CN1107331A - Sustained release pharmaceutical composition - Google Patents
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- CN1107331A CN1107331A CN 94115992 CN94115992A CN1107331A CN 1107331 A CN1107331 A CN 1107331A CN 94115992 CN94115992 CN 94115992 CN 94115992 A CN94115992 A CN 94115992A CN 1107331 A CN1107331 A CN 1107331A
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Abstract
The utility model discloses a continuous release drug combination and the preparation method. The combination comprises a core element of a morphine compound and a core coating for the core. The core coating is partially dissolved in strong acid pH and the morphine compound inside the coating continuously releases with a relative constant velocity for a period of time in the intestine for the absorption, which keeps a blood concentration of the morphine within a therapeutic range for a period. The combination is applied to treat the acute or chronic pain, especially a pain related later disease such as the cancer, chronic back pain and postoperative pain.
Description
The present invention relates to a kind of pharmaceutical composition of lasting release, especially a kind of lasting release of pharmaceutical compositions that comprises the high water soluble active ingredient, and the preparation method of said composition.
Known as prior art, in the therapeutic process of numerous disease, no matter be from treatment or from preventing angle all to need a kind of active pharmaceutical ingredients of sustained release form.In general this lasting release is preferably in a kind of constant release rate was provided in a period of time.Although known in the state of the art have some extended release preparations, the active pharmaceutical ingredients that will have high water soluble is applied to extended release preparation and is greatly limited.The high water soluble that has been found that active ingredient in the art is easy to generate a kind of product, and this product is easy to form the phenomenon that is referred to as " dosage accumulation ".That is to say, a period of time hangover of active ingredient, but in a single day discharging, this release rate is just very high.And fluctuation appears in the plasma concentration of active ingredient easily, thereby has increased toxic probability.Also have, changing between to a certain degree daytime appears in the plasma concentration of having found active ingredient.
Preparation of the prior art may also have other shortcoming, and for example the biological activity of preparation of the prior art can be weakened by food.Because compound dosed administration can't produce allergia, so this also is very important.
For example, typical highly-water-soluble active ingredient comprises the opium medicine, and this medicine still plays an important role when treatment acute and chronic pain, is particularly useful for treating the pain with terminal illness such as related to cancer.
Morphine is considered to the Opium class medicine that a kind of selection is used for the treatment of cancerous pain.If knownly seek out enough pain relief preferred oral and can be created in the effect of paying that the order of severity and incidence rate aspect can be accepted for thing approach, this administration.Up to now, the liquid of morphine or fast release tablet formulations are that the internist is used for the treatment of that cancerous pain institute is getable only a peroral dosage form.
Oral administration to morphine has a lot of criticisms in the prior art, and this critic points out that mainly it lacks effectiveness.But the evidence of some accumulation especially obtains data from hospital, show if each patient is made its dosage and the concrete optimization of spacing of doses, then this criticism is invalid, should give the morphine of doses before pain occurs, and the regularity of strict its administering mode.Specifically, this dosage that just refers to morphine is from 10mg to 500mg at the most, and spacing of doses is per 2 hours to 6 hours.In a kind of relation of having set up after the iatrotechnics and aspect the cancerous pain between morphine blood concentration and the pain relief.
This studies show that for each patient has a morphine minimum effective drug concentration (MEC).MEC has patient's differences of 5 times in the treatment postoperative pain, to cancerous pain even bigger.This MEC notion that is used for Opium class medicine also is applicable to the multiple oral or parenteral dosed administration generation blood opioid fluctuation of concentration of pethidine, methadone, fentanyl and cetobemidone, peak concentration causes the effect of paying sometimes, and low concentration is usually with sufficiently alleviating pain is relevant.Therefore, a kind of morphine preparation that can reduce blood opioid fluctuation of concentration and the long-time alleviating pain (extended release preparation) of energy has potentiality widely for the pain relief that improves end-stage patients.
At present, have only a kind of this preparation (MST Continus or MS Contin) to sell in the world.But pharmacokinetics and pharmacodynamics data combine and show that this product is actually a kind of continuous preparation of putting of delay with some lasting release characteristic.Although manufacturer's recommended doses is spaced apart 12 hours, long-term clinical experience shows 8 hours, and control is more actual for constant pain at interval.
Therefore, one of purpose of the present invention is to overcome, and perhaps alleviates one or several difficult problem of being correlated with in the prior art at least.
Therefore, first content of the present invention just provides a kind of pill compositions of lasting release, comprising:
A drug core composition, this drug core comprise at least a active ingredient with at least 1/30 water solubility; With
The core coating of said medicine core composition, this coating be in peracidity PH lower part dissolving, thus make wherein active ingredient can be in one period long period by intestinal with one relatively constant speed absorb.
This wide used term " continues to discharge " rate of release that is meant its active ingredient can make it in blood level remains on therapeutic domain but be lower than toxic level in for example 10 to 24 hours or more time in interval.
Term used herein " bioavailability " is absorbed degree of active pharmaceutical ingredients and the degree that reaches the drug effect position in the drug products.
One group of forming of the following composition of the optional freedom of this active ingredient: hydryllin, antibiotic, tuberculosis, cholinergic agent, antimuscarinic drug, sympathomimetic, sympatholytic, autonomic drug, iron preparation, hemorrhage, cardiac drug, antihypertensive drug vasodilator drug, on-steroidal antiinflammatory, opioid agonist, anticonvulsant, tranquilizer, analeptic, barbiturate, tranquilizer, expectorant, Bendectin, gastrointestinal drug, heavy metal antagonist, antithyroid drug, loose dose of genito-urinary system smooth muscle and vitamin.No matter the solubility characteristics of medicine is PH dependency or PH dependent/non-dependent, the active ingredient of high-dissolvability all is applicable to the present invention.
Listed the active ingredient example of high-dissolvability in the following table
Drug solubility (in the water) PKA
Antihistaminic
Azatadine maleate very easily molten 9.3
Brompheniramine maleate 1/5 3.59,9.12
Carbinoxamine maleate 1/1 8.1
Chlorphenamine 1/4 9.2
Dexbrompheniramine maleate 1/1/1
Doxylamine succinate 1/1 5.8,9.3
Promethazine 1/0.6 9.1
Proactidil (triprolidine hydrochloride) 1/2 3.6,9.0
Antibiotic
Potassium v calcium 1/1.5 0.5
Brispen easy molten 2.7
Sodium ethoxynaphthamidopenicillanate easy molten 2.7
Bristopen 1/3.5 2.8
Carbenicillin indanyl sodium easy molten 2.6,2.7,3.3
Tetramycin hydrochloride 1/2 3.3,7.3,9.1
P chloromethylbenzoic acid lincomycin 1/2.5 7.7
Clindamycin hydrochloride 1/2 7.7
The clindamycin hydrochloride palmitate is easily molten-
Lincomycin hydrochloride 1/1 7.6
Novobiocin monosodium 1/5 4.2,9.1
Furadantin sodium solvable 7.2
Antitubercular agent
Isoniazid 1/8 1.8,3.5,10.8
Cholinergic drug
Beautiful this bright 1/5
Neostigmine 1/0.5 12.0
Pyridinium bromide this bright 1/1
Antitoxin potash medicine
Octatropine is solvable
Bromine silicon ring diphenyl ester is solvable
Bentrl hydrothloride 1,/20 9
Glycopyrrolate 1/5
Tralin is easily molten
Homapin 1/6 9.9
Banthine bromide 1/5
Oxyphenonii bromidum easy molten 3.2
Probanthine very easily molten 9.0
Sympathomimetic
Methanesulfonic acid Bitolterol 9.1
The false ephedrine 1/1 9.8 of hydrochloric acid
Sympatholytic
Various self-disciplining medicines
Nicotine solvable 7.9
Iron preparation
Gluconic acid [Asia] ferrum 1/10
Hemorrhage
6-Aminocaproic Acid 1/1.5 4.43,10.73
Cardiac drug
Hydrochloric acid sulfur nitrogen
Ketone easy molten 7.7
Gluconic acid silicon Ni Dingyi molten 4.0,8.6
Timolol maleate easy molten 9
Hydrochloric acid Tocainide easy molten 7.8
Antihypertensive drug
Captopril easy molten 3.7,9.8
Lopresor very easily molten 9.68
Vasodilator
Nonsteroid anti-inflammatory drugs
Choline salicylate is very easily molten
Meclofenamate sodium easy molten 4.0
Naproxen sodium solvable 4.15
Tolmetin sodium easy molten 3.5
Opioid agonist
Treat because of 1/4 8.2 on the phosphoric acid right side
Dihydro-morphinone hydrochloride 1/3 8.2
Pethidine hydrochloride very easily molten 8.7
Anticonvulsant
Phenytoin Sodium easy molten 8.3
Tranquilizer
Hydrochloric acid trichlorine promonta 1/2 8.1
Molindone hydrochloride easy molten 6.9
Analeptic
Didrex easy molten 6.6
Diethylpropion hydrochloride is easily molten
Fenfluramine hydrochloride 1,/20 9.1
Methylphenidate hydrochloride easy molten 8.8
Anoxine-T easy molten 7.6
Barbiturate
Neravan easy molten 7.9
Tranquilizer
Hydroxyzine hydrochloride 1/1 2.6,7.0
Expectorant
Bendectin
Gastrointestinal drug
Heavy metal antagonist
Distamine (Dista) 1/1 8.0,10.8
Antithyroid drug
The urogenital smooth muscle relaxant
Flavoxate hydrochloride is easily molten
Oxybutynin chloride easy molten 6.96
Vitamin
Non-classified medicament
Etidronate disodium is easily molten
Calcium folinate very easily molten 3.1,4.8,10.4
Methylene blue 1/25-1
In the following description, by with Opium class medicine, morphine is that example illustrates active ingredient.But this just is used to illustrate, and does not therefore limit the present invention.Preferred active ingredient is the Opium medicine that is selected from following a group, and they are codeine: the salt of loose pain, hydrocodone, hydrogenation morphine (hydromorphine), pethidine, methadone, morphine and dextropropoxyphene.The effect of morphine is mainly as central nervous system μ, K and may be as the agonist of δ receptor.Following pharmacological action can appear by acting on these receptors.Because maincenter causes analgesis to the effect of the pain sensation, be attended by regulating action to the pivot transmission of harmful consciousness.It also causes sleepy and sense of euphoria's (and stewed sensation is arranged sometimes, especially occur in the people of those no pain).
Pill compositions of the present invention can comprise the core composition of multiple coatings.
This pharmaceutical composition can provide with any suitable unit dosage form.Can use capsule formulation.
This medicine pellet composition can provide with pill or tablet form, can be by piller at random is pressed into tablet with the appropriate excipients of adding.
The present invention is preferred to be that this core coating can produce a kind of solubility curve that is used for this sustained-release composition in use on the one hand, and this solubility curve provides the needed minimal solubility of the bioavailability that equates substantially equal or bigger with at least a capsule, tablet or the liquid preparation of the active ingredient of form of can utilizing immediately that contains equivalent.
" solubility curve " used herein is meant the function curve of active ingredient burst size and time.Can use drug release test (724) to measure this solubility curve, the test USP of this test reference standard * * II1990.(Test(711)).This curvilinear characteristic is the condition of being selected.Therefore, can produce this solubility curve with preliminary election dissolution velocity, temperature and the PH of solvent.
Can under near the PH level of stomach, measure first solubility curve.Under near the pH value of at least one point of intestinal, can measure at least the second solubility curve.
Highly acid PH be similar to the PH of stomach and weak acid to alkaline PH near intestinal PH.Term used herein " highly acid PH " is meant the PH in about 1 to 4 scope.This term " weak acid is to alkaline PH " is meant greater than 4, the PH until about 7.5, preferred about 6 to 7.5.
Can use the PH of about 1.2 PH simulation stomach.
Can use the PH of about 6.0 to 7.5 preferred 7.5 PH simulation intestinal.
Therefore, of the present invention another preferred aspect, with PH level determination first solubility curve, and recording second solubility curve near intestinal PH level more at least near stomach; First and second solubility curves that are used for sustained-release composition are equal to or greater than respectively and contain at least a capsule, tablet or the liquid that can utilize the active ingredient of form immediately the basic required minimal solubility of bioavailability that equates is provided.
More preferably, said composition in use, with respect to the active ingredient of coating form not, this active constituent plasma concentration shows less fluctuation during 24 hours, be in steady statue, and/or with respect to the known capsules or the tablet of the active constituent that contains at least a sustained release form, the plasma concentration of this active constituent shows between less daytime and changes.
For example, the solubility curve that has obtained shows with commercial known morphine compositions and comprises MS Contin, the equal or better substantially bioavailability of MST Continus and morphine solution.
Therefore, a preferred aspect of the present invention pill compositions that provided a kind of lasting release comprises
A kind of core composition that contains morphine compounds; With
A kind of core coating that is used for this core composition, it can dissolve in highly acid PH condition lower part, and wherein Bao Guo morphine compounds can be absorbed and used with constant relatively speed in intestinal in a period of time, continues for some time thereby make the blood concentration of morphine remain in the therapeutic domain.
Should be understood that because morphine compounds provides to continue discharging pill, can in 24 hours, obtain the fluctuation of very little active ingredient plasma concentration and keep a steady statue, and with respect to the active ingredient of coating form not, can allow administration number of times still less.Can obtain more effective therapeutic activity like this and reduce toxicity.
Equally, have been found that bolus of drug compositions of the present invention changes between daytime than the active ingredient plasma concentration that known preparation shows still less, for example, when administration every day 2 times, when 3 times or 4 times.
And the phenomenon that dosage is piled up does not appear in bolus of drug compositions of the present invention.The relative bioavailability of the active ingredient that this bolus of drug compositions produces can not covered by food, thereby the factor that needn't consider diet like this when taking medicine has been improved the medicine effect effect.
Furtherly, because the core coating can for example this situation can occur in the dissolving of acid PH lower part in patient's stomach, the slow release of active ingredient can appear so under one's belt.The slow release rate of this active ingredient also is a kind of constant relatively speed.
Even do not have enough alkali conditions with the gastrointestinal tract that dissolves this intestinal core coating composition in this active ingredient also can be absorbed and used.
Therefore, this active ingredient can be absorbed and used in the absorption region after patient's sphincter of pylorus basically immediately.The general features of this absorption region is that PH is between 1.2 and 5.5.This absorption can occur in small intestinal, but because this absorption will continue for some time, phenomenon therefore also can occur partially absorbing after entering large intestine.
When active ingredient was a kind of morphine compounds, this morphine compounds can be any suitable form.Morphine compounds can be with anhydrous or have the water form to exist.This morphine compounds can be the form of salt, and is as described below
Compound water-soluble degree of separating
Pants health acid morphine 1/20
Low alkali formula phosphoric acid morphine 1/5
Morphine sulfate also is preferred, and especially preferred is Kadian (Zeneca).
Advantage according to lasting release pill compositions of the present invention can be summarized as follows
(I) is in the morphine plasma concentration of steady statue more than or equal to 75% maximal plasma concentration (t＞0.75C
Max) time time of being continued approximately be 3.5 hours or bigger (t＞0.75C
MaxFor MS Contin is 3.5 hours according to reports).
The blood plasma morphine concentration peak value that (II) is in steady statue to the variation of low ebb be between 60-100% (it is reported these of MS Contin change approximately be 300% and for morphine solution per 4 hours be about 200%)
(III) changes between daytime and can reduce
(IV) reduces the degree of morphine absorption or changes the speed that morphine absorbs when taking Shi Buhui jointly with food, and compares with the administration of inhibitory state, and food is unknown to the influence that morphine among the MS Contin absorbs)
Change between the individuality of (V) blood morphine pharmacokinetics and in individual and be reduced
Therefore, a preferred aspect of the present invention has provided a kind of lasting release oral administration pills compositions of morphine compounds, it is diseases related to be used for the treatment of pain in one period persistent period after administration, in at this moment, the morphine haemoconcentration that is in steady statue in the body is greater than 75% maximum haemoconcentration (t＞0.75C
Max) time of being continued approximately is 3.5 hours or longer.
Preferred t＞0.75C
MaxBe about 3.75 to 15 hours or longer, preferred approximately is 6 to 15 hours.
This pill compositions preferably produces a kind of solubility curve that is applicable to this sustained-release composition as defined above in use, it is equal to or greater than the capsule that can utilize the morphine compounds of form immediately that contains equivalent, and tablet or liquid provide the basic as previously mentioned required minimum solubility curve of equivalent bioavailability.
Another preferred aspect of the present invention provides a kind of lasting release oral administration pills compositions of morphine compounds, and it is diseases related to can be used for treating pain in one period persistent period after administration, in this time, reaches the time (t of peak value haemoconcentration in the body
Max) be 4.5 hours or longer, preferably 4.5 to 7.6 hours or longer.
More preferably, this pill compositions in use, can produce a kind of solubility curve that is used for sustained-release composition as defined above, it is equal to or greater than contains equivalent and can utilize capsule, tablet or the liquid of the morphine compounds of form to provide basic equivalent bioavailability as defined above required minimum solubility curve immediately.
Another preferred aspect of the present invention provides a kind of lasting release pill compositions, to be used at a predetermined close and to give patient's administration under the condition at interval, it contains a kind of core composition, this core composition contains at least a active ingredient with at least a thirtieth water solubility of a treatment effective dose, with a kind of coating that is wrapped on the said core composition, it comprises following composition:
(a) matrix polymer of at least 35% weight portion, this polymer is no matter how PH all is insoluble;
(b) 1 to 30% enteric coated polymers, it is insoluble basically under 1 to 4 PH, but is dissolved under 6 to 7.5 PH;
(c) compound is easily dissolved in 1 to 60% dissolved acid under 1 to 4 PH, to be enough to provide the slow release rate of this active ingredient under one's belt.
Said percentage ratio is to be the weight ratio of radix with component (a) and (b) and gross weight (c); The ratio of component (a) and (b) and (c) should reach effect like this so that this active ingredient discharges so that absorb with relative constant rate of release in the said coating in intestinal, make said composition during said predetermined space, send the said active constituent of patient's one treatment effective dose to, thereby the active ingredient haemoconcentration of at least 75% maximum haemoconcentration that remains in steady statue is more than 3 hours, and this active ingredient reaches time that its Cmax continues between about 2 to about 30 hours.
Preferred active ingredient is to be selected from following one group opioid agonist, and it comprises codeine, the salt of loose pain, hydrocodone, hydrogenation morphine, pethidine, methadone, morphine and dextropropoxyphene.
Preferred active ingredient is the morphine chemical compound.
The dissolution velocity of this core coating under highly acid PH will depend on that part acid dissolving composition, PH rely on and the amount of the non-dependence polymer of PH and the thickness of coating.Typical core coating can be in the scope of about 5 to 200 μ m, preferred about 25 to 50 μ m.Therefore, should be understood that thickness and/or component by changing the core coating can change its absorption rate.
Have been found that by changing the dissolution velocity that polymer ratio can change easy soluble drug under the different PH as required.Ternary system polymer of the present invention allows greater flexibility than the binary system polymer of well known in the prior art use.
Enteric coated polymers can be selected from cellulose acetate phthalate, phthalic acid hydroxypropyl methyl-cellulose (HPMCP), poly-phthalic acid acetic acid alkene ester, methacrylic acid copolymer, acetic acid succinic acid hydroxypropyl emthylcellulose, lac, acetic acid trimellitic acid cellulose and their mixture.Particularly preferred enteric coated polymers comprises that the synthetic tree that has carboxyl refers to.Found the methacrylate that trade name " Eudragit L100=55 " is sold: 1: 1 copolymer of ethyl acrylate also is suitable for.
The content of enteric coated polymers is approximately 1 to 60% weight ratio in the coating, preferred 2 to 20% weight ratios, and more preferably 5 to 15% weight portions, the gross weight that this percentage ratio is removed filler and plasticizer with the core coating is a radix.
This part solubility in acid composition can be selected from polymer, as polyvinylpyrrolidone, and hydroxy propyl cellulose, hydroxypropyl methyl fiber, Polyethylene Glycol, polyvinyl alcohol and their monomer are as sugar, salt or organic acid and composition thereof.
The content of this part acidic leach composition in coating can be about 1 to 60% weight ratio, preferred 15 to 40% weight ratios, and 20 to 35% weight ratios more preferably, the gross weight that this percentage ratio is removed filler and plasticizer with the core coating is a radix.
This insoluble matrix polymer can be no matter PH how and largely insoluble any suitable pharmaceutically acceptable polymer.This polymer can be selected from ethyl cellulose, and acrylic acid and/or methacrylate ester polymer or their mixture can use its analog.Can use the acrylate that has low quaternary amine content or the copolymer or the polymer of methacrylate.Found ethyl acrylate: the copolymer of methylmethacrylate (1: 1) is suitable for.
It can be about 1 to 85% weight ratio that the content of this insoluble matrix polymer in coating is wanted, and preferred 35 to 75% weight ratios are more preferably 45 to 65% weight ratios, and this percentage ratio is that the gross weight of removing filler and plasticizer with the core coating is a radix.
This core coating can also comprise at least a plasticizer; With selectable
At least a filler.
Therefore comprise 0 to about 50% weight ratio at a kind of preferred version center pericardium clothing, at least a plasticizer of preferred 2.5 to 30% weight ratios (gross weight with the core coating is a radix), it is selected from diethyl phthalate, triethyl citrate, CitroflexA-2, glycerol triacetate, tributyl citrate, Polyethylene Glycol and glycerol etc.; With
0 to the about 75%(gross weight with coating is a radix) filler, it is selected from insoluble material, as silicon dioxide, titanium dioxide, Talcum, silicon oxide, starch, potter's clay, Pclacrilin Potassium, Powderd cellulose and microcrystalline Cellulose and composition thereof.
Plasticizer can be selected from diethyl phthalate, triethyl citrate, CitroflexA-2, glyceryl triacetate, tributyl citrate, Polyethylene Glycol and glycerol and analog thereof.Be understood that institute's use plasticizer depends on employed polymer in the coated preparation to a great extent, and the compatibility of this plasticizer and coating solution or dispersion liquid.Should be noted that acid or water-soluble plasticizer also can be used as part solubility in acid composition.Plasticity can be used for improving the physical stability of core coating.A kind of particularly preferred plasticizer is a kind of have high-level transmission temperature and/or low-molecular-weight relatively polymer.
The content of plasticizer can be any suitable effective dose.Have been found that gross weight with the core coating is that the consumption of preferred 2.5 to 30% weight ratios of about 0 to 50% weight ratio of radix is suitable.
Filler can be any suitable effective dose.Found gross weight with the core coating be radix 0 to the content of preferred 15 to 60% weight portions of about 75% weight portion more preferably 25 to 45% weight be suitable.
Therefore, preferred one side is that the prescription of this core coating is
Ethyl cellulose 45-60%) % does not comprise
Methacrylate) plasticizer
Ethyl acrylate) and filler
1:1 copolymer 5-15%)
Polyethylene Glycol 20-35%)
Diethyl phthalate 2.5-30%
Talcum 25-45%
Gross weight with the core coating is a radix.
Active ingredient can be any suitable effective amount in the core composition.The consumption of active ingredient depends on the volume of effectiveness and the required dosage intensity and the unit dose of active ingredient in the drug products.Gross weight with the core composition is a radix, and the content of active ingredient approximately is 0.1 to 95% weight portion.Preferably a kind of morphine compounds of active ingredient.The content of morphine compounds is 10 to 60% weight portions during radix calculates approximately with core composition gross weight.With the gross weight of core composition is that the content that radix calculates binding agent approximately is 0.1 to 45% weight portion, preferred 0.1 to 20% weight portion.
Binding agent can be any suitable type.Suitable bonding is selected from polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, methylcellulose and hydroxyethyl-cellulose, sugar and composition thereof.Binding agent can be to provide with the particle solution form.Can comprise a kind of water or organic solvent.Can use methanol, ethanol or their mixture as solvent.
According to the amount of the active ingredient that comprises in the core, the size of this core heart seed and consumption change between about 100 μ m to 1700 μ m substantially.Therefore, according to the effectiveness of active ingredient, be radix with the gross weight of core composition, this core heart seed size changes between preferred 40 to 90% weight portions at about 5 to 99% weight portions.The diameter of this core heart seed should make final core composition diameter between about 200 to 2000 μ m.
Core heart seed can be any suitable type, can use a kind of sugared heart seed or a kind of active heart seed.
This core composition can further include other carrier or excipient, filler, stabilizing agent and coloring agent.Suitable filler can be to be selected from non-soluble substance such as silicon dioxide, Talcum, titanium dioxide, aluminium oxide, starch, Kaolin, Polacrilin Potassium, Powderd cellulose and microcrystalline Cellulose and composition thereof.The solubility filler can be to be selected from mannitol, sucrose, lactose, glucose, sodium chloride, sorbitol and composition thereof.
In a preferred version of the present invention, this core composition comprises at least a morphine compounds of an effective dose; Optionally comprise
At least a core heart seed; With
At least a binding agent.
This core composition can have following prescription
Hydroxypropyl emthylcellulose 0.1 to 10% weight portion
Perhaps this core composition has following prescription
Polyvinylpyrrolidone 2.5 to 10% weight portions
This core coated composition can be a solution, the form of dispersion liquid or suspension.
In solution dosage, the content of solvent is that radix calculating can be about 25 to 97% weight portions with the gross weight of core coated composition, preferred 85-97%.The solvent that is used for polymer can be a kind of solvent as water, methanol, ethanol, dichloromethane and composition thereof.
In dispersion liquid or suspension dosage form, it is preferred 75～97% that the content of this dilution media is with the gross weight of core coated composition that radix is calculated as about 25 to 97% weight portions, and it mainly is to comprise water.
Can prepare typical core coated preparation by following combination part content:
The core coated preparation
A. non-dissolubility matrix polymer 45-65%) % does not comprise
Enteric polymer 4-10%) % solvent and filler
Solubility in acid polymer 15-35%)
Plasticizer 4-30%
The total coated preparation of solvent 85-97%
B. non-dissolubility matrix polymer 45-65%) % do not comprise solvent and
Filler
Enteric coated polymers 4-15%)
Solubility in acid polymer 15-35%)
Plasticizer 4-30%
The total coated preparation of dilution solvent 75-97%
Perhaps, also can optionally add the filler that is no more than core coated preparation 50% outside desolventizing.Can use standard techniques to produce the pill of this coating, for example in the method described in the Australian Patent 617,573, whole disclosures that this paper has quoted this patent as a reference.
Can be according to employed similar dosage in the prior art with lasting release bolus of drug compositions of the present invention administration.
Many pimpled rubber wafer of sustained release form can be administered once by per 8 hours to 24 hours.
Another preferred aspect of the present invention has provided a kind of bolus of drug compositions that is combined with morphine compounds, if administration every day 2 times or 3 times or 4 times alleviating pain effectively.Various dosage such as 10mg, 20mg, 50mg, 100mg, 200mg, 500mg or any other required dose intensity capsule all can make.
This drug particles compositions can be many granules capsule, XIANGFEN agent, tablet.
According to a further aspect in the invention, provide a kind of diseases related method of pain for the treatment of to the patient who needs this treatment.This method comprises the lasting release drug particles compositions of using a kind of effective dose to patient, comprises
A kind of core composition, it comprises at least aly having water solubility and be at least 1/30 morphine compounds; With
A kind of core coating that wraps up this core composition, it is partly soluble under strong acid PH, wherein Bao Guo morphine compounds can discharge a period of time for absorbing with constant relatively speed in intestinal, makes the haemoconcentration of morphine remain in the therapeutic domain in a period of time.
In this respect Therapeutic Method is particularly useful for treating acute and chronic pain according to the present invention, particularly pain dependency later stage disorders such as cancers and chronic back pain and postoperative pain.
Preferred medicine sustained-release composition provides with unit dosage form, and with about 8 to 24 hours interval administration.
To be described in more detail the present invention with embodiment below, but should be noted that following description, and should not limit above-mentioned the present invention in any form on the whole just in order to explain the present invention.
1. fill a prescription 1
Kadian (Zeneca) 194g
Core heart seed (sugared heart seed) 170g
Polyvinylpyrrolidone 37g
Ethanol 185g
Mix core coating component 1
Polyethylene Glycol 12g
Ethyl cellulose 25g
Diethyl phthalate 2g
Methacrylic acid: acrylic acid
1: 1 copolymer 5g of ethyl ester
Talcum 22g
Ethanol 667g
2. fill a prescription 2
Kadian (Zeneca) 194g
Core heart seed (sugared heart seed) 170g
Polyvinylpyrrolidone 37g
Ethanol 185g
Various core coating components 2
Polyethylene Glycol 25g
Ethyl cellulose 41g
Diethyl phthalate 3g
Methacrylic acid: acrylic acid
1: 1 copolymer 4g of ethyl ester
Talcum 37g
Ethanol 1106g
3. fill a prescription 3
Core component 3
Kadian (Zeneca) 364g
Core heart seed (sugared heart seed) 733g
Hydroxypropyl emthylcellulose 14g
Ethanol 986g
Various blended core coating components 3
Polyethylene Glycol 47g
Ethyl cellulose 90g
Diethyl phthalate 19g
Methacrylic acid: acrylic acid
1: 1 copolymer 20g of ethyl ester
Talcum 88g
Ethanol 2509g
4. fill a prescription 4
Kadian (Zeneca) 1796g
Core heart seed (sugared heart seed) 6167g
Hydroxypropyl emthylcellulose 90g
Ethyl cellulose 644g
Polyethylene Glycol 230g
Eudragit L100-55 187g
Diethyl phthalate 131g
Talcum 625g
Spherical (Spheronised) core preparation (core component 1 and 2)
Core heart seed is placed balling machine (Spheronised), and the drying composite with a kind of active ingredient and inactive excipient wraps up this heart seed then, and simultaneous adds a kind of binder component solution.
The wet core that will so form then fluidizing drying bed dry one hour.
Rotation coating core preparation (core component 3 and 4)
This core heart seed is placed a kind of rotating fluidized bed machine, and suspension or the solution with a kind of active constituent and inactive excipient wraps up this core heart seed then, and said excipient comprises the binding agent of at least a suitable liquid form.So the wet core that forms was a kind of suitable drying 1 hour.
Preparation of granules
(a) exsiccant spherical core 1 and 2 is placed a kind of fluidized bed coating equipment. Core coating component 1 and 2 with mixture is sprayed onto on core 1 and 2 to form preparation 1 and 2 pills respectively then.When the method finishes, that piller is dry on fluid bed.
(b) exsiccant core 3 and 4 is placed on the fluid bed or traditional fluidized bed coating equipment of rotation.Then blended core coating component 3 and 4 is sprayed onto and forms preparation 3 pillers on core 3 and 4.
Use test method USP * * II 1990(experiment 711) pellet composition 1,2 and 3 is dissolved test.Sample is dissolved in the aqueous vehicles of degasification in advance and balance to 37 ℃.This solvent is USP PH 1.2 solvents and the PH7.5 phosphate buffer that does not contain ester.From the container of defined, when specified time interval, extract the sample of known volume, and test by suitable method of testing.The mg number and the function of time of morphine sulfate are depicted as curve as solubility curve.
This test is carried out under PH1.2 and PH7.5 condition.
The container that will contain sample is rotated with about 50r.p.m, and keeps aqueous vehicles at about 37 ℃.
The results are shown in table 1 to 6 and Fig. 1 to 6.Preparation 1 is shown in table 1 and 2 respectively at PH1.2 and 7.5 times measured results.Dissolving can appear in the mixing coating of parcel preparation 1 piller when PH1.2, can be observed the dissolution velocity of remarkable quickening when PH7.5.Preparation 2 pillers are shown in 3 and 4 respectively at PH1.2 and the result that obtains for 7.5 times, and they are similar to the result who obtains from compositions A.
The result who is recorded by preparation 3 pillers is similar to the result that preparation 1 records under PH7.5.But the presentation of results that preparation 3 is measured release significant prolongation that should the stage.
Table 1 preparation 1 is in the dissolution data (average datas of three samples) of PH1.2
Time (minute) the mg SD % release rate SD that discharges
30 0.00 0.00 0.00 0.00
60 2.29 0.09 4.04 0.15
120 8.43 0.18 14.88 0.28
180 14.66 0.39 25.87 0.71
The dissolution data (three increments originally average) of table 2 preparation 1 under PH7.5
The mg SD % release rate SD that time (branch) discharges
30 1.85 0.09 3.28 0.17
60 9.03 0.25 16.07 0.45
120 23.20 0.42 41.29 0.77
180 35.39 0.50 63.00 1.01
The dissolution data (three increments originally average data) of table 3 preparation 2 under the PH1.2 condition
The mg SD % release rate SD that time (branch) discharges
30 1.64 0.00 3.22 0.01
60 6.26 0.09 12.25 0.16
120 20.24 0.18 39.63 0.46
180 36.39 0.27 71.27 0.72
240 47.47 0.49 92.97 1.12
The dissolution data (three increments originally average data) of table 4 preparation 2 under PH1.5
The mg SD % release rate SD that time (branch) discharges
30 2.63 0.00 5.12 0.03
60 8.69 0.09 16.94 0.11
120 21.62 0.33 42.13 0.40
180 33.66 0.59 65.60 0.79
240 42.47 0.82 82.78 1.13
The dissolution data (three increments originally average data) of table 5 preparation 3 under PH1.2
The mg SD % release rate SD that time (branch) discharges
30 1.44 0.39 2.12 0.53
60 3.03 0.33 4.48 0.39
120 6.78 0.30 10.03 0.36
180 10.17 0.18 15.04 0.34
240 13.87 0.41 20.51 0.29
300 17.45 0.31 25.81 0.30
360 21.29 0.21 31.49 0.27
420 24.75 0.32 36.62 0.46
480 28.60 0.64 42.30 0.37
540 32.63 0.42 48.28 0.45
600 35.80 0.92 52.95 0.37
24 hours 67.60 1.26 100.04 3.79
The dissolution data (three increments originally average) of table 6 preparation 3 under PH7.5
The mg SD % release rate SD that time (branch) discharges
30 2.19 0.11 3.23 0.17
60 7.05 0.89 10.38 1.26
120 18.07 1.05 26.63 1.44
180 28.12 1.03 41.44 1.35
240 37.86 1.05 55.80 1.32
300 47.60 1.48 70.16 1.96
360 56.33 0.54 83.03 0.47
420 63.03 2.01 92.90 2.76
480 65.97 0.61 97.23 0.75
540 69.13 0.41 101.89 0.79
600 70.20 0.43 103.47 0.45
24 hours 74.76 2.36 110.19 3.04
The SD=standard deviation
On one's body two lasting morphine compositionss that discharge of the present invention are tested in the patient's (feed and fasting) and the healthy premenopausal volunteers (fasting) of backache.The result of these tests show Faulding existing a kind of than coml product MS Contin at more superior product aspect the morphine sustained delivery.And food studied the influence that morphine absorbs.
Lasting release oral Morphine compositions called after preparation 1 of the present invention and preparation 2.
1.A part
6 patients that suffer from the chronic pain disease under fasted conditions, carry out on one's body a kind of single dose 3 by way of crossing research.In three times in the week of being separated by, patient accepts a 50mg oral Morphine dosage, can be that a kind of solution (with reference to dosage form) or two kinds of conducts are wrapped in one of extended release preparation of piller in the capsule (called after preparation 1, a kind of PH dependent release formulation; With preparation 2, a kind of PH dependent/non-dependent delivery formulations).Administration after through the fasting at a night.Extracting vein blood sample during specified time interval after administration was being got blood in 30 hours after the administration and the pharmaceutical solutions of reference was being got blood in 10 hours after administration extended release preparation.Use the high pressure liquid chromatographic analysis (HPLC) of charged chemical detection that morphine concentration in the blood sample is carried out quantitative assay.Table 3.1 has been summarized the average area under the curve (AUC); C
Max(maximum haemoconcentration), T
Max(reaching the time of peak value haemoconcentration); The significant terminal half-life of T1/2(); T 〉=0.75C
Max(haemoconcentration is greater than 75%C
MaxTime) and relative bioavailability (F%).
This result shows that preparation 1 and preparation 2 all provide lasting release with respect to reference solution, and this can be estimated by following data:
(1) C of preparation
MaxLower;
(2) T of preparation
MaxLonger; With
(3) morphine concentration reaches and is higher than 0.75C in the blood of preparation
MaxTime longer.
The C of each preparation compares with reference solution
MaxValue has significant reduction.Average (± SD) the C of this solution
MaxBe 73.6 ± 30.9ng/ml and the analog value of preparation 1 and 2 is respectively 21.6 ± 7.1ng/ml and 23.2 ± 4.8ng/ml.Preparation of representing with variation coefficient 1 and 2 C
MaxTransmutability is significantly less than the solution transmutability of same patient.
Compare the T of said preparation with the numerical value that obtains with reference solution
MaxValue significantly increases.Should be average for solution (± SD) T
MaxIt is 1.07 ± 1.09 hours and be respectively 5.33 ± 1.2 hours and 4.25 ± 1.33 hours with 2 identical value for preparation 1.For preparation T
MaxThe transmutability of value is less than the T that obtains with solution in the same patient
MaxValue.
For preparation of the present invention, the blood morphine concentration is more than or equal to 0.75C
MaxTime obviously greater than time of reference solution dosage, for average time of preparation 1 be 190 minutes, and to the time of preparation 2 be 237 minutes, Comparatively speaking, have only 59 minutes with reference to the time of solution.Represent these data with the percentage ratio of reference solution time, morphine concentration is greater than 0.75C in the blood
MaxTime for solution, preparation 1 is 322% and preparation 2 had for 400% longer time.
By not having significant difference (table 3.1) between preparation and the AUC with reference to the solution acquisition.
Calculate the relative bioavailability of each patient by the AUC of appropriate formulation with ratio to preparation with reference to the AUC of solution.For the relative bioavailability of preparation 1 is 83.5% and be 102.6% to preparation 2.
AUC shows that with the relative bioavailability data degree of absorption of three kinds of different preparation morphines is similar, and C
Max, T
MaxAnd T 〉=0.75C
MaxData show that preparation of the present invention shows a kind of slow and prolongation absorption of typical case of real extended release preparation.
The result of table 3.1A part Study
The observed average of average average is observed
DIFF DIFF
AUC 199.77 170.72 -29.05 193.77 -6.0
(ng.h/mL)
SD ±66.32 ±86.3 ±46.35
CV% 33 51 24
C
max73.57 21.60 -52.0 23.16 -50.4
(ng/mL)
SD ±30.92 ±7.12 ±4.76
CV% 42 33 21
T
max1.07 5.33 4.26 4.25 3.18
(hour)
SD ±1.1 ±1.21 ±1.33
CV% 103 23 31
Bioavailability 100.0 83.53-16.47 102.62 2.62
(F%)
SD ±0.00 ±27.87 ±25.77
T
1/23.02 6.58 3.56 7.65 4.63
(hour)
SD ±1.97 ±5.33 ±5.59
CV% 65 81 73
t
≥0.75Cmax59.0 189.8 130.8 237.3 178.3
(minute)
SD ±37 ±76 ±95
CV% 63 40 40
2./B part
Under the feed condition, carry out a kind of single dose 3 approach crossing research on one's body 6 patients that suffer from chronic pain.Partly use identical patient in the A of this research part with B.In three times in 1 week of being separated by, patient accepts a kind of 50mg oral Morphine medicament, and preparation can be a kind of solution (with reference to dosage form) or be wrapped in one of two kinds of extended release preparations of particle form in the capsule (called after preparation 1, a kind of PH dependent release formulation; With preparation 2, a kind of PH dependent/non-dependent releasing agent).Administration after overnight fast.Specified time interval behind dosed administration is taked venous samples can, and administration was got blood after 10 hours for getting blood in 30 hours after the extended release preparation administration and to reference solution.Use the morphine concentration in high pressure liquid chromatographic analysis (HPLC) the quantitative assay blood sample of charged chemical detection.Table 3.2 has been summarized the average area under the curve (AUC); C
Max(maximum blood level); T
Max(reaching the time of peak value blood concentration); T 〉=0.75C
Max(blood concentration is greater than 75%C
MaxTime) and relative bioavailability (F%).
Having the result in the presence of the food to show that preparation 1 and 2 provides a kind of lasting release with respect to reference solution, this can be estimated by following situation:
(1) C of preparation
MaxLower;
(2) T of preparation
MaxLonger; With
(3) concerning preparation in the blood morphine concentration greater than 0.75C
MaxTime longer.
Compare the C of every kind of preparation with reference solution
MaxValue significantly reduces.Average (± SD) the C of solution
MaxBe 80.7 ± 26.4ng/ml and the respective value of preparation 1 and preparation 2 is respectively 22.0 ± 8.1ng/ml(and 32.6 ± 18.1ng/ml.Preparation of representing with variation coefficient 1 and 2 C
MaxTransmutability is similar to all preparations.The C of the every kind of preparation that obtains under the condition on the feed
MaxValue is similar to the C that (A part) same patient obtains under fasted conditions
MaxValue.
The T of preparation of the present invention for using the numerical value that obtains with reference to solution
MaxValue significantly increases.Average (± SD) T to solution
MaxIt is 1.32 ± 1.65 hours and be respectively 5.83 ± 0.75 and 4.5 ± 0.84 hours for the identical numerical value of preparation 1 and preparation 2.T for preparation of the present invention
MaxThe value transmutability is less than the numerical value that obtains with solution.Concerning every kind of preparation on the feed with the T of fasted conditions
MaxValue is similar.
With the reference solution dosage Comparatively speaking, morphine concentration is more than or equal to 0.75C in the blood of preparation of the present invention
MaxTime obviously increase.For average time of preparation 1 be 231.2 minutes and for time of preparation 2 be 168.5 minutes, Comparatively speaking, have only 52.5 minutes with reference to solution.Represent these data with the percent of reference solution time, compare that morphine concentration is greater than 0.75C in the blood with reference solution
MaxTime preparation 1 be 443% and preparation 2 had for 323% longer time.For every kind of preparation, on the feed with fasted conditions under greater than 0.75C
MaxTime data be similar.
Under the condition, obtain between the AUC significant difference (table 3.2) is arranged on the feed, have bigger AUC than arbitrary preparation with reference to solution by the AUC of said preparation acquisition with by reference solution.Average area is closely similar concerning preparation, and the meansigma methods of preparation 1 and preparation 2 is respectively 204.13 ± 106.11ng.h/ml and 225.09 ± 138.52ng.h/ml.The average A UC of solution is 281.98 ± 112.58ng.h/ml under the condition on the feed.As represented by variation coefficient, it is similar all changing between the AUC individuality between the preparation.
On the feed with fasted conditions under the AUC data that obtain comparison shows that the AUC with reference to solution that represents with feed/fasting ratio is a 1.41(scope 0.94 to 1.9), have only a patient bigger than Board Lot.A kind of similar trend is arranged for preparation, and that is exactly that the identical value that obtains than under fasting state as the average A UC that is obtained during drug-delivery preparation immediately after the meal is big.
A basic conception can be arranged, and promptly " dosage accumulation " can not appear in every kind of preparation.Data show that the bioavailability of morphine in the situation preparation that has food to exist equals at least and might be greater than the bioavailability of same preparation under fasting state, and preparation is similar to the performance of solution aspect the influence that morphine is absorbed at food.
The relative bioavailability of preparation is with respect to the bioavailability that reference solution obtains: preparation 1 is 79.4% and preparation 2 is 78.2%.
AUC and relative bioavailability data show that the morphine degree of absorption of preparation is similar to but are slightly littler than the solution under the feed state, and C
Max, T
MaxAnd T 〉=0.75C
MaxData show that preparation has shown a kind of slow and prolongation absorption of typical case of real extended release preparation.
The result of table 3.2B part Study
The observed meansigma methods of meansigma methods meansigma methods is observed
DIFF DIFF
AUC 281.98 204.13 -77.85 225.09 -56.89
(ng.h/mL)
SD ±112.58 ±106.11 ±138.52
C
max80.66 22.00 -58.66 32.63 -48.03
(ng/mL)
SD ±26.44 ±8.05 ±18.07
CV% 33 37 55
T
max1.32 5.83 4.51 4.50 3.18
(hour)
SD ±1.65 ±0.75 ±0.84
CV% 125 13 19
Bioavailability 100.0 79.4-20.6 78.2-21.8
(F%)
SD ±0.00 ±47.3 ±27.1
t
≥0.75Camx52.2 231.2 179.0 168.5 116.3
(minute)
SD ≥39.3 ≥73.9 ≥55.5
CV% 75 32 33
Embodiment 3
It is two by way of crossing research to carry out a kind of single dose on one's body 8 adult patients that suffer from chronic pain dependency disease in non-latter stage.All research dosage are to take under fasting, and in fasting in preceding 12 hours of each conceptual phase.The average data representative is by 8 clothes patient and 9 data that formulation 3 capsular patients obtain with reference to solution.
In two times in the week of being separated by, volunteer is accepted the oral Morphine of a 100mg dosage, at solution or a kind of lasting release particles preparation (preparation 3, a kind of PH dependent release formulation) that is wrapped in the capsule of 0.4 and 8 hour administration 33.33mg dosage.This capsule formulation is obeyed 200ml water when administration, and 4 hours and the liquid of obeying 200ml in 8 hours again reflect the Liquid Absorption of morphine solution dosage after administration.The administration of morphine solution dosage (100mg) was to give three equal 33.33mg dosage at 0.4 and 8 hour, and the clothes cumulative volume is a 200ml liquid when each administration.18 hours special time and 32 hours collection venous blood after the extended release preparation administration before administration and after the first time of three oral administration solution dosage.Use the morphine concentration in high pressure liquid chromatographic analysis (HPLC) the quantitative Analysis research blood sample of charged chemical detection.Table 4.1 has been summarized the average area (AUC) under 0 to 18 hour concentration and the time graph; C
Max(maximum observed blood concentration); T
Max(reaching the time of maximum observed blood concentration); T 〉=
0.75Cmax(maximum observed blood concentration is more than or equal to 75%C
MaxTime) and relative bioavailability (F%).
Result of study shows that under fasted conditions, the administration of test products preparation 3 provides a kind of and discharged constantly with respect to reference solution, and this can be estimated by following content:
(1) C of preparation 3
MaxBe worth lower;
(2) T of preparation 3
MaxBe worth longer; With
(3) T of preparation 3 〉=
0.75CmaxParameter value is longer.
The C of preparation 3 compares with reference solution
MaxValue significantly reduces, the meansigma methods of preparation 3 and solution (± SD) be respectively (34.24 ± 12.25) ng/ml and (157.72 ± 59.76) ng/ml.The C of this solution
MaxValue is thought C after first time of three solution dosed administrations
MaxThe value three times.The preparation of representing with variation coefficient 3 and the C of solution
MaxTransmutability is minimum for two products.
For each solution administration obtains numerical value, the T that preparation 3 obtains
MaxValue has remarkable increase.Average (± SD) the T of solution
MaxBe that (0.63 ± 0.23) hour and preparation 3 are (7.67 ± 2.06) hour.Preparation 3T
MaxThe value (27% to 37%) that the transmutability of value obtains less than solution.
Maximum observed blood concentration is more than or equal to 0.75C
MaxAverage time be 6.25 hours to preparation 3, show that this product is that enough lasting release characteristics are arranged.
Reference solution and preparation 3 AUC(0 to 18 hour) there is not significant difference (table 4.1) between the value.
Relative bioavailability with respect to the preparation 3 of reference solution is (102.06%), shows that the morphine degree of absorption of preparation 3 is enough.
The T that after preparation 3 administrations, obtains
MaxAnd T＞0.75
CmaxThe value explanation under fasted conditions, is compared with the characteristic of preparation 2 with first kind of prototype formulations 1, and preparation 3 has the lasting release characteristics of improvement.Curve for preparation 3 concentration and time average numerical value has also confirmed this viewpoint.
The meansigma methods as a result of table 4.1 fasting research
The parameter pharmaceutical solutions
The meansigma methods meansigma methods is observed
(n=8) (n=9) difference
AUC(0-18h) 374.21 361.03 -13.18
(ng.h/mL)
SD 155.52 131.94
CV% 42 37
C
max157.72 34.24 -123.48
(ng/mL)
SD 59/76 12.25
CV% 38 36
T
max0.63 7.67 7.04
(h)
SD 0.23 2.06
CV% 37 27
Bioavailability 100.0 102.06 2.06
(F%)
SD 0.00 18.47
t
1/23.48 5.77 2.29
(h)
SD 2.20 3.70
CV% 63 64
t
≥0.75CmaxNA 6.25 NA
(h)
SD 1.28
NA=does not survey
Carry out a kind of at random, the 3-phase, open-label research is with more following steady statue pharmacokinetics:
(A) oral rapid release OMS Concentrate;
(B) oral preparation of the present invention 4;
(C) oral sustained release morphine sulfate tablet (MSC Continus
).
50 patients in the research live through medium patient to serious carcinous stable pain.In the middle of these 50 patients, 34 be random packet and 24 patients have finished research.After random packet, there are 10 patients to withdraw from.
Suitable patient begins to accept solution (A) at least in 8 days per 4 hours at preliminary stage.Dosage level transfers to the energy pain management, and keeps a constant level at least three days these stages.
At overlaping stages, all patients accepted capsule (B) in per 12 hours, accepted solution (A) in per 4 hours and accepted tablet (C) in per 12 hours, took 7 days with a kind of interleaved mode at random.24 hours dosage levels with in the middle of last three days of preliminary stage, provide enough pain relief desired level identical.
The result
A B C
C
max(μg.L) 48.3 32.1 42.3
T
max(H
r) 0.7 5.7 3.4
AUC(μg-H
r/L) 268 298 272
C
min(μg/L) 12.4 17.7 9.2
t
≥0.75Cmax- 9.14 3.12
*Fluct 1 3.70 0.91 4.27
** 2 1.73 0.60 1.51
* Fluct1 is (C
Max-C
Min)/C
Min
* Fluct2 is (C
Max-C
Min)/AV concentration
Figure1 represents the morphine blood plasma level of preliminary stage
0-12 hour expansion among Figure2-Fig. 1
Conclusion
(ⅰ) A, B are similar with the AUC value of morphine among the C;
(ⅱ) preparation of the present invention shows a kind of real lasting release profiles, also, and t 〉=
0.75CmaxBe more than 9 hours, compare that low-down fluctuation index is arranged with the data that discharge solution (A) and MSC tablet (C) immediately.
At last, should be understood that under the situation that does not deviate from spirit of the present invention as described herein and can carry out various other modifications and variations the present invention.
Claims (29)
1, a kind of lasting release medicine pellet composition comprises
A kind of core composition, this composition comprise at least a active ingredient with at least 1/30 water solubility; With
A kind of core coating of this core composition, it is partly soluble under highly acid PH, and active ingredient wherein continues for some time for absorption with a kind of constant relatively speed release in intestinal.
2, according to the lasting release medicine pellet composition of claim 1, active ingredient wherein is a kind of following one group opioid agonist that is selected from, and comprises the salt of codeine, diffusing pain, dihydrocodeinone, hydrogenation morphine, pethidine, methadone, morphine and the third oxygen sweet smell.
3, according to a kind of lasting release medicine pellet composition of claim 2, active ingredient wherein is the morphine chemical compound.
4, according to a kind of lasting release medicine pellet composition of claim 2, core coating wherein produces a kind of solubility curve that is used for this sustained-release composition as defined above in use, and it is equal to or greater than contains equivalent and can utilize capsule, tablet or the liquid of form active ingredient to provide basic identical bioavailability as defined above required minimum solubility curve immediately.
5, according to a kind of lasting release medicine pellet composition of claim 4, wherein under near the PH level conditions of stomach, measure first solubility curve, near intestinal, measure second solubility curve under more at least the PH level; First and second solubility curves of this sustained-release composition are equal to or can utilize capsule, tablet or the liquid of form active ingredient to provide basic identical bioavailability required minimum solubility curve immediately greater than containing equivalent.
6, according to a kind of lasting release medicine pellet composition of claim 5, the active ingredient plasma concentration that compositions wherein is in steady statue with respect to the active ingredient of coating form not in use shows fluctuation seldom in during 24 hours, and/or active ingredient plasma concentration of the present invention shows between less daytime and changes for capsule that contains the sustained release form active ingredient in the prior art or tablet.
7, a kind of being used for to patient with the predetermined close and the lasting release medicine pellet composition of administration at interval, it comprises a kind of at least a core composition with active ingredient of at least 1/30 water solubility for the treatment of effective dose that contains, with a kind of coating composition that is wrapped on the said core composition, this coating composition comprises following composition:
(a) matrix polymer of at least 35% weight ratio, it is non-PH dependency insoluble matter;
(b) 1 to 30% enteric coated polymers, it is insoluble basically under 1 to 4 PH, but is dissolved under 6 to 7.5PH;
(c) 1 to 60% soluble solubility in acid chemical compound under PH1-4, it can provide the slow release rate of active ingredient under one's belt;
Said percentage ratio is that the gross weight with component (a) and (b), (c) is the percentage ratio of radix; The ratio of component (a) and (b), (c) should reach effect like this so that this active ingredient discharges for absorption with a constant relatively speed in the said coating in intestinal, thereby make said composition during said predetermined space, send a kind of said active ingredient for the treatment of effective dose of patient to, with the active ingredient blood level that keeps steady statue at least 75% maximum haemoconcentration (T＞0.75
Max) about 3.5 hours or longer, and this active ingredient reaches the time (TC of its Cmax
Max) be 4.5 hours or longer.
8, a kind of lasting release medicine pellet composition according to claim 7, active ingredient wherein is a kind of following one group opioid agonist that is selected from, and comprises the salt of codeine, diffusing pain, dihydrocodeinone, hydrogenation morphine, pethidine, methadone, morphine and the third oxygen sweet smell.
9, a kind of lasting release medicine pellet composition according to Claim 8, active ingredient wherein is a kind of morphine compounds.
10, a kind of lasting release medicine pellet composition according to claim 9, coating wherein contains:
As ethyl cellulose, the acrylate polymer of component (a), metering system ester polymer, a kind of ethyl acrylate: methyl methacrylate (1: 1) copolymer, or its mixture;
Cellulose acetate phthalate as component (b), Hydroxypropyl Methylcellulose Phathalate, poly-acetic acid O-phthalic vinyl acetate, methacrylic acid: 1: 1 copolymer of ethyl acrylate, HPMC-AS, Lac, acetic acid benzenetricarboxylic acid cellulose and composition thereof; With
As the polyvinylpyrrolidone of component (c), hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Polyethylene Glycol, polyvinyl alcohol and their monomer and composition thereof.
11, a kind of lasting release medicine pellet composition according to claim 10, coating wherein comprises
The insoluble matrix polymer of about 35 to 75% weight ratios;
The enteric polymer of about 2 to 30% weight ratios; With
The part solubility in acid composition of about 15 to 40% weight ratios.
12, a kind of medicine of unit dosage form continues release products, comprises many piller granules, and each piller granule comprises
A core composition, it comprises at least a active ingredient with at least 1/30 water solubility; With
A kind of core coating that is used for this core composition, it dissolves in highly acid PH lower part, and active ingredient wherein discharges a period of time for absorption with a constant relatively speed in intestinal, make the blood level of active ingredient remain in the therapeutic domain in a period of time.
13, a kind of lasting release medicine pellet composition comprises
A kind of core composition that contains morphine compounds; With
A kind of core coating that is used for this core, it dissolves in highly acid PH lower part, and morphine compounds wherein continues for some time for absorption with a kind of constant relatively speed release in intestinal, makes the blood level of morphine remain in the therapeutic domain in a period of time.
14, a kind of lasting release medicine pellet composition according to claim 13, morphine compounds wherein is a kind of morphine sulfate chemical compound.
15, a kind of lasting release medicine pellet composition according to claim 13, said composition wherein, morphine compounds with respect to sustained release form in the prior art, in use, the plasma concentration that is in the morphine compounds of steady statue showed less fluctuation during 24 hours, and/or showed less plasma concentration the morphine compounds of sustained release form change between daytime in prior art.
16, a kind of oral pellet composition of lasting release of morphine compounds, it is diseases related that it can be used for the treatment of pain in a period of time after administration, wherein, the morphine compounds blood level is under the steady statue time (T＞0.75C greater than 75% maximum blood level in vivo
Max) approximately be 3.5 hours or longer.
17, a kind of oral pellet composition of lasting release, wherein this T＞0.75C according to claim 16
MaxIt approximately is 3.75 to 15 hours or longer.
18, according to the oral pellet composition of a kind of lasting release of claim 17, T＞0.75C wherein
MaxIt approximately is 6 to 15 hours.
19, according to the oral pellet composition of a kind of lasting release of claim 16, wherein this pellet composition can produce a kind of solubility curve that is used for sustained-release composition as defined above in use, it is equal to or greater than contains the capsule that equivalent can be utilized the form morphine compounds immediately, and tablet or liquid provide basic identical bioavailability as defined above required minimum solubility curve.
20, according to the oral pellet composition of a kind of lasting release of claim 19, wherein said composition compare with the morphine compounds of coating form not in use the less fluctuation that shows 24 hours steady statue morphine compounds plasma concentration and/or with prior art in contain the capsule of sustained release form of morphine compounds or tablet and compare between the less daytime that shows plasma concentration and change.
21, a kind of oral pellet composition of lasting release of morphine compounds, it can be used for the treatment of pain in a period of time after administration diseases related, wherein, reaches the time (T of peak value blood level in vivo
Max) be 4.5 hours or longer.
22, according to the oral pellet composition of a kind of lasting release of claim 21, T wherein
MaxIt is 4.5 to 7.6 hours.
23, according to the oral pellet composition of a kind of lasting release of claim 22, wherein pellet composition produces a kind of solubility curve that is used for sustained-release composition as defined above in use, and it is equal to or greater than contains equivalent and can utilize capsule, tablet or the liquid of form morphine compounds to provide basic identical bioavailability as defined above required minimum solubility curve immediately.
24, a kind of oral pellet composition of lasting release according to claim 23, wherein said composition shows the less fluctuation of morphine compounds plasma concentration of 24 hours steady statues and/or shows less plasma concentration with respect to the capsule of the sustained release form that contains morphine compounds in the prior art or tablet and change between daytime in use for the morphine compounds of coating form not.
25, a kind of patient to this treatment of needs treats the diseases related method of pain, this method comprises the lasting release pilule compositions that uses an effective dose to patient, comprises a kind of at least a core composition with morphine compounds of at least 1/30 water solubility that contains; With
A kind of core coating composition of this core, it dissolves in highly acid PH lower part, morphine compounds wherein continues for some time for absorption with a kind of constant relatively speed release in intestinal, makes the blood level of morphine remain in the therapeutic domain in a period of time.
26, a kind of method according to claim 25, pain wherein is diseases related to be related to acute and treatment chronic pain.
27, a kind of method according to claim 26, lasting release medicine pellet composition wherein provides with unit dosage form, and in about 8 to 24 hours interval administration.
28, a kind of oral pellet composition of lasting release that is used for the diseases related morphine compounds of after administration a period of time internal therapy pain, wherein, in vivo, the morphine blood level is in steady statue (T＞0.75max) approximately is 9 hours or longer greater than time of 75% maximum blood level.
29, a kind of lasting release medicine pellet composition comprises
A kind of core composition comprises
The morphine compounds of about 10-25%;
The core heart seed of about 65-89.9% weight ratio; With
A kind of binding agent of about 0.1% to 10% weight ratio; With
A kind of core coating that is used for the core composition, it is in the dissolving of highly acid PH lower part, and wherein active ingredient discharges for absorption in a period of time with a kind of constant relatively speed in intestinal.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU41654/93A AU668174C (en) | 1993-06-30 | Sustained release pharmaceutical composition | |
| AU41654/93 | 1993-06-30 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA021219125A Division CN1468597A (en) | 1993-06-30 | 2002-05-24 | Continuous released medical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1107331A true CN1107331A (en) | 1995-08-30 |
Family
ID=3729020
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 94115992 Pending CN1107331A (en) | 1993-06-30 | 1994-06-30 | Sustained release pharmaceutical composition |
| CNA021219125A Pending CN1468597A (en) | 1993-06-30 | 2002-05-24 | Continuous released medical composition |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA021219125A Pending CN1468597A (en) | 1993-06-30 | 2002-05-24 | Continuous released medical composition |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN1107331A (en) |
| NZ (1) | NZ248166A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104983709A (en) * | 2015-07-07 | 2015-10-21 | 成都智加鑫医药科技有限公司 | Novel metformin hydrochloride solid medicinal preparation and preparation method thereof |
-
1993
- 1993-07-16 NZ NZ24816693A patent/NZ248166A/en unknown
-
1994
- 1994-06-30 CN CN 94115992 patent/CN1107331A/en active Pending
-
2002
- 2002-05-24 CN CNA021219125A patent/CN1468597A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104983709A (en) * | 2015-07-07 | 2015-10-21 | 成都智加鑫医药科技有限公司 | Novel metformin hydrochloride solid medicinal preparation and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1468597A (en) | 2004-01-21 |
| AU4165493A (en) | 1995-02-16 |
| NZ248166A (en) | 1995-04-27 |
| AU668174B2 (en) | 1996-04-26 |
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|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |