CN1686133A - Soft capsule medicinal preparation - Google Patents
Soft capsule medicinal preparation Download PDFInfo
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- CN1686133A CN1686133A CN 200510059783 CN200510059783A CN1686133A CN 1686133 A CN1686133 A CN 1686133A CN 200510059783 CN200510059783 CN 200510059783 CN 200510059783 A CN200510059783 A CN 200510059783A CN 1686133 A CN1686133 A CN 1686133A
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- soft capsule
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Abstract
An orally taken capsule of fluorocinnarizine hydrochloride is disclosed, which features quickly taking its high curative effect.
Description
Technical field
The present invention relates to comprise the drug oral preparation of flunarizine hydrochloride, specifically relate to strengthen the soft capsule dosage form of flunarizine hydrochloride beneficial effect.
Background technology
Flunarizine hydrochloride (flunarizine hydrochloride) is the selectivity calcium ion antagonist, be used for treatment of diseases such as the maintenance treatment of brain and peripheral circulation obstacle and migraine, oral and be its first-selected route of administration through gastrointestinal absorption, at present peroral dosage forms such as existing tablet, capsule and oral liquid are (referring to Li Yang etc., China Dispensary, 2000,11 (3): 120-122; Tongji Medical Univ's journal, 2001,30 (2): 137-141; And CN1109333A).
Those skilled in the art know, and solid preparation need experience the process of disintegrate, stripping, absorption, and performance is very disadvantageous for effectiveness of insoluble drug for this, and oral liquid accurately fractionated dose, carry inconvenience and instability.Unfortunately, flunarizine hydrochloride promptly belongs to poorly water soluble drugs (the 1g medicine dissolves) in 100-1000ml water.The operation instructions of commercially available YANSUAN FUGUILIQIN JIAONANG point out, behind the oral flunarizine, and blood drug level peaking about 2-4 hour, this patient who is difficult to satisfy diseases such as migraine is to the urgent needs of relief of symptoms as early as possible.Therefore, develop the flunarizine hydrochloride oral formulations that to bring into play therapeutical effect fast and become the technical problem that those skilled in the art face.
Seemingly a kind of technical scheme that addresses the above problem of soft (gelatin) capsule formulation.Yet up to now, nobody provides the foundation of science to the development of flunarizine hydrochloride soft capsule dosage form.The Chinese patent application that with the publication number is CN139189A is an example, and the applicant has disclosed a kind of soft gelatin capsule technology of flunarizine hydrochloride, claims " flunarizine hydrochloride is sealed in the soft gelatin capsule with liquid condition ", but does not indicate the true concrete state of liquid.The inventor attempts to reappear its invention by a large amount of experiments.Regrettably, the inventor finds that there is following substantial limitations in the technology of CN139189A:
1) liquid that obtains is non-transparent state, wherein is mixed with the not crystallization of dissolved substance in the fluid matrix.Those skilled in the art know, and the crystal formation of medicine and drug effect and poisonous side effect of medicine are closely related, and the crystalline drug that exists in the solution through regular meeting crystal formation change or medicine gathering takes place, and so just exist and make the probability that drug effect reduces or toxic and side effects increases;
2) active component that the technology that discloses of CN139189A can not load clinical demand amount.For example, the heavy 400-600mg of its every seed lac ball that makes, and the flunarizine hydrochloride content in every seed lac ball only is 0.5mg (adjuvant almost accounts for 100%) by flunarizine.And existing preparation specification before this be 5mg or 10mg (by flunarizine) and every day dose be 10-20mg (by flunarizine), this shows by CN139189A drug prepared use amount every day up to the 20-40 grain, and this has greatly increased patient's financial burden and compliance not.
3) according to the description of CN139189A, those skilled in the art be difficult to prediction and implement this application people described " it is sealed in the soft gelatin capsule with liquid form; it can guarantee that this medicine is relatively stable at the intravital dissolution rate of people; and can guarantee its bioavailability ", therefore should to be considered as be deterioration to prior art to this technology.
Therefore, those skilled in the art are readily appreciated that, also wish to develop the soft capsule dosage form of flunarizine class medicine urgently, and it is the beneficial effect of onset and enhanced activity composition rapidly, and can be easily, without any the administration of uncomfortable ground.
Summary of the invention
The object of the invention has provided a kind of soft capsule, comprises that the flunarizine hydrochloride for the treatment of effective dose is as active component.In context, be understandable that, described active component is not limited to the hydrochlorate of flunarizine, and comprise inorganic acid salt, acylate beyond the acceptable demineralizing acid pharmaceutically, amino acid salts, the first-selected inorganic acid salt that adopts also comprises flunarizine or derivatives thereof or its various esters (being flunarizine or its officinal salt or ester), for example cinnarizine, methanesulfonic acid flunarizine, flunarizine phosphate ester etc.
As mentioned above, flunarizine hydrochloride belongs to insoluble drug, and when it was carried in the soft capsule with non-complete dissolved state, the treatment concentration that is difficult to remain valid also was subjected to greatly influencing of individual patient condition.But, when adopting conventional solvent in order to obtain clear and bright solution, can make the soft capsule system that unpredicted trouble takes place, for example soft capsule content leakage, drug migration, solvent migration, rubber degeneration cause disintegrate defective and cause medicine can't discharge not onset etc.Therefore, at first will provide the fluid composition that is suitable for preparing soft capsule, said composition should be stable and not reduce the bioavailability of active component, even improve the bioavailability of active component significantly.
We have carried out deep research to the physicochemical property of flunarizine hydrochloride, particularly by screening and prescription to adjuvants such as soft capsule mesostroma and surfactants, address the above problem effectively, and the present invention has promptly been finished in further research on this basis.Compare with existing hard capsule, the rapid peaking of blood drug level behind the soft capsule oral of the present invention, and relative bioavailability significantly improves, and this effect is that those skilled in the art are unpredictable.
In one embodiment of the invention,, and improve its bioavailability thus, in the content of described soft capsule, added surfactant for better promotion active component stripping.Described surfactant is selected from: the alcohol of spans, Tweens, brejs, polyoxyethylene oil, polyethylene glycol hydrogenated oil, polyvinylpyrrolidone (PVP), Ka Bopu, pluronic, poloxamer, (hydrogenation) fabaceous lecithin, (hydrogenation) lecithin, (deoxidation) sodium cholate, C1-C15 with and ester and ethers or their mixed system.Preferred Tween 80, PVP, 1,2 or 1, ammediol, glycerol, triglyceride, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, pluronic, or their mixed system.Unfavorable phenomenons such as after adding above-mentioned surfactant, described soft capsule does not become turbid after placing for a long time, crystallize, this is to keeping bioavailability of medicament very favourable.Can think thus, preparation of the present invention except the dosage that has soft capsule preparation itself and have accurately, the characteristics such as stable storage, also have stable, the advantage that significantly improves of peaking and bioavailability rapidly of content.
In another embodiment of the present invention, it is optional in the described soft capsule that also to comprise aqueous matrix be content, described aqueous matrix is selected from: Polyethylene Glycol and ester thereof and ethers, C1-C20 alcohol with and ester and ethers (comprising its dehydrate) or their mixed system.Preferred Macrogol 200-1000, sorbitol, anhydro sorbitol, fatty acid esters of sorbitan, Isosorbide dimethyl ether or their mixed system.
In the content of soft capsule of the present invention is formed, the weight proportion of key component is: active component/surfactant/substrate=0.1-10: 1-300: 0-300, the preferred weight proportioning is an active component: surfactant: substrate=0.15-8: 5-200: 2-200, more preferably active component: surfactant: substrate=0.2-5: 10-100: 5-100.Wherein, the content of active component of the present invention is by flunarizine.
In one embodiment, soft capsule of the present invention comprises: 1) flunarizine hydrochloride (or its officinal salt or ester), content (by flunarizine) be at 1-50mg, preferred 1.5-35mg, more preferably 2.5-20mg; With 2) water-soluble base, preferred polyethylene glycols, content is 0-3000mg, preferred 20-2000mg; With 3) surfactant, for example C1-C6 alcohol or Tweens (for example tween 80), content is 10-2000mg, preferred 50-1000mg; With optional 4) cosurfactant, the alcohol of C1-C15 for example, PVP, preferably glycerine, 1,2-propylene glycol, content are 10-2000mg, preferred 100-1000mg.
Under the inappropriate condition of humidity, with PEG-400 is the soft capsule of substrate, it can absorb the balance that moisture in the soft capsule skin reaches self moisture, the highlyest can reach 20%, and the medicine that is present in the PEG substrate can move or diluted (showing as the fluctuated of content) also with the migration of moisture in the substrate.Therefore, in another embodiment, soft capsule content of the present invention comprises: 1) content (by flunarizine) is 1-50mg, preferred 1.5-35mg, more preferably 2.5-20mg; With 2) surfactant, Tweens (for example tween 80) for example, content is 10-3000mg, preferred 50-2000mg; With optional 3) cosurfactant, C1-C15 alcohol for example, PVP, preferably glycerine, 1,2-propylene glycol, sorbitol, content are 10-2000mg, preferred 100-1000mg.
At present clinically about the instruction of the beneficial effect of flunarizine hydrochloride and other active component coupling (for example referring to Zhejiang combination of Chinese and Western medicine magazine, 2004 1 phases; Chinese Journal of New Drugs and Clinical Remedies, 1997 5 phases; Guangdong Medical College's journal, 1999 2 phases; The medicine Leader, the 20th the 7th phase of volume of July calendar year 2001; The practical sacred disease magazine in Hebei, 6 phases of calendar year 2001 etc.), but the oral formulations that the someone hints or clearly instruction comprises flunarizine hydrochloride and other active component simultaneously as yet so far.The invention provides this technology, successfully in the flunarizine hydrochloride soft capsule, added other active component, for example two hydrogen Ergota (poison) alkali, sodium valproate, mountain (east) hyoscyamine, Cyproheptadine, betahistine, nimodipine, aspirin, analgesic (as: caffeine, lignocaine, tetracaine), ligustrazine, propylene glycol alginate sodium sulfate, propranolol, lomerizine, various vitamin, acetylcysteine, Chinese medicine extract (for example Radix Salviae Miltiorrhizae extract) or its extract active component etc., to improve the curative effect of flunarizine hydrochloride, and/or overcome untoward reaction behind the oral hydrochloride flunarizine, and/or reach synergism.
Other adjuvants in the soft capsule of the present invention can comprise antioxidant etc., and its weight percentage accounts for 0-20%.
Soft capsule material of the present invention is advisable with suitable elasticity, comprise sizing material and solvent, sizing material comprises plant gum and animal glue, as: arabic gum, carrageenin, xanthan gum, Algin, starch (derivant that comprises starch deep processed product or starch) glue, glutinous rice foxtail millet (Oryza glutinosa), foxtail millet corn, gelatin etc., preferred gelatin; General selection water is solvent;
For solving soft capsule poor stability, oil impregnate and the slow shortcoming of disintegrate, the present invention takes selected sizing material control viscosity, iron-holder and kinetic parameter reached the purpose of strict screening capsule material.
In addition, aldehyde material and gelatin autoxidation process all can make gelatin take place crosslinked and influence disintegrate, for overcoming these influence factors, adopt to add an amount of plasticizer and buffer agent in the capsule material, through a large amount of tests, have successfully overcome the defective of above-mentioned soft capsule.Wherein plasticizer comprises glycerol, xylitol, sorbitol (acid anhydride), dimethicone, propylene glycol, Polyethylene Glycol, cyclodextrin, starch (derivant that comprises starch deep processed product or starch) class, various acid etc., preferably glycerine, Polyethylene Glycol, sorbitol (acid anhydride), citric acid, glycine.Buffer agent comprises various salt, acid and mixture
Each composition weight composition of this product capsule material is generally ratio and is: sizing material/plasticizer/water=1.0: 0.05-2.0: 0.1-2.5.Preferred 1.0: 0.3-1.0: 0.7-1.5.Glue pH is at 1.0-12.0, preferably in 2.5-8.0, final glue shell water content at 0.5%-25%, preferred 1%-10%.
For making capsule more stable and sensation is better, can in glue, add an amount of antiseptic, antioxidant, opacifier, aromatic and pigment etc.
The present invention does not make specific limited to the preparation method of soft capsule, can adopt this area conventional method, for example pressing or dropping preparation method (drop pill method).The face shaping of described soft capsule is not made specific limited, can be existing arbitrary shape.Every heavy 50-5000mg of content in the soft capsule of the present invention, preferred 200-1000mg, more preferably 300-700mg.
Embodiment 1
Prescription
Constituent content (mg/ capsule/grain)
Flunarizine hydrochloride 6
PEG-400????????????????????????????100
Sorbitol 100
Tween 80 80
Glycerol 50
Amount to 336
Technology:
Get recipe quantity PEG-400, sorbitol, tween 80 and glycerol, about 40 ℃, fully stir and make dissolving and mix homogeneously fully, add flunarizine hydrochloride and be stirred to dissolving fully, be chilled to the room temperature post-treatment and become soft capsule.
Embodiment 2
Prescription
Constituent content (mg/ capsule/grain)
Flunarizine hydrochloride 5
PEG-400??????????????????200
1,2 propylene glycol 100
Amount to 305
Technology:
Get the recipe quantity flunarizine hydrochloride, add PEG-400 and 1, the 2-propylene glycol fully stirs about 40 ℃, and medicine is dissolved fully, is chilled to the room temperature post-treatment and becomes soft capsule.
Embodiment 3
Prescription
Constituent content (mg/ capsule/grain)
Flunarizine hydrochloride 7
PEG-400???????????????100
1,2 propylene glycol 100
Tween 80 65
Amount to 272
Technology:
Get the recipe quantity flunarizine hydrochloride, add PEG-400, tween 80 and 1, the 2-propylene glycol, stirring is dissolved medicine fully about 40 ℃, is chilled to the room temperature post-treatment and becomes soft capsule.
Embodiment 4
Prescription
Constituent content (mg/ capsule/grain)
Flunarizine hydrochloride 4
PEG-400???????????????100
Tween 80 80
Amount to 184
Technology:
Get the recipe quantity flunarizine hydrochloride, add PEG-400, tween 80, stirring is dissolved medicine fully under 30-40 ℃ of condition, is chilled to the room temperature post-treatment and becomes soft capsule.
Embodiment 5
Prescription
Constituent content (mg/ capsule/grain)
Flunarizine hydrochloride 8
Tween 80 100
1,2 propylene glycol 200
PVP?????????????????????????50
Amount to 358
Technology:
Get the recipe quantity flunarizine hydrochloride, add tween 80 and 1, the 2-propylene glycol, stirring is at room temperature dissolved medicine fully, is processed into finished product.
Embodiment 6
Prescription
Constituent content (mg/ capsule/grain)
Flunarizine hydrochloride 12
PEG-400????????????????????200
PEG-1000???????????????????50
Fatty acid esters of sorbitan 150
1,2 propylene glycol 150
Polyoxyethylene alcohol 30
Triglyceride 80
Amount to 672
Technology:
Get recipe quantity PEG-400, PEG-1000,1,2 propylene glycol, fatty acid esters of sorbitan, polyoxyethylene alcohol and triglyceride, about 40 ℃, fully stir and make dissolving and mix homogeneously fully, add flunarizine hydrochloride and be stirred to dissolving fully, be chilled to the room temperature post-treatment and become soft capsule.
Embodiment 7
Prescription
Constituent content (mg/ capsule/grain)
Phosphoric acid flunarizine 7
Tween 80 70
1,2 propylene glycol 150
Amount to 227
Technology:
Get recipe quantity phosphoric acid flunarizine, add tween 80 and 1, the 2-propylene glycol, stirring is at room temperature dissolved medicine fully, is processed into finished product.
Embodiment 8
Prescription
Constituent content (mg/ capsule/grain)
Flunarizine hydrochloride 3
Nimodipine 20
Ethanol 1
Tween 80 210
Isosorbide dimethyl ether 60
Glycerol 45
Amount to 339
Technology
Get recipe quantity tween 80, Isosorbide dimethyl ether and glycerol, about 40 ℃, fully stir and make dissolving and mix homogeneously fully, add flunarizine hydrochloride and be stirred to dissolving fully; Standby.
Other gets the recipe quantity nimodipine, adds dissolve with ethanol, adds in the above-mentioned reserve liquid, stirs post-treatment and becomes soft capsule.
Embodiment 9
Prescription
Constituent content (mg/ capsule/grain)
Flunarizine hydrochloride 3
Radix Salviae Miltiorrhizae extract 100
PEG-400?????????????300
Glycerol 20
Tween 80 100
Cera Flava 11
Lecithin 100
Hydrogenated palm oil 100
Amount to 734
Technology
Get the recipe quantity Radix Salviae Miltiorrhizae extract, fully grind, behind 200 mesh sieves, standby excessively.
Get recipe quantity PEG-400, glycerol, tween 80, about 40 ℃, fully stir and make mix homogeneously, add flunarizine hydrochloride and be stirred to dissolving fully, add after standby Radix Salviae Miltiorrhizae extract is chilled to room temperature, add Cera Flava, lecithin and hydrogenated palm oil, the mix homogeneously post-treatment becomes soft capsule.
Comparative test 1 slaking test
Press the method for measuring inspection technique disintegration in two appendix of Chinese Pharmacopoeia version in 2000, the sample that the method by embodiment 1 prepares is measured.Determination data sees Table 1.
Comparative test 2 external dissolution tests
Press and measure method of dissolution in two appendix of Chinese Pharmacopoeia version in 2000 (XC second method), the sample for preparing by the method for implementing 1 is measured.With the 500ml hydrochloric acid solution is dissolution medium, adopts high performance liquid chromatography to measure, and is filler with the base silane bonded silica gel wherein; Methanol: water: glacial acetic acid: triethylamine (70: 30: 0.15: 0.1) be mobile phase; Detect wavelength 254nm; Calculate by external standard method with peak area.Data see Table 1
Comparative test 3 bioavailability
Adopt high performance liquid chromatography-fluorescence detection, the relative bioavailability of measuring the homemade YANSUAN FUGUILIQIN JIAONANG of single oral (selecting the YANSUAN FUGUILIQIN JIAONANG of Xi'an Yang Sen), pressing sample, example 1 sample and the reference preparation (selecting the YANSUAN FUGUILIQIN JIAONANG of Xi'an Yang Sen) of the preparation of CN139189A method adopts the 3p97 deal with data that the relative bioavailability of three and reference preparation is estimated.The result shows, preparation of the present invention significantly improves in the body and absorbs, and significantly improves bioavailability, significantly is better than existing flunarizine hard capsule preparation.
Table 1: comparative test result
| Project | Commercially available capsule | The CN139189A prescription | The prescription of embodiment 1 |
| Drug content (flunarizine) | ????5mg | ????0.5mg | ????5mg |
| External disintegration time | 8 minutes | 8 minutes | 7 minutes |
| External dissolution test | ????84％ | ????6.1％ | ????97％ |
| The peak time of bioavailability test in the body | ?????2.97±0.62hr | ????2.20±1.07hr | ????1.94±0.76hr |
| Relative bioavailability | ?????----- | ????16.01±14.75％ | ????116.18±13.22％ |
Claims (10)
1. pastille soft capsule dosage form comprises:
A. active component is by flunarizine, and content is flunarizine or its officinal salt or the ester of 1-50mg;
B. content is the surfactant of 10-5000mg.
2. according to the soft capsule dosage form of claim 1, described surfactant is selected from: the alcohol of spans, Tweens, brejs, polyoxyethylene oil, polyethylene glycol hydrogenated oil, polyvinylpyrrolidone (PVP), Ka Bopu, pluronic, poloxamer, fabaceous lecithin, hydrogenated soybean lecithin, lecithin, hydrolecithin, sodium cholate, NaTDC, C1-C15 with and ester and ethers or their mixed system.
3. according to the soft capsule dosage form of claim 1, described surfactant is selected from: Tween 80, PVP, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, pluronic, or their mixed system, its content are 10-5000mg.
4. according to the soft capsule dosage form of one of claim 1-3, the alcohol that further comprises C1-C15 with and ester and ethers, its content is 10-2000mg.
5. according to the soft capsule dosage form of claim 4, the alcohol of described C1-C15 with and ester and ethers be 1,2 or 1, ammediol, glycerol or triglyceride, its content are 100-1000mg.
6. according to the soft capsule dosage form of one of claim 1-5, further comprise water-soluble base, its content is 0-3000mg.
7. according to the soft capsule dosage form of claim 6, described water-soluble base is selected from: Polyethylene Glycol and ester thereof and ethers, C1-C20 alcohol with and ester, ethers, dehydrate, or their mixed system.
8. according to the soft capsule dosage form of claim 7, further contain the active component that is selected from 9,10-Dihydroergotoxine, two hydrogen ergotoxine, sodium valproate, Anisodamine, scopolamine, Cyproheptadine, betahistine, nimodipine, aspirin, analgesic, ligustrazine, propylene glycol alginate sodium sulfate, propranolol, lomerizine, various vitamin, acetylcysteine, Chinese medicine extract.
9. according to the soft capsule dosage form of one of claim 1-8, described flunarizine or its officinal salt or ester are meant its acid-addition salts, and its content is 1.5-35mg.
10. according to the soft capsule dosage form of one of claim 1-8, described acid-addition salts is meant flunarizine hydrochloride, and its content is 2.5-20mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510059783 CN1686133A (en) | 2005-04-01 | 2005-04-01 | Soft capsule medicinal preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510059783 CN1686133A (en) | 2005-04-01 | 2005-04-01 | Soft capsule medicinal preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1686133A true CN1686133A (en) | 2005-10-26 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510059783 Pending CN1686133A (en) | 2005-04-01 | 2005-04-01 | Soft capsule medicinal preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1686133A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111728954A (en) * | 2020-04-10 | 2020-10-02 | 锦州九泰药业有限责任公司 | Betahistine hydrochloride soft capsule and preparation method thereof |
-
2005
- 2005-04-01 CN CN 200510059783 patent/CN1686133A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111728954A (en) * | 2020-04-10 | 2020-10-02 | 锦州九泰药业有限责任公司 | Betahistine hydrochloride soft capsule and preparation method thereof |
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