giving sieve size perforate is opened with sieve size The relation curve in hole) determine half mass particle size.For determine aquogel type hygroscopic polymeric composition granule particle size this A little methods are further described in the United States Patent (USP) 5,061,259 that on October 29th, 1991 authorizes Goldman etc., and the document introduces For reference.
The Stability Determination of preparation Release Performance (or disintegration swelling behavior of polymer composition)
Measure respectively in McIlvaine (ionic strength 0.398) and Eurand (ionic strength 0.076) buffer solution Under special time disintegration time limited (TD) or dissolution rate (or release (at least nine (interval appropriate) time point, when it is m- In release (two dimension) figure, basic reflection preparation drug release situation overall picture can be formed by connecting the release under these time points Drug release profiles) (RD) (operating method is shown in Chinese Pharmacopoeia annex the correlation technique recorded), then calculated by following equation The result measured in McIlvaine buffer solutions is relative to the results change value (rate) measured in Eurand buffer solutions, with the value Reflect the stability (/ situation of change) of preparation Release Performance (or disintegration swelling behavior of polymer composition)：
Disintegration time limited change rate (A)=(TDM/TDE- 1) × 100%, or
Dissolution rate (or release) change rate (B)=(RDM/RDE- 1) × 100%, or
Front and rear phase drug release rate change rate (C)=(TRD70~100%/TRD0~30%- 1) × 100%
Wherein, TDM、RDMDisintegration time limited (TD) in McIlvaine buffer solutions under special time, dissolution rate are represented respectively Or release (RD), TDE、RDERepresent respectively disintegration time limited (TD) in Eurand buffer solutions under special time, dissolution rate or Release (RD), TRD0~30%、TRD70~100%Respectively represent (being determined by any of the above-described drug release profiles) early period drug release from 0 to Required elapsed-time standards when required elapsed-time standards, later stage drug release are from 70 to 100% release during 30% release.
McIlvaine buffer solutions (pH7.2) (100ml) (J.Biol.Chem.49,183 (1921)) are by 13.05ml citrons The Na of acid solution (0.1M) and 86.95ml2HPO4·2H2O solution (0.2M) forms.The McIlvaine buffer solutions have than The ionic strength of Eurand buffer solution highers, wherein dissolution test are normally carried out.At ph 7.2, McIlvaine buffer solutions from Sub- intensity is 0.398.
Eurand buffer solutions (pH7.2) (100ml) are by 19ml sodium hydroxide solutions (0.2N) and the KH of 0.087g2PO4Group Into.PH value of solution is adjusted to 7.2 with hydrochloric acid (1N) and is diluted with water to the ionic strength of the 100ml. Eurand buffer solutions (pH7.2) For 0.076.
If medicine water solubility is bad (water-insoluble), appropriate surface can be added in dissolution fluid (i.e. above-mentioned buffer solution) Activating agent such as 1~2 (such as 1.5) % lauryl sodium sulfate strengthens drug-eluting.
Embodiment 1
It is formulated (1000)：Lavo-ofloxacin hydrochloride 200g, microcrystalline cellulose 40g, Ac-Di-Sol 50g, Sodium Polyacrylate 10g, povidone (K30) 10g, magnesium stearate 5g, superfine silica gel powder 5g.
Reference examples 1
Only Sodium Polyacrylate is replaced by drum-type drying waxy corn starch (full pregelatinated) in embodiment 1, other (including system Method, dosage etc.) it is constant.
Explanation：(in above-described embodiment or reference examples) Ac-Di-Sol, Sodium Polyacrylate, drum-type dry wax The APP values of shape cornstarch three respectively 3.5g/g, 19.5g/g, 0.4g/g, the TCC values respectively 5.6g/g of three, 24.5g/g, 0.7g/g, half mass particle size be 180 microns, 125 microns, 125 microns, the 1st, 2 mixtures (between the two weight Amount is more identical than with embodiment or reference examples) AAP values be 10.7g/g, the 1st, 3 mixtures (weight ratio and embodiment between the two Or reference examples are identical) AAP values be 2.0g/g.
Disintegration time limited change rate (A) measurement result：Embodiment：32.7%, reference examples：226%.
Dissolution rate (20min) change rate (B) measurement result：Embodiment：- 38.2%, reference examples：- 243%.
Embodiment 2
It is formulated (1)：Acyclovir (200mg) 40%, lactose 21.5%, microcrystalline cellulose 24%, sodium carboxymethyl starch 10%, poly- hydroxyethylacrylate sodium 2%, polyvinylpyrrolidone 0.5%, magnesium stearate 1% and superfine silica gel powder 1%.
Reference examples 2
Only poly- hydroxyethylacrylate sodium is replaced by (part) starch,pregelatinized in embodiment 2, other (including preparation method, Dosage etc.) it is constant.
Explanation：(in above-described embodiment or reference examples) sodium carboxymethyl starch, poly- hydroxyethylacrylate sodium, pregelatinized The APP values of starch three respectively 2.6g/g, 12.5g/g, 1.4g/g, TCC values respectively 3.7g/g, 20.2g/g of three, 2.6g/g, half mass particle size are 212 microns, 150 microns, 150 microns, the 1st, 2 mixtures (weight ratio and reality between the two Apply example or reference examples be identical) AAP values be 7.2g/g, the 1st, 3 mixtures (weight ratio and embodiment or reference examples phase between the two AAP values together) are 1.5g/g.
Disintegration time limited change rate (A) measurement result：Embodiment：41.5%, reference examples：189%.
Dissolution rate (15min) change rate (B) measurement result：Embodiment：- 46.3%, reference examples：- 217%.
Embodiment 3
It is formulated (1000)：Telmisartan 10.0g, starch 52.0g, lactose 30.0g, crosslinked polyvinylpyrrolidone is interior to be added The additional 4g of 16.0g, polylysine hydrochloride 10.0g, superfine silica gel powder 3.0g, magnesium stearate 1.0g.
Reference examples 3
Only polylysine hydrochloride is replaced by (part) starch,pregelatinized in embodiment 3, other (including preparation method, dosage Deng) constant.
Explanation：(in above-described embodiment or reference examples) crosslinked polyvinylpyrrolidone, polylysine hydrochloride, pregel The APP values of change starch three respectively 3.3g/g, 16.2g/g, 1.1g/g, TCC values respectively 4.7g/g, 21.4g/g of three, 2.3g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 11.3g/g, the 1st, 3 The AAP values of person's mixture (weight ratio is identical with embodiment or reference examples between the two) are 1.6g/g.
Disintegration time limited change rate (A) measurement result：Embodiment：34.8%, reference examples：255%.
Dissolution rate (10min) change rate (B) measurement result：Embodiment：- 36.8%, reference examples：- 279%.
Embodiment 4
It is formulated (1000)：：Verapamil hydrochloride 40.0g, microcrystalline cellulose 120.0g, partially pregelatinized starch is interior to be added 25.0g additional 6g, chitosan hydrochloride 3g, superfine silica gel powder 4.0g.
Reference examples 4
Only chitosan hydrochloride is replaced by drum-type drying waxy corn starch (full pregelatinated) in embodiment 4, its His (including preparation method, dosage etc.) is constant.
Explanation：(in above-described embodiment or reference examples) partially pregelatinized starch, chitosan hydrochloride, drum-type are done The APP values of dry waxy corn starch three respectively 2.8g/g, 3.5g/g, 0.3g/g, the TCC values respectively 4.3g/g of three, 5.8g/g、0.2g/g。
Disintegration time limited change rate (A) measurement result：Embodiment：72.2%, reference examples：231%.
Dissolution rate (25min) change rate (B) measurement result：Embodiment：- 85.6%, reference examples：- 273%.
Embodiment 5
It is formulated (1000)：Valsartan 80.0g, starch 170.0g, microcrystalline cellulose 110.0g, in sodium starch glycollate Add the additional 10.0g of 35.0g, cellulose graft acrylate copolymer sodium salt 20g, superfine silica gel powder 8.0g.
Reference examples 5
Only cellulose graft acrylate copolymer sodium salt is by drum-type drying waxy corn starch (full pregelatinated) in embodiment 5 Replace, other (including preparation method, dosages etc.) are constant.
Explanation：(in above-described embodiment or reference examples) sodium starch glycollate, cellulose graft acrylate copolymer sodium Salt, the APP values of drum-type drying waxy corn starch three are respectively 10.7g/g, 15.3g/g, 0.3g/g, and the TCC values of three are divided Not Wei 14.5g/g, 21.6g/g, 0.4g/g, the 1st, 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) AAP values are 16.4g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 4.6g/ g。
Disintegration time limited change rate (A) measurement result：Embodiment：43.6%, reference examples：219%.
Dissolution rate (15min) change rate (B) measurement result：Embodiment：- 48.6%, reference examples：- 265%.
Embodiment 6
It is formulated (1)：Moxifloxacin hydrochloride 436.8mg, microcrystalline cellulose 80.0mg, starch 124.0mg, calcium alginate 16mg, Ac-Di-Sol 16.0mg, starch graft acrylic acid polymer sodium salt 50mg, magnesium stearate 6.0mg.
Reference examples 6
Only starch graft acrylic acid polymer sodium salt is replaced by (part) starch,pregelatinized in embodiment 6, other (including Preparation method, dosage etc.) it is constant.
Explanation：(in above-described embodiment or reference examples) calcium alginate connects with Ac-Di-Sol mixture, starch Branch acrylate copolymer sodium salt, APP values respectively 5.8g/g, 18.8g/g, 1.3g/g of starch,pregelatinized three, three's TCC values are respectively 7.5g/g, 29.6g/g, 2.6g/g, and the 1st, 2 mixtures (weight ratio and embodiment or reference examples phase between the two AAP values together) are 22.5g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 2.6g/g。
Disintegration time limited change rate (A) measurement result：Embodiment：44.2%, reference examples：232%.
Dissolution rate (15min) change rate (B) measurement result：Embodiment：- 50.4%, reference examples：- 271%.
Embodiment 7
It is formulated (1000)：Asparagine (anhydride) 250.0g, starch 14.8g, dextrin 20.0g, methylcellulose 13.3g, poly-aspartate sodium salt 1.1g, magnesium stearate 2.1g.
Reference examples 7
Only poly-aspartate sodium salt is replaced by (part) starch,pregelatinized in embodiment 7, other (including preparation method, dosage Deng) constant.
Explanation：(in above-described embodiment or reference examples) methylcellulose, poly-aspartate sodium salt, starch,pregelatinized three The APP values of person respectively 1.2g/g, 13.5g/g, 1.5g/g, TCC values respectively 2.6g/g, 28.5g/g, 2.8g/g of three, 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) are 6.8g/g, the 1st, 3 mixtures The AAP values of (weight ratio is identical with embodiment or reference examples between the two) are 1.1g/g.
Disintegration time limited change rate (A) measurement result：Embodiment：84.7%, reference examples：263%.
Dissolution rate (10min) change rate (B) measurement result：Embodiment：- 90.2%, reference examples：- 285%.
Embodiment 8
It is formulated (1)：1 part of Oxiracetam (400mg), 0.5 part of starch, 0.04 part of magnesium stearate, Stepanol MG 0.02 part, 0.45 part of calcium carboxymethylcellulose, 1.0 parts of polyethylenepolyamine hydrochloride, 10% 1.0 parts of povidone ethanol solution.
Reference examples 8
Only polyethylenepolyamine hydrochloride is replaced by (part) starch,pregelatinized in embodiment 8, other (including preparation method, use Amount etc.) it is constant.
Explanation：(in above-described embodiment or reference examples) calcium carboxymethylcellulose, polyethylenepolyamine hydrochloride, pregelatinized The APP values of starch three respectively 2.8g/g, 12.6g/g, 2.3g/g, TCC values respectively 4.7g/g, 28.5g/g of three, 3.5g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 13.5g/g, the 1st, 3 The AAP values of person's mixture (weight ratio is identical with embodiment or reference examples between the two) are 1.8g/g.
Disintegration time limited change rate (A) measurement result：Embodiment：54.3%, reference examples：169%.
Dissolution rate (15min) change rate (B) measurement result：Embodiment：- 59.5%, reference examples：- 181%.
Embodiment 9
It is formulated (1 sheet weight ratio)：Tamoxifen citrate (15.2mg) 5.0%, sodium alginate (interior to add) 2.0% (additional) 2.0%, polyvinyl alcohol-acrylic block copolymers sodium salt (interior to add) 2.0% (additional) 2.0%, microcrystalline cellulose 25%, lactose 60.2%, magnesium stearate 0.5%, lauryl sodium sulfate 0.3%, polyvinylpyrrolidone 1.0%.
Reference examples 9
Only polyvinyl alcohol-acrylic block copolymers sodium salt is replaced by (part) starch,pregelatinized in embodiment 9, other (including preparation method, dosage etc.) is constant.
Explanation：(in above-described embodiment or reference examples) sodium alginate, polyvinyl alcohol-acrylic block copolymers sodium salt, The APP values of starch,pregelatinized three respectively 4.8g/g, 15.3g/g, 2.4g/g, the TCC values respectively 7.9g/g of three, 30.2g/g, 4.8g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 16.2g/ G, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 3.1g/g.
Disintegration time limited change rate (A) measurement result：Embodiment：58.6%, reference examples：232%.
Dissolution rate (5min) change rate (B) measurement result：Embodiment：- 67.2%, reference examples：- 254%.
Embodiment 10
It is formulated (1 sheet weight ratio)：Yixintong 15% (32mg, is micronized to below 300 mesh), lactose 58%, microcrystalline cellulose Element 17%, sodium carboxymethyl starch 4%, poly arginine sulfate 2%, magnesium stearate 1%, polyvinylpyrrolidone 2% and 12 Sodium alkyl sulfate 1%.
Reference examples 10
Only poly arginine sulfate is replaced by (part) starch,pregelatinized in embodiment 10, other (including preparation method, dosage Deng) constant.
Explanation：(in above-described embodiment or reference examples) sodium carboxymethyl starch, poly arginine sulfate, starch,pregelatinized The APP values of three respectively 12.8g/g, 19.3g/g, 2.8g/g, TCC values respectively 20.3g/g, 30.7g/g of three, 5.5g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 20.7g/g, the 1st, 3 The AAP values of person's mixture (weight ratio is identical with embodiment or reference examples between the two) are 6.8g/g.
Disintegration time limited change rate (A) measurement result：Embodiment：38.2%, reference examples：134%.
Dissolution rate (5min) change rate (B) measurement result：Embodiment：- 42.5%, reference examples：- 152%.
Embodiment 11
It is formulated (1)：Rasagiline 0.5mg, mannitol 91mg, guar gum 6mg, poly arginine-glutamic acid (1：1) 3mg, superfine silica gel powder 2mg, magnesium stearate 0.5mg.
Reference examples 11
Only poly arginine-glutamic acid is replaced by (part) starch,pregelatinized in embodiment 11, other (including preparation method, use Amount etc.) it is constant.
Explanation：(in above-described embodiment or reference examples) guar gum, poly arginine-glutamic acid, starch,pregelatinized three The APP values of person respectively 1.3g/g, 16.7g/g, 2.1g/g, TCC values respectively 3.5g/g, 28.4g/g, 4.6g/g of three, 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) are 7.4g/g, the 1st, 3 mixtures The AAP values of (weight ratio is identical with embodiment or reference examples between the two) are 1.6g/g.
Disintegration time limited change rate (A) measurement result：Embodiment：42.7%, reference examples：163%.
Dissolution rate (15min) change rate (B) measurement result：Embodiment：- 48.5%, reference examples：- 185%.
Embodiment 12
It is formulated (800)：Acarbose 80.0g, microcrystalline cellulose 18.0g, starch 94.0g, carboxyrnethyl starch sodium 6.3g, third Olefin(e) acid-acrylate polymer sodium salt 1g, silica 1 0.5g, magnesium stearate 1.05g.
Reference examples 12
Only acrylic acid-acrylic ester polymer sodium salt is replaced by (part) starch,pregelatinized in embodiment 12, other (bags Include preparation method, dosage etc.) it is constant.
Explanation：(in above-described embodiment or reference examples) carboxyrnethyl starch sodium, polyacrylic acid-methyl acrylate polymer sodium Salt, the APP values of starch,pregelatinized three are respectively 3.4g/g, 28.7g/g, 2.6g/g, and the TCC values of three are respectively 6.2g/ G, 38.1g/g, 5.3g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 21.4g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 2.3g/g.
Disintegration time limited change rate (A) measurement result：Embodiment：41.5%, reference examples：198%.
Dissolution rate (10min) change rate (B) measurement result：Embodiment：- 48.5%, reference examples：- 213%.
Embodiment 13
It is formulated (1 sheet weight ratio)：Olanzapine (10mg) 5%, mannitol 45.1%, lactose 40.3%, crosslinked polyethylene pyrrole Pyrrolidone (PVPP) 5%, hydrolyzed starch-acrylonitrile graft copolymer 2%, aspartame 0.6%, fragrant citrus essence 0.5% are stearic Sour magnesium 1.5%.
Reference examples 13
Only hydrolyzed starch-acrylonitrile graft copolymer is replaced by the crosslinked polyvinylpyrrolidone of equivalent in embodiment 13, Other are constant (including preparation method etc.).
Explanation：(in above-described embodiment or reference examples) crosslinked polyvinylpyrrolidone, hydrolyzed starch-acrylonitrile grafting are altogether The APP values of both polymers are respectively 3.2g/g, 20.5g/g, and the TCC values of the two are respectively 5.7g/g, 33.1g/g, the two is mixed The AAP values of thing (weight ratio is identical with embodiment or reference examples between the two) are 18.8g/g.
Disintegration time limited change rate (A) measurement result：Embodiment：48.4%, reference examples：282%.
Dissolution rate (10min) change rate (B) measurement result：Embodiment：- 56.2%, reference examples：- 291%.
Embodiment 14
It is formulated (1 sheet weight ratio)：Tadalafei (5mg) 2.5%, mannitol 43.1%, lactose 24.5%, microcrystalline cellulose 10.3%, low-substituted hydroxypropyl cellulose 13%, starch-acrylate graft copolymer sodium salt 4%, aspartame 0.6%, fragrant citrus perfume Essence 0.5%, magnesium stearate 1.5%.
Reference examples 14
Only starch-acrylate graft copolymer sodium salt is by drum-type drying waxy corn starch (full pregelatinated) in embodiment 14 Replace, other (including preparation method, dosages etc.) are constant.
Explanation：(in above-described embodiment or reference examples) low-substituted hydroxypropyl cellulose, starch-acrylate graft copolymer sodium Salt, the APP values of drum-type drying waxy corn starch three are respectively 2.7g/g, 18.2g/g, 0.3g/g, and the TCC values of three are distinguished For 4.5g/g, 24.4g/g, 0.5g/g, the 1st, the AAP of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) Be worth for 10.2g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 1.4g/g.
Disintegration time limited change rate (A) measurement result：Embodiment：38.6%, reference examples：211%.
Dissolution rate (10min) change rate (B) measurement result：Embodiment：- 43.5%, reference examples：- 243%.
Embodiment 15
It is formulated (1 sheet weight ratio)：1 part of cefteram pivoxil (75mg), 0.90 part of starch, 0.10 part of lactose, crystallite are fine 0.10 part of dimension element, 0.20 part of sodium carboxymethylcellulose, 0.20 part of sapond vinyl acetate-acrylate copolymer, it is stearic Sour 0.01 part of magnesium.
Reference examples 15
Only sapond vinyl acetate-acrylate copolymer is replaced by (part) starch,pregelatinized in embodiment 15 Change, other (including preparation method, dosages etc.) are constant.
Explanation：(in above-described embodiment or reference examples) sodium carboxymethylcellulose, sapond vinyl acetate-acrylic Ester copolymer, the APP values of starch,pregelatinized three are respectively 3.3g/g, 17.5g/g, 2.8g/g, and the TCC values of three are respectively 5.9g/g, 28.6g/g, 5.3g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) For 18.4g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 2.2g/g.
Disintegration time limited change rate (A) measurement result：Embodiment：46.3%, reference examples：187%.
Dissolution rate (15min) change rate (B) measurement result：Embodiment：- 51.2%, reference examples：- 194%.
Embodiment 16
It is formulated (1 sheet weight ratio)：Bambuter (10mg) 8.6%, starch 31.6%, lactose 38.7%, chitosan 12.7%, polyethyleneimine mesylate 5%, talcum powder 2.8%, magnesium stearate 0.6%.
Reference examples 16
Only polyethyleneimine mesylate is replaced by (part) starch,pregelatinized in embodiment 16, other (including preparation method, Dosage etc.) it is constant.
Explanation：(in above-described embodiment or reference examples) chitosan, polyethyleneimine mesylate, starch,pregelatinized three The APP values of person respectively 4.8g/g, 28.6g/g, 2.4g/g, TCC values respectively 7.2g/g, 40.2g/g, 5.1g/g of three, 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) are 16.8g/g, the 1st, 3 mixtures The AAP values of (weight ratio is identical with embodiment or reference examples between the two) are 3.7g/g.
Disintegration time limited change rate (A) measurement result：Embodiment：43.5%, reference examples：152%.
Dissolution rate (5min) change rate (B) measurement result：Embodiment：- 48.7%, reference examples：- 178%.
Explanation：(in above-described embodiment or reference examples) embodiment and reference examples 1~16 are common (non-slow control) preparation, are pressed (such as supplementary material is finely ground, sieves, mixing for the preparation method of conventional ordinary preparation；System material, dry, material all in one piece；Add lubricant, help stream Agent (or additional disintegrant) etc. mixes, and tabletting/encapsulated etc.；Or finely ground, sieving, dry powder direct tabletting after mixing/encapsulated) system It is standby, do not specially require.
It is sustained embodiment DE
Embodiment DE1
It is formulated (every/capsule)：Cisapride-(L)-tartrate 52.92mg, lactose monohydrate (200 mesh) 274.83mg, hydroxypropyl methyl cellulose (2208) 34.2mg, hydroxypropyl cellulose 142.5mg, Sodium Polyacrylate 28.5mg, firmly Fatty acid magnesium 2.85mg, colloidal anhydrous silicon dioxide 5.7mg.
Preparation method：In planetary-type mixer, by active ingredient, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polypropylene Sour sodium (or drum drying waxy corn starch), and in the case of using 200 mesh of lactose monohydrate, lactose bulking agents mix Close, be then compacted using dry compacting machine.Compact is crushed, sieve and in planetary-type mixer with colloidal, anhydrous titanium dioxide Silicon mixes, and adds magnesium stearate and mixes.Using eccentric tablet press machine, by obtained blend tabletting or wait and be packed into capsulae vacuus In.
Reference examples DE1
Only Sodium Polyacrylate is replaced by drum-type drying waxy corn starch (full pregelatinated) in embodiment DE1, other (including Preparation method, dosage etc.) it is constant.
Explanation：The mixture (1 of (in above-described embodiment or reference examples) hydroxypropyl methyl cellulose and hydroxypropyl cellulose : 4.17, weight ratio, following ratio is herewith), Sodium Polyacrylate, the APP values of drum-type drying waxy corn starch three be respectively 0.2g/g, 19.3g/g, 0.2g/g, the TCC values of three are respectively 0.6g/g, 28.2g/g, 0.7g/g, and half mass particle size is 180 microns, 125 microns, 125 microns, the 1st, the AAP of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) Be worth for 5.4g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 0.2g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：38.4%, reference examples：232%；8 it is small when：Implement Example：40.3%, reference examples：243%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：23.2%, reference examples： 82.5%；
Eurand buffer solutions：Embodiment：27.8%, reference examples：97.4%.
Embodiment DE2
It is formulated (every/capsule)：Clarithromycin 500mg, hydroxyethyl cellulose 170mg, polyglutamic acid sodium 60mg, polyethylene Pyrrolidones (K30) 18mg, magnesium stearate 10mg, talcum powder 5mg, lactose 175mg, citric acid 100mg.
Preparation method：Polyvinylpyrrolidone (K30) is dissolved in ethanol solution, is prepared into alcoholic solution.By 50-80 mesh sieves Clarithromycin, hydroxyethyl cellulose, polyglutamic acid sodium, citric acid, lactose be placed in efficient mixed granulation machine and be sufficiently mixed, add Enter polyvinylpyrrolidone alcoholic solution, soft material is made.Magnesium stearate, talcum powder are added after above-mentioned soft material is dried, is mixed Close powder.Mixed powder all adds Mixers with Multi-direction Movement.Use swinging lozenge machine tabletting.
Reference examples DE2
In embodiment DE2 only polyglutamic acid sodium by (part) pregelatinized starch replace, other (including preparation method, dosages etc.) no Become.
Explanation：(in above-described embodiment or reference examples) hydroxyethyl cellulose, polyglutamic acid sodium, (part) pregelatinized starch The APP values of three are respectively 1.6g/g, 15.6g/g, 1.8g/g, and the TCC values of three are respectively 3.2g/g, 23.4g/g, 3.9g/ G, half mass particle size are 212 microns, 150 microns, 150 microns, the 1st, 2 mixtures (weight ratio and embodiment between the two Or reference examples are identical) AAP values be 10.8g/g, the 1st, 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) AAP values be 1.6g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：45.7%, reference examples：253%；8 it is small when：Implement Example：51.6%, reference examples：278%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：27.6%, reference examples： 95.4%；
Eurand buffer solutions：Embodiment：34.5%, reference examples：123%.
Embodiment DE3
It is formulated (every 1000/capsule)：250 grams of naproxen bulk pharmaceutical chemicals, 75 grams of Eudragit (L100), Eudragit (S100) 50 grams, 20 grams of the polycarbophil (sodium salt) of complete neutralization, 200 grams of maltodextrin, 50 grams of starch, 15 grams of talcum powder, firmly 2 grams of fatty acid magnesium.
Preparation method：The above is former, auxiliary material crosses 100 mesh sieves respectively, is uniformly mixed, and adds the granulation of adhesive ethanol in proper amount, crosses 20 mesh Sieve；It is dry below 60 degree of temperature；Add talcum powder, magnesium stearate tabletting.
Reference examples DE3
The polycarbophil (sodium salt) only neutralized in embodiment DE3 is replaced by (part) pregelatinized starch, other (including system Method, dosage etc.) it is constant.
Explanation：The mixture of (in above-described embodiment or reference examples) Eudragit (L100) and Eudragit (S100) The polycarbophil (sodium salt) of (1.5: 1), complete neutralization, the APP values of (part) pregelatinized starch three respectively 1.1g/g, 16.7g/g, 2.4g/g, the TCC values of three are respectively 2.5g/g, 20.4g/g, 3.2g/g, and half mass particle size is micro- for 212 Rice, 150 microns, 150 microns, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 9.3g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 1.4g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：42.8%, reference examples：231%；8 it is small when：Implement Example：47.4%, reference examples：253%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：24.3%, reference examples： 92.3%；
Eurand buffer solutions：Embodiment：31.3%, reference examples：124%.
Embodiment DE4
It is formulated (every 1000)：Caffeine 320g, the ratio between polyvinyl acetate and polyvinylpyrrolidone are 8: 2 preparation Mixture 260g, polyglutamine 60g, magnesium stearate 3.2g.
Preparation method：Various powdered ingredients are crossed into 800 μm of sieves, are mixed 10 minutes in Turbula mixers.By each tablet (8mm, circular, biplane, with bevel edge) is suppressed in a rotary press (Korsch PH106) with the pressure of 10kN.
Reference examples DE4
Only polyglutamine is replaced by drum-type drying waxy corn starch (full pregelatinated) in embodiment DE4, other (including Preparation method, dosage etc.) it is constant.
Explanation：(in above-described embodiment or reference examples) the ratio between polyvinyl acetate and polyvinylpyrrolidone is 8: 2 Preparating mixture, polyglutamine, drum-type drying waxy corn starch three APP values respectively 0.8g/g, 5.5g/g, 0.3g/g, the TCC values of three are respectively 1.4g/g, 11.4g/g, 0.5g/g, and half mass particle size is 180 microns, 125 micro- Rice, 125 microns, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 3.8g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) are 0.4g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：34.7%, reference examples：217%；8 it is small when：Implement Example：37.2%, reference examples：231%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：28.7%, reference examples： 87.6%；
Eurand buffer solutions：Embodiment：35.8%, reference examples：99.6%.
Embodiment DE5
It is formulated (every)：Metroprolol succinate 47.5mg, lactose 45mg, polyvinylpyrrolidone and vinyl acetate Copolymer (9: 1) 170mg, calcium alginate 60mg, HPMC (100 centipoise) 35mg, magnesium stearate 3mg.
Preparation method：Metroprolol succinate, each auxiliary material are crossed into 100 mesh sieves respectively.The U.S. support of butanedioic acid of recipe quantity is weighed respectively Luo Er, the copolymer of polyvinylpyrrolidone and vinyl acetate, calcium alginate, hydroxypropyl methylcellulose (viscosity：100 centipoises) and Lactose mixes, and adds 50% ethanol water softwood, pelletizes through 20 mesh, 55 degree of dryings, 20 mesh whole grains.Added in dry particl hard Fatty acid magnesium mixes, tabletting.
Reference examples DE5
Only calcium alginate is replaced by drum-type drying waxy corn starch (full pregelatinated) in embodiment DE5, other (including system Method, dosage etc.) it is constant.
Explanation：The copolymer (9: 1) of (in above-described embodiment or reference examples) polyvinylpyrrolidone and vinyl acetate, Calcium alginate, drum-type drying waxy corn starch three APP values respectively 2.4g/g, 3.1g/g, 0.2g/g, the TCC of three Value is respectively 3.8g/g, 5.1g/g, 0.4g/g, and the 1st, 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) AAP values be 3.7g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 1.2g/ g。
Release change rate measures (B) result：4 it is small when：Embodiment：78.3%, reference examples：232%；8 it is small when：Implement Example：84.6%, reference examples：247%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：43.4%, reference examples： 102%；
Eurand buffer solutions：Embodiment：50.2%, reference examples：128%.
Embodiment DE6
It is formulated (every)：Aminophylline 75mg, sodium carboxymethyl starch 180mg, polyallylamine hydrochloride 50mg, polyethylene glycol (1500) 40mg and and filler microcrystalline cellulose 80mg.
Preparation method：According to the ratio of above-mentioned formula ratio by aminophylline and polyethylene glycol and sodium carboxymethyl starch, polypropylene amine salt Hydrochlorate and filler microcrystalline cellulose are mixed and stirred for uniformly；Suitable aqueous is added, diameter is made about with extrusion spheronization machine The pellet of 1.0mm and drying, load capsule.
Reference examples DE6
Only polyallylamine hydrochloride is replaced by (part) pregelatinized starch in embodiment DE6, other (including preparation method, dosage Deng) constant.
Explanation：(in above-described embodiment or reference examples) sodium carboxymethyl starch, polyallylamine hydrochloride, (part) pregelatinated The APP values of starch three respectively 2.6g/g, 12.8g/g, 2.4g/g, TCC values respectively 4.3g/g, 18.4g/g of three, 3.7g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 9.7g/g, the 1st, 3 The AAP values of mixture (weight ratio is identical with embodiment or reference examples between the two) are 2.2g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：46.2%, reference examples：201%；8 it is small when：Implement Example：49.7%, reference examples：221%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：33.8%, reference examples： 94.5%；
Eurand buffer solutions：Embodiment：38.5%, reference examples：114%.
Embodiment DE7
It is formulated (every bag)：Methoxyphenamine 40mg, hydroxybutyl cellulose 65mg, polyfructosan 38mg, acrylic acid-acrylic acid second Ester polymer sodium salt 65mg, microcrystalline cellulose 65mg, sodium carboxymethylcellulose 14mg, flavoring orange essence 1mg, Aspartame 1mg.
Preparation method：By methoxyphenamine and slow-release auxiliary material hydroxybutyl cellulose, polyfructosan, the polymerization of acrylic acid-acrylic acetoacetic ester Thing sodium salt and filler microcrystalline cellulose (2/3 amount) simultaneously add suitable solvent and are made particle, add suspending composition microcrystalline cellulose Plain (1/3 amount) and sodium carboxymethylcellulose, flavoring composition flavoring orange essence and Aspartame, stir evenly.It is fitted into bag, before taking It is added to the water appropriate stirring.
Reference examples DE7
Only acrylic acid-acrylic acetoacetic ester polymer sodium salt is replaced by (part) pregelatinized starch in embodiment DE7, other (including preparation method, dosage etc.) is constant.
Explanation：(in above-described embodiment or reference examples) hydroxybutyl cellulose and polyfructosan mixture (weight ratio 1.71: 1), acrylic acid-acrylic acetoacetic ester polymer sodium salt, the APP values of (part) pregelatinized starch three are respectively 3.2g/g, 23.5g/ G, 2.8g/g, the TCC values of three are respectively 5.6g/g, 27.2g/g, 4.3g/g, the 1st, 2 mixtures (between the two weight ratio with Embodiment or reference examples are identical) AAP values be 25.2g/g, the 1st, 3 mixtures (weight ratio and embodiment or compare between the two Example it is identical) AAP values be 2.7g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：41.3%, reference examples：224%；8 it is small when：Implement Example：46.3%, reference examples：235%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：35.3%, reference examples： 114%；
Eurand buffer solutions：Embodiment：39.6%, reference examples：121%.
Embodiment DE8
It is formulated (every 1000) and preparation method：Take quetiapine fumarate (in terms of Quetiapine) 200g to crush, cross 100 mesh sieves, with 60g is modified (complete) pregelatinized starch, and 20g cellulose graft acrylate copolymer sodium salts, mix, with 9g10% polyvinylpyrrolidines Ketone K-30 is adhesive softwood；The granulation of 18 mesh sieves is crossed, it is dry, with 18 mesh sieve whole grains, 3g magnesium stearates are added, are mixed, tabletting.
Reference examples DE8
Only cellulose graft acrylate copolymer sodium salt is replaced by (part) pregelatinized starch in embodiment DE8, other (bags Include preparation method, dosage etc.) it is constant.
Explanation：(in above-described embodiment or reference examples) modified (complete) pregelatinized starch, cellulose graft acroleic acid polymerization Thing sodium salt, the APP values of (part) pregelatinized starch three are respectively 0.2g/g, 18.2g/g, 2.8g/g, and the TCC values of three are distinguished For 0.3g/g, 27.3g/g, 4.1g/g, the 1st, the AAP of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) Be worth for 12.3g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 1.0g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：34.7%, reference examples：186%；8 it is small when：Implement Example：42.4%, reference examples：203%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：31.3%, reference examples： 91.2%；
Eurand buffer solutions：Embodiment：34.4%, reference examples：102%.
Embodiment DE9
It is formulated (every/capsule)：225 milligrams of propafenone hydrochloride, 110 milligrams of methylcellulose, (part) pregelatinated form sediment Powder 50mg, microcrystalline cellulose 5mg, lactose 5mg, magnesium stearate 2mg.
Preparation method：Each auxiliary material is weighed according to recipe quantity, raw material propafenone hydrochloride and auxiliary material are passed through into 100 sieves, 80 mesh respectively Sieve spare；Auxiliary material is mixed with propafenone hydrochloride with equal increments method after mixing；Add appropriate wetting agent (50% second Alcohol) mix after, be granulated with 14 mesh sieves, and in 60 DEG C of oven for baking to drying；Particle is collected, adds lubricant, tabletting or dress Capsule.
Reference examples DE9
Only (part) pregelatinized starch is replaced by drum-type drying waxy corn starch (full pregelatinated) in embodiment DE9, its His (including preparation method, dosage etc.) is constant.
Explanation：(in above-described embodiment or reference examples) methylcellulose, (part) pregelatinized starch, drum-type drying are wax-like The APP values of cornstarch (full pregelatinated) three are respectively 0.4g/g, 3.2g/g, 0.2g/g, and the TCC values of three are respectively 0.6g/g, 4.6g/g, 0.4g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 3.8g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 0.3g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：75.3%, reference examples：234%；8 it is small when：Implement Example：77.3%, reference examples：241%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：46.8%, reference examples： 125%；
Eurand buffer solutions：Embodiment：53.6%, reference examples：137%.
Embodiment DE10
It is formulated (being often sustained diaphragm)：Carbomer (940P) 2.3%, (part neutralizes) chitin 1%, hydroxypropyl methyl fiber Plain (100 centipoise) 4.5%, polyethylene glycol (4000) 0.2%, glycerine 3.0%, N5- (3 '-hydroxyls -4 '-methoxyl group-phenyl methylidene Base) huperzine 4.0%, remaining is water (finally flinging to).
Preparation method：Take carbomer and hydroxypropyl methyl cellulose to be sprinkled into appropriate 50 DEG C of distilled water, be slowly stirred, stand 16h Carbomer and hydroxypropyl methyl cellulose, (part neutralizes) chitin is set fully to be swollen.Macrogol 4000 is sequentially added, it is sweet Oil, N5- (3 '-hydroxyl -4 '-methoxyl group-phenylmethylene) huperzine mixing, stirs evenly, and triethanolamine is added dropwise and adjusts pH To 6~8, gel is ground to uniformly without obvious grumeleuse, adds water, centrifugation, bubble removing, plastic film mulch, drying, is cut, is sterilized under ultraviolet 30min, packaging.
Reference examples DE10
Only (part neutralizes) chitin is replaced by drum-type drying waxy corn starch (full pregelatinated) in embodiment DE10, its His (including preparation method, dosage etc.) is constant.
Explanation：(in above-described embodiment or reference examples) carbomer (940P), (part neutralizes) chitin, drum-type dry wax The APP values of shape cornstarch (full pregelatinated) three are respectively 1.8g/g, 3.1g/g, 0.3g/g, and the TCC values of three are respectively 2.4g/g, 4.3g/g, 0.4g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 3.6g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 1.1g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：44.3%, reference examples：253%；8 it is small when：Implement Example：48.2%, reference examples：272%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：26.4%, reference examples： 142%；
Eurand buffer solutions：Embodiment：32.4%, reference examples：153%.
Embodiment DE11
It is formulated (every)：Gastrodin (100mg) 15%, microcrystalline cellulose 15%, carrageenan 40%, the smart ammonia of polysalt acid Acid 5%, lactose 15%, hypromellose (100 centipoise) 9%, magnesium stearate 1%.
Preparation method：By main ingredient and carrageenan, poly- R-gene, hypromellose, lactose, microcrystalline cellulose, Pelletized with 65% ethanol, drying, whole grain, stiffened fatty acid magnesium tabletting.
Reference examples DE11
Only poly- R-gene is replaced by (part) pregelatinized starch in embodiment DE11, other (including preparation method, dosage Deng) constant.
Explanation：(in above-described embodiment or reference examples) carrageenan, poly- R-gene, (part) pregelatinized starch The APP values of three are respectively 3.8g/g, 23.5g/g, 3.6g/g, and the TCC values of three are respectively 6.3g/g, 32.2g/g, 5.4g/ G, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 7.2g/g, the 1st, 3 mixing The AAP values of thing (weight ratio is identical with embodiment or reference examples between the two) are 3.6g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：36.2%, reference examples：211%；8 it is small when：Implement Example：40.4%, reference examples：231%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：29.6%, reference examples： 132%；
Eurand buffer solutions：Embodiment：34.1%, reference examples：156%.
Embodiment DE12
It is formulated (every 1000)：Propranolol 150g, carbopol (934) 150g, gather mixing lysine-aspartate (3： 1) 30g, microcrystalline cellulose 50g, sodium carbonate 50g, superfine silica gel powder 5g.
Preparation method：By Propranolol, lactose, carbopol, poly- mixing lysine-aspartate, microcrystalline cellulose, micro mist silicon Tabletting after glue is mixed by equal increments method.
Reference examples DE12
Only poly- mixing lysine-aspartate (3 in embodiment DE12：1) replaced by (part) pregelatinized starch, other (including preparation method, dosage etc.) is constant.
Explanation：(in above-described embodiment or reference examples) carbopol (934), poly- mixing lysine-aspartate (3：1)、 The APP values of (part) pregelatinized starch three are respectively 1.5g/g, 20.2g/g, 2.9g/g, and the TCC values of three are respectively 4.3g/ G, 27.2g/g, 4.7g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 10.8g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 1.6g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：32.7%, reference examples：202%；8 it is small when：Implement Example：37.5%, reference examples：214%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：23.8%, reference examples： 102%；
Eurand buffer solutions：Embodiment：26.8%, reference examples：116%.
Embodiment DE13：
It is formulated (every 1000)：Quercetin 120g, lauryl sodium sulfate 15g, chitosan 45g, sodium polymethacrylate 5g, poloxamer (F68) 30g, lactose 85g, superfine silica gel powder 2g, magnesium stearate 3g.
Preparation method：Bulk pharmaceutical chemicals, auxiliary material are crossed into 100 mesh sieves, tabletting after mixing respectively.
Reference examples DE13
Only sodium polymethacrylate is replaced by drum-type drying waxy corn starch (full pregelatinated) in embodiment DE13, other (including preparation method, dosage etc.) is constant.
Explanation：(in above-described embodiment or reference examples) chitosan, sodium polymethacrylate, drum-type drying Waxy maize form sediment The APP values of powder (full pregelatinated) three respectively 3.5g/g, 24.8g/g, 0.3g/g, the TCC values respectively 5.8g/g of three, 32.7g/g, 0.7g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 7.7g/ G, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 1.9g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：48.4%, reference examples：233%；8 it is small when：Implement Example：54.7%, reference examples：241%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：35.3%, reference examples： 115%；
Eurand buffer solutions：Embodiment：39.2%, reference examples：132%.
Embodiment DE14
It is formulated (every 1000)：Mei Duotaxin 250g, galactomannans 200g, propylene glycol alginate acid sodium 20g, humic acid (degree of neutralization 20%) 100g, lactose 50g, superfine silica gel powder 5g.
Preparation method：Mei Duotaxin, galactomannans, propylene glycol alginate acid sodium, humic acid (degree of neutralization 20%), lactose are pressed Equal increments method mixes, and adds appropriate 80% ethanol solution of wetting agent to prepare softwood, crosses the granulation of 18 mesh sieves, dry, whole grain, adds micro- Powder silica gel, is uniformly mixed, tabletting.
Reference examples DE14
Only humic acid (degree of neutralization 20%) is replaced by drum-type drying waxy corn starch (full pregelatinated) in embodiment DE14, Other (including preparation method, dosages etc.) are constant.
Explanation：The mixture of (in above-described embodiment or reference examples) galactomannans and propylene glycol alginate acid sodium (10: 1), humic acid (degree of neutralization 20%), drum-type drying waxy corn starch (full pregelatinated) three APP values respectively 2.1g/g, 2.8g/g, 0.3g/g, the TCC values of three are respectively 3.8g/g, 4.7g/g, 0.8g/g, and the 1st, 2 mixtures (weight between the two It is more identical than with embodiment or reference examples) AAP values be 3.8g/g, the 1st, 3 mixtures (weight ratio and embodiment or right between the two It is identical as usual) AAP values be 1.3g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：34.7%, reference examples：241%；8 it is small when：Implement Example：42.2%, reference examples：253%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：32.1%, reference examples： 108%；
Eurand buffer solutions：Embodiment：39.3%, reference examples：116%.
Embodiment DE15
It is formulated (every 1000)：Diclofenac 200g, polyacrylic resin (II) 150g, polyethylenepolyamine hydrochloric acid Salt 50g, microcrystalline cellulose 50g, lactose 50g, superfine silica gel powder 5g.
Preparation method：By diclofenac, lactose, polyacrylic resin (II), polyethylenepolyamine hydrochloride, microcrystalline cellulose Element, superfine silica gel powder are mixed by equal increments method, tabletting.
Reference examples DE15
Only polyethylenepolyamine hydrochloride is replaced by (part) pregelatinized starch in embodiment DE15, other (including preparation method, use Amount etc.) it is constant.
Explanation：(in above-described embodiment or reference examples) polyacrylic resin (II), polyethylenepolyamine hydrochloride, (part) The APP values of pregelatinized starch three respectively 1.7g/g, 32.2g/g, 2.8g/g, the TCC values respectively 3.8g/g of three, 37.2g/g, 4.4g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 15.6g/ G, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 1.8g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：37.2%, reference examples：216%；8 it is small when：Implement Example：41.5%, reference examples：232%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：42.2%, reference examples： 153%；
Eurand buffer solutions：Embodiment：49.3%, reference examples：167%.
Embodiment DE16
It is formulated (every 1000)：Trimebutine Maleate 300.0g, gellan gum 50.0g, part neutralize (50%) starch- Acrylonitrile graft copolymer 50.0g, 8% polyvinylpyrrolidone ethanol solution 40.0ml (ethanol is flung to), magnesium stearate 1.0g.
Preparation method：Starch-Acrylontirile Graft Copolymer, the Trimebutine Maleate that gellan gum, part are neutralized to (50%) are pressed Equal increments method mixes, and adds 8% polyvinylpyrrolidone ethanol solution to prepare softwood, crosses the granulation of 18 mesh sieves, dry, whole grain, adds Enter magnesium stearate, be uniformly mixed, tabletting.
Reference examples DE16
Only part neutralizes the Starch-Acrylontirile Graft Copolymer of (50%) by (part) pregelatinized starch in embodiment DE16 Replace, other (including preparation method, dosages etc.) are constant.
Explanation：The starch-acrylonitrile graft that (in above-described embodiment or reference examples) gellan gum, part neutralize (50%) is total to Polymers, the APP values of (part) pregelatinized starch three are respectively 2.5g/g, 17.3g/g, 3.1g/g, and the TCC values of three are respectively 3.6g/g, 28.4g/g, 5.8g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) For 20.4g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 3.1g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：33.7%, reference examples：184%；8 it is small when：Implement Example：40.2%, reference examples：192%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：31.4%, reference examples： 135%；
Eurand buffer solutions：Embodiment：36.2%, reference examples：145%.
Embodiment DE17：
It is formulated (every 1000)：Metolazone 10g, polyoxyethylene (molecular weight 400,000 and 800,000, weight ratio 1: 2) 100g, Part neutralizes the polyvinyl alcohol-acrylic block copolymers 35g, microcrystalline cellulose 85g, magnesium stearate 5g of (70%), 90% second Appropriate alcohol (is flung to).
Preparation method：It is spare that 100 mesh sieves are crossed after former, auxiliary material is crushed respectively；Metolazone and polyoxyethylene, part are neutralized (70%) polyvinyl alcohol-acrylic block copolymers, microcrystalline cellulose is crossed 100 mesh sieves and is uniformly mixed, with appropriate 90% ethanol Softwood processed, the granulation of 20 mesh sieves, 60 ± 5 DEG C of dryings of wet granular, 20 mesh sieve whole grains；Add magnesium stearate, mix, it is encapsulated to obtain the final product.
Reference examples DE17
Only part neutralizes the Starch-Acrylontirile Graft Copolymer of (50%) by (part) pregelatinized starch in embodiment DE17 Replace, other (including preparation method, dosages etc.) are constant.
Explanation：2), portion (in above-described embodiment or reference examples) polyoxyethylene (molecular weight 400,000 and 800,000, weight ratio 1: Point neutralize the polyvinyl alcohol-acrylic block copolymers of (70%), the APP values of (part) pregelatinized starch three are respectively 4.3g/g, 23.7g/g, 3.3g/g, TCC values respectively 6.7g/g, 30.2g/g, 5.6g/g of three, the 1st, 2 mixtures (two Weight ratio is identical with embodiment or reference examples between person) AAP values be 15.5g/g, the 1st, 3 mixtures (between the two weight ratio with Embodiment or reference examples are identical) AAP values be 4.0g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：39.3%, reference examples：178%；8 it is small when：Implement Example：46.5%, reference examples：196%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：35.8%, reference examples： 112%；
Eurand buffer solutions：Embodiment：42.5%, reference examples：127%.
Embodiment DE18：
It is formulated (every 1000)：Inderal 100g, sodium alginate 90g, part neutralize the poly- hydroxymethyl propylene of (90%) Amine 10g, lactose 50g, microcrystalline cellulose 45g, magnesium stearate 5g, 90% appropriate amount of ethanol (are flung to).
Preparation method：It is spare that 100 mesh sieves are crossed after former, auxiliary material is crushed respectively；Weigh the inderal and alginic acid of recipe quantity Sodium, microcrystalline cellulose and lactose, cross 100 mesh sieves and are uniformly mixed, with appropriate 90% ethanol softwood, the granulation of 20 mesh sieves, wet granular 60 ± 5 DEG C of dryings, 20 mesh sieve whole grains；Add magnesium stearate, mix, it is encapsulated to obtain the final product.
Reference examples DE18
Only part neutralizes poly- hydroxymethyl allylamine quilt (part) pregelatinized starch replacement of (90%) in embodiment DE18, Other (including preparation method, dosages etc.) are constant.
Explanation：(in above-described embodiment or reference examples) sodium alginate, part neutralize the poly- hydroxymethyl propylene of (90%) Amine, the APP values of (part) pregelatinized starch three are respectively 3.8g/g, 16.6g/g, 3.1g/g, and the TCC values of three are respectively 6.3g/g, 24.6g/g, 5.2g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) For 7.2g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 3.2g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：42.6%, reference examples：214%；8 it is small when：Implement Example：48.3%, reference examples：235%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：37.2%, reference examples： 131%；
Eurand buffer solutions：Embodiment：45.8%, reference examples：143%.
Embodiment DE19
It is formulated (every 1000)：Perospirone Hydrochloride 8g, glycogen-calcium alginate (glycogen-calcium chloride-alginates) conjugate 90g, poly-aspartate-asparagine (1: 2) 30g, lactose 50g, microcrystalline cellulose 45g, magnesium stearate 5g, appropriate amount of water (are waved Go).
Preparation method：Cross 100 mesh sieves after prescription Central Plains, auxiliary material are crushed respectively to be uniformly mixed, with suitable quantity of water softwood, 20 mesh sieves Granulation, 60 ± 5 DEG C of dryings of wet granular, 20 mesh sieve whole grains；Magnesium stearate is added, is mixed, tabletting.
Explanation：In (in above-described embodiment or reference examples) glycogen-calcium alginate (glycogen-calcium chloride-alginates) conjugate Glycogen-calcium alginate mass ratio is 80/20 (referring to CN101909608B)
Glycogen：Polglumyt, according to EP 654, the glycogen of the operation preparation described in 048, including the nitrogen less than 60ppm With the reduced sugar less than 0.25 weight %.
Alginates：Mosanom derived from brown alga, 2% solution is about 250cPs in 25 DEG C of viscosity.Manufacturer Sigma-Aldrich.The code of manufacturer is SIGMA A2158.
Reference examples DE19
Only poly-aspartate-asparagine (1: 2) is replaced by (part) pregelatinized starch in embodiment DE19, other (bags Include preparation method, dosage etc.) it is constant.
Explanation：(in above-described embodiment or reference examples) glycogen-calcium alginate (glycogen-calcium chloride-alginates) conjugate, gather Aspartic acid-asparagine (1: 2), the APP values of (part) pregelatinized starch three are respectively 4.3g/g, 12.5g/g, 2.6g/ G, the TCC values of three are respectively 6.6g/g, 17.3g/g, 4.8g/g, the 1st, 2 mixtures (between the two weight ratio and embodiment or Reference examples are identical) AAP values be 10.3g/g, the 1st, 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) AAP values are 2.9g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：28.6%, reference examples：179%；8 it is small when：Implement Example：35.2%, reference examples：175%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：33.4%, reference examples： 124%；
Eurand buffer solutions：Embodiment：41.3%, reference examples：138%.
Embodiment DE20
It is formulated (every)：Hydrochloric acid Trospium chloride 40mg, sustained-release matrix 258mg, the polyethyleneimine 20mg of complete neutralization, firmly Resin acid 2mg.
Preparation method：1) sustained-release matrix is prepared：By required xanthans (50% weight ratio), calcium sulfate (35% weight ratio), PEG2000 (15% weight ratio) puts in water (ratio of water is 2~4 times of sustained-release matrix total amount), and stirring, makes it fully dissolve, As slow-release matrix solution, spray drying is carried out in spray dryer and prepares particulate, spray drying inlet temperature is 90 DEG C, is gone out Mouth temperature is 80 DEG C, and feed rate 6ml/min, nebulizer pressure 75kpa, collects particulate in cyclone separator, obtains micro- Grain；
2) sustained-release matrix prepared, is uniformly mixed with the polyethyleneimine of the desired amount of medicine, complete neutralization, adds Magnesium stearate, is uniformly mixed, tabletting.
Reference examples DE20
Only the polyethyleneimine of complete neutralization is replaced by (part) pregelatinized starch in embodiment DE20, other (including system Method, dosage etc.) it is constant.
Explanation：(in above-described embodiment or reference examples) sustained-release matrix, the polyethyleneimine of complete neutralization, (part) pre- glue The APP values of change starch three respectively 4.7g/g, 15.7g/g, 2.3g/g, TCC values respectively 7.2g/g, 21.5g/g of three, 4.5g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 7.1g/g, the 1st, 3 The AAP values of mixture (weight ratio is identical with embodiment or reference examples between the two) are 3.2g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：35.4%, reference examples：183%；8 it is small when：Implement Example：41.7%, reference examples：192%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：39.2%, reference examples： 117%；
Eurand buffer solutions：Embodiment：46.5%, reference examples：135%.
Embodiment DE21：
It is formulated (every 1000)：Roxithromycin 150g, Pluronic (F127) 120g, (hydrolysis) starch-acrylonitrile graft Copolymer 45g, lactose 50g, microcrystalline cellulose 45g, magnesium stearate 5g, 90% appropriate amount of ethanol (are flung to).
Preparation method：It is spare that 100 mesh sieves are crossed after former, auxiliary material is crushed respectively；Weigh the roxithromycin of recipe quantity with Pluronic, (hydrolysis) Starch-Acrylontirile Graft Copolymer, microcrystalline cellulose and lactose, cross 100 mesh sieves and are uniformly mixed, with suitable Measure 90% ethanol softwood, the granulation of 20 mesh sieves, 60 ± 5 DEG C of dryings of wet granular, 20 mesh sieve whole grains；Magnesium stearate is added, is mixed, dress Capsule to obtain the final product.
Reference examples DE21
It is (complete pre- by drum-type drying waxy corn starch that Starch-Acrylontirile Graft Copolymer only (is hydrolyzed) in embodiment DE21 Gelatinization) to replace, other (including preparation method, dosages etc.) are constant.
Explanation：(in above-described embodiment or reference examples) Pluronic (F127), the copolymerization of (hydrolysis) starch-acrylonitrile graft Thing, APP values respectively 1.5g/g, 21.4g/g, 0.3g/g of drum-type drying waxy corn starch (full pregelatinated) three, three TCC values be respectively 3.7g/g, 28.5g/g, 0.4g/g, the 1st, 2 mixtures (weight ratio and embodiment or reference examples between the two It is identical) AAP values be 10.8g/g, the 1st, the AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) For 0.9g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：28.3%, reference examples：232%；8 it is small when：Implement Example：29.2%, reference examples：245%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：32.7%, reference examples： 143%；
Eurand buffer solutions：Embodiment：37.5%, reference examples：152%.
Embodiment DE22
It is formulated (every)：Nicardipine (60mg) 8.6%, polyvinylpyrrolidone (K90) 14.1%, part neutralize poly- The crosslinked polymer 37.8% of microgrid shape of acrylic acid, hydroxypropyl methyl cellulose (100 centipoise) 8%, microcrystalline cellulose 31%, Magnesium stearate 0.5%.
Preparation method：Add the crosslinked polymerization of microgrid shape of nicardipine, polyvinylpyrrolidone, the polyacrylic acid partly neutralized Thing, hydroxypropyl methyl cellulose, microcrystalline cellulose, magnesium stearate, mix, tabletting.
Reference examples DE22-1,2
The crosslinked polymer of microgrid shape of the only polyacrylic acid that part neutralizes is crosslinked carboxymethyl cellulose in embodiment DE22 Plain sodium (DE22-1) or drum-type drying waxy corn starch (full pregelatinated) DE22-2 are replaced, other (including preparation method, dosages etc.) It is constant.
Explanation：The microgrid for the polyacrylic acid that (in above-described embodiment or reference examples) polyvinylpyrrolidone, part neutralize The crosslinked polymer of shape, Ac-Di-Sol, the APP values point of drum-type drying waxy corn starch (full pregelatinated) four Not Wei 2.7g/g, 32.9g/g, 2.3g/g, 0.4g/g, four TCC values are respectively 4.5g/g, 44.8g/g, 3.8g/g, 0.6g/ G, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 35.4g/g, the 1st, 3 mixing The AAP values of thing (weight ratio is identical with embodiment or reference examples between the two) are 2.4g/g, the 1st, 4 mixtures (weight between the two It is more identical than with embodiment or reference examples) AAP values be 0.9g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：21.2%, reference examples (DE22-1)：178%, control Example (DE22-2)：243%；8 it is small when：Embodiment：24.4%, reference examples (DE22-1)：165%, reference examples (DE22-2)： 223%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：32.7%, reference examples： 143%；
Eurand buffer solutions：Embodiment：37.5%, reference examples：152%.
Embodiment DE23
It is formulated (every)：Agit 3mg, pectin 25mg, poly-asparagine 50mg, hydroxypropyl methyl fiber Element (12~18mpas) 12mg, sorbierite 29.5mg, magnesium stearate 0.5mg.
Preparation method：By agit, carboxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, tristearin Sour magnesium mixes, tabletting.
Reference examples DE23
Only poly-asparagine is replaced by drum-type drying waxy corn starch (full pregelatinated) in embodiment DE23, other (bags Include preparation method, dosage etc.) it is constant.
Explanation：(in above-described embodiment or reference examples) pectin, poly-asparagine, drum-type drying waxy corn starch are (complete Pregelatinated) the APP values of three are respectively 2.4g/g, 17.6g/g, 0.4g/g, the TCC values of three respectively 4.5g/g, 24.4g/ G, 0.6g/g, the 1st, the AAP values of 2 mixtures (weight ratio is identical with embodiment or reference examples between the two) be 19.2g/g, the 1st, The AAP values of 3 mixtures (weight ratio is identical with embodiment or reference examples between the two) are 0.9g/g.
Release change rate measures (B) result：4 it is small when：Embodiment：37.6%, reference examples：227%；8 it is small when：Implement Example：43.5%, reference examples：242%.
Front and rear phase drug release rate change rate (C) measurement result：McIlvaine buffer solutions：Embodiment：37.5%, reference examples： 246%；
Eurand buffer solutions：Embodiment：45.5%, reference examples：257%.

Claims (10)

  1. A kind of 1. (particularly, in the ionic strength of change or in the dissolution medium of higher salinity) disintegration (or swelling) performance The composition for the hydrogel-forming polymer that (stability) improves, said composition include one hydrophilic polymers I and AAP values (i.e. Absorption Against Pressure values, or pressure-bearing expansion (swelling) value, value reflection polymer resistance Disintegration Swelling Capacity under pressure, similarly hereinafter) 1.25 times of (containing) higher than hydrophilic polymer I (it is preferred that the AAP values are also done than drum-type 1.25 times of dry wax-like (matter) cornstarch high (containing)) it is one it is water-insoluble (including " slightly molten " on ordinary meaning, " slightly soluble ", " almost insoluble " or " fairly insoluble " etc. looks like, and " water-insoluble " implication is herewith below) hydrophilic polymer II.
  2. A kind of 2. ((particularly, in the ionic strength of change or in the dissolution medium of higher salinity) disintegration (or swelling) performance (stability) (or Release Performance (stability)) improves) (particularly, hydrophilic slow (/ control) release formulation) preparation, said preparation Including one (or more) kinds of medicines, a kind of composition of hydrogel-forming polymer (and optionally pharmaceutically acceptable formula agent), The composition of the hydrogel-forming polymer includes one hydrophilic polymers I and AAP values are higher than hydrophilic polymer I (containing) Preferably, the one (or more) kinds of 1.25 times (which also dries 1.25 times of wax-like (matter) cornstarch high (containing) than drum-type) Water-insoluble hydrophilic polymer II.
  3. 3. according to the composition or preparation of the hydrogel-forming polymer of claim 1 or 2, it is characterised in that the hydrophilic polymer I (particle) is AAP relative to the absorption value of a pressure1, the hydrophilic polymer II (particle) relative to a pressure absorption value For AAP2, the absorption value relative to a pressure of the two mixture is AAP1,2, AAP1,2/(w·AAP1+p·AAP2) ＞ 1 is (more preferably Ground >=1.25), wherein, w for the hydrophilic polymer I (particle) account for the hydrophilic polymer I and the hydrophilic polymer II ( Grain) gross weight percentage, p accounts for the hydrophilic polymer I and the hydrophilic polymer for the hydrophilic polymer II (particle) The percentage of II (particle) gross weight, and p+w=1, described relative to the absorption value AAP of pressure is in 21.1g/cm2 Between (0.3psi) and 70.3g/cm2 (1psi), preferably between 35.2g/cm2 (0.5psi) and 56.2g/cm2 (0.8psi) Pressure under measure, the measure of the absorption value AAP carries out under identical conditions (pressure).
  4. 4. according to the composition or preparation of the hydrogel-forming polymer of claim 1 or 2, it is characterised in that the hydrophilic polymer The TCC values of II (particle) are higher than the TCC values of the hydrophilic polymer I (particle), and the AAP values of the mixture of the two are higher than the parent The AAP values of any of aqueous polymer I (particle) and the hydrophilic polymer II (particle), wherein the suction relative to pressure Receipts value be between 21.1g/cm2 (0.3psi) and 70.3g/cm2 (1psi), preferably in 35.2g/cm2 (0.5psi) and Measured under pressure between 56.2g/cm2 (0.8psi), the measure of the absorption value AAP be under identical conditions (pressure) into Capable.
  5. 5. according to the composition or preparation of the hydrogel-forming polymer of claim 1 or 2, it is characterised in that the hydrophilic polymer The weight of I (particle) accounts at least the 10% of hydrophilic polymer I and the hydrophilic polymer II (particle) gross weight.
  6. 6. according to the composition or preparation of the hydrogel-forming polymer of claim 1 or 2, it is characterised in that the hydrophilic polymer Half mass particle size of I particle is substantially not less than half mass particle size of II particle of hydrophilic polymer.
  7. 7. according to the composition or preparation of the hydrogel-forming polymer of claim 1 or 2, it is characterised in that the hydrophilic polymer Half mass particle size of II particle is between 10 microns and 250 microns, half mass particle ruler of I particle of hydrophilic polymer It is very little between 20 microns and 400 microns.
  8. 8. according to the composition or preparation of the hydrogel-forming polymer of claim 1 or 2, it is characterised in that the hydrophilic polymer I selected from polysaccharide, cellulose derivative (slow (/ control) is released) material：
    - alkylcellulose, such as methylcellulose；
    - hydroxy alkyl cellulose, such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose (including low-substituted hydroxypropyl fiber Element) and hydroxybutyl cellulose；
    - hydroxyalkylalkylcellulose, such as hydroxyethylmethylcellulose and hydroxypropyl methyl cellulose；
    - carboxyl alkyl cellulose, such as carboxymethyl cellulose；
    The alkali metal salt of the alkali metal salt of-carboxyl alkyl cellulose, crosslinked carboxyl alkyl cellulose, such as sodium carboxymethylcellulose, Ac-Di-Sol；
    - carboxyalkyl alkylcellulose, such as carboxymethylethylcellulose；
    - carboxyl alkyl cellulose ester；
    - other natural, semi-synthetic or synthesis polysaccharide, for example, alginic acid and its alkali metal salt and ammonium salt, carrageenan, Galactomannans, bassora gum, agar, Arabic gum, guar gum, xanthans, starch, hydroxypropul starch, pectin, gellan gum, Sodium carboxymethyl starch or acrylic acid branch (branch) connect sodium starch, chitin derivative such as chitosan, polyfructosan, inula Pollen；
    Crylic acid resin (slow (/ control) is released) material：
    - polyacrylic acid and their salt；
    - polymethylacrylic acid and their salt, methacrylate copolymer；
    Polyethylene kind (slow (/ control) is released) material：
    - polyvinyl alcohol；Polyvinyl acetate；Carbopol (carbopol)；Polyoxyethylene；
    - polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, the copolymer of polyvinylpyrrolidone and vinyl acetate；
    The composition of-polyvinyl alcohol and polyvinylpyrrolidone；
    - polyalkylene oxide class such as polyethylene oxide and polypropylene oxide and the copolymer of ethylene oxide and propylene oxide, Ru Boluo Husky nurse (F127)；
    Preferable hydrophilic polymer is polysaccharide, is more particularly cellulose derivative and most specifically for cellulose ether derivative；
    Most preferred cellulose ether derivative is hydroxypropyl methyl cellulose and hydroxypropyl cellulose.
  9. 9. according to the composition or preparation of the hydrogel-forming polymer of claim 1 or 2, it is characterised in that the hydrophilic polymer II, selected from a variety of anionic functional groups, such as sulfonic group, and the more typically such as polymer of carboxyl is contained (in molecular structure), is applicable in In those polymer that the example of this polymer includes preparing from polymerizable, undersaturated, acidiferous monomer, (this monomer Including ethylenic unsaturated acid and acid anhydride containing at least one carbon-to-carbon olefinic double bond, more specifically, these monomers may be selected from olefinic insatiable hunger With carboxylic acid and acid anhydrides, olefinic unsaturated sulfonic acid and its mixture).
  10. 10. a kind of purposes of the composition of hydrogel-forming polymer, the composition of the hydrogel-forming polymer includes a kind of (or more Kind) (preferably, the AAP values are also more wax-like than drum-type drying for 1.25 times of hydrophilic polymer I and AAP values (containing) higher than hydrophilic polymer I (matter) cornstarch height 1.25 times of (containing)) one water-insoluble hydrophilic polymers II, which polymerize The composition of thing be used to improving the composition comprising one medicines and above-mentioned hydrogel-forming polymer (particularly, Hydrophilic slow (/ control) release formulation) preparation (particularly, in the ionic strength of change or in the dissolution medium of higher salinity) drug release The purposes of performance (stability), in other words, the ion that the composition of the hydrogel-forming polymer is used to offset dissolution medium are strong Degree (salinity) discharges medicine the purposes of the detrimental effect of (particularly slow (/ control) release) from said preparation, particularly, is used for Prevent in fasting and on the feed under the conditions of, dumped along the drug dose from said preparation of whole intestines and stomach or drug dose Substantially the purposes not discharged).
CN201610888909.4A 2016-10-12 2016-10-12 The composition of hydrophilic polymer Pending CN107929747A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113101406A (en) * 2021-04-06 2021-07-13 浙江工业大学 Starch composition and application thereof in preparation of hemostatic material
CN116236451A (en) * 2023-04-18 2023-06-09 淄博市中心医院 Acarbose tablet, preparation method and application

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CN1151707A (en) * 1994-07-05 1997-06-11 普罗克特和甘保尔公司 Absorbent gelling material made of at least two hydrogel-forming particles and prepn. thereof
CN101085361A (en) * 2007-06-18 2007-12-12 浙江大学 Application of gellan gum in slow release preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1151707A (en) * 1994-07-05 1997-06-11 普罗克特和甘保尔公司 Absorbent gelling material made of at least two hydrogel-forming particles and prepn. thereof
CN101085361A (en) * 2007-06-18 2007-12-12 浙江大学 Application of gellan gum in slow release preparation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113101406A (en) * 2021-04-06 2021-07-13 浙江工业大学 Starch composition and application thereof in preparation of hemostatic material
CN113101406B (en) * 2021-04-06 2022-06-21 浙江工业大学 Starch composition and application thereof in preparation of hemostatic material
CN116236451A (en) * 2023-04-18 2023-06-09 淄博市中心医院 Acarbose tablet, preparation method and application
CN116236451B (en) * 2023-04-18 2024-04-19 淄博市中心医院 Acarbose tablet, preparation method and application

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