CN1259870A - Fatty emulsing contg. reducing sugar and method for sterilizing same - Google Patents
Fatty emulsing contg. reducing sugar and method for sterilizing same Download PDFInfo
- Publication number
- CN1259870A CN1259870A CN97182319A CN97182319A CN1259870A CN 1259870 A CN1259870 A CN 1259870A CN 97182319 A CN97182319 A CN 97182319A CN 97182319 A CN97182319 A CN 97182319A CN 1259870 A CN1259870 A CN 1259870A
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- CN
- China
- Prior art keywords
- reducing sugar
- carbon dioxide
- lipomul
- fat
- medicinal liquid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 235000004626 essential fatty acids Nutrition 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- FOYKKGHVWRFIBD-UHFFFAOYSA-N gamma-tocopherol acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 FOYKKGHVWRFIBD-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 235000019382 gum benzoic Nutrition 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002506 iron compounds Chemical class 0.000 description 1
- LDHBWEYLDHLIBQ-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide;hydrate Chemical compound O.[OH-].[O-2].[Fe+3] LDHBWEYLDHLIBQ-UHFFFAOYSA-M 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 229920000092 linear low density polyethylene Polymers 0.000 description 1
- 239000004707 linear low-density polyethylene Substances 0.000 description 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 229910052756 noble gas Inorganic materials 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- MBWXNTAXLNYFJB-NKFFZRIASA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-NKFFZRIASA-N 0.000 description 1
- 235000019175 phylloquinone Nutrition 0.000 description 1
- 239000011772 phylloquinone Substances 0.000 description 1
- 229960001898 phytomenadione Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- DVQHRBFGRZHMSR-UHFFFAOYSA-N sodium methyl 2,2-dimethyl-4,6-dioxo-5-(N-prop-2-enoxy-C-propylcarbonimidoyl)cyclohexane-1-carboxylate Chemical compound [Na+].C=CCON=C(CCC)[C-]1C(=O)CC(C)(C)C(C(=O)OC)C1=O DVQHRBFGRZHMSR-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- BAVBEHWEOJMHDS-UHFFFAOYSA-M sodium;4-[3-(4-hydroxy-2-methyl-5-propan-2-ylphenyl)-1,1-dioxo-2,1$l^{6}-benzoxathiol-3-yl]-5-methyl-2-propan-2-ylphenolate Chemical compound [Na+].C1=C(O)C(C(C)C)=CC(C2(C3=CC=CC=C3S(=O)(=O)O2)C=2C(=CC([O-])=C(C(C)C)C=2)C)=C1C BAVBEHWEOJMHDS-UHFFFAOYSA-M 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 229960000344 thiamine hydrochloride Drugs 0.000 description 1
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 1
- 239000011747 thiamine hydrochloride Substances 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000004711 α-olefin Substances 0.000 description 1
Images
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
Abstract
A fatty emulsion containing a reducing sugar, being an oil-in-water emulsion prepared by emulsifying fat or oil with an emulsifying agent wherein the aqueous phase contains both a reducing sugar and a buffer consisting of an organic acid exhibiting an acid dissociation constant of 5.0 to 7.5 in water or a salt thereof and the pH is adjusted to 5.0 to 7.5; a packaged fatty emulsion containing a reducing sugar, wherein a liquid medicine that contains a reducing sugar and fat or oil and that is sterilized in a state containing carbon dioxide dissolved therein is held in a plastic container for infusion fluid and the plastic container is held together with a carbon dioxide absorbent in a substantially oxygen-impermeable outer container; a process for the production of them; and a method for sterilizing the same. These fatty emulsions are suppressed in formation of free fatty acids and in composition of the sugar, thus being high-quality stable ones little causing discoloration.
Description
Technical field
The present invention relates to be applicable to the lipomul that contains reducing sugar and the sterilizing methods thereof of intravenous injection such as intravenous hyperalimentation therapy, the present invention is specifically related to a kind of high-quality stable lipomul, though wherein contain reducing sugar but, and the variable color due to having suppressed to decompose by reducing sugar seldom because of heat sterilization forms free fatty.
Background technology
Because many patients that accept gastrointestinal procedures can't take food through the oral cavity, so adopt intravenous hyperalimentation method (IVH) to ensure to this type of patient's nutrient by central vein usually.Described IVH can very keep in above-mentioned patient's the nutritional status effectively accelerating its rehabilitation and recovery from illness, and is widely used in thus in the surgical intervention field.
Simultaneously, the strict control operation process of described IVH and have some defective is as infecting and the danger of metabolic complication (as hyperglycemia).So, trend in recent years be should be as much as possible from the peripheral vein feed, even also be like this to the IVH taboo but before art in the nutritional status good patient, in the slighter relatively patient of those operation involvement levels and among can't the oral feeding phase not oversize patient of those expections at those.
Under any circumstance, not only need consider in to patient's nutrient provides carbohydrate, aminoacid and electrolyte to the patient, also must consider to supply with fat.Especially when peripheral vein is taken food, need the main fat milk that can be used as the portion of energy source that uses, satisfy caloric requirement thus, prevent that as much as possible the infusion osmotic pressure from increasing simultaneously.
Simultaneously, the desirable dosage form of this type of high trophotherapy is the single packing dosage form that contains whole administration components a packing.Yet known sugars and aminoacid can become brownly because of the MeillardShi reaction takes place, and coexistent fat milk and electrolyte (concrete as polyvalent cation) can cause the emulsion grain gathering.Therefore, said components can't be formulated in the same packing, and provides with the double pack dosage form usually, and one of them packing contains reducing sugar and fat milk, and another packing contains aminoacid and electrolyte.
But the aqueous solution of reducing sugar such as glucose pH decline can occur when sterilization and after the sterilization, and when this solution is mixed with fat milk, the pH of this decline will cause fat and emulsifying agent hydrolysis, generate free fatty.Obviously, the side effect relevant with the fat milk administration should be attributed to the free fatty that is generated as heating and headache, therefore, should avoid the appearance of free fatty as much as possible.So the pH due to the major defect of this type of mix preparation is to sterilize descends and causes the generation of free fatty.
In order to overcome above-mentioned shortcoming, people study along some approach, but do not obtain satisfied result all the time.So, existing people attempts (as the open H5-65220 of Japan special permission) and prevents the rising of free-fat acid concentration by mix L-histidine and/or three (hydroxyl-methyl) aminomethane in containing the fat milk of reducing sugar as buffer agent, but this method still can't suppress the formation of free fatty fully.
Also the someone to attempt by add final concentration in containing the fat milk of reducing sugar be that 3mM-20mM phosphate (the open H7-277989 of Japan's special permission) solves the problems referred to above, but because emulsion grain especially is tending towards assembling behind heat sterilization, so this method and be not suitable for stably producing and providing high-quality Emulsion.
In addition, the shortcoming that contains the reducing sugar fat milk also is, during heat sterilization and the catabolite that reducing sugar generated in the storage life subsequently cause the Emulsion variable color.This defective can overcome by Emulsion being maintained low-level pH usually, but in fact Emulsion is with heavy dose of administration, and the pH of suitable product preferably can not differ greatly with blood circulation pH.
In view of this reason, the pH that contains the lipomul of reducing sugar is regulated and control between about 5-7.5 usually, and except that pH regulator, generally be to mix painted inhibitor such as dithioglycerol or dithiothreitol, DTT to prevent above-mentioned painted (for example open H5-9112 of Japan's special permission) relevant with reducing sugar.
Yet, add irrelevant component painted inhibitor as described such as any and high alimentation and do not expect and should give and avoid.And painted inhibitor makes this infusion have the abnormal flavour of sulfur.So, people expect sincerely to study and develop capable of being industrialized do not contain painted inhibitor and do not have that reducing sugar decomposes the discoloration problem that causes and can suppress that free fatty produces contain the reducing sugar fat milk.
The objective of the invention is exploitation and provide a kind of its stability to be able to improved reducing sugar lipomul and the manufacturing technology thereof of containing, this is that this industry is expected for a long time, Emulsion simulation physiological pH of the present invention, even do not having assisting of painted inhibitor not occur down yet or can significantly suppress by the variable color due to the reducing sugar decomposition, the generation of free fatty also is inhibited, and does not become the emulsion grain clustering phenomena of one of existing lipomul shortcoming.
To achieve these goals, the inventor has at first surveyed a large amount of buffer substances and has found and can positively improve the stability that contains the reducing sugar lipomul when using some organic acid or its salt in the certain pH scope.
In addition, the present inventor finds, when before heat sterilization, being dissolved in carbon dioxide in the drug system that contains reducing sugar and fat milk, the pH of this drug system (pH is between about 5.0-7.5) will temporaryly reduce, sterilization back carbon dioxide is removed from drug system, suppresses reducing sugar at heat sterilization with between the storage life and decomposes, simultaneously, can inhibition system variable color under the condition that the non-coloring inhibitor exists, obtain the gratifying reducing sugar lipomul that contains.
In addition, the present inventor finds, utilize the carbon dioxide gas absorbent can after sterilization, from drug system, promptly remove carbon dioxide gas, when adopting described carbon dioxide gas absorbent, also eliminated the detrimental effect of oxygen to drug system, suppressed reducing sugar thus and between sterilization and storage life, decomposed, thereby not only prevented the Emulsion variable color, also stoped to generate free fatty.The present invention develops on the basis of above-mentioned discovery.
Disclosure of the Invention
The invention provides a kind of lipomul that contains reducing sugar, contain in this Emulsion and derive from fat by means of the emulsive oil-in-water type fat breast of emulsifying agent, and the water that contains reducing sugar and at least a buffer substance, and the pH of Emulsion is regulated and control between 5.0-7.5, organic acid and salt thereof that it is 5.0-7.5 that described buffer substance is selected from those acid dissociation exponents in water.
On the other hand, the invention provides a kind of lipomul that contains reducing sugar, comprising the medicinal liquid that contains reducing sugar and fatty ingredient, this medicinal liquid is dissolved under wherein the condition sterilization and is packaged in the plastics infusion container (after this it being called primary containment vessel) at existing carbon dioxide gas, and this primary containment vessel is packaged in substantially not in the external container of oxygen flow (after this being referred to as further receptacle) with the carbon dioxide gas absorbent subsequently.
Again on the one hand, the invention provides a kind of method that is used to contain the sterilization of reducing sugar lipomul, this method comprises and is dissolved in the medicinal liquid that contains reducing sugar and fat carbon dioxide gas and sterilization.The present invention also provides a kind of sterilized reducing sugar lipomul that contains by this sterilization manufacturing.
Contain the component of reducing sugar lipomul as the present invention, described fat milk is tantamount to be usually used in the fat milk of intravenous feed, i.e. the oil-in-water type fat breast that makes with the emulsifying agent chyle fat.
The fat that is applicable to Emulsion of the present invention can also be as the oil ﹠ fat of origin of heat (energy source) in any high alimentation of being everlasting etc., comprising: various plants oil, as Oleum Glycines, Oleum Gossypii semen, safflower oil, Semen Maydis oil, cocos nucifera oil, perilla oil, Storax oil, Semen Lini wet goods; Fish oil is as pilchard oil, cod-liver oil etc.; Chain fatty acid triglycerides (LCT) as the essential fatty acid source; And carbon number is generally the MCT Oil (MCT) of 8-10, it is characterized by to be easy to absorb, to be easy to burning and to accumulate trend little, and its exemplary is Panacete
TM(NOF company) and ODO
TM(The Nisshin Oil Mills, Ltd.).In addition, described fat also comprises the triglyceride of chemistry definition, 2-Caulis et Folium Lini acyl group-1 for example, 3-two caprylyl glycerol, 2-Caulis et Folium Lini acyl group-1,3-didecyl acylglycerol etc.These materials can use separately, also can use with.The final concentration that is blended in the fat in the product of the present invention suits to be about 1.5-20% (w/v), or is more preferably 2-8% (w/v).
The present invention can adopt any conventional emulsifying agent that uses, and for example, phospholipid is as Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, soybean lecithin, hydrogenated soy phosphatidyl choline etc.; With synthetic surfactant (commercially available prod for example, as Tween 80, HCO-60, Pluronic (polyoxyethylene polyoxypropylene block copolymer) F68 etc.).To the ratio of emulsifying agent without limits, but preferably about 30-300mg/g fat.
Contain another kind of energy source in the reducing sugar lipomul as the present invention, described reducing sugar can be a glucide commonly used in any this type of transfusion.Preferred example is glucose, fructose and maltose.These saccharides can use separately or use with.Can after the emulsifying stage of fat milk or emulsifying, add above-mentioned reducing sugar.The ratio of reducing sugar generally is about 5-50% (w/v), is preferably about 6-25% (w/v).Consider the first-selected glucose that adopts from the viewpoint of blood sugar control.If desired, also can be mixed with the non-reducing sugar of debita spissitudo in the compositions of the present invention, as xylitol, sorbitol, glycerol etc.
In pharmaceutical composition of the present invention, the organic acid that to add at least a acid dissociation exponent that is selected from water be 5.0-7.5 and the buffer substance of salt thereof are crucial.Used organic acid can be selected from multiple aliphatic carboxylic acid or aromatic carboxylic acids, sulfonic acid, phosphonic acids etc.Carboxylic acid is particularly preferred.These organic acid can be the unit price organic acid, also can be the multivalence organic acid.Noteworthy organic acid instantiation comprises: succinic acid, malonic acid, 1,3-propanedicarboxylic acid, maleic acid, malic acid etc.Preferred especially succinic acid.
Be meant the pKa value that records under the room temperature at this used term " acid dissociation exponent " in water, this term is meant dissociated dissociation index for the second time when being example with the dicarboxylic acids, and this term is meant dissociated for the third time dissociation index for tricarboxylic acids.
As above-mentioned organic acid salt, noteworthy exemplary can be alkali metal salt such as sodium salt, potassium salt etc. and magnesium salt.
The consumption of buffer substance should be based on the content of fat and reducing sugar, and in general, the content of buffer substance is preferably about 0.005-0.05% (w/v) (based on whole compositions).
When described buffer substance is free acid, the pH that the present invention contains the reducing sugar lipomul is transferred to 5.0-7.5 with alkali.The alkali that is usually used in this purpose comprises alkali-metal hydroxide, for example sodium hydroxide and potassium hydroxide.On the other hand, when adopting acylate, use acid or alkali that the pH regulator of Emulsion is arrived in the above-mentioned scope as described buffer substance.The preferential acid of adopting includes, but is not limited to hydrochloric acid, sulphuric acid and acetic acid.Used alkali as mentioned above.Preferred pH scope is 5.5-6.5.
The present invention of gained like this contains the reducing sugar lipomul and can be used as the end-product use.Yet in fact Emulsion normally is used in combination as aminoacid and electrolyte with other component, so preferred fat Emulsion provides with the double pack dosage form.Like this, Emulsion is contained in the compartment of multichamber vessel, aminoacid and electrolyte are contained in another compartment, have in the described multichamber vessel and make the spacer that each compartment can't intercommunication, so, before administration, need this spacer pierced through or stave so that the content in two compartments mixes mutually.
Example as described multichamber vessel, noteworthy have that (1) is a kind of to have container (open H2-4671 of Japan's special permission that easy heat-sealing separates spacer, the open H5-5138 of Japanese Utility Model), (2) a kind of container (the open S63-309263 of Japan's special permission) of spacer and a kind of container (the open S63-20550 of Japan's special permission) that (3) spacer wherein has intercommunicating device cut off.Wherein, preferred first kind of container (1) is because this container is suitable for big production and each compartment is easy to be connected.
The preferred breathable plastic material that adopts is made said vesse, makes the plastic material that medical container is used always as those.The object lesson of being worth mentioning is: polyethylene, polypropylene, polrvinyl chloride, cross-linked ethylene vinyl acetate co-polymer, ethene-alpha-olefin copolymer, above-mentioned mixture of polymers and the laminate that contains above-mentioned polymer.
Described component can be filled in separately the compartment and sterilization by conventional method.For example, under inert atmosphere (as carbon dioxide or nitrogen), be filled in the compartment each component fluids and after sealing, whole heat sterilization.The method of heat sterilization comprises multiple known method, for example sterilization by saturated steam under pressure (autoclaving), disinfection with hot water method and heat water-spraying's sterilization.If desired, described heat sterilization can carry out under inert atmosphere such as nitrogen.
Suit further to be packaged together in air-locked further receptacle, to its objective is to prevent transfusion degraded and oxidation with the reducing sugar lipomul that contains of transfusion packaged in primary containment vessel with state and the oxygen absorbent that is suitable for described primary containment vessel more surely.Especially when adopting above-mentioned (1) type container, suitable spacer along further receptacle self carries out FOLD AND PACK, and spacer will can not break because of external pressure is accidental each compartment is communicated with like this.In addition, if desired, can carry out above-mentioned the packing with noble gas packing method.
The Air Proof Packing package material that is applicable to secondary package can be any known vessel with shroud of gas character, and this includes, but is not limited to polyethylene terephthalate (PET), PEN (PEN), ethylene-vinyl alcohol copolymer (EVOH), polyvinylidene chloride (PVDC), nylon and polyester.Preferably make further receptacle, or thin film or the thin slice made by arbitrary above-mentioned material with the material molding that is selected from above-mentioned material, the laminated film of above-mentioned material or laminated foil, or have the thin film or the thin slice of the steam decomposition layer of silicon dioxide and/or aluminium oxide; And more preferably be made into plural layers.
Described oxygen absorbent comprises multiple known materials, and for example those contain ferrum or iron compound (as hydrated ferric oxide., ferrum oxide, the iron carbide etc.) material as active component.Typical this type of commercially available prod is " Ageless " (being made by Mistubishi Gas Chemical), " Moduran " (being made by Nippon Kayaku) and " Secur " (being made by Nippon Soda).
When charge into carbon dioxide atmosphere and in the sealing after after finishing heat sterilization under the blanket of nitrogen, the carbon dioxide absorption agent of packing in further receptacle that suits is so that thoroughly remove the carbon dioxide of remnants (in medicinal liquid head space and medicinal liquid).The above-mentioned carbon dioxide gas absorbent of being worth mentioning comprises the commercially available prod, " Wakolime " that produces by Wako Pure Chemical Industries for example, " Ageless E " and the product " Baralyme " of AicaKogyo produced by Mistubishi Gas Chemical.
Contain in the administration of reducing sugar lipomul in the present invention, can randomly add other component such as vitamin and trace element (inorganic matter).Described vitamin comprises various water miscible or fat-soluble vitamin, for example, Palimitate-A alcohol ester, thiamine hydrochloride, riboflavin, pyridoxine hydrochloride, vitamin B12, ascorbic acid, vitamin D3, tocopheryl acetate, nicotiamide, calcium pantothenate, folic acid, biotin and vitamin K1.
The present invention also provides a kind of lipomul of reducing sugar and sterilizing methods of this lipomul of containing, wherein, the medicinal liquid that will contain reducing sugar and fatty ingredient is sterilized with the carbon dioxide that is dissolved in the medicinal liquid, this medicinal liquid is packaged in the plastics infusion container, this container and carbon dioxide absorption agent are packaged together in substantially not in the further receptacle of oxygen flow subsequently again.
Adopt the sterilizing methods of carbon dioxide and carbon dioxide absorption agent by the invention described above, the lipomul that gained contains reducing sugar has physiological pH, and can thoroughly prevent its variable color and form free fatty under need not by means of the condition of painted inhibitor.
In addition, by using oxygen absorbent, can more effectively stop transfusion variable color and free fatty to generate.
In above-mentioned process, reduce pH so that the sterilization, other operating condition such as sterilization time and temperature are all similar with conventional sterilization technology except must at first utilizing the carbon dioxide that is dissolved in wherein to the medicinal liquid sterilization by means of carbon dioxide.Preferably under 102-121 ℃ temperature, carry out sterilization in 2-60 minute.
Usually, following carbon dioxide is dissolved in the medicinal liquid: reach predetermined pH until liquid by in containing the preparation jar of medicinal liquid, setting up carbon dioxide atmosphere, subsequently with suitable pressure or atmospheric pressure, both can feed mist (nitrogen-carbon dioxide gas for example, air-carbon dioxide gas etc.), wherein the dividing potential drop of carbon dioxide helps above-mentioned pH balance, also can feed carbon dioxide separately, so that pH is maintained above-mentioned level.After this, medicinal liquid is distributed in the primary containment vessel, this primary containment vessel comprises the plastics infusion container, as transfusion bag and infusion bottle etc., and discharge internal gas with similar mist or carbon dioxide, again primary containment vessel is carried out autoclaving (autoclaving), disinfection with hot water or heat water-spraying's sterilization, to finish required sterilization.As long as can prevent that reducing sugar from decomposing in sterilization process, above-mentioned pH is not just had strict the qualification, but in general preferred pH is 4-6.5.
In sterilizing methods of the present invention, the carbon dioxide that is dissolved in the medicinal liquid is released in sterilization process gradually, so that behind disinfecting action, the pH of sterilization transfusion finally returns to the preceding pH level of sterilization that is similar to.So the advantage of pharmaceutical composition of the present invention is, avoided forming the degraded danger that causes because of free fatty due to the acidify.Therefore, the plastics infusion bag that is used to preserve transfusion of the present invention is preferably made by those medical containers and the normal breathable plastic material that uses of vessel.The object lesson of this container material is described hereinbefore.
When the plastics infusion bag of preserving medicinal liquid further is packaged in the further receptacle with shroud of gas character, discharge carbon dioxide fully and become quite difficult, make the pH value of medicinal liquid in long-time, continue to tend to acidity.So reducing sugar is tending towards generating 5-HMF (5 hydroxymethyl 2 furaldehyde), thereby the danger that free fatty is formed increases.
In the present invention, in order effectively to suppress the formation of 5-HMF and free fatty,, the plastics infusion container of sterilization medicinal liquid and carbon-dioxide absorbent and optional oxygen absorbent be packaged together in substantially not in the further receptacle of oxygen flow being housed.Utilize this method, the pH of medicinal liquid returns to the pH level before the dissolved carbon dioxide gas within a short period of time, consequently, not only the pH of medicinal liquid is controlled in the scope of physiological pH (about 5.0-7.5), but also has prevented to form and the danger of free fatty generation because of the 5-HMF due to the excessive acidify.
In addition, owing to contain the reducing sugar lipomul and be packaged in the described further receptacle, have side effects so can prevent that block enters in the further receptacle, like this with oxygen absorbent, can more effectively suppress the generation of free fatty, and also effectively stop the reducing sugar decomposition.
Above-mentioned substantially not the oxygen flow further receptacle can be any known container with shroud of gas character, raw material that be fit to make this container comprises (but being not limited to) polyethylene terephthalate (PET), PEN (PEN), ethylene-vinyl alcohol copolymer (EVOH), polyvinylidene chloride (PVDC), nylon and polyester.Further receptacle preferably makes with the material molding that is selected from above-mentioned material, or by the laminated film or the laminated foil of the thin film of arbitrary above-mentioned material or thin slice, above-mentioned material or have silicon dioxide and/or the thin film or the thin slice of the steam decomposition layer of aluminium oxide are made; And more preferably make by plural layers.
Used term in present specification and claims " substantially not oxygen flow " is meant that the permeability of oxygen generally is not more than about 10ml/m
2. day, preferably be not more than about 1ml/m
2. day.
Described carbon dioxide gas absorbent can be any known carbon dioxide gas absorbent, and comprising the commercially available prod, for example " E200 ", " E400 " and " E500 " (by MitsubishiGas Chemical) make.Not concrete qualification of occupation mode to absorbent.In the situation of using fine powder, the powder of necessary amount can be filled in the ventilative pouch and use.For the absorbent of beadlet, bar-shaped and other shape, both can place them in the bag and use, also can directly use.
The consumption of carbon dioxide gas absorbent should be enough to absorb the 500ml carbon dioxide of being emitted corresponding to 700ml medicinal liquid in the plastics infusion container at least.
No matter above-mentioned oxygen absorbent is directly to use or when being packaged in form in the ventilative pouch (depending on its occupation mode) and using, all can be packaging together with the carbon dioxide absorption agent in described plastics infusion container (primary containment vessel) and the further receptacle.The consumption of oxygen absorbent should be enough to absorb the 200ml oxygen corresponding to 700ml medicinal liquid in the primary containment vessel at least.
So long as be sealed in the space between primary containment vessel and the further receptacle with isolated with primary containment vessel, above-mentioned carbon dioxide absorption agent and oxygen absorbent need not independent packaging.For example, two kinds of absorbent can be loaded in mixture in a bag.
The reducing sugar lipomul that contains of the present invention can make by the way.This lipomul can be used as conventional infusion product and uses in the same manner.For example, open secondary package, the content that is contained in the primary containment vessel is used separately, or after other material such as amino acid preparation mix, using.By in need infusion patient's vein, using transfusion or mixture, can reach required nutritional supplementation.
The accompanying drawing summary
Fig. 1 is that an expression is according to test example 1 described method lipomul of the present invention that records and the curve chart that contrasts free content of fatty acid in the lipomul.
Implement best mode of the present invention
Following example of formulations (work embodiment) and experimental example are used to further describe and of the present inventionly contain the reducing sugar lipomul, limit but never in any form scope of the present invention is constituted.
Embodiment 1
Pure Oleum Glycines, pure Ovum Gallus domesticus Flavus lecithin, glucose and succinic acid are joined in the water for injection, utilize the TK homo-mixer that mixture is descended thick emulsifying 30 minutes at 65-75 ℃.Subsequently, with Manton-Gaulin homogenizer (Gaulin, 15M-8TA) should rough emulsion at 400kg/cm
2Pressure under carry out the smart emulsifying of 10 circulation.Make the volume of this emulsion reach 10L and pH be transferred to 6.0, with the carbon dioxide pressurization, through 1.2 μ m membrane filtrations with the 1N sodium hydroxide solution.Under carbon dioxide atmosphere, filtrate distribution in the polyethylene infusion bag, with its heat sterilization under blanket of nitrogen, is obtained lipomul of the present invention composed as follows subsequently:
Pure Oleum Glycines 44.4g/l
Pure Ovum Gallus domesticus Flavus lecithin 5.33
Glucose 114.3
Succinic acid 0.2
Reference examples 1
The preparation of lipomul is by replacing the succinic acid among the embodiment 1 with the L-histidine of same amount, and with hydrochloric acid pH is transferred to 6, through 1.2 μ m membrane filtrations and with filtrate distribution in the polyethylene infusion bag.With being filled with the sack heat sterilization of content, obtain contrasting lipomul.
Experimental example 1
Will be in embodiment 1 and reference examples 1 lipomul of the present invention and the contrast lipomul of preparation are sealed in airtight outer bag with oxygen absorbent and carbon dioxide gas absorbent respectively.With nitrogen venting inner air, sack is stored under the condition of 60 ℃ and 75%R.H. (relative humidity).Free fatty acid content when measure producing the instant free fatty acid content in back and producing the back the 7th day and the 14th day.
With the normal heptane extraction liquid of each test specimen of 0.01N sodium hydrate aqueous solution titration, measure free fatty acid content wherein.In nitrogen current, carry out above-mentioned titration as indicator with thymol blue solution.Titration end-point is that redness becomes the blue moment.
The result as shown in Figure 1.In Fig. 1, (1) representative lipomul and (2) representative contrast lipomul that contains reducing sugar of the present invention.Obviously, as can be seen from Figure 1, compare with the contrast lipomul, the generation of free fatty acid is suppressed really in the lipomul of the present invention.
Embodiment 2
According to following prescription distilled water for injection is joined in pure Oleum Glycines, pure Ovum Gallus domesticus Flavus lecithin, glucose and the organic acid (succinic acid), and utilize the TK homo-mixer that mixture is descended thick emulsifyings 30 minutes at 70 ℃.Subsequently, should the smart emulsifying (400kg/cm of rough emulsion with Manton-Gaulin homogenizer
2, 10 times), obtain a kind of Emulsion.Make the volume of this Emulsion reach 10L and pH be transferred to 6.0 with the 1N sodium hydrate aqueous solution.
Prescription
Pure Oleum Glycines 44.4g/l
Pure Ovum Gallus domesticus Flavus lecithin (12%) 5.33g/l based on Oleum Glycines
Glucose 114.3 g/l
Succinic acid 0.2 g/l
Sodium hydroxide (pH regulator agent) is an amount of
Distilled water for injection is an amount of
Pressurize so that the pH of Emulsion reaches 5.2 with free space on the liquid level of carbon dioxide in Emulsion preparation jar.Subsequently, mist (CO will be full of in the jar
2: N
2=45: 55), wherein the dividing potential drop of carbon dioxide helps reaching above-mentioned pH balance.With this understanding Emulsion is filled in the infusion bag and is full of each sack with same gaseous mixture, subsequently with infusion bag in autoclave, sterilized 40 minutes down in 110 ℃, the present invention who obtains the infusion dosage form contains the reducing sugar lipomul.
Test example 2
The reducing sugar lipomul that contains of preparation among the embodiment 2 is stored 14 days and monitors its variable color degree under the condition of 60 ℃ and 75%R.H..
Between detection period, the outward appearance of scouting sample; Meanwhile, under 450nm, measure the absorbance that contains water section (T%) of infusion sample gained behind ultrafiltration-centrifugal (Kubota Model KR-180A) with ShimadzuUV-160.
Simultaneously, utilize pH, the free fatty in the sample (FFA) content (meq/l) of titrimetry and liquid chromatography for measuring sample and represent the content (ppm) of the 5 hydroxymethyl 2 furaldehyde of reducing sugar content hydrolysis products respectively.
Purpose is in order to reference also carried out identical test to control sample, and the preparation of this control sample is to carry out according to the method identical with embodiment 2, just dispenses the carbon dioxide dissolving step, just only is full of preparation jar and fills infusion bag with nitrogen.
Free fatty acid content when measure producing the instant free fatty acid content in back and producing the back the 7th day and the 14th day, result of the test is as shown in table 1.
Table 1
| Sample | Parameter | After the instant sterilization | Store after 7 days | Store after 14 days |
| Sample of the present invention | Outward appearance | Colourless | Slightly coloured | Coloured |
| ????T％ | ????99.4 | ????97.4 | ????95.3 | |
| ????pH | ????5.80 | ????5.53 | ????5.35 | |
| ????FFA | ????0.53 | ????0.84 | ????1.56 | |
| ????5-HMA | ????0.31 | ????1.55 | ????3.93 | |
| Control sample | Outward appearance | Slightly coloured | Coloured | Coloured |
| ????T％ | ????98.7 | ????96.7 | ????94.3 | |
| ????pH | ????5.52 | ????5.28 | ????5.12 | |
| ????FFA | ????0.55 | ????1.27 | ????2.45 | |
| ????5-HMF | ????0.29 | ????3.11 | ????8.04 |
Obviously can find out from table 1, infer according to its high-transmission rate that the reducing sugar lipomul that contains of the present invention has obviously suppressed other the generation of catabolite of the formation of 5-HMF and glucose, so its quality is satisfactory, the degree of variable color simultaneously is extremely low.Can also infer that the generation that has the breakdown of glucose product of tart flavour has been reduced to minimum.Because can the pH of lipomul of the present invention be returned to pH level before the sterilization by removing carbon dioxide dissolved gas, be suppressed so As time goes on Emulsion become tart variation, and the formation of free fatty also is suppressed between the storage life.
Embodiment 3
According to following prescription distilled water for injection is joined in pure Oleum Glycines, pure Ovum Gallus domesticus Flavus lecithin, glucose and the organic acid (succinic acid), and utilize the TK homo-mixer that mixture is descended thick emulsifyings 30 minutes at 70 ℃.Subsequently, should the smart emulsifying (400kg/cm of rough emulsion with Manton-Gaulin homogenizer
2, 10 times), obtain a kind of Emulsion.Make the volume of this Emulsion reach 10L and pH be transferred to 6.0, obtain a kind of transfusion with the 1N sodium hydroxide solution.
Prescription
Pure Oleum Glycines 44.4g/l
Pure Ovum Gallus domesticus Flavus lecithin (12%) 6.66g/l based on Oleum Glycines
Glucose 114.3g/l
Succinic acid 0.2g/l
Sodium hydroxide (pH regulator agent) is an amount of
Distilled water for injection is an amount of
Pressurize so that the pH of transfusion reaches 5.2 with free space on the liquid level of carbon dioxide in Emulsion preparation jar.Subsequently, mist (CO will be full of in the jar
2: N
2=45: 55) to keep this pH, wherein the dividing potential drop of carbon dioxide helps reaching the pH balance of transfusion, and transfusion is filled in the infusion bag (made by polyethylene, thickness 250 μ m, capacity is 1000ml) with the 700ml equal portions.After the air in discharging between each bags empty, infusion bag in autoclave, in 110 ℃ of following sterilizations 40 minutes, is obtained infusion bag with same gaseous mixture.
After the cooling, with infusion bag and " E500 " (Mitsubishi Gas Chemical, a kind of carbon dioxide gas absorbent) and " Ageless ZH200 ' (Mitsubishi Gas Chemical; a kind of oxygen absorbent) is placed in 5 layers of [oriented polypropylene (OPP) (OPP)/nylon/EVOH/ nylon/low-density straight linear polyethylene (LLDPE)] lamination bag (volume is 1500-1600ml) together, obtains product of the present invention.
The said goods is stored 18 days under 25 ℃ and 60%R.H., detect the pH and the time dependent process of carbon dioxide of infusion content in the bag.
The result is as shown in table 2.In table 2, also listed the pH and the amount of carbon dioxide of transfusion before the sterilization.
Give the result of reference product I and reference product II in the table 2, reference product I prepares according to mode same as described above, but does not adopt " E500 " (only that " Ageless ZH200 " is packaging together with infusion bag); The preparation method of reference product II comprises, only uses nitrogen (not using carbon dioxide) to discharge internal gas in the preparation jar and the gas in the infusion bag when sterilization, do not use " E500 " and only employing " Ageless ZH200 " simultaneously.
Table 2
| Sample | Before the sterilization | After the instant sterilization | After 4 days | After 10 days | After 18 days | |
| Product of the present invention | ????pH | ??5.20 | ????5.30 | ??5.64 | ??5.82 | ??5.88 |
| ?CO 2Content (%) | ??45.0 | ????27.5 | ??4.63 | ??0.48 | ??0.06 | |
| Reference product I | ????pH | ??5.20 | ????5.30 | ??5.55 | ??5.57 | ??5.60 |
| ?CO 2Content (%) | ??45.0 | ????27.5 | ??7.47 | ??7.19 | ??5.86 | |
| Reference product II | ????pH | ??5.96 | ????5.59 | ??- | ??5.58 | ??5.58 |
| ?CO 2Content (%) | ??0.06 | ????0.16 | ??- | ??0.02 | ??0.02 |
Obviously can find out that from table 2 in infusion product of the present invention, carbon dioxide almost completely was removed in about 10 days, the pH of transfusion is increased to and approaches initial level, suppresses to pass in time the formation of the free fatty that brings thus.
Claims (15)
1. lipomul that contains reducing sugar, wherein contain emulsified dose of emulsive oil-in-water type fat breast of fat, wherein reducing sugar and at least a buffer substance are present in its water simultaneously, the pH of this Emulsion is adjusted to 5.0-7.5, and described buffer substance is selected from that acid dissociation exponent is organic acid and the salt thereof of 5.0-7.5 in water.
2. the described lipomul that contains reducing sugar of claim 1, wherein in by weight/volume, the consumption of described oil is 1.5-20%, and the consumption of described reducing sugar is 5-50%, and the consumption of described emulsifying agent is the described fat of 30-300 milligram/restrain.
3. claim 1 or the 2 described lipomuls that contain reducing sugar, wherein said reducing sugar is a glucose.
4. each described lipomul that contains reducing sugar among the claim 1-3, wherein said buffer substance is at least a material that is selected from succinic acid and alkali metal salt thereof.
5. each described lipomul that contains reducing sugar among the claim 1-4, the consumption of wherein said buffer substance is counted 0.005-0.05% with by weight/volume.
6. each described lipomul that contains reducing sugar among the claim 1-5, this Emulsion is packaged in the compartment of gas-pervious flexiplast infusion container of a plurality of chambers, and after sterilization, further be packaged in air-locked further receptacle with oxygen absorbent.
7. lipomul product that contains reducing sugar, this product comprises the medicinal liquid that contains reducing sugar and fat, this medicinal liquid is sterilized and is filled in the plastics infusion container with being dissolved in wherein carbon dioxide, and described plastics infusion container is packaged in again substantially not in the further receptacle of oxygen flow with the carbon dioxide gas absorbent.
8. the described lipomul that contains reducing sugar of claim 7, wherein said plastics infusion container and carbon dioxide gas absorbent further are packaged in the described further receptacle with oxygen absorbent.
9. claim 7 or the 8 described lipomuls that contain reducing sugar, the pH of wherein said medicinal liquid reaches 4-6.5 at once after carbon dioxide is dissolved in wherein.
10. each described lipomul that contains reducing sugar among the claim 7-9, the pH of wherein said medicinal liquid all are in the scope of 5.0-7.5 before carbon dioxide is dissolved in wherein and after sterilization.
11. each described lipomul that contains reducing sugar among the claim 7-10, wherein said reducing sugar is one of glucose, fructose and maltose at least.
12. a sterilizing methods that contains the reducing sugar lipomul is comprising the medicinal liquid that contains reducing sugar and fat that wherein is dissolved with carbon dioxide is sterilized.
13. the described sterilizing methods of claim 12, the pH of wherein said medicinal liquid reach 4-6.5 at once after carbon dioxide is dissolved in wherein.
14. claim 12 or 13 described sterilizing methods, the pH of wherein said medicinal liquid all are in the scope of 5.0-7.5 before carbon dioxide is dissolved in wherein and after sterilization.
15. each described sterilizing methods among the claim 12-14, wherein said reducing sugar is one of glucose, fructose and maltose at least.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB971823197A CN1163232C (en) | 1997-07-25 | 1997-07-25 | Fatty emulsing contg. reducing sugar and method for sterilizing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB971823197A CN1163232C (en) | 1997-07-25 | 1997-07-25 | Fatty emulsing contg. reducing sugar and method for sterilizing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1259870A true CN1259870A (en) | 2000-07-12 |
| CN1163232C CN1163232C (en) | 2004-08-25 |
Family
ID=5178392
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB971823197A Expired - Lifetime CN1163232C (en) | 1997-07-25 | 1997-07-25 | Fatty emulsing contg. reducing sugar and method for sterilizing same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1163232C (en) |
-
1997
- 1997-07-25 CN CNB971823197A patent/CN1163232C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CN1163232C (en) | 2004-08-25 |
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