CN101773484B - 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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- CN101773484B CN101773484B CN2010101392045A CN201010139204A CN101773484B CN 101773484 B CN101773484 B CN 101773484B CN 2010101392045 A CN2010101392045 A CN 2010101392045A CN 201010139204 A CN201010139204 A CN 201010139204A CN 101773484 B CN101773484 B CN 101773484B
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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, substantially meets zero level release dynamics rule.The common oral preparation blood concentration fluctuation is large, and patient dependence is poor, is unfavorable for clinical treatment, its exploitation slow controlled release constant speed delivery formulations is once-a-day met to the needs of clinical development.The osmotic pump type controlled release preparation that the osmotic pressure of take is main release power is one of topmost constant speed delivery formulations, it is because external enwergy in design time maintains constant permeable pressure head, in preparation, meet water dissolution or evenly the medicine of suspendible discharge constant release power be provided with zero level.The constant release of medicine has been avoided the peak valley phenomenon of blood drug level in body effectively, has reduced the drug side effect caused 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 in sheet, osmotic pressure is higher than external agency, and drug solution or suspension constantly are released from aperture.
Location discharges can be increased local therapeutic effects or increase the absorption of specific absorption position to medicine.Although most controlled release system can well be controlled drug release, the bioavailability of medicine 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 medicine is discharged at gastric at stomach, delaying gastric emptying is the corresponding soak time that extended, and can obviously improve absorbtivity.The float type gastric retention system is one of most important location delivery formulations, mainly refer to according to the fluid dynamic equilibrium principle design, can in gastric juice, keep the system of floating state.Can be divided into again non-effervescence type floating system and the floating gastric retention system of effervescence type according to this system of floating mechanism.Non-effervescent float type gastric retention system utilizes autologous density to be less than gastric content density and be floating state 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 made 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 is to provide a kind of gastric-floating osmotic pump non-homogeneous film capsule controlled release system and preparation method thereof.
Non-homogeneous film capsule in the present invention is a kind of asymmetric double-deck putamina be prepared from by capsule material liquid and quenching liquid, refers to Fig. 1.Its skin be fine and close thin layer in order to guarantee the rigidity of shell, 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 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, occur afterwards to change mutually, liquid capsule material liquid changes into gradually solid-state and is deposited on mould.After mould dip quench liquid, due to the non-solvent in capsule material liquid and polymer immiscible but mix with quenching liquid, therefore non-solvent breaks away from solid-state capsule material liquid, from the semi permeability compacted zone, flow out and enter quenching liquid, then in solid-state capsule material liquid, form 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 the adjuvant compacting step of going forward side by side is in flakes made, and the present invention directly pours into the pharmacological active substance in order to suppress osmotic pump preparation and adjuvant in non-homogeneous film capsule with powder type, by capsule cap and the fastening of capsule body sealing, make a call to an aperture at the either side of capsule, see Fig. 2.Whole system has been simulated the structure of common osmotic tablet: in the present invention, the powder of pharmacological active substance and adjuvant is identical with the label of common osmotic pumps compacting, the semi permeability polymer film-coat function class of non-homogeneous film capsule shell and common osmotic pump tablet outsourcing in the present invention seemingly, and all punch and Mechanism of Drug Release consistent.Different, the present invention is directly with the powder filling capsule, and the whole capsule that gently makes of powder density is similar to hollow, take osmotic pressure in the power constant speed release medicine, and system can float on medium all the time.Therefore oral medicine-releasing system be prolong drug release time under one's belt greatly, improved 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 defect that bioavailability is not high, and system is the same with common osmotic pump type preparation, take osmotic pressure as power constant speed release medicine (seeing Fig. 3), effectively avoided the peak valley phenomenon of blood drug level in body, reduced 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 with 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 be prepared from by capsule material liquid and quenching liquid, and skin is for fine and close thin layer in order to guarantee the rigidity of shell, and internal layer is that the porous thick-layer is in order to guarantee the water flowing of shell; It is comprised of capsule cap and capsule body; Pharmacological active substance and adjuvant are directly loaded wherein with powder type, and with capsule material liquid, capsule cap and capsule body are sealed; Because light this feature of the density of powder makes system at floating in stomach, take osmotic pressure as the dynamic Control release simultaneously.Pharmacological active substance comprises all materials that 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 suspensoid is selected from polyoxyethylene that molecular weight is 100000～500000 and/or one or more in arabic gum and/or sodium alginate and/or hypromellose; 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 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 that any at capsule makes a call to the aperture that a diameter is 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 acetylbutyrylcellulose; Described solvent is selected from one or more in acetone and/or ethanol and/or isopropyl alcohol and/or butanols and/or 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 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 comprises the following steps:
The preparation of A, non-homogeneous film capsule shell:
(1) 10 seconds of capsule hat cone tool immersion capsule material liquid that the capsule body mould that is 5mm by internal diameter and internal diameter are 6mm;
(2) slowly mould is extracted out with the speed of 0.2-0.3cm/s, kept die horizontal and rotated for 5 seconds, make capsule material liquid uniform settlement around mould;
(3) by mould dip quench liquid 60 minutes;
(4) mould is taken out and peels off immediately, softgel shell is dry more than 12 hours under room temperature, then according to the amount of content, capsule cap and capsule body are cut into to suitable length;
The preparation of B, stomach floating system:
(1) pharmacological active substance, suspensoid and penetrating agent are crossed to 80 mesh sieves, by recipe quantity, take above material, mix homogeneously;
(2) above-mentioned mixed-powder is poured into to the non-homogeneous film capsule body, the capsule cap is held in outside the capsule body, use capsule material fluid-tight mouth simultaneously, dry under room temperature;
(3) any at capsule punches with laser or power auger.Pharmacokinetic studies in Beagle dog body
The test preparation that is subject to of choosing is famotidine gastric-floating osmotic pump non-homogeneous film capsule controlled release system prepared by embodiment 1, and the reference preparation of choosing is commercially available famotidine tablets.6 Beagle dogs are divided into to two groups at random, on an empty stomach lower Beagle dog (fasting 12h before administration) is carried out to single-dose, the clean phase in each cycle is one week, and dosage is 40mg.First three week of administration and experimental session must not be taken any other medicine, during administration, freely drink water, and unified feed after administration 4h.Concrete dosage regimen sees the following form:
Reference preparation is before administration, after 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 subject to test preparation before administration, after 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, respectively at the about 4ml of dog lower limb venous blood sampling, put into the centrifuge tube that scribbles heparin, the centrifugal 10min of 4000r/min, isolate blood plasma and save backup in-20 ℃ immediately.Get 0.6ml during plasma treatment, be placed in 15ml tool plug test tube, add interior mark 50 μ l, 7.5% oxammonium hydrochloride. aqueous solution 100 μ l and saturated sodium carbonate 200 μ l, vortex vibration 2min, then add chromatographically pure ethyl acetate 6ml, vortex vibration 5min, the centrifugal 10min of 4000r/min, separate organic layer in another centrifuge tube, with nitrogen, dries up under 60 ℃, 100 μ l mobile phases redissolution 5min for the gained enriched substance, get 100 μ l solution sample introductions after the 10000r/min high speed centrifugation.
The determination of plasma concentration result is as following table:
Reference preparation
Be subject to test preparation
Its plasma concentration curve is shown in Fig. 4.By DAS software, data are processed, drawn following result: in the reference preparation body, each mean parameter is T
1/2=14.511h, C
max=5.212 μ g/ml, T
max=2.083h, AUC
(0-∞)=35.739 μ g/mlh; Being subject to each mean parameter in the 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-∞)tested/AUC
(0-∞) reference=50.400/35.739=141.022%.
As can be seen here, in the present invention, the beneficial effect of gastric-floating osmotic pump non-homogeneous film capsule controlled release system is remarkable: at first, compare with ordinary preparation and effectively avoided the peak valley phenomenon of blood drug level in the body, reduced drug side effect, extend the release time of medicine, played slow controlled-release effect; Simultaneously, due to system holdup time prolongation under one's belt, increased the absorption of medicine in effective site, thereby bioavailability is significantly improved.
The accompanying drawing explanation
Fig. 1 is non-homogeneous film capsule shell cross-sectional scans Electronic Speculum picture
Fig. 2 is the non-homogeneous film capsule outside drawing
Fig. 3 is the 12 hours release percent-time graphs of gastric-floating osmotic pump non-homogeneous film capsule controlled release system cumulative in vitro according to embodiment 1 preparation
The blood drug level that Fig. 4 is famotidine gastric-floating osmotic pump non-homogeneous film capsule controlled release system and commercially available famotidine tablets 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) 10 seconds of capsule hat cone tool immersion capsule material liquid that the capsule body mould that is 5mm by internal diameter and internal diameter are 6mm;
(2) slowly mould is extracted out with the speed of 0.3cm/s, kept die horizontal and rotated for 5 seconds, make capsule material liquid uniform settlement around mould;
(3) by mould dip quench liquid 60 minutes;
(4) mould is taken out and to peel off immediately, softgel shell is dry more than 12 hours under room temperature, then according to the amount of content by capsule cap and the 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 to 80 sieves, by recipe quantity, take above material, mix homogeneously;
(2) above-mentioned mixed-powder is poured into to the non-homogeneous film capsule body, the capsule cap is held in outside the capsule body, use capsule material fluid-tight mouth simultaneously, dry under room temperature;
(3) any at capsule beats the 0.4mm aperture with power auger, obtains 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: with embodiment 1, obtain famotidine gastric-floating osmotic pump non-homogeneous film capsule controlled release system.
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: with embodiment 1, obtain atenolol gastric-floating osmotic pump non-homogeneous film capsule controlled release system.
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, supplement equal-volume equality of temperature release medium simultaneously.Suitably dilute after crossing 0.8 μ m microporous filter membrane, take release medium as blank, measure trap in the 266nm place, calculate the cumulative release degree.
What Fig. 3 meaned is the 12 hours release percent-time graphs of gastric-floating osmotic pump non-homogeneous film capsule controlled release system cumulative in vitro according to embodiment 1 preparation, and result shows that this system release is complete, and release profiles is linear good, is zero-order release.
Claims (1)
1. a gastric-floating osmotic pump non-homogeneous film capsule controlled release system, it is comprised of the non-homogeneous film capsule shell with drug release hole and the content that is loaded in the inside, and it is characterized in that: its prescription consists of:
The content prescription:
Famotidine 40mg
The polyoxyethylene 200mg of molecular weight 1,000,000
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) 10 seconds of capsule hat cone tool immersion capsule material liquid that the capsule body mould that is 5mm by internal diameter and internal diameter are 6mm;
(2) slowly mould is extracted out with the speed of 0.3cm/s, kept die horizontal and rotated for 5 seconds, make capsule material liquid uniform settlement around mould;
(3) by mould dip quench liquid 60 minutes;
(4) mould is taken out and to peel off immediately, softgel shell is dry more than 12 hours under room temperature, then according to the amount of content by capsule cap and the 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 to 80 mesh sieves, by recipe quantity, take above material, mix homogeneously;
(2) above-mentioned mixed-powder is poured into to the non-homogeneous film capsule body, the capsule cap is held in outside the capsule body, use capsule material fluid-tight mouth simultaneously, dry under room temperature;
(3) any at capsule beats the 0.4mm aperture with power auger, obtains famotidine gastric-floating osmotic pump non-homogeneous film capsule controlled release system.
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| 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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| Publication Number | Publication Date |
|---|---|
| CN101773484A CN101773484A (en) | 2010-07-14 |
| CN101773484B true CN101773484B (en) | 2013-12-25 |
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| 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 |
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 | The anisotropic membrane of in discharging assembly, using |
| 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 | The anisotropic membrane of in discharging assembly, using |
| 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 |
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