CN101773484A - Gastric-floating osmotic pump non-homogeneous film capsule controlled release system and preparation method thereof - Google Patents
Gastric-floating osmotic pump non-homogeneous film capsule controlled release system and preparation method thereof Download PDFInfo
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- CN101773484A CN101773484A CN201010139204A CN201010139204A CN101773484A CN 101773484 A CN101773484 A CN 101773484A CN 201010139204 A CN201010139204 A CN 201010139204A CN 201010139204 A CN201010139204 A CN 201010139204A CN 101773484 A CN101773484 A CN 101773484A
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Abstract
The invention discloses a gastric-floating osmotic pump non-homogeneous film capsule controlled release system and a preparation method thereof, belonging to the technical field of medicinal preparation. The controlled release system comprises a non-homogeneous film capsule shell with drug release holes and contents loaded in the capsule shell. The contents comprise 5-30wt% of pharmacological active substance, 40-80wt% of suspension and 10-50wt% of penetrating agent. The non-homogeneous film capsule shell is an asymmetric two-layer film shell which is prepared from capsule material liquid and quenching liquid and comprises a capsule cap and a capsule body; the powdered contents are directly loaded in the capsule shell, the capsule material liquid is used to seal the capsule cap and the capsule body; a small opening with a diameter of 0.3-0.5 mm is drilled at any end of the capsule; and the powder has low density and the system can float in the stomach so as to overcome the defects of most of controlled release systems, such as short retention time in the stomach and intestine and low bioavailability.
Description
Technical field
The invention belongs to technical field of medicine, relate to a kind of gastric-floating osmotic pump non-homogeneous film capsule controlled release system and preparation method thereof.
Background technology
Sustained-release preparation can be divided into three kinds by the drug release type: constant speed, location and delayed release.The present invention relates to constant speed wherein and locate two types.
The constant speed release tech refers to that preparation discharges medicine in vivo with given pace, meets zero level release dynamics rule substantially.The common oral preparation blood concentration fluctuation is big, and patient dependence is poor, is unfavorable for clinical treatment, its exploitation slow controlled release constant speed delivery formulations is once-a-day met the needs of clinical development.With osmotic pressure is that the osmotic pump type controlled release preparation of main release power is one of topmost constant speed delivery formulations, itself since in design time external enwergy keep constant permeable pressure head, for meet in the preparation water dissolution or evenly the medicine of suspendible provide constant release power with zero level release.The constant release of medicine has been avoided the peak valley phenomenon of blood drug level in the body effectively, has reduced the drug side effect that causes because of peak concentration, has also improved patient's compliance simultaneously.The osmotic pump type preparation mostly is single-layer sheet and multilayer tablet form at present, and medicine and adjuvant are pressed into label, and the semipermeable polymer film-coat of outsourcing one deck is made a call to a hole with laser or machinery on film.In gastrointestinal tract, water can see through clothing film dissolved substance and adjuvant, and osmotic pressure is higher than external agency in the sheet, and drug solution or suspension constantly are released from aperture.
The location discharges can be increased local therapeutic effects or increase the absorption of specific absorption position to medicine.Though most controlled release system energy better controlled drug release, bioavailability of medicament is not high, and this is because these preparations are too short in the gastrointestinal holdup time, and many medicines are not released, absorb and just passed through absorption site.So, if preparation can be detained at stomach medicine is discharged at gastric, delaying gastric emptying is the corresponding soak time that prolonged, and then can obviously improve absorbtivity.The float type gastric retention system is one of most important location delivery formulations, mainly refers to according to the system fluid dynamic equilibrium principle design, can keep floating state in gastric juice.Can be divided into non-effervescence type floating system and the floating gastric retention system of effervescence type again according to this system of buoyant mechanism.Non-effervescent float type gastric retention system utilizes autologous density to be floating state less than gastric content density in gastric juice; Effervescent float type gastric retention system mainly utilizes the effervescent composition to run into gastric acid release gas or makes the fluid matrix gasification produce a kind of motion that makes progress and keep floating state.
The present invention combines the osmotic pump controlled-releasing principle and the novel stomach targeting sustained and controlled release preparation that obtains with the float type gastric retention system.
Summary of the invention
Technical problem to be solved by this invention provides a kind of gastric-floating osmotic pump non-homogeneous film capsule controlled release system and preparation method thereof.
Non-homogeneous film capsule among the present invention is a kind of asymmetric double-deck putamina that is prepared from by capsule material liquid and quenching liquid, sees Fig. 1 for details.Its skin is the rigidity of fine and close thin layer in order to the assurance shell, and internal layer is that the porous thick-layer is in order to guarantee the water flowing of shell.Its formation principle is: contain cellulosic polymer and solvent and non-solvent in the capsule material liquid, after mould immerses capsule material liquid and extracts out, the solvent evaporates on top layer, cause dissolving polymer wherein at first to form thin compacted zone, take place afterwards to change mutually, liquid capsule material liquid changes into solid-state gradually and is deposited on the mould.Behind mould dip quench liquid, because non-solvent and polymer in the capsule material liquid are immiscible but mix with quenching liquid,, enter quenching liquid from the outflow of semi permeability compacted zone so non-solvent breaks away from solid-state capsule material liquid, then in solid-state capsule material liquid, form the duct.Just formed the non-homogeneous film capsule of internal layer porous outer layer densification after the drying of peeling off.
Common osmotic pump type preparation is that pharmacological active substance and adjuvant compacting step of going forward side by side is in flakes made, and the present invention directly pours into pharmacological active substance and adjuvant in order to the compacting osmotic pump preparation in the non-homogeneous film capsule with powder type, with capsule medicated cap and the fastening of capsule body and seal, make a call to an aperture at capsular either side, see Fig. 2.Whole system simulation the structure of common osmotic tablet: the powder of pharmacological active substance and adjuvant is identical with the label of common osmotic pumps compacting among the present invention, the semi permeability polymer film-coat function class of non-homogeneous film capsule shell and common osmotic pump tablet outsourcing among the present invention seemingly and is all punched and release mechanism unanimity.Different is, the present invention is directly with powder fill capsule, and the whole capsule that gently makes of powder density is similar to hollow, and when being the power constant speed release medicine with the osmotic pressure, system can float on the medium all the time.So oral medicine-releasing system be prolong drug release time under one's belt greatly, improved the absorbtivity and the bioavailability of medicine.
To sum up, the objective of the invention is: a kind of gastric-floating osmotic pump non-homogeneous film capsule controlled release system and preparation method thereof is provided, by non-homogeneous film capsule and medicine and this combination of adjuvant powder, reduce system density, it is detained under one's belt, thereby it is too short in the gastrointestinal holdup time to overcome most controlled release system, the defective that bioavailability is not high, and system is the same with common osmotic pump type preparation, with the osmotic pressure is power constant speed release medicine (see figure 3), avoided the peak valley phenomenon of blood drug level in the body effectively, reduce drug side effect, improved patient's compliance.
The present invention is achieved through the following technical solutions:
The present invention by the non-homogeneous film capsule shell that has drug release hole and be loaded in the inside pharmacological active substance and adjuvant form.Described non-homogeneous film capsule shell is a kind of asymmetric double-deck putamina that is prepared from by capsule material liquid and quenching liquid, and skin is the rigidity of fine and close thin layer in order to the assurance shell, and internal layer is that the porous thick-layer is in order to guarantee the water flowing of shell; It is made up of capsule medicated cap and capsule body; Pharmacological active substance and adjuvant are directly loaded wherein with powder type, and capsule medicated cap and capsule body are sealed with capsule material liquid; Because of light this feature of the density of powder makes system at floating in stomach, be the dynamic Control release with the osmotic pressure simultaneously.Pharmacological active substance comprises the material that all are applicable to controlled release system, comprises anti-arrhythmic, vasodilation, antihypertensive, beta-blocker, oral antidiabetic, antirheumatic, antibiotic medicine, antidepressants, diuretic, antuepileptic, tranquilizer, antibiotic, analgesic, vitamin, hormone, antibacterial, polypeptide, enzyme and mucopolysaccharide, Chinese medicine extract.Adjuvant comprises suspensoid and penetrating agent, and wherein to be selected from molecular weight be 100000～500000 polyoxyethylene and/or in arabic gum and/or sodium alginate and/or the hypromellose one or more to suspensoid; Penetrating agent is selected from one or more in sodium chloride and/or potassium chloride and/or magnesium sulfate and/or sodium sulfate and/or sucrose and/or lactose and/or the mannitol.The percentage by weight of pharmacological active substance, suspensoid and penetrating agent is: pharmacological active substance 5%-30%, suspensoid 40%-80%, penetrating agent 10%-50%.Described drug release hole is at capsular any aperture that to make a call to a diameter be 0.3-0.5mm.
Capsule material liquid contains following component by weight percentage: cellulosic polymer 10%-20%, solvent 60%-80%, porogen 2%-20%, plasticizer 0%-10%.Wherein cellulosic polymer is selected from one or more in cellulose acetate and/or ethyl cellulose and/or the acetylbutyrylcellulose; Described solvent is selected from one or more in acetone and/or ethanol and/or isopropyl alcohol and/or butanols and/or the capryl alcohol; Described porogen is selected from glycerol and/or PEG400 and/or Macrogol 600; Described plasticizer is selected from one or more in triethyl citrate and/or dimethyl phthalate and/or diethyl phthalate and/or dioctyl phthalate and/or the DMEP.
Quenching liquid contains following component by weight percentage: water 65%-95%, glycerol 5%-35%.
The preparation method of gastric-floating osmotic pump non-homogeneous film capsule controlled release system may further comprise the steps:
The preparation of A, non-homogeneous film capsule shell:
(1) be that the capsule body mould of 5mm and capsule hat cone tool that internal diameter is 6mm immerse 10 seconds of capsule material liquid with internal diameter;
(2) slowly mould is extracted out with the speed of 0.2-0.3cm/s, the maintenance die horizontal also rotated for 5 seconds, made capsule material liquid uniform settlement around mould;
(3) with in the mould dip quench liquid 60 minutes;
(4) the mould taking-up is peeled off immediately, in dry more than 12 hours under the room temperature, the amount according to content cuts into suitable length with capsule medicated cap and capsule body then with softgel shell;
The preparation of B, stomach floating system:
(1) pharmacological active substance, suspensoid and penetrating agent are crossed 80 mesh sieves, take by weighing above material, mix homogeneously by recipe quantity;
(2) above-mentioned mixed-powder is poured into the non-homogeneous film capsule body, the capsule medicated cap is held in outside the capsule body, use capsule material fluid-tight mouth simultaneously, dry under the room temperature;
(3) capsular any one with the punching of laser or power auger.Pharmacokinetic studies in the Beagle dog body
The test preparation of choosing that is subjected to is the famotidine gastric-floating osmotic pump non-homogeneous film capsule controlled release system of embodiment 1 preparation, and the reference preparation of choosing is commercially available famotidine sheet.6 Beagle dogs are divided into two groups at random, and (fasting 12h before the administration) carries out single-dose to Beagle dog under the empty stomach, and the clean phase in each cycle is a week, and dosage is 40mg.First three week of administration and experimental session must not be taken any other medicine, freely drink water unified feed behind the administration 4h during the administration.Concrete dosage regimen sees the following form:
Reference preparation is before administration, after the administration 0.25,0.5,1.0,1.5,2.0,3.0,4.0,5.0,6.0,8.0,10.0,12.0,16.0 and 24.0h, be subjected to test preparation before administration, after the administration 0.5,1.0,1.5,2.0,3.0,4.0,5.0,6.0,8.0,10.0,12.0,16.0,24.0,32.0 and 36h, get the about 4ml of blood respectively at dog lower limb vein, put into the centrifuge tube that scribbles heparin, the centrifugal 10min of 4000r/min immediately, it is standby in-20 ℃ of preservations to isolate blood plasma.Get 0.6ml during plasma treatment, place 15ml tool plug test tube, mark 50 μ l, 7.5% oxammonium hydrochloride. aqueous solution, 100 μ l and saturated sodium carbonate 200 μ l in adding, vortex vibration 2min adds chromatographically pure ethyl acetate 6ml again, vortex vibration 5min, the centrifugal 10min of 4000r/min separates organic layer in another centrifuge tube, dries up with nitrogen under 60 ℃, the gained enriched substance is got 100 μ l solution sample introductions with 100 μ l mobile phases redissolution 5min behind the 10000r/min high speed centrifugation.
Determination of plasma concentration result such as following table:
Reference preparation
Be subjected to test preparation
Its plasma concentration curve is seen Fig. 4.By DAS software data are handled, drawn following result: each mean parameter is T in the reference preparation body
1/2=14.511h, C
Max=5.212 μ g/ml, T
Max=2.083h, AUC
(0-∞)=35.739 μ g/mlh; Being subjected to interior each mean parameter of test preparation body is T
1/2=23.634h, C
Max=2.924 μ g/ml, T
Max=4.000h, AUC
(0-∞)=50.400 μ g/mlh; Relative bioavailability=AUC
(0-∞)Be subjected to examination/AUC
(0-∞) reference=50.400/35.739=141.022%.
This shows, the beneficial effect of gastric-floating osmotic pump non-homogeneous film capsule controlled release system is remarkable among the present invention: at first, compare with ordinary preparation and to have avoided the peak valley phenomenon of blood drug level in the body effectively, reduced drug side effect, prolong the release time of medicine, played slow controlled-release effect; Simultaneously, because system's holdup time prolongation has under one's belt increased the absorption of medicine in effective site, thereby bioavailability is significantly improved.
Description of drawings
Fig. 1 is a non-homogeneous film capsule shell cross-sectional scans Electronic Speculum picture
Fig. 2 is the non-homogeneous film capsule outside drawing
Fig. 3 is gastric-floating osmotic pump non-homogeneous film capsule controlled release system cumulative in vitro release in the 12 hours percent-time graph according to embodiment 1 preparation
Fig. 4 be famotidine gastric-floating osmotic pump non-homogeneous film capsule controlled release system and commercially available famotidine sheet blood drug level through the time curve
The specific embodiment
Embodiment 1
The content prescription:
Famotidine 40mg
Polyoxyethylene (molecular weight 1,000,000) 200mg
Sodium chloride 100mg
Capsule material liquid prescription:
Cellulose acetate 15g
Acetone 65g
Isopropyl alcohol 35g
Glycerol 10g
Triethyl citrate 10g
The quenching liquid prescription:
Glycerol 35g
Water 65g
Preparation technology:
The preparation of A, non-homogeneous film capsule shell:
(1) be that the capsule body mould of 5mm and capsule hat cone tool that internal diameter is 6mm immerse 10 seconds of capsule material liquid with internal diameter;
(2) slowly mould is extracted out with the speed of 0.3cm/s, the maintenance die horizontal also rotated for 5 seconds, made capsule material liquid uniform settlement around mould;
(3) with in the mould dip quench liquid 60 minutes;
(4) mould taken out peel off immediately, with softgel shell in dry more than 12 hours under the room temperature, then according to the amount of content with capsule medicated cap and other cut growth 0.8cm of capsule status and 2cm;
The preparation of B, stomach floating system:
(1) famotidine, polyoxyethylene and sodium chloride are crossed 80 sieves, taken by weighing above material, mix homogeneously by recipe quantity;
(2) above-mentioned mixed-powder is poured into the non-homogeneous film capsule body, the capsule medicated cap is held in outside the capsule body, use capsule material fluid-tight mouth simultaneously, dry under the room temperature;
(3) beat the 0.4mm aperture at capsular any one with power auger, promptly get famotidine gastric-floating osmotic pump non-homogeneous film capsule controlled release system.
The content prescription:
Famotidine 40mg
Polyoxyethylene (molecular weight 2,000,000) 200mg
Sodium chloride 50mg
Capsule material liquid prescription:
Ethyl cellulose 15g
Acetone 65g
Ethanol 25g
Macrogol 600 3g
The quenching liquid prescription:
Glycerol 5g
Water 95g
Preparation technology:, promptly get famotidine gastric-floating osmotic pump non-homogeneous film capsule controlled release system with embodiment 1.
Embodiment 3
The content prescription:
Atenolol 25mg
Arabic gum 200mg
Lactose 125mg
Capsule material liquid prescription:
Cellulose acetate 15g
Acetone 100g
PEG400 8g
Diethyl phthalate 10g
The quenching liquid prescription:
Glycerol 22g
Water 78g
Preparation technology:, promptly get atenolol gastric-floating osmotic pump non-homogeneous film capsule controlled release system with embodiment 1.
Embodiment 4:
The famotidine floating osmotic pump non-homogeneous film capsule controlled release system cumulative in vitro drug release determination of embodiment 1 preparation:
According to two drug release determination method first methods of " The People's Republic of China's pharmacopeia " version in 2005, release medium is 900mL 0.1mo lL
-1HCl, rotating speed 100rmin
-1, medium temperature (37 ± 0.5) ℃.Respectively at 2,4,6,8,10 and 12h sampling 5mL, replenish equal-volume equality of temperature release medium simultaneously.Suitably diluting after crossing 0.8 μ m microporous filter membrane, is blank with the release medium, measures trap in the 266nm place, calculates the cumulative release degree.
What Fig. 3 represented is to discharge percent-time graph in 12 hours according to the gastric-floating osmotic pump non-homogeneous film capsule controlled release system cumulative in vitro that embodiment 1 prepares, and the result shows that this system's release is complete, and release profiles is linear good, is zero-order release.
Claims (8)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101392045A CN101773484B (en) | 2009-05-12 | 2010-03-10 | Gastric-floating osmotic pump non-homogeneous film capsule controlled release system and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100114980A CN101548964A (en) | 2009-05-12 | 2009-05-12 | Osmotic pump typed non-homogeneous membrane capsule sustained and controlled release system floating in stomach and preparation method thereof |
| CN200910011498.0 | 2009-05-12 | ||
| CN2010101392045A CN101773484B (en) | 2009-05-12 | 2010-03-10 | Gastric-floating osmotic pump non-homogeneous film capsule controlled release system and preparation method thereof |
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| CN101773484B CN101773484B (en) | 2013-12-25 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102379861A (en) * | 2011-11-02 | 2012-03-21 | 沈阳药科大学 | Osmotic-pump timing sustained and controlled release capsule and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1042072A (en) * | 1988-08-30 | 1990-05-16 | 美国辉瑞有限公司 | Asymmetric membranes for use in release assemblies |
| US5612059A (en) * | 1988-08-30 | 1997-03-18 | Pfizer Inc. | Use of asymmetric membranes in delivery devices |
| CN101569616A (en) * | 2009-06-09 | 2009-11-04 | 沈阳药科大学 | Sustained-controlled release system with intra-gastric floating osmotic-pump type non-uniform membrane capsules, and preparation method thereof |
-
2010
- 2010-03-10 CN CN2010101392045A patent/CN101773484B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1042072A (en) * | 1988-08-30 | 1990-05-16 | 美国辉瑞有限公司 | Asymmetric membranes for use in release assemblies |
| US5612059A (en) * | 1988-08-30 | 1997-03-18 | Pfizer Inc. | Use of asymmetric membranes in delivery devices |
| US5698220A (en) * | 1988-08-30 | 1997-12-16 | Pfizer Inc. | Asymmetric membranes in delivery devices |
| CN101569616A (en) * | 2009-06-09 | 2009-11-04 | 沈阳药科大学 | Sustained-controlled release system with intra-gastric floating osmotic-pump type non-uniform membrane capsules, and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102379861A (en) * | 2011-11-02 | 2012-03-21 | 沈阳药科大学 | Osmotic-pump timing sustained and controlled release capsule and preparation method thereof |
| CN102379861B (en) * | 2011-11-02 | 2013-06-19 | 沈阳药科大学 | Osmotic-pump timing sustained and controlled release capsule and preparation method thereof |
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