CN101772352B - Liquid composition for soft-capsule filling - Google Patents
Liquid composition for soft-capsule filling Download PDFInfo
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- CN101772352B CN101772352B CN2008801018522A CN200880101852A CN101772352B CN 101772352 B CN101772352 B CN 101772352B CN 2008801018522 A CN2008801018522 A CN 2008801018522A CN 200880101852 A CN200880101852 A CN 200880101852A CN 101772352 B CN101772352 B CN 101772352B
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- monoglyceride
- soft
- composition
- slightly solubility
- fatty acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
- A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
- A23D9/007—Other edible oils or fats, e.g. shortenings, cooking oils characterised by ingredients other than fatty acid triglycerides
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
- A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
- A23D9/007—Other edible oils or fats, e.g. shortenings, cooking oils characterised by ingredients other than fatty acid triglycerides
- A23D9/013—Other fatty acid esters, e.g. phosphatides
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/10—Foods or foodstuffs containing additives; Preparation or treatment thereof containing emulsifiers
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P10/00—Shaping or working of foodstuffs characterised by the products
- A23P10/30—Encapsulation of particles, e.g. foodstuff additives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P10/00—Shaping or working of foodstuffs characterised by the products
- A23P10/30—Encapsulation of particles, e.g. foodstuff additives
- A23P10/35—Encapsulation of particles, e.g. foodstuff additives with oils, lipids, monoglycerides or diglycerides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
Abstract
A liquid composition for filling soft capsules which comprises an edible oil and a sparingly oil-soluble ingredient dispersed therein, characterized by containing a reacted monoglyceride and a distilled monoglyceride as dispersion stabilizers for dispersing the sparingly oil-soluble ingredient.
Description
Technical field
The present invention relates to liquid composition for soft-capsule filling.
Background technology
The soft capsule that contains oily slightly solubility, pulverous effective ingredient is prepared as follows usually: in edible oil and fat, disperse effective ingredient to prepare dispersion liquid, this dispersion liquid is filled into in the capsule of gelatin as film, prepare above-mentioned soft capsule.At this moment, as be used for stable effective ingredients be dispersed in the dispersant of edible oil and fat, used fatty acid glyceride or Cera Flava (with reference to patent documentation 1) in the past.
But,, then might be able to not give full play to the effect of effective ingredient in vivo if known dispersant uses Cera Flava.Therefore, be dispersed in the technical scheme in the edible oil and fat as not using Cera Flava with making stable effective ingredients, for example proposed to process compositions (with reference to patent documentation 2) that greasy combination forms the effective ingredient suspensionization etc. through fatty acid glyceride and hydrogenation.
Yet, to compare with using mellisic existing thing, the dispersibility of effective ingredient existing problems in the above-mentioned technology may not be satisfactory.
Patent documentation 1: japanese kokai publication hei 7-138151 communique, paragraph " 0019 "
Patent documentation 2: TOHKEMY 2005-112753 communique, paragraph " 0020 "
Summary of the invention
The objective of the invention is to, provide and do not use Cera Flava, and have and use the liquid composition for soft-capsule filling of the dispersion stabilization of the equal above oily slightly solubility composition of mellisic existing prescription.In addition, the objective of the invention is to, provide oily slightly solubility composition dispersibility in vivo to use mellisic all right liquid composition for soft-capsule filling than dispersant.
The inventor furthers investigate in order to solve above-mentioned problem, and the result obtains following discovery.
(i) through using reaction monoglyceride and distillation monoglyceride as being used for the dispersion stabilizer of dispersed oil slightly solubility composition, though do not use Cera Flava also with oily slightly solubility stable components be dispersed in the edible oil and fat.
If (ii) further using the monoesters body burden is the diglycerine fatty acid ester more than 50%, the dispersibility of then oily slightly solubility composition in simulated gastric fluid is significantly improved.
The present invention is based on above-mentioned discovery and accomplishes, and following liquid composition for soft-capsule filling is provided.
That is, the present invention relates to:
(1) liquid composition for soft-capsule filling, it is dispersed oil slightly solubility composition forms in edible oil and fat compositions, it is characterized in that, contain as the reaction monoglyceride of the dispersion stabilizer that is used to disperse this oil slightly solubility composition and distillation monoglyceride and
(2) above-mentioned (1) described liquid composition for soft-capsule filling is characterized in that, further containing the monoesters body burden is the diglycerine fatty acid ester more than 50%.
In addition, the present invention relates to:
(3) process for dispersing of oily slightly solubility composition in edible oil and fat is characterized in that, comprise with the compositions that contains edible oil and fat, oily slightly solubility composition, reaction monoglyceride and distillation monoglyceride mix and the operation that stirs and
(4) above-mentioned (3) described process for dispersing is characterized in that, it is the diglycerine fatty acid ester more than 50% that compositions further contains the monoesters body burden.
Liquid composition for soft-capsule filling of the present invention does not contain Cera Flava.
Liquid composition for soft-capsule filling of the present invention has the dispersion stabilization that uses the equal above oily slightly solubility composition of mellisic existing thing with dispersant.Further; If it is the diglycerine fatty acid ester more than 50% that liquid composition for soft-capsule filling of the present invention contains the monoesters body burden; Then use mellisic existing thing to compare with dispersant, the dispersibility of oily slightly solubility composition in simulated gastric fluid is significantly improved.
The specific embodiment
Liquid composition for soft-capsule filling of the present invention is dispersed oil slightly solubility composition forms in edible oil and fat compositions, contains reaction monoglyceride and distillation monoglyceride as the dispersion stabilizer that is used to disperse this oil slightly solubility composition.Be preferably and further contain the compositions that the monoesters body burden is the diglycerine fatty acid ester more than 50%.Because through containing the monoesters body burden is the diglycerine fatty acid ester more than 50%, oily slightly solubility composition dispersibility in vivo is significantly improved, and gives full play to the effect of oily slightly solubility composition (effective ingredient) in vivo.
Edible oil and fat
The edible oil and fat that use among the present invention are if can be used as the edible oil and fat that the carrier of oily slightly solubility composition uses; Then not restriction especially; Can enumerate for example olive oil, Oleum sesami, Miyou, safflower oil, soybean oil, Semen Maydis oil, Oleum Brassicae campestris, Petiolus Trachycarpi oil, palm olein, palm-kernel oil, Oleum helianthi, grapefruit, Oleum Gossypii semen, Oleum Cocois, Semen arachidis hypogaeae wet goods Vegetable oil lipoprotein; In and fatty acid triglyceride, Squalene, fish oil etc.Edible oil and fat among the present invention are preferably Vegetable oil lipoprotein, are preferably the salad oil of Vegetable oil lipoprotein especially, wherein, are preferably the Flos Carthami salad oil.In the present invention, can use a kind of edible oil and fat, use but also combination in any is two or more.
Oil slightly solubility composition
The oily slightly solubility composition that uses among the present invention is made up of the low material of lipophile, has constituted the effective ingredient of liquid composition for soft-capsule filling of the present invention.
Oily slightly solubility composition among the present invention is a powder morphology, refers to this powder 1g to be joined among the edible oil and fat 100g and when mixing down for 20 ℃ undissolved material in 30 minutes.
This oily slightly solubility composition for example can be enumerated, nutritional supplementation compositions such as vitamins (particularly water soluble vitamins such as ascorbic acid, vitamin B1, vitamin B2, vitamin B6, vitamin B12), citric acid, hyaluronic acid, calcium powder; Health food compositions such as Lac regis apis extract powder (powder), propolis extract powder, vaccinium uliginosum extract powder, gill fungi extract powder, shark cartilage extract powder, Turmeric Root, ginkgo leaf extract powder, Gymnema Sylvestre extract powder, other animals and plants powder, lactose, oligosaccharide, chitosan, dietary fiber; Or active ingredient such as extracts from crude drugs powder, Chinese medicine, pharmaceutical composition.Wherein, be preferably vaccinium uliginosum extract powder, ginkgo leaf extract powder, vitamins.Oil slightly solubility composition can use a kind of or make up two or more the use.
The reaction monoglyceride
Unreacted glycerol obtains the reaction monoglyceride that uses among the present invention in order from the ester exchange reaction product of the esterification product of glycerol and fatty acid or glycerol and oils and fats (triglyceride), to remove as much as possible, for containing the mixture of monoglyceride (fatty acid monoglyceride), diglyceride (dialycerides fat acid esters) and triglyceride (fatty acid triglyceride).It is about 40～60% that the content of the monoglyceride in this reaction monoglyceride 100% is generally, and is preferably about 45～55%.In addition, it is about 15～40% that the content of the diglyceride of reaction in the monoglyceride 100% is generally, and is preferably about 20～30%.It is about 1～10% that the content of the triglyceride of reaction in the monoglyceride 100% is generally, and is preferably about 1～5%.
The composition of above-mentioned reaction monoglyceride promptly reacts the content of monoglyceride, diglyceride and triglyceride in the monoglyceride and tries to achieve through the reaction monoglyceride is analyzed with HPLC (HPLC).Specifically, can be under the analysis condition shown in following the analytical reactions monoglyceride, after the analysis,, measure peak area with integrator for the peak that is recorded in by data processing equipment on the chromatogram corresponding to each composition of test sample.Based on the peak area of measuring, try to achieve monoglyceride content, diacylglycerol content and content of triglyceride with area percentage rate mode.
The HPLC analysis condition below is shown.
(HPLC analysis condition)
Device: HPLC (model: LC-10AS; Society of Shimadzu Seisakusho Ltd. system)
Detector: RI detector (model: RID-6A; Society of Shimadzu Seisakusho Ltd. system)
Chromatographic column: connect two GPC chromatographic column (models: SHODEX KF-802; Clear and electrician society system)
Column temperature: 40 ℃
Mobile phase: THF
Flow: 1.0mL/min
Inspection liquid injection rate: 15 μ L
Constitute the fatty acid of the reaction monoglyceride that uses among the present invention; Preferably enumerate the carbon number that derives from edible animal and plant fat and be linear saturated fatty acids of 6～24 (for example caproic acid, sad, capric acid, lauric acid, myristic acid, Palmic acid, stearic acid, arachidic acid 、 behenic acid, lignoceric acid etc.) etc., more preferably Palmic acid, stearic acid 、 behenic acid etc.
As the method for making of the reaction monoglyceride that uses among the present invention, for example can enumerate the method for making that carry out through the esterification of glycerol and fatty acid the method for making that carry out through glycerol and greasy ester exchange reaction (1), (2).Below show these method for makings respectively briefly in (1) and (2).
The method for making of the reaction monoglyceride that (1) carries out through ester exchange reaction
For example; Glycerol and oils and fats joined with 2: 1 mol ratio have agitator, in the common reaction vessel of heating with sleeve pipe, baffle plate etc.; For example add sodium hydroxide as common catalyst and mix; Under nitrogen atmosphere, for example under about 180～260 ℃, preferred about 200～250 ℃, heat and carried out ester exchange reaction in about 0.5～15 hour, preferred about 1～3 hour.The reaction pressure condition optimization is under the normal pressure or under the decompression.The reactant liquor that obtains is the mixture that contains glycerol, fatty acid monoglyceride, dialycerides fat acid esters, fatty acid triglyceride etc.
After reaction finishes; Neutralization remains in the catalyst in the reactant liquor, then, residual glycerol is removed in the preferred distillation under reduced pressure of reactant liquor; Carry out processing such as desalination, decolouring, filtration as required, the reaction monoglyceride of 40～60% the monoglyceride of finally obtaining with respect to all contain having an appointment.
The method for making of the reaction monoglyceride that (2) carries out through esterification
For example; Glycerol and fatty acid joined with 1: 1 mol ratio have agitator, in the common reaction vessel of heating with sleeve pipe, baffle plate etc.; Add acid or alkali as required as catalyst; Under any inert gas atmosphere such as nitrogen or carbon dioxide, for example under about 180～260 ℃, preferred about 200～250 ℃, heat and carried out esterification in about 0.5～5 hour, preferred about 1～3 hour.The reactant liquor that obtains is the mixture that contains glycerol, fatty acid monoglyceride, dialycerides fat acid esters, fatty acid triglyceride etc.
After reaction finishes; Neutralization remains in the catalyst in the reactant liquor, then, residual glycerol is removed in the preferred distillation under reduced pressure of reactant liquor; Carry out processing such as desalination, decolouring, filtration as required, the reaction monoglyceride of 40～60% the monoglyceride of finally obtaining with respect to all contain having an appointment.
The reaction monoglyceride for example is at the Port エ of commercial preparation and sale system P-200 (ProductName; Monoglyceride content is about 52%, Riken Vitamin Co., Ltd.'s system), Port エ system V-200 (ProductName, monoglyceride content about 50%; Riken Vitamin Co., Ltd.'s system) and Port エ system B-200 (ProductName; Monoglyceride content is about 47%, Riken Vitamin Co., Ltd.'s system) etc., can use these commercially available article as the reaction monoglyceride among the present invention.
The distillation monoglyceride
The distillation monoglyceride that uses among the present invention obtains for the content that above-mentioned reaction monoglyceride is carried out purification, raising monoesters body, and the content of the monoesters body in the distillation monoglyceride 100% is generally about more than 90%.
Monoglyceride content in the distillation monoglyceride 100% is tried to achieve through the distillation monoglyceride is analyzed under above-mentioned analysis condition with HPLC.Specifically; Can be behind analytical distillation monoglyceride under the above-mentioned HPLC analysis condition; For the peak that is recorded in by data processing equipment on the chromatogram corresponding to each composition of test sample; Measure peak area with integrator,, try to achieve the content of monoglyceride with area percentage rate mode based on the peak area of measuring.
The method for preparing of the distillation monoglyceride that uses among the present invention can be enumerated the method for for example distilling above-mentioned reaction monoglyceride with falling film type molecular distillation apparatus or centrifugal molecular distillating device equal vacuum.Through using these methods to carry out purification, can obtain containing the distillation monoglyceride of whole about monoglycerides more than 90%.The upper limit of the monoglyceride content in the distillation monoglyceride is generally about 99%.
Diglycerine fatty acid ester
The diglycerine fatty acid ester that uses among the present invention is for will be as the diglycerine fatty acid ester purification of the esterification product of diglycerol and fatty acid with known method already, and the content that makes the monoesters body in this diglycerine fatty acid ester obtains more than 50% with respect to all being increased to approximately.The content of preferred monoesters body is with respect to all being about more than 70%.The upper limit of the content of monoesters body is generally about 96%.
The content of the monoesters body in the diglycerine fatty acid ester is tried to achieve through diglycerine fatty acid ester is analyzed under above-mentioned analysis condition with HPLC.Specifically; Can be after analyzing diglycerine fatty acid ester under the above-mentioned HPLC analysis condition; For the peak that is recorded in by data processing equipment on the chromatogram corresponding to each composition of test sample; Measure peak area with integrator,, try to achieve the content of monoesters body with the percentile mode of area based on the peak area of measuring.
As being used as the monoesters body burden of using among the present invention is the diglycerol of the raw material of the diglycerine fatty acid ester (the following diglycerine fatty acid ester that also abbreviates as) more than 50%; Can enumerate usually a spot of acid or alkali are added in the glycerol as catalyst; Make it at nitrogen or carbon dioxide etc. arbitrarily under the inert gas atmosphere, for example under about temperature more than 180 ℃, heat, the average degree of polymerization that the glycerol that polycondensation reaction obtains takes place is that about 1.5～2.4, preferred average degree of polymerization is about 2.0 diglycerol mixture.In addition, diglycerol also can be the diglycerol that (+)-2,3-Epoxy-1-propanol or epoxychloropropane etc. are obtained as raw material.After reaction finishes, can neutralize as required, processing such as desalination, decolouring.
In the present invention; Preferred for example the use with known method such as distillation or column chromatography etc. already with above-mentioned diglycerol purifying mixture, make the diglycerol content high-concentrationization that contains two molecule glycerol to whole about 50% or more, preferably about more than 70%, more preferably from about more than 90% and the high-purity diglycerol that obtains.
Fatty acid as the raw material that is used as the diglycerine fatty acid ester that uses among the present invention; Can enumerate carbon number for example and be 6～24 linear saturated fatty acids (for example caproic acid, sad, capric acid, lauric acid, myristic acid, Palmic acid, stearic acid, arachidic acid 、 behenic acid, lignoceric acid etc.); Unsaturated fatty acid (for example palmitoleic acid, oleic acid, elaidic acid, linoleic acid, gamma-Linolenic acid, alpha-linolenic acid, arachidonic acid, castor oil acid, condensation castor oil acid etc.) is preferably enumerated capric acid, lauric acid, myristic acid, oleic acid etc.As this fatty acid, the capric acid, lauric acid, myristic acid or the oleic fatty acid that contain more than 70% can be buied commercial, preferably use them among the present invention.This can enumerate for example commodity (1) NAA-122 by name (day oily society system), (2) Le Na Star Network L-98 (Hua Wangshe system), (3) myristic acid 98 (ミ ヨ シ oils and fats society system), (4) NAA-142 (day oily society system), (5) Le Na Star Network MY-98 (Hua Wangshe system), (6) エ キ ス ト ラ オ レ イ Application (day oily society system), (7) Le Na Star Network O-V (Hua Wangshe system), (8) Le Na Star Network O-P (Hua Wangshe system) etc. at the commercial fatty acid of buying.
The preferred method for making of the diglycerine fatty acid ester that uses among the present invention is described below briefly.For example; Diglycerol and fatty acid joined with about 1: 0.8～1: 1.2, preferred about 1: 1 mol ratio have agitator, in the common reaction vessel of heating with sleeve pipe, baffle plate etc.; Adding catalyst sodium hydroxide also mixes; Under nitrogen atmosphere, will be discharged to by the water that esterification generates outside the system, under set point of temperature, heat simultaneously.Reaction temperature is generally about 180～260 ℃, is preferably about 200～250 ℃.In addition, the reaction pressure condition is under the decompression or under the normal pressure, and the response time is about 0.5～15 hour, preferred about 1～3 hour.The acid number of the common assaying reaction mixture of reaction end, about with acid number is that benchmark is confirmed below 12.The reactant liquor that obtains is the mixture that contains unreacted fatty acid, unreacted diglycerol, diglycerol mono fatty acid ester, diglycerol di fatty acid ester, diglycerol tri-fatty acid ester, diglycerol four fatty acid esters etc.After reaction finishes, the reactant liquor that obtains is cooled to about more than 120 ℃ and be lower than 180 ℃, preferred about 130 ℃～150 ℃; Then add acid and come catalyst neutralisation; The preferred placement about 15 minutes～1 hour, unreacted diglycerol is removed when being separated in lower floor, obtains diglycerine fatty acid ester.
Further; Through this diglycerine fatty acid ester is for example carried out molecular distillation with falling film type molecular distillation apparatus or centrifugal molecular distillating device etc.; Perhaps carry out purification with known method such as column chromatography or liquid-liquid extraction etc. already; Can obtain with respect to all, contain about more than 50%, the preferred about diglycerine fatty acid ester more than 70% of monoesters body.
The monoesters body burden is that the diglycerine fatty acid ester more than 50% for example is in the Port エ of commercial preparation and sale system DM-100 (trade name; Riken Vitamin Co., Ltd.'s system), Port エ system DO-100V (trade name; Riken Vitamin Co., Ltd.'s system), Port エ system DL-100 (trade name; Riken Vitamin Co., Ltd.'s system) etc., can use these commercially available article among the present invention is the diglycerine fatty acid ester more than 50% as the monoesters body burden.
Other composition
As long as liquid composition for soft-capsule filling of the present invention plays effect of the present invention, then can also contain above-mentioned edible oil and fat, oily slightly solubility composition, reaction monoglyceride, distillation monoglyceride and monoesters body burden as required is the composition beyond the diglycerine fatty acid ester more than 50%.Other composition can be enumerated antioxidant (tocopherol that for example extracts, ascorbyl palmitate etc.) etc.Other composition can use a kind of or make up two or more the use.
The preparation of compositions method
Liquid composition for soft-capsule filling of the present invention makes these compositions disperse equably to prepare through above-mentioned edible oil and fat, oily slightly solubility composition, reaction monoglyceride and distillation monoglyceride being mixed and stirring simultaneously.When liquid composition for soft-capsule filling of the present invention contains the monoesters body burden and is the diglycerine fatty acid ester more than 50%; Through edible oil and fat, oily slightly solubility composition, reaction monoglyceride, distillation monoglyceride and this diglycerine fatty acid ester being mixed and stirring, make these compositions disperse equably to prepare simultaneously.
Specifically; For example with edible oil and fat, reaction monoglyceride and distillation monoglyceride and diglycerine fatty acid ester as required be heated to for example about 60～90 ℃, preferred about 70～80 ℃ and mix equably, stir after; It is cooled to for example about 40～60 ℃; And then add oily slightly solubility composition and mix equably, stir, thereby prepare compositions of the present invention.And reaction monoglyceride, distillation monoglyceride and diglycerine fatty acid ester can use in advance they are mixed, heat and make its fused mixture.To the not restriction especially of device that is used to mix, stir, for example can use biomixer, homomixer homogenizer or high speed disintegrators such as (Port モ ジ エ Star タ one).
Component ratio
Content to the edible oil and fat among the liquid composition for soft-capsule filling 100 quality % of the present invention does not limit especially, but for example is generally about 20～95 quality %, is preferably about 25～90 quality %, more preferably about 30～80 quality %.In the present invention, if the content of edible oil and fat is above-mentioned scope, oily slightly solubility composition is dispersed in the edible oil and fat fully, the dispersion stabilization of oily slightly solubility composition in edible oil and fat is good simultaneously.
To the not restriction especially of content of the oily slightly solubility composition among the liquid composition for soft-capsule filling 100 quality % of the present invention, but for example be generally about 1～70 quality %, be preferably about 3～60 quality %, more preferably about 10～50 quality %.In the present invention, be above-mentioned scope like the content of fruit oil slightly solubility composition, oily slightly solubility composition is dispersed in the edible oil and fat fully.In addition, because the dispersion stabilization of oily slightly solubility composition in edible oil and fat is good, the separation that in soft capsule, can not produce oily slightly solubility composition.Further, use in the soft capsule of liquid composition for soft-capsule filling preparation effective ingredient (oily slightly solubility composition) amount fully, if absorb this soft capsule, then give full play to the effect, for example physiologically active of oily slightly solubility composition etc. in vivo.
To the not restriction especially of content of the reaction monoglyceride among the liquid composition for soft-capsule filling 100 quality % of the present invention, but for example be generally about 0.5～15 quality %, be preferably about 0.5～10 quality %, more preferably about 1～8 quality %.In the present invention, if the content of this reaction monoglyceride is above-mentioned scope, the dispersion stabilization of then oily slightly solubility composition in edible oil and fat is good, the separation that therefore in soft capsule, can not produce oily slightly solubility composition.Further, the effective ingredient in the soft capsule (oily slightly solubility composition) amount fully if absorb this soft capsule, is then given full play to the effect of oily slightly solubility composition in vivo.
To the not restriction especially of content of the distillation monoglyceride among the liquid composition for soft-capsule filling 100 quality % of the present invention, but for example be generally about 0.5～15 quality %, be preferably about 0.5～10 quality %, more preferably about 1～8 quality %.In the present invention, if the content of this distillation monoglyceride is above-mentioned scope, the dispersion stabilization of then oily slightly solubility composition in edible oil and fat is good, the separation that therefore in soft capsule, can not produce oily slightly solubility composition.Further, the effective ingredient in the soft capsule (oily slightly solubility composition) amount fully if absorb this soft capsule, is then given full play to the effect of oily slightly solubility composition in vivo.
When liquid composition for soft-capsule filling of the present invention contains the monoesters body burden and is the diglycerine fatty acid ester more than 50%; To not restriction especially of this diglycerine fatty acid ester content among the said composition 100 quality %; But for example be generally about 0.05～1.5 quality %; Be preferably about 0.05～1 quality %, more preferably about 0.1～1 quality %.In the present invention, if this diglycerine fatty acid ester content is above-mentioned scope, then under the situation of the dispersivity test in having implemented following simulated gastric fluid, the dispersion stabilization of oily slightly solubility composition in simulated gastric fluid is good.That is, oily slightly solubility composition dispersibility in vivo is abundant.In addition, the effective ingredient in the soft capsule (oily slightly solubility composition) amount fully if therefore absorb this soft capsule, is then given full play to the effect of oily slightly solubility composition in vivo.
Preparation of soft capsule
According to conventional method, be the liquid composition for soft-capsule filling that the film parcel of main component so obtains in order to gelatin, can prepare soft capsule thus.Specifically, for example can a certain amount of liquid composition for soft-capsule filling as content be injected between two gelatin foils and prepare soft capsule through pressing.
The process for dispersing of oil slightly solubility composition
Compositions through containing edible oil and fat, oily slightly solubility composition, reaction monoglyceride and distillation monoglyceride is mixed and stirring, and oily slightly solubility composition is dispersed in the edible oil and fat well.Comprise that this compositions that will contain edible oil and fat, oily slightly solubility composition, reaction monoglyceride and distillation monoglyceride is mixed and the method that oily slightly solubility composition is distributed in the edible oil and fat of the operation of stirring also is a kind of scheme of the present invention.Preferably will contain compositions mixing and stirring that edible oil and fat, oily slightly solubility composition, reaction monoglyceride, distillation monoglyceride and monoesters body burden are the diglycerine fatty acid ester more than 50%.
Edible oil and fat in the process for dispersing of the present invention, oily slightly solubility composition, reaction monoglyceride, distillation monoglyceride and monoesters body burden are that diglycerine fatty acid ester and their optimal way more than 50% is identical with situation in the above-mentioned liquid composition for soft-capsule filling.Mixing and stirring method as the compositions that will contain these compositions, is that diglycerine fatty acid ester 50% or more mixes that also stirring method is identical with containing edible oil and fat, oily slightly solubility composition, reaction monoglyceride, distillation monoglyceride and monoesters body burden in the preparation of liquid composition for soft-capsule filling.For example; Preferably with edible oil and fat, reaction monoglyceride, distillation monoglyceride and monoesters body burden be diglycerine fatty acid ester 50% or more be heated to for example about 60～90 ℃, preferred about 70～80 ℃ also mix equably, stir after; It is cooled to for example about 40～60 ℃, and then adds oily slightly solubility composition and mix equably, stir.
Embodiment
Followingly the present invention more specifically is described, but the invention is not restricted to these embodiment according to embodiment.
1. the preparation of liquid composition for soft-capsule filling
Embodiment 1
To react monoglyceride (trade name: Port エ system B-200; Monoglyceride content about 47%; Riken Vitamin Co., Ltd.'s system) 5.0g and distillation monoglyceride (trade name: Port エ system S-100; Monoglyceride content is about 98%, Riken Vitamin Co., Ltd.'s system) 5.0g joins among Flos Carthami salad oil (the カ one ギ Le ジ ヤ パ Application society system) 80.0g, is heated to 80 ℃ and stirs and dissolving.This solution is naturally cooled to 50 ℃; To wherein adding riboflavin (Riken Vitamin Co., Ltd.'s system) 0.3g and L-ascorbic acid (the military field of BASF PVC タ ミ Application society system) 9.7g and further under 8000rpm, mixing, stirred 10 minutes with mixer (model ウ Le ト ラ タ ラ Star Network ス T-25 ベ one シ Star Network, IKA ジ ヤ パ Application society system).After the dispersion liquid that obtains carried out vacuum outgas and handle, be cooled to room temperature, obtain the about 100g of liquid composition for soft-capsule filling (enforcement article 1).
Embodiment 2
Except using reaction monoglyceride (trade name: Port エ system P-200; Monoglyceride content about 52%; Riken Vitamin Co., Ltd.'s system) 5.0g comes beyond the reaction monoglyceride 5.0g of record in the alternate embodiment 1; Likewise implement with embodiment 1, obtain the about 100g of liquid composition for soft-capsule filling (implementing article 2).
Embodiment 3
Except using distillation monoglyceride (trade name: Port エ system P-100; Monoglyceride content about 98%; Riken Vitamin Co., Ltd.'s system) 5.0g comes beyond the distillation monoglyceride 5.0g of record in the alternate embodiment 1; Likewise implement with embodiment 1, obtain the about 100g of liquid composition for soft-capsule filling (implementing article 3).
Comparative example 1
Except with Cera Flava (trade name: deodorizing and refining ミ Star ロ ウ peracid; The wild field of セ ラ リ カ society system) 5.0g comes beyond the reaction monoglyceride 5.0g of record in the alternate embodiment 1; Likewise implement with embodiment 1, obtain the about 100g of liquid composition for soft-capsule filling (relatively article 1).
Comparative example 2
Except using distillation monoglyceride (trade name: Port エ system S-100; Monoglyceride content about 98%; Riken Vitamin Co., Ltd.'s system) 10.0g comes the reaction monoglyceride 5.0g of record in the alternate embodiment 1 with beyond the distillation monoglyceride 5.0g; Likewise implement with embodiment 1, obtain the about 100g of liquid composition for soft-capsule filling (relatively article 2).
Comparative example 3
Except using reaction monoglyceride (trade name: Port エ system B-200; Monoglyceride content about 47%; Riken Vitamin Co., Ltd.'s system) 10.0g comes the reaction monoglyceride 5.0g of record in the alternate embodiment 1 with beyond the distillation monoglyceride 5.0g; Likewise implement with embodiment 1, obtain the about 100g of liquid composition for soft-capsule filling (relatively article 3).
Comparative example 4
Except using reaction monoglyceride (trade name: Port エ system V-200; Monoglyceride content about 50%; Riken Vitamin Co., Ltd.'s system) 10.0g comes the reaction monoglyceride 5.0g of record in the alternate embodiment 1 with beyond the distillation monoglyceride 5.0g; Likewise implement with embodiment 1, obtain the about 100g of liquid composition for soft-capsule filling (relatively article 4).
Comparative example 5
Except using reaction monoglyceride (trade name: Port エ system P-200; Monoglyceride content about 52%; Riken Vitamin Co., Ltd.'s system) 10.0g comes the reaction monoglyceride 5.0g of record in the alternate embodiment 1 with beyond the distillation monoglyceride 5.0g; Likewise implement with embodiment 1, obtain the about 100g of liquid composition for soft-capsule filling (relatively article 5).
Comparative example 6
Except using distillation monoglyceride (trade name: Port エ system P-100; Monoglyceride content about 98%; Riken Vitamin Co., Ltd.'s system) 10.0g comes the reaction monoglyceride 5.0g of record in the alternate embodiment 1 with beyond the distillation monoglyceride 5.0g; Likewise implement with embodiment 1, obtain the about 100g of liquid composition for soft-capsule filling (relatively article 6).
2. Test Example
The isolating evaluation of liquid composition for soft-capsule filling
Each liquid composition for soft-capsule filling that respectively will be through method for preparing (implement article 1～3 with relatively article 1～6) 30g adds in the centrifuge tube (capacity 50ml, be with and fill in); With centrifuge (model: SL-05, assistant is made society of institute system for a long time) under revolution 1500rpm with its centrifugal 20 minutes.Afterwards, from centrifugal separator, take out centrifuge tube, the sample visualization of centrifuge tube is had or not separating of oily slightly solubility composition (riboflavin and L-ascorbic acid).The result is shown in Table 1.
[table 1]
| Have or not the separation of oily slightly solubility composition | |
| Implement article 1 | Do not have |
| Implement article 2 | Do not have |
| Implement article 3 | Do not have |
| Relatively article 1 | Do not have |
| Relatively article 2 | Have |
| Relatively article 3 | Have |
| Relatively article 4 | Have |
| Relatively article 5 | Have |
| Relatively article 6 | Have |
Implement all not take place fully in the article 1～3 separation of oily slightly solubility composition.Hence one can see that, although liquid composition for soft-capsule filling of the present invention does not use Cera Flava, also has the dispersion stabilization that the equal oily slightly solubility composition of mellisic liquid composition for soft-capsule filling (relatively article 1) is arranged with use.On the other hand; Only use the liquid composition for soft-capsule filling (relatively article 2 and 6) of distillation monoglyceride all to take place separating of oily slightly solubility composition, compare significance difference with the article of enforcement with the liquid composition for soft-capsule filling (relatively article 3～5) that only uses the reaction monoglyceride.
3. the preparation of liquid composition for soft-capsule filling
Embodiment 4～9 and comparative example 7～9
(1) is used to prepare the raw material of liquid composition for soft-capsule filling
1) Flos Carthami salad oil (カ one ギ Le ジ ヤ パ Application society system)
2) riboflavin (Riken Vitamin Co., Ltd.'s system)
3) L-ascorbic acid (BASF ジ ヤ パ Application society system)
4) reaction monoglyceride (trade name: Port エ system B-200, monoglyceride content is about 47%, Riken Vitamin Co., Ltd.'s system)
5) reaction monoglyceride (trade name: Port エ system P-200, monoglyceride content is about 52%, Riken Vitamin Co., Ltd.'s system)
6) distillation monoglyceride (trade name: Port エ system S-100, monoglyceride content is about 98%, Riken Vitamin Co., Ltd.'s system)
7) distillation monoglyceride (trade name: Port エ system P-100, monoglyceride content is about 98%, Riken Vitamin Co., Ltd.'s system)
8) diglycerine fatty acid ester (trade name: Port エ system DM-100, the monoesters body burden is about 81%, Riken Vitamin Co., Ltd.'s system)
9) diglycerine fatty acid ester (trade name: Port エ system DO-100V, the monoesters body burden is about 88%, Riken Vitamin Co., Ltd.'s system)
10) diglycerine fatty acid ester (trade name: Port エ system DL-100, the monoesters body burden is about 77%, Riken Vitamin Co., Ltd.'s system)
11) diglycerine fatty acid ester (trade name: Port エ system J-2081V, the monoesters body burden is about 38%, Riken Vitamin Co., Ltd.'s system)
12) diglycerine fatty acid ester (trade name: Port エ system O-71-DE, the monoesters body burden is about 38%, Riken Vitamin Co., Ltd.'s system)
13) Cera Flava (trade name: deodorizing and refining ミ Star ロ ウ peracid, the wild field of セ ラ リ カ society system)
(2) raw-material cooperation is formed
Table 2 shows the raw-material cooperation composition that uses in the preparation of liquid composition for soft-capsule filling in embodiment 4～9 and the comparative example 7～9 (implement article 4～9 and relatively article 7～9).Wherein, implementing article 4～9 is the compositions of preparation in the embodiments of the invention 4～9, and relatively article 7～9 are the compositions that in comparative example 7～9 prepare relative with them.
[table 2]
(3) method for preparing
Form the preparation liquid composition for soft-capsule filling according to the cooperation shown in the table 2.That is, will react monoglyceride, distillation monoglyceride and/or diglycerine fatty acid ester or Cera Flava and join in the Flos Carthami salad oil, be heated to 80 ℃ and stirring, these compositions are dissolved in this salad oil.This solution at room temperature is cooled to 50 ℃; To wherein adding riboflavin (Riken Vitamin Co., Ltd.'s system) and L-ascorbic acid (BASF ジ ヤ パ Application society system) and further under 8000rpm, mixing, stirred 10 minutes with mixer (model: ウ Le ト ラ タ ラ Star Network ス T-25 ベ one シ Star Network, IKA ジ ヤ パ Application society system).After the dispersion liquid that obtains carried out vacuum outgas and handle, be cooled to room temperature, obtain the about 100g of liquid composition for soft-capsule filling (enforcement article 4～9 and relatively article 7～9).
4. the evaluation of liquid composition for soft-capsule filling
To implementing following test with each liquid composition for soft-capsule filling of method for preparing (implement article 4～9 and relatively article 7～9).The result is shown in Table 3.
(1) the isolating evaluation of oily slightly solubility composition
Respectively each liquid composition for soft-capsule filling (implement article 4～9 with relatively article 7～9) 30g is joined in the centrifuge tube (capacity 50ml, band plug), with centrifuge (model: SL-05, help of a specified duration between society of making institute system) under revolution 1500rpm with its centrifugal 20 minutes.Afterwards, from centrifugal separator, take out centrifuge tube, the sample visualization of centrifuge tube is had or not separating of oily slightly solubility composition (riboflavin and L-ascorbic acid).
(2) the dispersibility evaluation of oily slightly solubility composition in simulated gastric fluid
99g joins in the 200ml capacity glass beaker with liquid composition for soft-capsule filling (implement article 4～9 and relatively article 7～9) 1g and about 36 ℃ simulated gastric fluid (mass ratio that makes hydrochloric acid/NaCl/ ion exchange water is 7/2/991 simulated gastric fluid for preparing); With blender (ProductName: ス リ one ワ Application モ one タ one; Model: BL-600; New Dong Kexueshe system; 1 section of assembling 5cm diameter 4 blade type agitator) in about 36 ℃ tepidarium, stirred 30 minutes, liquid composition for soft-capsule filling is dispersed in the simulated gastric fluid.With analyzing the dispersion liquid that obtains with filter paper No.2 (diameter 125mm, ア De バ Application テ Star Network society system) natural filtration, residue and the filtrating of separating residual on this filter paper.The filtrating 10g that obtains is measured in the ware (diameter 70mm, height 50mm), and hot air drying was measured the quality that remains in the dry thing on this ware after 1 hour in 100 ℃ incubator.According to the quality and the following formula of the dry thing of measuring, obtain the dissolution rate (%) of oily slightly solubility composition.In addition, be that 60 minutes situation is also implemented identical evaluation test to the mixing time of carrying out through above-mentioned blender, obtain dissolution rate (%).
[mathematical expression 1]
And, among the numerical value in the above-mentioned formula, the quality of the NaCl that " 198 (mg) " is equivalent to contain among the simulated gastric fluid 99g, the quality of the oily slightly solubility composition that " 320 (mg) " is equivalent to contain among the liquid composition for soft-capsule filling 1g.
[table 3]
Result by table 3 can know, implements the separation that oily slightly solubility composition does not all take place article 4～7 fully, uses mellisic situation (relatively article 9) to compare with dispersant in addition, and the dissolution rate of oily slightly solubility composition in simulated gastric fluid significantly improves.On the other hand; Though contain the monoglyceride that responds with the distillation monoglyceride but use the monoesters body burden not under the situation (enforcement article 8 and 9) of the diglycerine fatty acid ester 50% or more; Do not produce and separate, but the stripping rate variance, in addition; Under the situation (relatively article 7 and 8) of any one in not using distillation monoglyceride or reaction monoglyceride, the separation that all produces oily slightly solubility composition.
Utilizability on the industry
Liquid composition for soft-capsule filling of the present invention does not contain Cera Flava, but the dispersion stabilization of oily slightly solubility composition is good, and the separation of oily slightly solubility composition does not take place in soft capsule.Further; If it is the diglycerine fatty acid ester more than 50% that liquid composition for soft-capsule filling of the present invention contains the monoesters body burden; Then oily slightly solubility composition dispersibility in vivo is significantly improved; So give full play to the effect of oily slightly solubility composition in vivo, for example physiologically active etc.Therefore, liquid composition for soft-capsule filling of the present invention is for being useful with oily slightly solubility composition as the preparation of soft capsule of effective ingredient.
Claims (2)
1. liquid composition for soft-capsule filling; It is the compositions that dispersed oil slightly solubility composition forms in edible oil and fat; It is characterized in that; Contain reaction monoglyceride and distillation monoglyceride as the dispersion stabilizer that is used to disperse this oil slightly solubility composition, said reaction monoglyceride contains 40～60% monoglyceride, 15～40% diglyceride and 1～10% triglyceride, and the content of the monoesters body in the said distillation monoglyceride 100% is more than 90%; Said reaction monoglyceride accounts for 0.5～15 quality % of compositions, and said distillation monoglyceride accounts for 0.5～15 quality % of compositions.
2. liquid composition for soft-capsule filling according to claim 1 is characterized in that, further containing the monoesters body burden is the diglycerine fatty acid ester of 0.05～1.5 quality % more than 50%, that account for compositions.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2007250358A JP5269373B2 (en) | 2007-09-27 | 2007-09-27 | Liquid composition for soft capsule filling |
| JP2007-250358 | 2007-09-27 | ||
| JP2008-093048 | 2008-03-31 | ||
| JP2008093048A JP5156458B2 (en) | 2008-03-31 | 2008-03-31 | Liquid composition for soft capsule filling |
| PCT/JP2008/058164 WO2009041105A1 (en) | 2007-09-27 | 2008-04-28 | Liquid composition for soft-capsule filling |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101772352A CN101772352A (en) | 2010-07-07 |
| CN101772352B true CN101772352B (en) | 2012-05-23 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2008801018522A Active CN101772352B (en) | 2007-09-27 | 2008-04-28 | Liquid composition for soft-capsule filling |
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| Country | Link |
|---|---|
| KR (1) | KR101503474B1 (en) |
| CN (1) | CN101772352B (en) |
| TW (1) | TWI425913B (en) |
| WO (1) | WO2009041105A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP5405242B2 (en) * | 2009-09-07 | 2014-02-05 | 理研ビタミン株式会社 | Liquid composition for soft capsule filling |
| CN108703955B (en) * | 2018-07-31 | 2020-02-21 | 荆楚理工学院 | Mineral soft capsule and preparation method thereof |
| WO2023120382A1 (en) * | 2021-12-23 | 2023-06-29 | サントリーホールディングス株式会社 | Oral composition and soft capsule agent |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1066183A (en) * | 1991-04-19 | 1992-11-18 | 联合生物技术公司 | Transformable microgranule microemulsion formulations |
| US5206219A (en) * | 1991-11-25 | 1993-04-27 | Applied Analytical Industries, Inc. | Oral compositions of proteinaceous medicaments |
| JP2005112753A (en) * | 2003-10-06 | 2005-04-28 | Sankyo:Kk | Soft capsule having improved bioavailability |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8822857D0 (en) * | 1988-09-29 | 1988-11-02 | Patralan Ltd | Pharmaceutical formulations |
| DE3919982A1 (en) * | 1989-06-19 | 1990-12-20 | Liedtke Pharmed Gmbh | ORAL LIPID MEDICINE FORM |
| WO1994008604A1 (en) * | 1992-10-16 | 1994-04-28 | Affinity Biotech, Inc. | Convertible microemulsion formulations |
| EP0597007B1 (en) * | 1991-07-26 | 1996-10-16 | Smithkline Beecham Corporation | W/o microemulsions |
| JPH07138151A (en) * | 1993-11-15 | 1995-05-30 | Kanebo Ltd | Soft capsular agent and its production |
| US6309663B1 (en) * | 1999-08-17 | 2001-10-30 | Lipocine Inc. | Triglyceride-free compositions and methods for enhanced absorption of hydrophilic therapeutic agents |
| US8075910B2 (en) * | 2004-05-20 | 2011-12-13 | Pbm Pharmaceuticals, Inc. | Oral compositions comprising edible oils and vitamins and/or minerals and methods for making oral compositions |
-
2008
- 2008-04-28 KR KR1020107008383A patent/KR101503474B1/en not_active IP Right Cessation
- 2008-04-28 WO PCT/JP2008/058164 patent/WO2009041105A1/en active Application Filing
- 2008-04-28 CN CN2008801018522A patent/CN101772352B/en active Active
- 2008-05-20 TW TW097118456A patent/TWI425913B/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1066183A (en) * | 1991-04-19 | 1992-11-18 | 联合生物技术公司 | Transformable microgranule microemulsion formulations |
| US5206219A (en) * | 1991-11-25 | 1993-04-27 | Applied Analytical Industries, Inc. | Oral compositions of proteinaceous medicaments |
| JP2005112753A (en) * | 2003-10-06 | 2005-04-28 | Sankyo:Kk | Soft capsule having improved bioavailability |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20100077166A (en) | 2010-07-07 |
| TWI425913B (en) | 2014-02-11 |
| KR101503474B1 (en) | 2015-03-18 |
| CN101772352A (en) | 2010-07-07 |
| TW200913898A (en) | 2009-04-01 |
| WO2009041105A1 (en) | 2009-04-02 |
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