CN101347622A - Oral liquid-crystal sustained-release composition and preparation - Google Patents
Oral liquid-crystal sustained-release composition and preparation Download PDFInfo
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- CN101347622A CN101347622A CNA2008101964013A CN200810196401A CN101347622A CN 101347622 A CN101347622 A CN 101347622A CN A2008101964013 A CNA2008101964013 A CN A2008101964013A CN 200810196401 A CN200810196401 A CN 200810196401A CN 101347622 A CN101347622 A CN 101347622A
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Abstract
The invention relates to an oral liquid crystal sustained-released composition and a preparation method thereof. Active ingredients are distributed in glyceryl monooleate and lipid material in the composition to achieve the aim of slowly releasing the medicine. The preparation method of the pharmaceutical composition is as follows: the active ingredients, glyceryl monooleate and lipid material are prepared in a moderate method; the mixture is separately loaded in a hard capsule shell or soft capsule, and the sustained-released capsule is prepared. The content of the sustained-released capsule forms liquid crystal phase after encountering water to inhibit the release of the medicine. The pharmaceutical composition of the invention has simple preparing process, the active ingredients can be sustained-release, and the parameters influencing the release are few. Therefore, the composition of the invention is more suitable for industrial production with better safety.
Description
Technical field
The present invention relates to a kind of oral liquid-crystal sustained-release composition and preparation method thereof, belong to technical field of medicine.
Background technology
Oral slow-releasing preparation is a kind of in the regulation release medium, non-lentamente on request constant release, and per 24 hours medication number of times relatively are reduced to 1-2 time oral drug preparation from 3-4 time with corresponding ordinary preparation.In order to reduce administration number of times, reduce the fluctuation of blood drug level, the medicine of many types is suitable for making the slow releasing preparation application clinically.The gastrointestinal system medication is as Trimebutine Maleate; The treatment of respiratory diseases medicine, example hydrochloric acid ambroxol, acemetacin, salbutamol sulfate; Hypoglycemic drug, example hydrochloric acid metformin, gliclazide, glipizide, rosiglitazone; Antipyretic analgesic, example hydrochloric acid tramadol, diclofenac sodium, lornoxicam; Drug for urinary system, the example hydrochloric acid oxibutynin; The psychiatric department medication, example hydrochloric acid venlafaxine, BUPROPIONE HCl, sodium valproate, methylphenidate hydrochloride, fluoxetine; Depressor is as nisoldipine, indapamide, Amlodipine Besylate Tablet; Antineoplastic agent is as tacrolimus, Tamoxifen Citrate; The endocrine system disease curative is as kurarinone, stavudine, lamivudine; The blood lipid regulation medicine is as fenofibrate, lovastatin, fluvastatin sodium; Anti-anginal drug is as isosorbide mononitrate, diltiazem hydrochloride; Anti-infectives is as clarithromycin, levofloxacin hydrochloride, Roxithromycin, gentamycin sulfate, cefixime, cefaclor; The anaphylactic disease medication is as loratadine, mizolastine; Acetylcholinesterase inhibitor is as galanthamine hydrobromide, huperzine A; The cerebrovascular disease medication is as dihydroergotoxine methanesulfonate.
Slow releasing capsule is wherein a kind of main clinical sustained release pharmaceutical formulation type, and slow releasing capsule generally is made up of softgel shell and content, and the type of its content mainly comprises the released granular and the spacetabs type ball heart.The operating procedure complexity of released granular, the general wet granulation technology that adopts carries out: after adjuvants such as medicine and slow-release material are mixed, the adding binding agent is prepared into the soft material of suitable degree, again gained viscosity agglomerate is prepared into wet granular by technology such as extruding granulations, as content, carry out sustained release coating in case of necessity after drying.The spacetabs type ball adopts the slow release macromolecular material to carry out coating after feeling concerned about medicine and slow-release material being prepared into the ball heart of suitable intensity.The whole process of production long flow path, time consumption and energy consumption is many, the production cost height.
Release is the emphasis quality control project of oral sustained release capsule.When adopting above-mentioned slow-releasing granules technology or slow release ball heart technology to prepare slow releasing capsule, a subject matter of existence is: many preparation process parameters can influence drug release rate.For example: 1) selection and the consumption of binding agent during wet granulation: be easy to make granule really up to the mark or soft, correspondingly cause drug release to be lower than standard or take place that medicine is prominent to be released; 2) particulate size; 3) compactness extent of the granule or the ball heart: the compactness extent of structure is also for influencing the key factor of drug release; 4) coating finishes quality.The difference of these technological parameters will cause finished product bigger differences between batches and batch interior difference to occur in the continuous flow procedure, bigger blood concentration fluctuation will occur behind the oral administration in human body, even disengage now serious toxicity because of preparation is prominent.Therefore, develop the technology that a kind of production technology is simple, operating procedure is few, technological parameter is few and prepare slow release capsule preparation, all have crucial meaning for industrialized great production and data for clinical drug use.
Summary of the invention
The purpose of this invention is to provide that a kind of production technology is simple, technological parameter is few, slowly the liquid crystal slow releasing composition of release of active ingredients.
Another object of the present invention provides a kind of method of making above-mentioned composition.
Therefore, the invention provides a kind of oral liquid-crystal sustained-release composition, it comprises:
The active component of 100 weight portions;
The glyceryl monooleate of 100-5000 weight portion;
The pharmaceutically acceptable matrix material of 10-500 weight portion;
In a preferred embodiment of the present invention, described active component is selected from a kind of in acemetacin, gliclazide, lornoxicam, ditropan XL, VENLAFAXINE HCL, indapamide, galanthamine hydrobromide, kurarinone, fluvastatin sodium, dihydroergotoxine methanesulfonate, isosorbide mononitrate, clarithromycin, Tamoxifen Citrate, loratadine, the Trimebutine Maleate.
In a preferred embodiment of the present invention, described matrix material is selected from one or more in Gan You behenic acid ester, palmitic acid stearic acid ester of glycerol, glyceryl monostearate, tristearin, the polyethyleneglycol glyceride.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition also comprises the additive of 10-400 weight portion.Described additive is selected from one or more in pharmaceutically acceptable solvent, the pharmaceutically acceptable surfactant.
In a preferred embodiment of the present invention, the content of described glyceryl monooleate is the 150-3500 weight portion.
In a preferred embodiment of the present invention, the content of described matrix material is the 20-350 weight portion.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The isosorbide mononitrate of 100 weight portions;
Single olein of 1050 weight portions;
62.5 the Compritol ATO 888 of weight portion;
62.5 the Gelucire 43/01 of weight portion.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The acemetacin of 100 weight portions;
444.44 the glyceryl monooleate of weight portion;
44.44 the Compritol ATO 888 of weight portion;
The Gelucire 40/13 of 40 weight portions.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The gliclazide of 100 weight portions;
833.33 the glyceryl monooleate of weight portion;
66.67 the Compritol ATO 888 of weight portion;
The polyoxyethylene sorbitan monoleate of 50 weight portions.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The lornoxicam of 100 weight portions;
The glyceryl monooleate of 100 weight portions;
The glycerol of 50 weight portions.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The ditropan XL of 100 weight portions;
The glyceryl monooleate of 1050 weight portions;
The Gelucire50/13 of 200 weight portions.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The VENLAFAXINE HCL of 100 weight portions;
286.67 the glyceryl monooleate of weight portion;
13.333 the Gelucire50/13 of weight portion;
The Compritol ATO 888 of 24 weight portions.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The indapamide of 100 weight portions;
3333.3 the glyceryl monooleate of weight portion;
333.33 the Gelucire44/14 of weight portion.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The galanthamine hydrobromide of 100 weight portions;
The glyceryl monooleate of 1940 weight portions;
The Precirol of 150 weight portions
Ato 5.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The kurarinone of 100 weight portions;
253.33 the glyceryl monooleate of weight portion;
14.67 the Compritol ATO 888 of weight portion;
12.67 the Gelucire43/01 of weight portion.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The fluvastatin sodium of 100 weight portions;
The glyceryl monooleate of 1250 weight portions;
The Gelucire 33/01 of 100 weight portions.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The dihydroergotoxine methanesulfonate of 100 weight portions;
The glyceryl monooleate of 2720 weight portions;
The Gelucire 33/01 of 140 weight portions.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The clarithromycin of 100 weight portions;
The glyceryl monooleate of 152 weight portions;
The Gelucire 40/13 of 22 weight portions;
The PEG400 of 42 weight portions;
27.2 the Compritol ATO 888 of weight portion;
The polyoxyethylene sorbitan monoleate of 8 weight portions.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The Tamoxifen Citrate of 100 weight portions;
1266.7 the glyceryl monooleate of weight portion;
115.56 the Gelucire 40/13 of weight portion.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The loratadine of 100 weight portions;
The glyceryl monooleate of 2160 weight portions;
The Gelucire 40/13 of 160 weight portions;
The Compritol ATO 888 of 160 weight portions.
In a preferred embodiment of the present invention, described liquid crystal slow releasing composition comprises:
The Trimebutine Maleate of 100 weight portions;
The glyceryl monooleate of 380 weight portions;
The Gelucire 40/13 of 15 weight portions;
The propylene glycol of 63 weight portions;
The Compritol ATO 888 of 42 weight portions.
The present invention also provides the preparation method of described liquid crystal slow releasing composition, and it may further comprise the steps:
(a) glyceryl monooleate is formed solution in the fusing of 35-60 degree, add active component stirring and dissolving or homodisperse;
(b) adding matrix material stirs;
(c) with the gained liquid cools to uniform temperature, be filled in hard capsule case or the soft capsule shell, prepare slow releasing capsule;
In a preferred embodiment of the present invention, in described step (b), also can add other additives of 10-400 weight portion, described additive is selected from one or more in pharmaceutically acceptable solvent, the pharmaceutically acceptable surfactant.
Liquid crystal slow releasing composition preparation technology of the present invention is simple, slow release of active ingredients, and the parameter that influences release behavior is few.Therefore, compositions of the present invention is more suitable for suitability for industrialized production, and safety is better.
Description of drawings
Fig. 1 is isosorbide mononitrate liquid crystal slow releasing composition 1 provided by the present invention (embodiment 1) and commercially available isosorbide mononitrate sustained release tablets (specification: 40mg/ sheet, the special medicine company limited of Shandong southern Shandong shellfish is produced, trade name: Xin Kang, lot number: 060803), and each slow releasing capsule among the embodiment 2-15 provided by the present invention is according to the release in vitro of the drug release determination method gained line chart of writing music.
Wherein, abscissa be the time (hour), vertical coordinate is to discharge percentage rate (%).Described release percentage rate is meant that with the medicine total amount in whole capsule or the tablet be the drug release percent that benchmark calculates.
The specific embodiment
Glyceryl monooleate is the thermodynamically stable lipid bilayer of the spontaneous formation of meeting in solution, and then composition has the liquid crystal system (A.Tardieu of tridimensional network, V.Luzzati, Polymorphism of lipids.A novel cubic phase-a cage-like network of rods withenclosed spherical micelles, Biochim Biophys Acta, 1970,219 (1): 11-17; K.Larsson, K.Fontell, N.Krong, Structural relationships between lamellar, cubic and hexagonal phases in monoglyceride-water systems, ChemPhys Lipids, 1980,27 (4): 321-328; K.Larsson, Cubic lipid-water phases:structures and biomembrane aspects, J Phys Chem, 1989,93 (21): 7301-7314).Through a large amount of discovering, a certain amount of glyceryl monooleate and a certain amount of matrix material united to use make the liquid crystal slow releasing composition, both can keep forming liquid crystal and the character of control drug release after glyceryl monooleate is met water, and can reduce the consumption of glyceryl monooleate again.The production technology of this compositions is easy, and rate of release is easy to control, and the parameter that influences its release behavior is few, has better safety.
One aspect of the present invention provides a kind of liquid crystal slow releasing composition, and it comprises:
The active component of 100 weight portions;
The glyceryl monooleate of 100-5000 weight portion;
The pharmaceutically acceptable matrix material of 10-500 weight portion.
In the present invention, do not have any restriction for the type of active component, it can be to be suitable for being prepared into the active component that slow releasing preparation uses clinically.In a preferred embodiment of the present invention, described active component is selected from a kind of in acemetacin, gliclazide, lornoxicam, ditropan XL, VENLAFAXINE HCL, indapamide, galanthamine hydrobromide, kurarinone, fluvastatin sodium, dihydroergotoxine methanesulfonate, isosorbide mononitrate, clarithromycin, Tamoxifen Citrate, loratadine, the Trimebutine Maleate.
In the present invention, above-mentioned glyceryl monooleate specifically is the commodity RYLO MG19 PHARMA available from Denmark Danisco company.Glyceryl monooleate records in American Pharmacopeia (glyceryl monooleate), European Pharmacopoeia (Glycerol mono-oleates) and British Pharmacopoeia (Glycerolmono-oleates), is a kind of adjuvant that pharmaceutically allows.Glyceryl monooleate is formed by glycerol and oleic acid esterification, is the mixture of acyl group glycerol, and main component is a glyceryl monooleate, a spot of pair of acylglycerol and triacylglycerol.Glyceryl monooleate is a kind of white waxy solid at normal temperatures, and fusing point is 35 ℃, and boiling point is 238 ℃-240 ℃.In compositions of the present invention, the content of described glyceryl monooleate should be able to can form liquid crystal after meeting water, hinder the release of active component, therefore, the content of described glyceryl monooleate should be the 100-5000 weight portion, is preferably the 120-4000 weight portion, most preferably is the 150-3500 weight portion.
In the present invention, do not have any restriction for the type of matrix material, it can be a matrix material conventional in this area.In a preferred embodiment of the present invention, described matrix material is selected from one or more in Gan You behenic acid ester, palmitic acid stearic acid ester of glycerol, tristearin, polyethyleneglycol glyceride, the glyceryl monostearate.In another preferred embodiment of the present invention, described matrix material is selected from one or both in Gan You behenic acid ester, tristearin, the polyethyleneglycol glyceride.In compositions of the present invention, the liquid crystal that the amount of described matrix material should be able to enough be regulated glyceryl monooleate forms the zone, and the control liquid crystal forms speed, thereby controls the rate of release of medicine, but does not significantly reduce the release total amount of medicine.Therefore, the content of described matrix material should be the 10-500 weight portion, is preferably the 20-400 weight portion, most preferably is the 20-350 weight portion.
In the present invention, above-mentioned palmitic acid stearic acid ester of glycerol specifically is the commodity Precirol available from French Jia Fasai (Gattefoss é) company
Ato 5.Described palmitic acid stearic acid ester of glycerol records in European Pharmacopoeia (Glycerol distearate), it is formed by the Palmic acid stearic acid and the glycerine esterification of 16～18 carbon, mixture for the stearic single, double and triglyceride of Palmic acid, major part is a diester, outward appearance is white to the near-white fine-powder, melting range 53-57 ℃.
In the present invention, above-mentioned sweet oily behenic acid ester specifically is the commodity Compritol available from French Jia Fasai (Gatefosse) company
ATO 888.Described Gan You behenic acid ester records in American Pharmacopeia and European Pharmacopoeia (Glyceryl behenate), is a kind of adjuvant that pharmaceutically allows.Gan You behenic acid ester You behenic acid (22 carbon) and glycerine esterification form, and Wei the mixture of single, double nuclear triglyceride of behenic acid, major part is a diester, and outward appearance be an extremely subalbous fine-powder of white, and melting range is 69-74 ℃.
In the present invention, above-mentioned tristearin specifically is commodity Gelueire 33/01, Gelucire39/01 or the Gelucire43/01 available from French Jia Fasai (Gattefoss é) company.Described tristearin records in 24 editions/NF of American Pharmacopeia 19 editions, the semi-synthetic glyceride that it is made up of the satisfied fatty acid triglyceride of 8～18 carbon, and outward appearance is a waxy solid.
In the present invention, above-mentioned polyethyleneglycol glyceride specifically is commodity stearic acid polyethyleneglycol glyceride (Gelucire50/13) or the lauric acid polyethyleneglycol glyceride (Gelucire44/14) available from French Jia Fasai (Gattefoss é) company.Mixture by fatty acid glycerine one ester, diester, three esters and fatty acid polyglycol ethylene glycol one ester, diester, three esters of determining ratio are formed records in the European Pharmacopoeia third edition (stearic acid polyethyleneglycol glyceride), and outward appearance is a waxy solid.
In compositions of the present invention, also can comprise other pharmaceutically acceptable additives.Type for described additive does not have concrete restriction, can be additive conventional in this area, specifically is to be selected from pharmaceutically acceptable solvent, the pharmaceutically acceptable surfactant one or more.In a preferred embodiment of the present invention, described content of additive is the 10-400 weight portion.
In the present invention, do not have any restriction for the type of pharmaceutically acceptable solvent, it can be a solvent commonly used in this area.In a preferred embodiment of the present invention, described solvent is selected from propylene glycol, ethanol, glycerol and their mixture.In the present invention, do not have any restriction for the consumption of solvent, it can be the conventional amount used in this area.In an example of the present invention, the consumption of described solvent is the 10-200 weight portion, is preferably the 10-150 weight portion, more preferably the 20-120 weight portion.
In the present invention, do not have any restriction for the type of pharmaceutically acceptable surfactant, it can be a surfactant commonly used in this area.In a preferred embodiment of the present invention, described surfactant is selected from polyoxyethylene sorbitan monoleate, polyoxyethylene castor oil and their mixture.In the present invention, do not have any restriction for the consumption of surfactant, it can be the conventional amount used in this area.In an example of the present invention, the consumption of described surfactant is the 10-200 weight portion, is preferably the 20-160 weight portion, more preferably the 20-150 weight portion.
In the present invention, term " pharmaceutically acceptable " composition is meant and is applicable to people and/or animal and does not have excessive bad side reaction (as toxicity, stimulation and allergy) that the material of rational benefit/risk ratio is promptly arranged.
Used term " pharmaceutically acceptable additive " is meant the additive of pharmaceutically acceptable reinforcement preparation characteristic.Examples of such additives is well-known to those skilled in the art, comprises solvent, surfactant and other.Wherein solvent is ethanol, propylene glycol, glycerol and Polyethylene Glycol etc.Surfactant is polyoxyethylene sorbitan monoleate, polyoxyethylene castor oil etc.
In the present invention, term " liquid crystal slow release " is meant that the character of utilizing glyceryl monooleate to meet aqueous medium formation liquid crystal delays the release of medicine.
The use of compositions of the present invention is identical with common oral hard capsule agent or oral soft capsule agent.
The present invention provides a kind of method for preparing above-mentioned liquid crystal slow releasing composition on the other hand, and it may further comprise the steps:
(a) glyceryl monooleate is formed solution in the fusing of 35-60 degree, add active component stirring and dissolving or homodisperse;
(b) adding matrix material stirs;
(c) with the gained liquid cools to uniform temperature, be filled in hard capsule case or the soft capsule shell, prepare slow releasing capsule;
Also can add other additives of 10-400 weight portion in described step (b), described additive is selected from one or more in pharmaceutically acceptable solvent, the pharmaceutically acceptable surfactant.
For guaranteeing carrying out smoothly of filled capsules process, the optimum range of chilling temperature is the 30-50 degree.
Further describe the present invention below by specific embodiment, but do not limit the scope of the invention.
Embodiment 1
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 1
Constituent content (mg) in every in the preparation
Isosorbide mononitrate 40mg
Glyceryl monooleate 420mg
Compritol?ATO?888 25mg
Gelucire?43/01 25mg
Preparation method:
Glyceryl monooleate is heated to 45 ℃ of fusions, under stirring, add the isosorbide mononitrate stirring and dissolving, add Compritol ATO888 and Gelucire 43/01 again, after stirring, be cooled to about 40 degree, be filled in the hard capsule case, make the slow releasing capsule that every capsules contains isosorbide mononitrate 40mg.
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 2
Constituent content (mg) in every in the preparation
Acemetacin 90mg
Glyceryl monooleate 400mg
Compritol?ATO?888 40mg
Gelucire?40/13 18mg
Preparation method:
Glyceryl monooleate is heated to 50 ℃ of fusions, under stirring, adds acemetacin, add Compritol ATO 888 and Gelucire40/13 again, after stirring, be cooled to about 40 degree, be filled in the soft capsule, make the slow releasing capsule that every capsules contains acemetacin 90mg.
Embodiment 3
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 3
Constituent content (mg) in every in the preparation
Gliclazide 30mg
Glyceryl monooleate 250mg
Compritol?ATO?888 20mg
Polyoxyethylene sorbitan monoleate 15mg
Preparation method:
Glyceryl monooleate is heated to 60 ℃ of fusions, under stirring, adds gliclazide, add Compritol ATO 888 and polyoxyethylene sorbitan monoleate again, after stirring, be cooled to about 40 degree, be filled in the capsule shells, make the slow releasing capsule that contains gliclazide 30mg in every capsules.
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 4
Constituent content (mg) in every in the preparation
Lornoxicam 12mg
Glyceryl monooleate 12mg
Glycerol 6mg
Preparation method:
Glyceryl monooleate is heated to 45 ℃ of fusions, under stirring, adds the lornoxicam stirring and dissolving, add glycerol again, after stirring, be cooled to 35 degree, be filled in the soft capsule, make the slow releasing capsule of every capsules lornoxicam 12mg.
Embodiment 5
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 5
Constituent content (mg) in every in the preparation
Ditropan XL 10mg
Glyceryl monooleate 105mg
Gelucire50/13 20mg
Preparation method:
Glyceryl monooleate is heated to 45 ℃ of fusions, under stirring, adds the ditropan XL stirring and dissolving, add Gelucire50/13 again, after stirring, be cooled to about 40 degree, be filled in the hard capsule case, make the slow releasing capsule of the hydrochloric oxibutynin 10mg of every capsules.
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 6
Constituent content (mg) in every in the preparation
VENLAFAXINE HCL 150mg
Glyceryl monooleate 430mg
Polyoxyethylene castor oil 20mg
Compritol?ATO?888?36mg
Preparation method:
Glyceryl monooleate is heated to 45 ℃ of fusions, adding VENLAFAXINE HCL and the abundant dispersed with stirring of polyoxyethylene castor oil are even under stirring, add Compritol ATO 888 again, stir, be cooled to 40 degree, be filled in the soft capsule, make the slow releasing capsule of the hydrochloric venlafaxine 150mg of every capsules.
Embodiment 7
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 7
Constituent content (mg) in every in the preparation
Indapamide 1.5mg
Glyceryl monooleate 50mg
Gelucire44/14 5mg
Preparation method:
Glyceryl monooleate is heated to 45 ℃ of fusions, under stirring, adds the indapamide stirring and dissolving, add Gelucire44/14 again, after stirring, be cooled to about 38 degree, be filled in the hard capsule, make the slow releasing capsule that every capsules contains indapamide 1.5mg.
Embodiment 8
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 8
Constituent content (mg) in every in the preparation
Galanthamine hydrobromide 5mg
Glyceryl monooleate 97mg
Precirol
ato?5 7.5mg
Preparation method
Glyceryl monooleate is heated to 45 ℃ of fusions, under stirring, adds the galanthamine hydrobromide stirring and dissolving, add Precirol again
Ato5, stirring and dissolving is even, is cooled to about 40 degree, is filled in the hard capsule, makes the slow releasing capsule that every capsules contains hydrobromic acid galantamine 5mg.
Embodiment 9
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 9
Constituent content (mg) in every in the preparation
Kurarinone 150mg
Glyceryl monooleate 380mg
Compritol?ATO?888 22mg
Gelucire43/01 19mg
Preparation method:
Glyceryl monooleate is heated to 60 ℃ of fusions, it is even to add the kurarinone dispersed with stirring under stirring, add Compritol ATO 888 and Gelucire43/01 again, after stirring, be cooled to about 40 degree, be filled in the hard capsule case, make the slow releasing capsule that every capsules contains kurarinone 150mg.
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 10
Constituent content (mg) in every in the preparation
Fluvastatin sodium 30mg
Glyceryl monooleate 375mg
Gelucire?33/01 30mg
Preparation method:
Glyceryl monooleate is heated to 47 ℃ of fusions, under stirring, adds the fluvastatin sodium stirring and dissolving, add Gelucire 33/01 again, after stirring, be cooled to about 38 degree, be filled in the hard capsule case, make the slow releasing capsule that every capsules contains fluvastatin sodium 30mg.
Embodiment 11
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 11
Constituent content (mg) in every in the preparation
Dihydroergotoxine methanesulfonate 2.5mg
Glyceryl monooleate 68mg
Gelucire43/01 3.5mg
Preparation method:
Glyceryl monooleate is heated to 45 ℃ of fusions, under stirring, add the dihydroergotoxine methanesulfonate stirring and dissolving, add Gelucire43/01 again, after stirring and dissolving is even, be cooled to about 40 degree, be filled in the hard capsule, make the slow releasing capsule that every capsules contains dihydroergotoxine methanesulfonate 2.5mg.
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 12
Constituent content (mg) in every in the preparation
Glyceryl monooleate 380mg
Gelucire?40/13 55mg
PEG400 105mg
Compritol?ATO?888 68mg
Polyoxyethylene sorbitan monoleate 20mg
Preparation method:
Glyceryl monooleate is heated to 60 ℃ of fusions, it is even to add PEG400, polyoxyethylene sorbitan monoleate and clarithromycin dispersed with stirring under stirring, add Gelucire 40/13 and Compritol ATO 888 again, after stirring, be cooled to 35 degree, be filled in the soft capsule, make the slow releasing capsule that every soft capsule contains clamycin 2 50mg.
Embodiment 13
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 13
Constituent content (mg) in every in the preparation
Tamoxifen Citrate 22.5mg
Glyceryl monooleate 285mg
Gelucire?40/13 26mg
Preparation method:
Glyceryl monooleate is heated to 45 ℃ of fusions, under stirring, adds the Tamoxifen Citrate stirring and dissolving, add Gelucire 40/13 again, after stirring, be cooled to about 38 degree, be filled in the hard capsule, make the slow releasing capsule that every capsules contains Tamoxifen Citrate 22.5mg.
Embodiment 14
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 14
Constituent content (mg) in every in the preparation
Loratadine 5mg
Glyceryl monooleate 108mg
Gelucire?40/13 8mg
Compritol?ATO?888 8mg
Preparation method:
Glyceryl monooleate is heated to 45 ℃ of fusions, under stirring, adds the loratadine stirring and dissolving, add Gelucire 40/13 and Compritol ATO 888 again, after stirring, be cooled to 40 degree, be filled in the hard capsule, make the slow releasing capsule that every capsules contains loratadine 5mg.
Embodiment 15
The prescription of liquid crystal slow releasing composition (slow releasing capsule) 15
Constituent content (mg) in every in the preparation
Trimebutine Maleate 100mg
Glyceryl monooleate 380mg
Gelucire?40/13 15mg
Propylene glycol 63mg
Compritol?ATO?888 42mg
Preparation method:
Glyceryl monooleate is heated to 55 ℃ of fusions, under stirring, add propylene glycol and Trimebutine Maleate stirring and dissolving, add Gelucire 40/13 and Compritol ATO 888 again, after stirring, be cooled to about 38 degree, be sub-packed in the soft capsule shell, make the slow releasing capsule that contains love song U.S. cloth 100mg in Malaysia in every capsules.
The drug release determination of the slow releasing capsule among the embodiment 16 embodiment 1-15
Test objective
Release characteristic to the slow releasing capsule among the embodiment 1-15 compares, with assess liquid crystal slow releasing composition of the present invention whether can be in the solution of simulation human body environment slow release of active ingredients;
Assay method
The test determination of release in vitro degree is as follows:
(1) preparation of need testing solution:
Get among the embodiment 1～15 each 6 of each slow releasing capsule of preparation,, adopt dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005) second method (slurry method) device according to drug release determination method (two appendix XD of Chinese Pharmacopoeia version in 2005).Used release medium of each active component and rotating speed are as follows:
Acemetacin: with water-pH7.2 phosphate buffer (4: 1) is solvent, and rotating speed is 100 rev/mins
Gliclazide: 900ml is a solvent with phosphate buffer (pH7.4), and rotating speed is 100 rev/mins
Lornoxicam: with pH7.4 phosphate buffer 900ml is solvent, and rotating speed is 50 rev/mins
Ditropan XL: with water 900ml is solvent, and rotating speed is 50 rev/mins
VENLAFAXINE HCL: with water 900ml is solvent, and rotating speed is 75 rev/mins
Indapamide: 250ml is a solvent with alcohol-water (5: 895), and rotating speed is 75 rev/mins
Galanthamine hydrobromide: with the 0.1mol/L hydrochloric acid solution is solvent, and rotating speed is 75 rev/mins
Kurarinone: with hydrochloric acid solution (9-1000) 900ml, rotating speed is 50 rev/mins
Fluvastatin sodium: with water 500ml is solvent, and rotating speed is 50 rev/mins
Dihydroergotoxine methanesulfonate: with 0.1mol/L hydrochloric acid solution 250ml is solvent, and rotating speed is 75 rev/mins
Isosorbide mononitrate: with water 900ml is solvent, and rotating speed is 100 rev/mins
Clarithromycin: with 0.1mol/L acetate buffer 900ml is solvent, and rotating speed is 100 rev/mins
Tamoxifen Citrate: with 0.02mol/L hydrochloric acid solution 1000ml is solvent, and rotating speed is 100 rev/mins
Loratadine: 900ml is a solvent with hydrochloric acid solution (9-1000), and rotating speed is 50 rev/mins
Trimebutine Maleate: with water 900ml is solvent, and rotating speed is 100 rev/mins
Get solution 5ml respectively at the stipulated time, filter with 0.45 micron microporous filter membrane, subsequent filtrate suitably dilutes the back as need testing solution.
(2) preparation of reference substance solution:
It is an amount of that 105 degree of learning from else's experience are dried to each active component reference substance of constant weight, makes the contrast solution that contains 20 micrograms among every 1ml approximately with suitable solvent dissolving and dilution.
(3) sample determination:
Acemetacin: adopt determined by ultraviolet spectrophotometry, the place measures absorbance respectively at the 319nm wavelength.
Gliclazide: adopt determined by ultraviolet spectrophotometry, the place measures absorbance respectively at the 228nm wavelength.
Lornoxicam: adopt determined by ultraviolet spectrophotometry, the place measures absorbance respectively at the 376nm wavelength.
Ditropan XL: adopt determined by ultraviolet spectrophotometry.Getting each 20ml of need testing solution and reference substance solution puts in the separatory funnel, respectively add bromocresol green solution and [get bromocresol green 0.2g, add 0.05mol/L sodium hydroxide solution 50ml dissolving, add phosphate buffer (pH2.8) 200ml again, regulate pH to 2.8 with phosphoric acid in case of necessity] 2.0ml and chloroform 10.0ml, jolting 3 minutes was placed 1 hour, divide and get chloroform solution, the place measures absorbance respectively at the 415nm wavelength.
VENLAFAXINE HCL: adopt high effective liquid chromatography for measuring.Chromatographic column is a filler with octyl silane group silica gel, and mobile phase is acetonitrile-0.1mol/L Ammonium biphosphate (40: 60), and flow velocity 1.0ml/min detects wavelength 230nm.
Indapamide: adopt determined by ultraviolet spectrophotometry, the place measures absorbance respectively at the 242nm wavelength.
Galanthamine hydrobromide: adopt high effective liquid chromatography for measuring.Chromatographic column is filler with silica gel, and mobile phase is methylene chloride-methanol=92: 8, and flow velocity 1.0ml/min detects wavelength 288nm.
Kurarinone: adopt high effective liquid chromatography for measuring.Chromatographic column is a filler with the octane bonded silica gel, and mobile phase is that (850ml: 150ml: 1.0g), flow velocity 1.0ml/min detects wavelength 215nm to 0.05mol/L sodium dihydrogen phosphate (phosphoric acid 2ml/L)-methanol-sodium perchlorate.
Fluvastatin sodium: adopt determined by ultraviolet spectrophotometry, the place measures absorbance respectively at the 235nm wavelength.
Dihydroergotoxine methanesulfonate: adopt high effective liquid chromatography for measuring.Chromatographic column is to fill phase with the octadecyl silane, and mobile phase is 0.005mol/L ammonium dibasic phosphate solution (regulating pH with phosphoric acid is 2.0)-methanol (55: 45, volume ratio), and flow velocity is 1.0ml/min, and the detection wavelength is 280nm.
Isosorbide mononitrate: adopt high effective liquid chromatography for measuring.Chromatographic column is to fill phase with the octadecyl silane, and mobile phase is methanol-water (30: 70, volume ratio), and flow velocity 1.0ml/min detects wavelength 220nm.
Clarithromycin: adopt high effective liquid chromatography for measuring.Chromatographic column is to fill phase with the octadecyl silane, and mobile phase is mixture of acetonitrile-phosphate buffer (60: 40, volume ratio), and flow velocity is 1ml/min, and the detection wavelength is 210nm.
Tamoxifen Citrate: adopt determined by ultraviolet spectrophotometry, the place measures absorbance respectively at the 275nm wavelength.
Loratadine: adopt determined by ultraviolet spectrophotometry, the place measures absorbance respectively at the 275nm wavelength.
Trimebutine Maleate: adopt determined by ultraviolet spectrophotometry, the place measures absorbance respectively at the 267nm wavelength.
Result of the test
See Fig. 1 according to drug release determination experimental technique gained experimental result.
Fig. 1 result shows that (specification: the 40mg/ sheet, the special medicine company limited of Shandong southern Shandong shellfish is produced trade name: Xin Kang, lot number: 060803) have similar release in vitro behavior to embodiments of the invention 1 with commercially available isosorbide mononitrate sustained release tablets.Liquid crystal slow releasing composition provided by the present invention (slow releasing capsule) (embodiment 2-15) all has the obvious in-vitro slow release characteristic.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (5)
1, a kind of oral liquid-crystal sustained-release composition is characterized in that, it comprises:
The active component of 100 weight portions;
The glyceryl monooleate of 100-5000 weight portion;
The pharmaceutically acceptable matrix material of 10-500 weight portion;
Described active component is selected from acemetacin, gliclazide, lornoxicam, ditropan XL, VENLAFAXINE HCL, indapamide, galanthamine hydrobromide, kurarinone, fluvastatin sodium, dihydroergotoxine methanesulfonate, isosorbide mononitrate, clarithromycin, Tamoxifen Citrate, loratadine, Trimebutine Maleate;
Described matrix material is selected from one or more in Gan You behenic acid ester, palmitic acid stearic acid ester of glycerol, tristearin, polyethyleneglycol glyceride, the glyceryl monostearate.
2, liquid crystal slow releasing composition as claimed in claim 1 is characterized in that, also can contain the additive of 10-400 weight portion, and described additive is selected from one or more in pharmaceutically acceptable solvent, the pharmaceutically acceptable surfactant.
3, liquid crystal slow releasing composition as claimed in claim 1 is characterized in that, the content of described glyceryl monooleate is the 150-3500 weight portion.
4, liquid crystal slow releasing composition as claimed in claim 1 is characterized in that, the content of described matrix material is the 20-350 weight portion.
5, the preparation method of liquid crystal slow releasing composition as claimed in claim 1, it comprises the steps:
(a) glyceryl monooleate is formed solution in the fusing of 35-60 degree, add active component stirring and dissolving or homodisperse;
(b) adding matrix material stirs;
(c) with the gained liquid cools to uniform temperature, be filled in hard capsule case or the soft capsule shell, prepare slow releasing capsule;
Also can add other additives of 10-400 weight portion in described step (b), described additive is selected from one or more in pharmaceutically acceptable solvent, the pharmaceutically acceptable surfactant.
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| CN101953798A (en) * | 2010-09-21 | 2011-01-26 | 中国药科大学 | Spray drying sustained-release liquid crystal nano particles containing paeonol and preparation thereof |
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| CN109320428A (en) * | 2017-08-01 | 2019-02-12 | 浙江普利药业有限公司 | A kind of Trimebutine Maleate crystal form and preparation method thereof |
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| CN107375224B (en) * | 2017-08-02 | 2019-09-13 | 浙江康德药业集团股份有限公司 | A kind of Gliclazide sustained-release tablet |
| CN109549967A (en) * | 2018-12-20 | 2019-04-02 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of sophora alapecuroides slow-releasing granules and preparation method thereof |
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