CN103919715A - Controlled Release Drug Combination Containing Choline Alfoscerate Or Salt Thereof And Method For Preparing Same - Google Patents
Controlled Release Drug Combination Containing Choline Alfoscerate Or Salt Thereof And Method For Preparing Same Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
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Abstract
The present invention relates to a controlled release drug combination containing choline alfoscerate or salt thereof and a method for preparing the same. The controlled release drug combination contains the choline alfoscerate and a salt acceptable on medicine. After taking the drug composition, the concentration of the choline alfoscerate and the salt acceptable on medicine is kept above a baseline value for at least six hours.
Description
Technical field
The present invention relates to a kind of controlled release pharmaceutical compositions, it comprises choline alfoscerate or its pharmaceutically acceptable salt, and after oral this pharmaceutical composition, in blood, the concentration of choline alfoscerate or its pharmaceutically acceptable salt maintains baseline value at least 6 hours above.
Background technology
L-α-glyceryl phosphoryl choline (L-α-glyceryl phosphoryl choline as known choline alfoscerate (Choline alfoscerate), GPC) be the cholinergic precursor compound with following Chemical formula 1 structure, there is the cranial nerve cell of making and choline neurotransmission system is recovered normal function, therefore as cerebral metabolism activator or dementia treatment agent, be effectively utilized.
[Chemical formula 1]
Because choline alfoscerate has high-hygroscopicity and water solublity is extremely strong, there is the problem of damp proof insulation difficulty in granule or mixed method generally.Therefore the choline alfoscerate of, selling on the market is at present liquid choline alfoscerate to be contained in to the dosage form of soft capsule.But the soft capsule preparation that sell market exists active component As time goes on to the probability of water-soluble capsule film permeation, and need extra soft capsule production equipment during preparation.In addition, in order to reduce the probability of the microbial spoilage of soft capsule preparation, generally use preservative agent, because gelatine capsule is unfavorable for humidity and thermal environment, in preservation, may there is the problems such as disintegrate delay, for the weak high age level patient of swallow, have the inconvenient problem of taking especially.
In addition, although the bioavailability of choline alfoscerate reaches more than 90%, easily in body, absorb,, but when oral, the time (Tmax) that arrives blood Chinese medicine maximum concentration is 1.5 hours, and during intramuscular injection, the half-life is 1.5 hours, so the problem that in body, the persistent period falls short of.Because choline alfoscerate is for the medicine that advanced age is prepared by layer patient a little less than swallow, therefore need choline alfoscerate slow releasing preparation, thereby by taking this medicine, choline alfoscerate or its salt are slowly discharged in vivo, activity component concentration in blood is kept to a certain degree, and reduce medicining times to improve patient's drug compliance.But because the high-hygroscopicity of choline alfoscerate is difficult for making tablet, therefore so far, the technology of the slow releasing tablet of choline alfoscerate is not developed yet.
Be directed to this, the present inventor once disclosed and has utilized water-insoluble or water-swellable polymer to make film coating for choline alfoscerate, effectively to prevent the matrix type slow releasing preparation (Korean Patent Application No.: 10-2011-0069969) of choline alfoscerate moisture absorption.Yet, follow-up study found that, utilize the matrix type slow releasing preparation of water-insoluble or water-swellable polymer to there is advantage simultaneously to the slow release of hygroscopicity and water miscible choline alfoscerate, take medicine by after a while, because release amount of medicine reduces, for short patient of holdup time between part the intestines and stomach, the medicine in slow releasing preparation does not completely discharge and is just drained in vivo.Therefore, be necessary to develop and can either imitate the moisture absorption that prevents choline alfoscerate, can overcome again preparation and between gastrointestinal, in movement, at the interval latter half of release amount of medicine of intestinal, reduce the novel controlled release preparation of problem.
Summary of the invention
The invention provides a kind of slow releasing preparation with the choline alfoscerate of the hygroscopic coatings of preventing, in the high intestine and small intestine of pH, make tablet generation disintegrate and make preparation that medicine discharges completely before excretion and preparation method thereof.
More specifically, the object of the present invention is to provide a kind of controlled release pharmaceutical compositions, comprise choline alfoscerate or its pharmaceutically acceptable salt, after oral this pharmaceutical composition, in blood, the concentration of choline alfoscerate or its pharmaceutically acceptable salt maintains baseline value at least 6 hours above.
Another object of the present invention is to provide a kind of preparation method of described controlled release pharmaceutical compositions.
As a kind of embodiment addressing the above problem, the present invention relates to a kind of controlled release pharmaceutical compositions that comprises choline alfoscerate or its pharmaceutically acceptable salt.
As a kind of better embodiment of the present invention, the present invention relates to a kind of controlled release pharmaceutical compositions, comprise choline alfoscerate or its pharmaceutically acceptable salt, after oral this pharmaceutical composition, blood Chinese medicine concentration maintains baseline value at least 6 hours above.
As a kind of better embodiment of the present invention, the present invention relates to a kind of controlled release pharmaceutical compositions, comprise choline alfoscerate or its pharmaceutically acceptable salt, release polymer and pH dependent polymers, after oral this pharmaceutical composition, blood Chinese medicine concentration maintains baseline value at least 6 hours above.
As a kind of better embodiment of the present invention, the present invention relates to a kind of controlled release pharmaceutical compositions, the drug compartment outside that comprises active component in described pharmaceutical composition is formed with coating, described coating contains release polymer and pH dependent polymers, after oral this pharmaceutical composition, blood Chinese medicine concentration maintains baseline value at least 6 hours above.As a specific embodiment, controlled release pharmaceutical compositions of the present invention comprises:
(a) drug compartment that comprises choline alfoscerate or its pharmaceutically acceptable salt;
(b) coating that is formed at described drug compartment outside and contains release polymer and pH dependent polymers; And
(c) be positioned at the pharmaceutically acceptable additive of described coating outside.
Pharmaceutical composition of the present invention is characterised in that, after oral this pharmaceutical composition at least 6 hours, be preferably at least 8 hours, more preferably at least 10 hours, more than blood Chinese medicine concentration maintains baseline value.Therefore, pharmaceutical composition of the present invention is different from the existing matrix dosage form reducing at latter half of release amount of medicine, and in the higher intestine and small intestine of pH value, medicine will be able to whole release.
The present invention is described in detail below.
" choline alfoscerate " in the present invention claims again L-α-choline glycerophosphatide (L-α-glyceryl phosphoryl choline, GPC), refers to the compound having as Chemical formula 1:
[Chemical formula 1]
In addition, the choline alfoscerate described in description of the present invention refers to and comprises choline alfoscerate or its pharmaceutically acceptable salt, and the choline alfoscerate that comprises form of ownership.For example, choline alfoscerate of the present invention can be the form of crystallization polymorphs body, racemic modification, enantiomer, polymorph, hydras, anhydride and the solvent compound of amorphous choline alfoscerate or crystal choline alfoscerate etc., preferably, it can be choline alfoscerate sulfuric monohydrate, but is not limited to this.
Choline alfoscerate (for example can pass through the synthetic method of D-solketal, J.Am.Chem Soc.70,1394-1399,1948) or hydrolysis from the method for the lecithin of bean extraction (for example, european patent number 217765, U.S. Patent number 5250719) etc. be the existing various organic synthesis methods of representative, by chemical method, make.
The content of the choline alfoscerate comprising in drug compartment of the present invention can decide according to showing enough efficacy of drugs and the every daily dose having no side effect and the melting degree in solvent, and preferred content is about 100 milligrams to 1200 milligrams.If the content of described choline alfoscerate is lower than 100 milligrams, the concentration of choline alfoscerate is too low can not give full play to efficacy of drugs, and if content higher than 1200 milligrams, the concentration of choline alfoscerate is too high-leveled and difficult control to discharge.
Described drug compartment is in order to improve the rheological characteristic of medicine; make coating and granulating operation become easy; and enhancing releasing effect, in the scope of not destroying as the choline alfoscerate effect of effective ingredient, can additionally comprise the additives such as pharmaceutically acceptable lubricant, release polymer, rheological agent and water-insoluble excipient.Described additive can be ethyl cellulose, Talcum, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate (sodium stearyl fumarate), Magnesiumaluminumsilicate, Glyceryl Behenate, glyceryl monostearate, Palmic acid tristerin, silica sol and composition thereof etc., but be not limited to this.
The coating that described drug compartment outside forms not only can prevent the moisture absorption of medicine, and for controlling drug releasing rate and burst size, thereby it is slowly discharged, and make preparation generation disintegrate at the high intestine and small intestine of pH value, thereby play the effect being discharged completely at latter half of medicine.More specifically, described coating is characterised in that it comprises release polymer and pH dependent polymers.
Preferably, described release polymer comprises at least one in insoluble polymer, hydrophobic compound, water-swellable polymer, hydrophilic polymer and toughness polymer.
Described insoluble polymer or hydrophobic compound refer to for controlling material drug release, pharmaceutically acceptable undissolved water, and it can be water-insoluble cellulose, water-insoluble cellulose derivative, water-insoluble methacrylic acid copolymer, water-insoluble ammonium methacrylate ester copolymer, water-insoluble acrylic acid alkyl ester polymer, water-insoluble methacrylic acid-ethyl acrylate analog copolymer, fatty acid and fatty acid ester etc.
More specifically, insoluble polymer can be polyvinyl acetate (for example, Kollicoat SR30D), Eudragit NE30D (for example, strange NE30D especially), methyl methacrylate-ethyl acrylate-trimethyl amino-ethyl methacrylate copolymer (for example, strange RSPO especially), ammonium methacrylate ester copolymer, ethyl cellulose, cellulose esters, cellulose ether, cellulose acylate, two acylated celluloses, three acylated celluloses, cellulose acetate, cellulose diacetate, Triafol T, hydroxypropylmethyl cellulose phthalate, Palmic acid tristerin, glyceryl stearate, Glyceryl Behenate, spermol cetylate, glycerin mono-fatty acid ester etc.
In addition, described water-swellable polymer refers to have high water absorbing capacity and moisture-retaining capacity, and expands and the polymer of formation gel rapidly in water; Hydrophilic or toughness polymer refer to control drug release, pharmaceutically acceptable be dissolved in water, the sticking polymer of tool.Can be preferably polyvinyl alcohol, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, polyethylene glycol oxide, polyvinyl acetate-polyvinylpyrrolidone, sodium alginate, poly-Fructus Vitis viniferae amine sugar, natural gum or paragutta class (for example, xanthan gum, perverse locust bean gum).
In addition, described release polymer can be contained in coating, also can optionally be contained in drug compartment or medication coat outside.
In addition, preferably, described " pH dependent polymers " refers to the polymer that dissolves or decompose under specific pH condition, for example, enteric solubility cellulose derivative, enteric solubility methacrylic acid copolymer, enteric solubility ammonium methacrylate ester copolymer, enteric solubility alkyl acrylate copolymer, enteric solubility methacrylic acid-ethyl acrylate analog copolymer, enteric solubility maleic acid and enteric solubility polythene derivative etc.
More specifically, enteric polymer can be hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, Cellacefate, cellulose acetate succinate, acetic acid maleic acid cellulose, benzoic acid cellulose phthalate, cellulose propionate phthalic acid ester, methyl cellulose phthalate ester, carboxymethyl ethylether cellulose, ethylhydroxyethylcellulose phthalic acid ester, methyl hydroxyethylcellulose, styrene-propene acid copolymer, acrylic acid methyl ester .-acrylic copolymer, acrylic acid-methylmethacrylate copolymer, BA-St-acrylic copolymer, acrylic acid methyl ester .-methacrylic acid-1-Octyl acrylate copolymer, EUDRAGIT L100, EUDRAGIT L100-55, vinyl acetate-copolymer-maleic anhydride, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl methyl ether-copolymer-maleic anhydride, ethylene-copolymer-maleic anhydride, vinyl butyl ether-copolymer-maleic anhydride, acrylonitrile-acrylic acid methyl ester. copolymer-maleic anhydride, BA-St-copolymer-maleic anhydride, polyvinyl alcohol phthalic acid ester, Pioloform, polyvinyl acetal phthalic acid ester, polyvinyl butyrate phthalic acid ester and polyvinyl alcohol acetic acid acetal phthalic acid ester etc.
The content of the release polymer containing in described coating solution and pH dependent polymers is preferably 5 to 100 weight portions than choline alfoscerate 100 weight portions.If be less than described content, the hygroscopicity of choline alfoscerate plays a role and causes stability decreases, and if be greater than described content, the volume of preparation can become and causes greatly oral difficulty.
Described medication coat can further comprise pharmaceutically acceptable excipient, binding agent, plasticizer and lubricant etc.Described binding agent can be hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, plasdone, polyvinyl alcohol, xanthan gum, gellan gum etc., preferably can use hydroxypropyl emthylcellulose.Described plasticizer can reinforcing copolymer coating plasticity and increase recoating efficiency, and can promote the decomposition of coated polymeric.Described plasticizer can use the fatty acid lemon acid derivants such as the glycerol derivatives such as Polyethylene Glycol, glycerol and triacetyl glycerine and triethyl citrate, butyryl-n-hexyl citric acid etc.Described lubricant can use Talcum, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, Magnesiumaluminumsilicate, Glyceryl Behenate, glyceryl monostearate, Palmic acid tristerin, silica sol and composition thereof etc. conventionally.Preferably, can comprise at least one in hydroxypropyl emthylcellulose, triethyl citrate and Talcum.
Be used to form described medication coat coating solution can by by release polymer and pH dependent polymers optionally together with excipient, binding agent, plasticizer, lubricant etc., be distributed to the suitable solvents such as water, acetone, ethanol or its mixed flux and prepare.The coating solution of preparation is coated on to described choline alfoscerate drug compartment surface, thereby can accesses film-coated drug particles.
Controlled release pharmaceutical compositions of the present invention can also comprise in the outside of described medication coat pharmaceutically acceptable additive, and described additive can suitably be selected by those skilled in the art.Pharmaceutically acceptable additive does not refer to organism is carried out to fierce stimulation, and do not reduce the biologic activity of oral administration of compound and the carrier of characteristic or diluent.In addition, described additive can make preparation, compressibility, outward appearance and the taste of preparation be improved.Can add following additive as required, for example, stabilizing agent, surfactant, lubricant, solvable agent, buffer agent, sweeting agent, bodying agent, adsorbent, correctives, binding agent, suspending agent, firming agent, antioxidant, polishing agent, aromatic, flavoring agent, color element, coating, wetting agent, conditioning agent, filler, defoamer, cold-producing medium, masticatory, antistatic additive, coloring agent, sweet tablet agent, isotonic agent, softening agent, emulsifying agent, binding agent, thickening agent, foaming agent, pH adjusting agent, excipient, dispersant, disintegrating agent, agent discharges water, antiseptic, preservative agent, dissolution aids, solvent, rheological agent etc.
Preferably, excipient or lubricant can comprise Talcum, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, Magnesiumaluminumsilicate, Glyceryl Behenate, glyceryl monostearate, Palmic acid tristerin, silica sol and composition thereof etc.
Described pharmaceutically acceptable additive level is compared whole compositions and is about 0.1 to 30 % by weight, is preferably about 0.1 to 20 % by weight.
In addition, controlled release pharmaceutical compositions of the present invention can also contain release polymer in described medication coat outside, and now release polymer can be selected from foregoing insoluble polymer, hydrophobic compound, water-swellable, hydrophilic or toughness polymer.
Pharmaceutical composition of the present invention, if oral formulations is not particularly limited, can be tablet, capsule, granule, fine grained agent and microspheric form preparation.Can, as prevention and treatment senile dementia, can be used as prevention and the medicine for the treatment of Alzheimer's disease especially.
Form taken by preparation of the present invention and dose can be determined by the doctor in charge according to the weight of patient's feature especially age, body weight, living habit, symptom and concrete condition.Preferably, controlled release preparation of the present invention is taken once with rational form every day, thereby guarantees that the concentration of taking active component in rear blood plasma keeps certain, and by reducing medicining times so that the object of taking medicine can adapt to medicine.
Pharmaceutical composition of the present invention is characterised in that, oral rear blood middle concentration maintains baseline value at least 6 hours above, is preferably at least 8 hours, is more preferably at least 10 hours.The preparation of preparing for the present invention, carried out the experiment of the dynamic aspect of medicine Changing Pattern, result shows, than the solid formulation that does not comprise pH dependent polymers, preparation of the present invention is latter half of, can more successfully discharge medicine and improve blood Chinese medicine concentration, and find that blood Chinese medicine concentration surpasses baseline value 10 hours.Therefore, preparation of the present invention is different from the existing matrix type dosage form reducing at latter half of release amount of medicine, and latter half of, the more easy disintegrate of tablet and drug release are estimated more smooth.
As another embodiment of the invention, the present invention relates to a kind of preparation method of the controlled release pharmaceutical compositions that comprises choline alfoscerate or its pharmaceutically acceptable salt.
The preparation method of the controlled release pharmaceutical compositions the present invention relates to particularly, comprises the following steps:
(a) drug compartment that makes to comprise choline alfoscerate or its acceptable salt pharmaceutically flows, and sprays the coating solution that comprises release polymer and pH dependent polymers, thereby prepares film-coated drug particles; And
(b) to described film-coated drug particles, add pharmaceutically acceptable additive and mix.
In described preparation method, the step that forms medication coat can be by utilizing pharmaceutical field conventional process to realize to drug compartment applying coating liquid.For example, by using fluidized bed pelletizer etc. to spray the coating solution that contains release polymer and pH dependent polymers in drug compartment, dry removal solvent and making then.The release polymer containing in described coating solution and pH dependent polymers are as previously mentioned.In addition, the solvent using in coating operation can be the mixture that comprises at least one dichloromethane, ethanol, acetone, water etc., for improving the stability of jetting fluid, can add in addition additive.
In addition, as the controlled release pharmaceutical compositions of above-mentioned preparation can be according to common formulation method preparation.For example,, as the direct compression method of common solid formulation preparation method or compressing grains method etc.
Controlled release preparation of the present invention, by effective control, there is the choline alfoscerate of high-hygroscopicity or the rate of release of its pharmaceutically acceptable salt, thereby increased, take convenience (dosage form once a day), therefore can improve the compliance of taking object, and then have that disease is improved or preventive effect.Especially, controlled release preparation of the present invention has according to pH value disintegrating tablet in body, latter half of in vivo, the feature that medicine can more successfully be released.
Accompanying drawing explanation
Fig. 1 shows blood Chinese medicine concentration (n grams per milliliter) variation of (hr) in time of embodiment 4 preparations.
Fig. 2 shows blood Chinese medicine concentration (n grams per milliliter) variation of (hr) in time of comparative example 2 preparations.
Fig. 3 shows blood Chinese medicine concentration (n grams per milliliter) variation of (hr) in time of comparative example 1 preparation.
The specific embodiment
Below with reference to embodiment, describe the present invention in detail.Following examples are only for illustrating the present invention, and the present invention is not subject to the restriction of these embodiment.
The preparation of embodiment 1. choline alfoscerate controlled release preparations
Using 20.4 grams of the ammonium methacrylate ester copolymers as release polymer (especially strange RSPO), in 0.6 gram, 39.0 grams of the enteric solubility methacrylic acid copolymer (Eudragit L100-55) of pH dependent polymers and Talcum is scattered in 550 grams of ethanol/water mixed solvents, to prepare coating solution.By 180 grams of choline alfoscerate of crossing with 20 mesh sieves and ethyl cellulose (Ethocel7cp granule, rheological agent) (G), 24 grams, 1.5 grams, Talcum (lubricant) is put into fluidized bed pelletizer, and mixed flow in chamber is until particle temperature reaches 40 ℃.When temperature reaches 40 ℃, spray the coating solution of above-mentioned allotment to prepare granule and film-coated granule.Now, intake air temperature is 22 ℃ to 28 ℃, and delivery temperature is 21 ℃ to 26 ℃, and expulsion pressure is 0.5bar.In the granule making, the content of choline alfoscerate is about 73%.And mix 0.6% the magnesium stearate account for film-coated granule total weight and be lubricated rear compression.
The preparation of embodiment 2. choline alfoscerate controlled release preparations
Using 16.2 grams of the ethyl celluloses as release polymer (Ethocel7cp FP), in 0.3 gram, 24 grams of the enteric solubility methacrylic acid copolymer (Eudragit L100-55) of pH dependent polymers and Talcum is scattered in 450 grams of ethanol/water mixed solvents, to prepare coating solution.By 180 grams of choline alfoscerate of crossing with 20 mesh sieves and ethyl cellulose (Ethocel7cp granule, rheological agent) (G) 24 grams put into fluidized bed pelletizer with 1.5 grams, Talcum (lubricant), mixed flow in chamber is until particle temperature reaches 40 ℃.When temperature reaches 40 ℃, spray the coating solution of above-mentioned allotment to prepare granule and film-coated granule.Now, intake air temperature is 22 ℃ to 26 ℃, and delivery temperature is 19 ℃ to 25 ℃, and expulsion pressure is 0.5bar.In the granule making, the content of choline alfoscerate is about 73%.And 0.6% the magnesium stearate of mixing the total weight account for film-coated granule is lubricated rear compression.
The preparation of embodiment 3. choline alfoscerate controlled release preparations
Using 18.6 grams of the ammonium methacrylate ester copolymers as release polymer (especially strange RSPO), in 0.6 gram, 28.8 grams of the enteric solubility methacrylic acid copolymer (Eudragit L100-55) of pH dependent polymers and Talcum is scattered in 450 grams of ethanol/water mixed solvents, to prepare coating solution.1.5 grams, 180 grams of choline alfoscerate of crossing with 20 mesh sieves and 3 grams of sodium stearyl fumarates (Pruv/JRS society, lubricant) and Talcum (lubricant) put into fluidized bed pelletizer, and mixed flow in chamber is until particle temperature reaches 40 ℃.When temperature reaches 40 ℃, spray the coating solution of above-mentioned allotment to prepare granule and film-coated granule.Now, intake air temperature is 20 ℃ to 30 ℃, and delivery temperature is 20 ℃ to 29 ℃, and expulsion pressure is 0.5bar.In the granule making, the content of choline alfoscerate is about 77%.And mix 10% ethyl cellulose (Ethocel7cp FP, slow releasing agent) of the total weight account for film-coated granule and 0.6% sodium stearyl fumarate (Pruv) is lubricated rear compression.
The preparation of embodiment 4. choline alfoscerate controlled release preparations
In 0.6 gram, 17.4 grams of the ammonium methacrylate ester copolymers as release polymer (especially strange RSPO), 26.4 grams of enteric solubility methacrylic acid copolymer (Eudragit L100-55) as pH dependent polymers, 0.6 gram of triethyl citrate (plasticizer) and Talcum (lubricant) is scattered in 450 grams of ethanol/water mixed solvents, to prepare coating solution.1.5 grams, 180 grams of choline alfoscerate of crossing with 20 mesh sieves and 10.5 grams of aluminium-magnesium silicates (Neusilin US2, lubricant), Talcum (lubricant) put into fluidized bed pelletizer, and mixed flow in chamber is until particle temperature reaches 40 ℃.When temperature reaches 40 ℃, spray the coating solution of above-mentioned allotment, to prepare granule and film-coated granule.Now, intake air temperature is 22 ℃ to 28 ℃, and delivery temperature is 20 ℃ to 28 ℃, and expulsion pressure is 0.5bar.In the granule making, the content of choline alfoscerate is approximately 76%.And mix 9% ethyl cellulose (Ethocel7cp FP, slow releasing agent) of the total weight account for film-coated granule and 0.6% magnesium stearate (lubricant) is lubricated rear compression.
The commercially available soft capsule preparation of comparative example 1.
Use commercially available choline alfoscerate soft capsule preparation (
, great Xiong pharmacy).
Comparative example 2. is relatively used the preparation of preparation
In 1.0 grams, 90 grams of the ammonium methacrylate ester copolymers as release polymer (especially strange RSPO), 10.0 grams of triethyl citrates (plasticizer) and Talcum (lubricant) is scattered in 300.0 grams of ethanol/water mixed solvents, to prepare coating solution.180 grams of choline alfoscerate are put into fluidized bed pelletizer, in chamber, flow until particle temperature reaches 40 ℃.When temperature reaches 40 ℃, spray the coating solution of above-mentioned allotment, to prepare film-coated granule.Now, intake air temperature is 36 ℃, and delivery temperature is 33 ℃, and expulsion pressure is 0.5bar.It is 32 % by weight that the film coating rate of the granule making is compared active component (choline alfoscerate).Tablet mixes and utilizes direct compression to make with the ratio of 7 milligrams of 793 milligrams of described film coating granules, ethyl cellulose FP70 milligram (Ethocel7cp FP, slow releasing agent), magnesium stearate (lubricant).
Experimental example 1. medicine dynamic tests
1-1. experimental technique
12 of male beasle dogs that utilize 7 to 12 kg body weight at 16 to 17 monthly ages, have carried out choline alfoscerate oral drugs dynamic test.Under airconditioning condition, maintain temperature and the 50 ± 10%(RH of 21 ± 2 ℃) in the receptacle of humidity, by the beasle dog that is no more than average weight 3% laboratory animal special feed, with once-a-day approximately 300 grams supply with experimental subjecies, carried out medicine dynamic test, for statistical disposition, the experimental subject of each experimental group is that 6 or cross-over experiment object are 12.Under following LC/MS/MS condition quantitative analysis the plasma samples that obtain of different blood sampling time points, use the HPLC of Agilent company, the API2000(triple quadrupole bar mass spectrograph of ABSCIEX company), with MRM(multiple reaction monitoring) method detects choline (m/z104.2>60.1) and the internal standard material choline chloride trimethyl-d9(m/z113.3>69.3 in plasma sample).In order to process plasma sample, vortex after the preservation plasma sample of subzero 80 ℃ is at room temperature thawed, 3600rpm, after centrifugal 5 minutes, be take 80ul as unit sample postprecipitation protein, filtering supernatant then, and extract 5ul and analyze.
1-2. experimental result
By the tablet of preparation in embodiment 4, after oral to beasle dog according to described method, with (0) before taking medicine, take medicine after 0.5,1,1.5,2,2.5,3,3.5,4,5,6,8,10,12 sampling time point, altogether sample 14 times, utilize this plasma sample of 14 times, confirm medicine the result of dynamic test.Dynamically as shown in Figure 1, Tmax is 2.6hr ± 1.12hr to result medicine, after taking medicine through the approximately 10 hours dense arrival degree of blood Chinese medicine baseline concentrations.
In addition, by the tablet of preparation in comparative example 2, after oral to beasle dog according to described method, with (0) before taking medicine, take medicine after 0.5,1,1.5,2,2.5,3,4,5,6,8,10,12 sampling time point, altogether sample 13 times, utilize this plasma sample of 13 times, confirm medicine the result of dynamic test.Dynamically as shown in Figure 2, Tmax is 2hr ± 0.38 to result medicine, after taking medicine through the approximately 5 hours dense arrival degree of medicine blood baseline concentrations.
In addition, by comparative example 1 preparation tablet, according to described method to beasle dog oral once after, with (0) before taking medicine, take medicine after 0.5,1,1.5,2,3,4,12 sampling time point, altogether sample 8 times, utilize this plasma sample of 8 times, confirm medicine the result of dynamic test.Result medicine dynamically as shown in Figure 3, after taking medicine through the approximately 4 hours dense arrival degree of medicine blood baseline concentrations.
From the dynamic comparative result of medicine of Fig. 1 and Fig. 2, can find out, in utilizing the test of the intestines and stomach holdup time short beasle dog than people, the solid formulation that comprises pH dependent polymers, latter half of in vivo, because drug release is more smooth, can effectively improve blood Chinese medicine concentration, finally find, there is the continuable effect of concentration in blood.Therefore, the preparation that utilizes pH dependent polymers that embodiment 4 relates to, that in matrix type drug form burst size, reduces is latter half of, is more prone to disintegrate, more smooth thereby drug release is estimated.
Claims (12)
1. a controlled release pharmaceutical compositions, comprises choline alfoscerate or its pharmaceutically acceptable salt, and after oral this pharmaceutical composition, in blood, the concentration of choline alfoscerate or its pharmaceutically acceptable salt maintains baseline value at least 6 hours above.
2. controlled release pharmaceutical compositions according to claim 1, after oral this pharmaceutical composition, in blood, the concentration of choline alfoscerate or its pharmaceutically acceptable salt maintains baseline value at least 8 hours above.
3. controlled release pharmaceutical compositions according to claim 1, after oral this pharmaceutical composition, in blood, the concentration of choline alfoscerate or its pharmaceutically acceptable salt maintains baseline value at least 10 hours above.
4. controlled release pharmaceutical compositions according to claim 1, comprises release polymer and pH dependent polymers.
5. controlled release pharmaceutical compositions according to claim 4, comprises the drug compartment that (a) contains choline alfoscerate or its pharmaceutically acceptable salt; (b) be formed at the outside of described drug compartment, and the coating that comprises release polymer and pH dependent polymers; And the pharmaceutically acceptable additive that (c) is positioned at described coating outside.
6. according to the controlled release pharmaceutical compositions described in claim 4 or 5, described release polymer comprises by polyvinyl acetate, methacrylic acid copolymer, methyl-ethyl acrylate copolymer, methyl methacrylate-ethyl acrylate-trimethyl amino-ethyl methacrylate copolymer, ammonium methacrylate ester copolymer, ethyl cellulose, hydroxypropylmethyl cellulose phthalate, Glyceryl Behenate, polyvinyl alcohol, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyethylene glycol oxide, polyvinyl acetate-polyvinylpyrrolidone, sodium alginate, in the group that natural gum and rubber polymer form at least one.
7. according to the controlled release pharmaceutical compositions described in claim 4 or 5, described pH dependent polymers is a kind of enteric polymer, comprises by hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, methyl cellulose phthalate ester, carboxymethyl ethylether cellulose, ethylhydroxyethylcellulose phthalic acid ester, methyl hydroxyethylcellulose, styrene-propene acid copolymer, methacrylic acid copolymer, acrylic acid methyl ester .-acrylic copolymer, acrylic acid-methylmethacrylate copolymer, BA-St-acrylic copolymer, acrylic acid methyl ester .-methacrylic acid-1-Octyl acrylate copolymer, EUDRAGIT L100, EUDRAGIT L100-55, polyvinyl alcohol phthalic acid ester, Pioloform, polyvinyl acetal phthalic acid ester, in the group that polyvinyl butyrate phthalic acid ester and polyvinyl alcohol acetic acid acetal phthalic acid ester form at least one.
8. controlled release pharmaceutical compositions according to claim 5, described drug compartment comprises 100 to 1200 milligrams of choline alfoscerate.
9. controlled release pharmaceutical compositions according to claim 5, described drug compartment also comprises pharmaceutically acceptable lubricant, release polymer, rheological agent and excipient.
10. controlled release pharmaceutical compositions according to claim 5, described coating also comprises pharmaceutically acceptable excipient, binding agent, plasticizer and lubricant.
11. controlled release pharmaceutical compositions according to claim 5, the outside of described coating also comprises release polymer.
12. controlled release pharmaceutical compositions according to claim 5, described pharmaceutically acceptable additive is pharmaceutically acceptable lubricant or excipient.
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| KR1020130004070A KR102008490B1 (en) | 2013-01-14 | 2013-01-14 | Controlled release pharmaceutical composition comprising choline alfoscerate or pharmaceutically acceptable salt thereof and method for manufacturing the same |
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Cited By (2)
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| CN109730321A (en) * | 2018-12-29 | 2019-05-10 | 中山百灵生物技术有限公司 | A kind of gel beads and preparation method thereof containing GPC |
| CN112137971A (en) * | 2019-06-28 | 2020-12-29 | 北京万全德众医药生物技术有限公司 | Orally disintegrating tablet of choline alfoscerate and preparation method thereof |
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| KR101628937B1 (en) * | 2014-11-06 | 2016-06-09 | 환인제약 주식회사 | Pharmaceutical tablet comprising Choline Alphoscerate and method for manufacturing the same |
| KR101796628B1 (en) * | 2016-05-25 | 2017-11-10 | 한국프라임제약주식회사 | Moisture-resistant tablet comprising choline alfoscerate, and method for preparing the same |
| CN108938562A (en) * | 2017-05-25 | 2018-12-07 | 北京万全德众医药生物技术有限公司 | Choline Glycerophosphate oral solution |
| KR101864384B1 (en) * | 2017-12-11 | 2018-06-04 | (주)나노스템 | Composition and Method for Treating, relieving or Preventing Muscle Cramps |
| KR101841654B1 (en) * | 2017-12-19 | 2018-03-26 | (주)나노스템 | Composition and Method for Treating, relieving or Preventing Neuropathic Pain |
| KR102149020B1 (en) | 2018-11-20 | 2020-08-28 | 주식회사 코피텍 | Film-coated tablet having high damp proof property |
| KR102285886B1 (en) * | 2019-10-22 | 2021-08-05 | 한국유나이티드제약 주식회사 | Sustained-Release Minimized Oral Dosage Formulation Comprising Choline Alfoscerate |
| KR102381836B1 (en) * | 2019-10-22 | 2022-04-05 | 한국유나이티드제약 주식회사 | Minimized and Sustained Released Pharmaceutical Dosage Form Comprising Choline Alfoscerate |
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| KR100762846B1 (en) * | 2003-09-29 | 2007-10-04 | 씨제이 주식회사 | Sustained-release formulations |
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| KR101499533B1 (en) * | 2008-02-15 | 2015-03-09 | 주식회사 씨티씨바이오 | Pharmaceutical preparation containing choline alfoscerate |
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| US20050266082A1 (en) * | 2004-05-26 | 2005-12-01 | Patel Satishkumar A | Preparation of stable paroxetine HC1 ER tablets using a melt granulation process |
| CN102548544A (en) * | 2009-10-09 | 2012-07-04 | 永进药品工业株式会社 | Pharmaceutical composition with both immediate and extended release characteristics |
| CN103717223A (en) * | 2011-07-14 | 2014-04-09 | 柏法迪斯有限公司 | Sustained/release pharmaceutical composition comripising choline alfoscerate or pharmaceutically acceptable salt thereof and method for manufacturing the same |
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| CN112137971A (en) * | 2019-06-28 | 2020-12-29 | 北京万全德众医药生物技术有限公司 | Orally disintegrating tablet of choline alfoscerate and preparation method thereof |
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| KR102008490B1 (en) | 2019-08-08 |
| KR20140094679A (en) | 2014-07-31 |
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