CN1161150C - Pharmaceutical compositions - Google Patents
Pharmaceutical compositions Download PDFInfo
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- CN1161150C CN1161150C CNB988033569A CN98803356A CN1161150C CN 1161150 C CN1161150 C CN 1161150C CN B988033569 A CNB988033569 A CN B988033569A CN 98803356 A CN98803356 A CN 98803356A CN 1161150 C CN1161150 C CN 1161150C
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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Abstract
The present invention relates to a cyclosporin-containing soft capsule preparation which comprises a composition containing cyclosporin as an active ingredient; a hydrophilic component polyethylene glycol or a non-hydrophilic component propylene carbonate or their mixture, one or a mixture of two or more selected from the group consisting of an esterified compound of fatty acid and primary alcohol, medium chain fatty acid triglyceride and fatty acid monoglyceride as an oil component; and a surfactant having an HLB (Hydrophilic Lipophilic Balance) value of 8 to 17.
Description
The present invention relates to a kind of preparation that contains as the cyclosporin of active component, for example soft capsule.More particularly, the present invention relates to a kind of soft capsule preparation, it comprises: as the cyclosporin of active component; Propylene carbonate or Polyethylene Glycol or its mixture; Be selected from down the material of group or two or more are selected from down the mixture of organizing material: the carboxylate of fatty acid and primary alconol, MCT Oil and fatty acid monoglyceride as oil component a kind of; And HLB (hydrophile-lipophile balance) value is 8～17 surfactant.
Cyclosporin is a kind of special macromole that is made of 11 aminoacid (molecular weight 1202.64) cyclic peptide compounds, and it has useful pharmacologically active, especially immunosuppressive activity and the anti-inflammatory activity of wide region.Therefore, cyclosporin has been used to suppress the inborn immune response of live body, this response by the tissue and organ transplantation cause, for example, the transplanting of heart, lung, liver, kidney, pancreas, bone marrow, skin and cornea, the transplanting of especially outer source tissue and organ.In addition, cyclosporin is applicable to and suppresses hematopathy (for example anemia), various autoimmune diseases (for example systemic lupus erythematosus (sle), spontaneous malabsorption syndrome etc.), and inflammation (for example arthritis, rheumatoid disease etc.).Cyclosporin is applicable to the treatment protozoacide, for example malaria, schistosomicide etc., and in addition, it also is used to chemotherapy recently.
Cyclosporin is a height lipotropy and hydrophobic.Thereby cyclosporin is slightly soluble in water, and is dissolved in this class organic solvent, for example methanol, ethanol, acetone, ether, chloroform etc.Owing to have the low aqueous solubility of the cyclosporin of aforementioned properties,, and may be subjected to the tremendous influence of individual patient situation so when oral cyclosporin, its bioavailability is extremely low.Therefore, be difficult to the treatment concentration of remaining valid.In addition, cyclosporin may show sizable side effect, for example pnehrotoxicity.So cyclosporin is owing to its low aqueous solubility is difficult to be mixed with oral formulations.Therefore, carried out big quantity research widely and tried to find out and be fit to the preparation of effective oral cyclosporin, said preparation should be able to provide suitable uniform dose and suitable bioavailability.
In the prior art, be fit to the form that the oral preparation that is slightly soluble in the cyclosporin of water is formulated into the pre-concentration emulsion usually.
The U.S. Patent No. 4,388,307 of issue on June 14 nineteen eighty-three has been enlightened a kind of typical method of this combination of application.This patent disclosure the alcoholic acid liquid formulation of cyclosporine of a kind of application.By disclosed method in this US Patent specification, with cyclosporin and a kind of carrier combinations and form described liquid preparation, this carrier comprises: as the ethanol of cosurfactant, as the olive oil of vegetable oil, and as the crude vegetal triglyceride of surfactant and the transesterification products of polyalkylene polyhydric alcohol.
Yet, the liquid preparation that forms to be used as containing water diluent, it is difficult to make the curee to adapt to its dispenser, and is difficult to the uniform dose that provides oral.
In order to alleviate the inconvenience of the described cyclosporin fluid composition of dilute with water before oral, the fluid composition that will be the pre-concentration emulsion form is mixed with soft capsule preparation, and said preparation can be purchased by Sandimmune (registered trade mark) now.Cyclosporin soft capsule contains ethanol under this situation, and this is because the dissolubility requirement of cyclosporin.But, but because the capsular gelatin shell of ethanol infiltrate (even because ethanol also is volatile at normal temperatures), so in order to prevent that ethanol volatilizees from soft capsule preparation in storage and sales process, soft capsule preparation can be wrapped in the specific packaging material, for example aluminum-aluminum foaming body packing.
May develop a kind of like this cyclosporin formulations recently, it has bin stability and roughly constant bioavailability further is provided, and also zero difference roughly between the individual curee is so can keep the biological effect unanimity of cyclosporin.One of Kai Fa preparation is disclosed among Korea S's publication (Korean Laid-open Patent) publication number 93-113 for this reason.Said preparation is with registered trade mark " Sandimmun Neoral " commercialization.Yet, because said preparation has also been used ethanol, so it may have existing contain some such shortcoming of ethanol preparation, the variation of for example bin stability aspect, and ethanol content.
Therefore, the inventor has studied the multiple combination of various surfactants, oil component, cosurfactant etc., attempt to seek a kind of like this herbicide-safener combination: it is stable, and provides from the pharmacokinetics performance and consider difference than content the blood between higher bioavailability of existing cyclosporin formulations and the lower individual curee.As a result, we have found that a kind of herbicide-safener combination of the composition that hereinafter defines that comprises can satisfy above-mentioned requirements, so finished the present invention.
Therefore, one aspect of the present invention provides a kind of compositions that is fit to be mixed with soft capsule, and it comprises: as the cyclosporin of active component; Hydroaropic substance Polyethylene Glycol or non-hydroaropic substance propylene carbonate or its mixture; Hereinafter Ding Yi oil component, and surfactant.
Another aspect of the present invention provides a kind of soft capsule preparation that comprises a kind of compositions, and said composition contains: as the cyclosporin of active component; Hydroaropic substance Polyethylene Glycol or non-hydroaropic substance propylene carbonate or its mixture; Be selected from down the material of group or two or more are selected from down the mixture of organizing material: the carboxylate of fatty acid and primary alconol, MCT Oil (if necessary) and fatty acid monoglyceride as oil component a kind of; And HLB (hydrophile-lipophile balance) value is 8～17 surfactant.
Another aspect of the present invention provides a kind of method for preparing soft-gelatin capsule formulation defined above.
Though this paper has described the present invention at Perle especially, should understand that the present invention has covered compositions itself, but the said composition former state perhaps is other unit dosage forms as for example drinking liquid (as " SandimmunNeoral ").
On the one hand, the present invention relates to contain the capsule of cyclosporin, it has high-storage stability, its composition changes little in time like this, it also has the bioavailability that increases, and this capsule contains a kind of compositions, and said composition comprises: as the cyclosporin of active component; Hydroaropic substance Polyethylene Glycol or non-hydroaropic substance propylene carbonate or its mixture as second kind of composition; Ding Yi oil component hereinafter; And surfactant.
This compositions that contains cyclosporin soft capsule preparation to be mixed with, just gelatin shell must be used.Yet, when this soft capsule during with the conventional capsule shells preparation that contains as the glycerol of plasticizer, this soft capsule preparation has some shortcoming, the emulsifying attitude that is described pre-concentration emulsion may change because of flowing into emulsion in the glycerol, so the dissolubility of cyclosporin greatly reduces, cause cyclosporin from emulsion, to be separated out.
Therefore, in the present invention, the gelatin shell that the preferred mixture (rather than glycerol) of selecting to use propylene glycol and Polyethylene Glycol is made plasticizer is as described soft capsule shell, it can solve with glycerol in the relevant problem of stream.
But, when preparing the capsule shells band that the present invention contains propylene glycol and Polyethylene Glycol by the water-cooled valve that is usually used in chilling roll, be not easy it to be peeled off from cylinder, this capsule shells band can improve by this chilling roll of sub-cooled from the rippability of chilling roll, promptly by recirculated cooling water continuously and the temperature of described band is dropped to about 17 ℃.Yet, be cooled to more that the capsule shells band of low temperature may provide the sealing of low degree in encapsulation process, and may cause the reduction of productivity ratio.
Therefore, the present invention's preparation does not contain the method for the gelatin shell band of glycerol plasticizer and takes air-cooling to replace existing water-cooled valve, wherein by provide air flow described capsule shells band can be cooled to optimum temperature from ventilate fan, so can easily it be peeled off from chilling roll, in addition, thus it is maintained at about 21 ℃ optimum temperature improves the seal degree in the encapsulation process and guarantees high production rate.
As previously mentioned, this product can be produced by using not glycerinated gelatine capsule shell and air cooling method being applied to described compositions, said composition does not contain the ethanol as the low boiling volatile solvent, thereby has a high-storage stability, said composition changes for a short time in time like this, and has the bioavailability that increases.
More particularly, the present invention relates to a kind of cyclosporin formulations, it comprises the compositions that contains following composition:
1) as the cyclosporin of active component;
2) Polyethylene Glycol or propylene carbonate or its mixture;
3) be selected from down the material of group as oil component a kind of or two or more are selected from down the mixture of organizing material: the carboxylate of fatty acid and primary alconol, MCT Oil and fatty acid monoglyceride, and
4) HLB (hydrophile-lipophile balance) value is 8～17 surfactant,
For example be in the gelatin shell that contains as the Polyethylene Glycol of plasticizer and propylene glycol.Another aspect of the present invention provides a kind of cyclosporin formulations, and it comprises the compositions that contains following composition:
1) as the cyclosporin of active component; And
2) propylene carbonate.In another aspect of the invention, said composition does not contain Polyethylene Glycol.
This compositions (it also is a kind of compositions of the present invention) can be chosen wantonly and comprise other any composition as herein described (if necessary with amount as herein described) in addition.
As previously mentioned, the cyclosporin as present composition Chinese medicine active component is a kind of cyclic peptide compounds with useful immunosuppressive activity and anti-inflammatory activity.Though cyclosporin A, B, C, D, G etc. can be used as cyclosporin composition of the present invention, cyclosporin A is most preferred, because its clinical effectiveness and pharmacological properties have all been confirmed in present technique fully.
As the second kind of composition (and it can play cosurfactant) in the present composition, can use propylene carbonate or Polyethylene Glycol or its mixture.
Propylene carbonate can be used as described non-hydroaropic substance, and it has high boiling point (about 242 ℃), is nonvolatile matter, shows low hygroscopicity and shell permeability, and cyclosporin is had highly dissoluble.
Alternatively, Polyethylene Glycol also can be used as described hydroaropic substance, and it has high boiling point, is nonvolatile matter, and it is the gelatin shell of infiltrate soft capsule not, and cyclosporin is had highly dissoluble.In compositions of the present invention, though any Polyethylene Glycol that is liquefied all can be used, molecular weight is that 200～600 Polyethylene Glycol (PEG), especially PEG 200 can be by advantageous applications.
In the present invention, also can use the mixture of previously defined non-hydroaropic substance and hydroaropic substance.When the mixture of Polyethylene Glycol and propylene carbonate was used as composition among the present invention, they generally can be by the ratio combination that based on weight is 1: 0.1～5, preferred 1: 0.1～3, most preferably 1: 0.2～2.
In the present invention, the application of Polyethylene Glycol and propylene carbonate provides some advantage, that is, the bin stability that contains the compositions of cyclosporin has been enhanced, so as one man kept being contained in the content of composition wherein basically.In addition, the application of propylene carbonate even can increase the dissolubility of active component cyclosporin and suppress water and in gelatine capsule shell, flow into described compositions, thus more stable compositions is provided.
In compositions of the present invention, the ratio of second kind of composition of application is: per 1 weight portion cyclosporin is preferably 0.1～10 weight portion, and more preferably 0.5～8 weight portion most preferably is 1～5 weight portion.
The third composition that is used for pre-concentration emulsion of the present invention is an oil component.As the oil component among the present invention, can use a kind of material that is selected from down group or two or more are selected from down the mixture of organizing material: the carboxylate of fatty acid and primary alconol, MCT Oil (when existing) and fatty acid monoglyceride.The carboxylate that can be used for described fatty acid of the present invention and primary alconol can comprise the fatty acid with 8～20 carbon atoms and have the carboxylate of the primary alconol of 2～3 carbon atoms, for example isopropyl myristate, isopropyl palmitate, Ethyl linoleate, ethyl oleate etc. are particularly preferred with linoleic acid and alcoholic acid carboxylate.In addition,, can use the triglyceride of satisfied fatty acid, most preferably use caprylic/capric triglyceride as the vegetable oil triglyceride of satisfied fatty acid with 8～10 carbon atoms as MCT Oil (when existing).The fatty acid monoglyceride that also can be used as the oil component among the present invention comprises the monoglyceride of the fatty acid with 18～20 carbon atoms, especially oleic monoglyceride.
In pre-concentration microemulsion of the present invention, the oil component ratio of application can be: per 1 weight portion cyclosporin is 1～10 weight portion, is preferably 2～6 weight portions.
Preferably, when fatty acid monoglyceride and fatty acid ester exist as oil component for example with 1: 1～1: 2 ratio, as 1: 1～1: 1.2.
The optional caprylic/capric triglyceride that also exists is for example with 1: 0.1～0.2 the ratio with respect to Ethyl linoleate.
In being used as the oil mixture of oil component of the present invention, fatty acid monoglyceride: the carboxylate of fatty acid and primary alconol: the mixing ratio of MCT Oil (when existing) can be in 1: 0.1～5: 0.1～10 the scope, preferably in 1: 0.1～3.0: 0.1～3.0 scope based on weight usually.
The 4th kind of composition that is used for the present composition is surfactant.Be used for suitable surfactant of the present invention and comprise that any HLB (hydrophile-lipophile balance) value is 8～17 pharmaceutically acceptable surfactant, they can be stably stably be emulsified in the lipophile part (comprising the oil component that contains cyclosporin) of described compositions and hydrophilic parts (comprising cosurfactant) in the water and formation stable microemulsion liquid.Preferred surfactants example of the present invention comprises: the polyoxyethylene product of hydrogenated vegetable oil, polyoxyethylene sorbitan fatty acid ester etc., for example, NIKKOLHCO-50, NIKKOLHCO-40, NIKKOL HCO-60, TWEEN20, TWEEN 21, TWEEN 40, TWEEN 60, TWEEN 80, TWEEN 81 etc.Especially but the advantageous applications acid number is lower than 1, saponification number is about 48～56, hydroxyl value be about 45～55 and pH value (5%) be that (it is with trade mark NIKKOL HCO-50 (NIKKO Chemical Co. Lt.) has become commercialized) and polyoxyethylene (20) Span-20 (it has become commercialized with trade mark TWEEN 20 (ICIChemicals)) for 4.5～7.0 polyoxyethylene (50) castor oil hydrogenated.
Described surfactant can comprise any above-mentioned surfactant, is the combining form that two or more are selected from the surfactant of above-mentioned surfactant individually or preferably.In compositions of the present invention, the described surfactant ratio of application can be: per 1 weight portion cyclosporin is 1～10 weight portion, preferably with the ratio of 2～8 weight portions.
In addition, when the mixture of two kinds of surfactants (being polyoxyethylene (50) castor oil hydrogenated and polyoxyethylene (20) Span-20) is used in the compositions of the present invention, polyoxyethylene (50) castor oil hydrogenated: the component ratio of polyoxyethylene (20) Span-20 based on weight preferably in 1: 0.1～5 scope, more preferably in 1: 0.5～4 scope.
In compositions of the present invention, the ratio (weight ratio) that described four kinds of compositions exist is preferably: cyclosporin: second kind of composition: oil component: surfactant=1: 0.1～10: 1～10: 1～10, more preferably cyclosporin: second kind of composition: oil component: surfactant=1: 0.5～8: 2～6: 2～8.
Except said composition, can mention the compositions set forth among the embodiment hereinafter as the further preferred compositions of the present invention.
Oral as if being used for, the compositions of the present invention that contains aforementioned composition can be formulated into the soft capsule form.Because soft capsule preparation of the present invention is not used ethanol as the low boiling volatile solvent, so it is stable on the medicine, and can form desired improvement, comprises the improvement of bioavailability.
But, may be difficult to as conventional soft capsule shell, repeat preparation by the conventional method of preparation soft capsule.When with containing when preparing this soft capsule as the conventional capsule shells of the glycerol of plasticizer, may there be some shortcoming in Zhi Bei soft capsule like this, the emulsifying attitude that is described pre-concentration emulsion will change because of flowing into emulsion in the glycerol, so the dissolubility of cyclosporin greatly reduces, will cause cyclosporin from emulsion, to be separated out like this.
Therefore, in another aspect of this invention in, found when preparing this capsule shells as plasticizer, can obtain long-time stable soft capsule preparation by the mixture (rather than glycerol) of using Polyethylene Glycol and propylene glycol.Though any Polyethylene Glycol that is liquefied all can be used as plasticizer, the advantageous applications molecular weight is 200～600 Polyethylene Glycol.
Especially advantageous applications Macrogol 200.In soft capsule shell of the present invention, the Polyethylene Glycol of using and the ratio of propylene glycol mixture are preferably 0.1～0.5 weight portion with respect to a weight portion is used to prepare the gelatin of this capsule shells, more preferably 0.1～0.4 weight portion most preferably is 0.2～0.3 weight portion.In the mixture as the Polyethylene Glycol of plasticizer and propylene glycol, the ratio of the propylene glycol of combination is preferably 1～10 weight portion with respect to a weight portion Polyethylene Glycol, and more preferably 3～8 weight portions most preferably are 3～6 weight portions.
In order to improve the rippability that described soft capsule shell band is peeled off from chilling roll, the method for preparing gelatine capsule shell band of the present invention adopts air-cooling to replace water-cooled valve.By this air-cooling, because described capsule shells band is not overheated,, keep about 21 ℃ optimum temperature simultaneously so can easily peel off from chilling roll, the seal degree height in this encapsulation process, thus guarantee high production rate, therefore, this method can be implemented effectively.
When preparation soft capsule of the present invention, the suitable volume of air flow of supply chilling roll cooling capsule shells is 5～15m preferably
3/ min, most preferably from about 10m
3/ min.
Since as the propylene carbonate of second kind of component among the present invention can be separately with or as its main component, so consider the dissolubility of cyclosporin and the stability of soft capsule, in gelatin shell, do not use certain plasticizer and just can prepare the long-time stable soft capsule preparation that contains cyclosporin.
In this gelatin shell, as for described plasticizer, can there be any material that one or more are selected from down group of restrictedly using: glycerol, Sorbitol, hexanetriol, propylene carbonate, hexanediol, sorbitan, tetrahydrofurfuryl alcohol ether, carbiphene, 1,3-dimethyl-2-imidazolone, Isosorbide dimethyl ether etc.Yet, should understand, can be applicable to plasticizer of the present invention be not limited to above-mentioned those.
When compositions of the present invention was mixed with soft capsule, if necessary, this capsule preparations can further comprise the pharmaceutically acceptable additive that is usually used in preparing soft capsule.This class additive for example comprises: lecithin, viscosity modifier, spice (for example Herba Menthae wet goods), antioxidant (for example tocopherol, vitamin E etc.), antiseptic (for example p-Hydroxybenzoate), coloring agent, aminoacid etc.
Soft capsule preparation of the present invention can prepare like this: described cosurfactant, oil component and surfactant are mixed equably, under agitation cyclosporin is dissolved in wherein, and slowly be heated to about 60 ℃ temperature, then under the situation that is with or without the aforementioned pharmaceutically acceptable additive that is usually used in preparing soft capsule, the concentrate that forms is placed to prepare in the machine of soft capsule by air-cooling and makes required suitable cyclosporin soft capsule with containing gelatin shell as the Polyethylene Glycol of plasticizer and propylene glycol.
Compositions of the present invention is the same with known herbicide-safener combination with preparation to be applicable to identical indication and can to use by identical mode and dosage range, if necessary, regulate dosage based on standard biological utilization rate test (as described below such) to animal (for example Canis familiaris L.) or people.
This paper does not specifically describe the details of the compositions of any excipient or component as yet, done description in the document, H.P.Fiedler for example, Lexikon der Hilfsstoffe, Edito Cantor Verlag, Aulendorf, Germany (Germany), the 4th edition (1996), handbook of pharmaceutical excipients (Handbook of Pharmaceutical Excipients), U.S. pharmacy association, Washington, and pharmacy association (The Pharmaceutical Society), London, the 2nd edition (1994), and the korean patent application 94-29208 of 9.11.94 submission.
To more specifically set forth the present invention by following embodiment.But, should understand that the present invention is subjected to the restriction of these embodiment never in any form. embodiment 12345 component contents (mg/ capsule) cyclosporin 25 25 25 25 25 Macrogol 200 45 70 100 45 45 propylene carbonate 25-50,25 25 polyoxyethylene (50) rilanit special 35 35 35 50 35 polyoxyethylene (20) Span-20s 85 85 85 100 85 ethyl linoleates 40 40 40 40 80 caprylic/capric triglyceride 5555 10 oleic acid monoglycerides 35 35 35 35 70 amount to 295mg 295mg 375mg 325mg 375mg
Embodiment 6:
The composition of using following glue softgel shell from the preparation of compositions of embodiment 1 soft capsule preparation, estimated the performance that causes because of stream in the glycerol and the variation of inclusions state then.
(6.1 contrast groups)
Weight ratio of constituents
Gelatin 20
Purified water 16
Glycerol 9
(6.2 test group)
Weight ratio of constituents
Gelatin 20
Purified water 16
Propylene glycol 4
Macrogol 200 1
Observed result is described in the following table 1:
Table 1: the stability of the capsule preparations inclusions of described capsule shells
Capsular just after after after after after 1 day 2 days 5 days 10 days 30 days
After becoming assignment system
Contrast groups 0++ ++ ++ ++ ++
Test group 000000
The described inclusions of note: 0=is stable
The emulsifying of +=difference
The precipitation of ++=a little
++ +=precipitation
The result who from table 1, describes as seen, the capsule preparations of using composition (containing the glycerol as the plasticizer) preparation of 6.1 contrast groups causes some problem, it comprises the sedimentary formation that causes because of stream in the glycerol; But the capsule preparations of using composition (containing Polyethylene Glycol and propylene glycol as the plasticizer) preparation of 6.2 test group keeps stable status.
Embodiment 7:
The soft capsule preparation of the compositions with embodiment 1 is formed, prepared by water-cooled valve (water temperature is about 12 ℃) and air-cooling (the volume of air flow is about 10m3/min) respectively to the capsule shells of using 6.2 test group of using in the foregoing description 6.
Under each situation, observe and compared the rippability that this capsule shells band is peeled off from chilling roll.With the results are described in the following table 2 of observing.
Table 2: the rippability of peeling off from chilling roll by this gelatin shell band of cooling means decision
Unit (angle)
Shell is formed the water-cooled valve air-cooling
Embodiment 6.2＞100 degree＜50 degree
(rippability is poor) (rippability is good)
The result who from last table 2, describes as seen, the soft capsule preparation by air-cooling preparation of the present invention shows than by the much better rippability of peeling off from chilling roll of the preparation of water-cooled valve preparation.Specifically, it has been generally acknowledged that if the angle of peeling off the gelatin shell band from chilling roll is about 70 or bigger, then rippability is poor, be lower than approximately 70 that then rippability is good if peel off the angle number of this shell band.By the soft capsule preparation of water-cooled valve preparation, in addition when 100 spend or bigger angle under can not peel off from chilling roll satisfactorily when peeling off.
In contrast, the soft capsule preparation by air-cooling of the present invention preparation also can easily be peeled off from chilling roll under 50 degree and lower angle, thereby good sealing intensity and productivity ratio can be provided.
Embodiment 8:
The bioavailability of the preparation (as test preparation) that will prepare by the compositions of gelatin shell encapsulate embodiment 1 with the composition with embodiment 6.2 is contrasted with the bioavailability that contains alcoholic acid commodity " SANDIMMUN capsule " (preparation as a comparison), thereby estimates the influence of cyclosporin formulations of the present invention to cyclosporin bioavailability and the difference between testee's individuality thereof.
In this test, test preparation and Comparative formulation are all used with the amount of every kg rabbit 300mg cyclosporin.
Under the identical condition, the unified rabbit that is put to the test with conventional rabbit solid feed compositions raising reaches 4 days or more of a specified duration in wire cage.When the dosage forms for oral administration preparation, rabbit is placed on by fasting in the constraint cage of steel making 48 hours, allow rabbit arbitrarily drink water during this period.
With diameter is that the levin's tube surface of 5mm is coated vaseline (so that reducing friction) back and inserted the 30cm depths by esophagus.With every part of test preparation of 50ml water and milkization and Comparative formulation, inject then with syringe that levin's tube is connected in.With dimethylbenzene the ear vein of rabbit is expanded, the disposable syringe of handling by heparin after 0.5,1,1.5,2,3,4,6,10 and 24 hour with test before test is from the ear vein blood sampling of every rabbit then.Add 0.5ml saturated sodium-chloride water solution and 2ml ether in the blood sample that obtains like this toward 1ml, then this mixture was swayed 5 minutes, more centrifugal 10 minutes and separation of supernatant (ether layer) under 5000rpm.Collect the 1ml supernatant, again in active silica Sep-Pak (Sep-pak
R) (Waters) interior expansion.Unfolded Sep-Pak is washed reuse 2ml methanol-eluted fractions with the 5ml normal hexane.Evaporation of eluate is extremely done under the decompression in nitrogen.By HPLC (high performance liquid chromatography) method (HPLC condition: post, μ-Bondapak
RC
18(Waters); Mobile phase, CH
3CN:MeOH:H
2O-55:15:30; Detect 210nm; Flow velocity, 10ml/min; Column temperature, 70 ℃; Sensitivity, 0.01Aufs.; Annotate the sample volume, 100 μ l) the analysis residue.
To be set forth in the following table 3 from the result of test preparation and Comparative formulation acquisition:
Table 3: test preparation of the present invention and commodity (SANDIMMUN
R) bioavailability
Parameter comparison preparation (A) test preparation (B)
(B/A) M±S.D. CV％ M±S.D. CV％
(n＝6) (S.D./M) (n＝6) (S.D./M)
AUC 13.5±10.0 74.0％ 57.0±17.0 29.8％
4.1(μg.hr/ml)
C
max 0.8±0.3 37.5％ 6.0±1.5 25.0％
7.5(μg.hr/ml)
Note: the area of AUC=haemoconcentration curve below
C
MaxThe maximum haemoconcentration of=cyclosporin
M ± S.D.=meansigma methods ± standard deviation
The ratio of CV=standard deviation and meansigma methods
The ratio of P (the B/A)=meansigma methods of test preparation and the meansigma methods of Comparative formulation
From last table as seen, test preparation shows the AUC value and the C of increase
MaxValue, they are respectively about 4 times or bigger and about 7 times or bigger of analog value of Comparative formulation.Therefore can determine that the bioavailability of test preparation has enlarged markedly with comparing of Comparative formulation.In addition, compare with Comparative formulation, test preparation of the present invention shows as the reduction effect of testee's interindividual variation (CV%): the CV% of AUC value reduces about 2 times or more, C
MaxThe CV% of value reduces about 1.5 times.
Therefore can determine, when dosage forms for oral administration soft capsule preparation of the present invention, it shows the cyclosporin bioavailability that increases: be about existing capsular 4 times high of the alcoholic acid commodity SANDIMMUNR that contains, and be presented at the reduction of the difference of cyclosporin bioavailability between testee's individuality, simultaneously, during long term store, keep stable and do not have any variation.Therefore, obvious soft capsule preparation of the present invention provides significant improvement in the preparation field of cyclosporin soft capsule.
Embodiment 9:
Preparation contains the soft gel of following ingredients:
| I | II | |
| Cyclosporin A | 25mg | 100mg |
| Macrogol 200 | 45mg | 180mg |
| Propylene carbonate | 25mg | 100mg |
| Polyoxyethylene 50-castor oil hydrogenated | 40mg | 160mg |
| Polysorbate 20 | 85mg | 340mg |
| Ethyl linoleate | 40mg | 160mg |
| Glyceryl monooleate | 40mg | 160mg |
| Vitamin E | 1mg | 4mg |
| Amount to | 301mg | 1204mg |
Embodiment:
| Embodiment: composition | 10 | 11 | 12 | 13 | 14 |
| Content (mg/ capsule) | |||||
| Cyclosporin | 25 | 25 | 100 | 25 | 25 |
| Propylene carbonate | 50 | 100 | 200 | 50 | 100 |
| Polyoxyethylene (50) castor oil hydrogenated | 90 | 80 | 300 | 90 | 90 |
| Polyoxyethylene (20) Span-20 | 80 | 80 | 280 | 80 | 80 |
| Ethyl linoleate | 40 | 30 | 150 | - | 40 |
| Caprylic/capric triglyceride | 5 | 10 | 20 | 5 | 5 |
| The oleic acid monoglyceride | 35 | 50 | 120 | 35 | 35 |
| Labrafil | - | - | 50 | - | - |
| Amount to | 325mg | 375mg | 1220mg | 285mg | 375mg |
| Embodiment: composition | 15 | 16 | 17 | 18 |
| Content (mg/ capsule) | ||||
| Cyclosporin | 25 | 25 | 25 | 25 |
| Macrogol 200 | 35 | 50 | 25 | 20 |
| Propylene carbonate | 45 | 100 | 45 | 80 |
| Polyoxyethylene (50) castor oil hydrogenated | 30 | 35 | 50 | 35 |
| Polyoxyethylene (20) Span-20 | 80 | 90 | 75 | 85 |
| Ethyl linoleate | 35 | 40 | 40 | 80 |
| Caprylic/capric triglyceride | 5 | 5 | 5 | 10 |
| The oleic acid monoglyceride | 35 | 30 | 35 | 85 |
| Amount to | 290mg | 375mg | 300mg | 420mg |
Embodiment 19:
Bioavailability from the soft capsule preparation (as test preparation) of the preparation of compositions of embodiment 10 is according to a conventional method contrasted with the bioavailability that contains alcoholic acid commodity " SANDIMMUN capsule " (preparation as a comparison), thereby estimate the influence of cyclosporin formulations of the present invention cyclosporin bioavailability and the difference between testee's individuality thereof.
That describes among experimental program and the embodiment 8 is identical.
To be set forth in the following table 4 from the result of test preparation and Comparative formulation acquisition:
Table 4: test preparation of the present invention and commodity (SANDIMMUN
R) bioavailability
Parameter comparison preparation (A) test preparation (B)
P(B/A) M±S.D. CV％ M±S.D. CV％
(n＝6) (S.D./M) (n＝6) (S.D./M)
AUC 13.5±10.0 74.0％ 60.1±18.0 30.8％
4.4(μg.hr/ml)
C
max 0.8±0.3 37.5％ 6.2±1.5 24.2％
7.7(μg.hr/ml)
Note: the area of AUC=haemoconcentration curve below
C
MaxThe maximum haemoconcentration of=cyclosporin
M ± S.D.=meansigma methods ± standard deviation
The ratio of CV=standard deviation and meansigma methods
The ratio of P (the B/A)=meansigma methods of test preparation and the meansigma methods of Comparative formulation
From last table as seen, test preparation shows the AUC value and the C of increase
MaxValue, they are respectively about 4 times or bigger and about 7 times or bigger of analog value of Comparative formulation.Therefore can determine that the bioavailability of test preparation has enlarged markedly with comparing of Comparative formulation.In addition, compare with Comparative formulation, test preparation of the present invention shows as the reduction effect of testee's interindividual variation (CV%): the CV% of AUC value reduces about 2 times or bigger, C
MaxThe CV% of value reduces about 1.5 times.
Therefore can determine that when dosage forms for oral administration soft capsule preparation of the present invention, it shows the cyclosporin bioavailability that increases: be about the existing alcoholic acid commodity SANDIMMUN that contains
RCapsular 4 times high, and be presented at the reduction of the difference of cyclosporin bioavailability between testee's individuality, simultaneously, during long term store, keep stable and do not have any variation.Therefore, obvious soft capsule preparation of the present invention provides significant improvement in the preparation field of cyclosporin soft capsule.
Claims (16)
1. pharmaceutical composition comprises:
(1) cyclosporin of pharmacologically effective dose,
(2) propylene carbonate,
(3) be selected from down the material of group or two kinds as oil component a kind of and be selected from down the mixture of organizing material: the carboxylate of fatty acid and primary alconol, MCT Oil and fatty acid monoglyceride, and
(4) HLB (hydrophile-lipophile balance) value is 8～17 surfactant,
Wherein said cyclosporin, described propylene carbonate, described oil component and described surfactant exist to be respectively 1: 0.1～10: 1～10: 1～10 ratio based on weight.
2. the pharmaceutical composition of claim 1, wherein said MCT Oil comprises the triglyceride of the fatty acid with 8-10 carbon atom.
3. the pharmaceutical composition of claim 2, wherein said MCT Oil is a caprylic/capric triglyceride.
4. the pharmaceutical composition of claim 1, wherein said fatty acid monoglyceride is oleic monoglyceride.
5. the pharmaceutical composition of claim 1, the carboxylate of wherein said fatty acid and primary alconol comprise the fatty acid with 8-20 carbon atom and have the primary alconol of 2-3 carbon atom.
6. the pharmaceutical composition of claim 5, the carboxylate of wherein said fatty acid and primary alconol is inferior grease ethyl ester.
7. the pharmaceutical composition of claim 1, wherein said surfactant is selected from the polyoxyethylene product and the polyoxyethylene sorbitan fatty acid ester of hydrogenated vegetable oil.
8. the pharmaceutical composition of claim 7, wherein said surfactant comprise with based on polyoxyethylene (50) castor oil hydrogenated of the mixing ratio of weight 1: 0.1～5 and the mixture of polyoxyethylene (20) Span-20.
9. the pharmaceutical composition of claim 1, wherein said cyclosporin, described propylene carbonate, described oil component and described surfactant are being that 1: 0.5～8: 2～6: 2～8 ratio exists based on weight.
10. the pharmaceutical composition of claim 1 also comprises the Polyethylene Glycol that molecular weight is 200-600, and described Polyethylene Glycol and described propylene carbonate exist with the ratio based on weight 1: 0.1-5.
11. the pharmaceutical composition of claim 1, it does not contain Polyethylene Glycol.
12. the pharmaceutical composition of claim 1, wherein said oil component are the carboxylate of described fatty acid and primary alconol and the mixture of described fatty acid monoglyceride.
13. the pharmaceutical composition of claim 12, the carboxylate of wherein said fatty acid and primary alconol: the ratio of described fatty-acid monoester glyceride is based on weight 1: 1-2.
14. the pharmaceutical composition of claim 1, wherein said oil component are the mixture of described MCT Oil and described fatty acid monoglyceride.
15. the pharmaceutical composition of claim 1, wherein said pharmaceutical composition is encapsulated into gelatine capsule, described gelatine capsule comprises the mixture of propylene glycol and Polyethylene Glycol as plasticizer, and the mixture of described propylene glycol and Polyethylene Glycol exists with the ratio of 0.1-0.5 weight portion with respect to 1 weight portion gelatin.
16. the pharmaceutical composition of claim 15, wherein said plasticizer propylene glycol is with the ratio combination of 1-10 weight portion with respect to 1 weight portion Polyethylene Glycol.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1997/8750 | 1997-03-14 | ||
| KR1019970008750A KR19980073479A (en) | 1997-03-14 | 1997-03-14 | Cyclosporine-containing soft capsules |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1250378A CN1250378A (en) | 2000-04-12 |
| CN1161150C true CN1161150C (en) | 2004-08-11 |
Family
ID=19499792
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB988033569A Expired - Fee Related CN1161150C (en) | 1997-03-14 | 1998-03-12 | Pharmaceutical compositions |
Country Status (24)
| Country | Link |
|---|---|
| EP (1) | EP0969857A1 (en) |
| JP (1) | JP3748573B2 (en) |
| KR (2) | KR19980073479A (en) |
| CN (1) | CN1161150C (en) |
| AR (1) | AR012054A1 (en) |
| AU (1) | AU741923B2 (en) |
| BR (1) | BR9808324A (en) |
| CA (1) | CA2283901A1 (en) |
| CO (1) | CO4940404A1 (en) |
| CZ (1) | CZ324399A3 (en) |
| DE (1) | DE19882184T1 (en) |
| GB (1) | GB2337703A (en) |
| HU (1) | HUP0001515A3 (en) |
| ID (1) | ID23531A (en) |
| IL (1) | IL131703A0 (en) |
| MY (1) | MY118614A (en) |
| NO (1) | NO994436L (en) |
| PE (1) | PE59499A1 (en) |
| PL (1) | PL335729A1 (en) |
| RU (1) | RU2185188C2 (en) |
| SK (1) | SK123299A3 (en) |
| TR (1) | TR199902229T2 (en) |
| WO (1) | WO1998041225A1 (en) |
| ZA (1) | ZA982117B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2380674B (en) * | 1998-03-06 | 2003-05-28 | Novartis Ag | Emulsion preconcentrates containing cyclosporin or a macrolide |
| US7203158B2 (en) * | 2000-12-06 | 2007-04-10 | Matsushita Electric Industrial Co., Ltd. | OFDM signal transmission system, portable terminal, and e-commerce system |
| GB0526419D0 (en) * | 2005-12-23 | 2006-02-08 | Cyclacel Ltd | Formulation |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5603951A (en) * | 1994-11-09 | 1997-02-18 | Hanmi Pharm. Ind. Co., Ltd. | Cyclosporin-containing soft capsule compositions |
| KR0167613B1 (en) * | 1994-12-28 | 1999-01-15 | 한스 루돌프 하우스, 니콜 케르커 | Cyclosporin-containing soft capsule compositions |
| SK283361B6 (en) * | 1996-06-19 | 2003-06-03 | Novartis Ag | Cyclosporin-containing soft capsule preparations |
| KR0183449B1 (en) * | 1996-06-19 | 1999-05-01 | 한스 루돌프 하우스, 니콜 케르커 | Cyclosporin-containing soft capsule preparations |
-
1997
- 1997-03-14 KR KR1019970008750A patent/KR19980073479A/en active Application Filing
-
1998
- 1998-03-12 PL PL98335729A patent/PL335729A1/en unknown
- 1998-03-12 BR BR9808324-4A patent/BR9808324A/en not_active Application Discontinuation
- 1998-03-12 ZA ZA982117A patent/ZA982117B/en unknown
- 1998-03-12 MY MYPI98001086A patent/MY118614A/en unknown
- 1998-03-12 WO PCT/EP1998/001432 patent/WO1998041225A1/en not_active Application Discontinuation
- 1998-03-12 JP JP54011298A patent/JP3748573B2/en not_active Expired - Fee Related
- 1998-03-12 KR KR1019997008022A patent/KR20000075940A/en not_active Application Discontinuation
- 1998-03-12 CN CNB988033569A patent/CN1161150C/en not_active Expired - Fee Related
- 1998-03-12 EP EP98912470A patent/EP0969857A1/en not_active Withdrawn
- 1998-03-12 ID IDW990997A patent/ID23531A/en unknown
- 1998-03-12 HU HU0001515A patent/HUP0001515A3/en unknown
- 1998-03-12 IL IL13170398A patent/IL131703A0/en unknown
- 1998-03-12 AU AU67293/98A patent/AU741923B2/en not_active Ceased
- 1998-03-12 TR TR1999/02229T patent/TR199902229T2/en unknown
- 1998-03-12 SK SK1232-99A patent/SK123299A3/en unknown
- 1998-03-12 PE PE1998000174A patent/PE59499A1/en not_active Application Discontinuation
- 1998-03-12 CA CA002283901A patent/CA2283901A1/en not_active Abandoned
- 1998-03-12 GB GB9921495A patent/GB2337703A/en not_active Withdrawn
- 1998-03-12 DE DE19882184T patent/DE19882184T1/en not_active Withdrawn
- 1998-03-12 CZ CZ993243A patent/CZ324399A3/en unknown
- 1998-03-12 RU RU99121398/14A patent/RU2185188C2/en not_active IP Right Cessation
- 1998-03-13 AR ARP980101125A patent/AR012054A1/en not_active Application Discontinuation
- 1998-03-13 CO CO98014254A patent/CO4940404A1/en unknown
-
1999
- 1999-09-13 NO NO994436A patent/NO994436L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DE19882184T1 (en) | 2000-02-10 |
| AU741923B2 (en) | 2001-12-13 |
| CA2283901A1 (en) | 1998-09-24 |
| BR9808324A (en) | 2000-05-16 |
| CZ324399A3 (en) | 1999-12-15 |
| GB9921495D0 (en) | 1999-11-17 |
| EP0969857A1 (en) | 2000-01-12 |
| JP2000514831A (en) | 2000-11-07 |
| TR199902229T2 (en) | 1999-12-21 |
| PL335729A1 (en) | 2000-05-08 |
| AR012054A1 (en) | 2000-09-27 |
| CN1250378A (en) | 2000-04-12 |
| JP3748573B2 (en) | 2006-02-22 |
| KR19980073479A (en) | 1998-11-05 |
| NO994436D0 (en) | 1999-09-13 |
| PE59499A1 (en) | 1999-07-05 |
| NO994436L (en) | 1999-09-13 |
| MY118614A (en) | 2004-12-31 |
| SK123299A3 (en) | 2000-02-14 |
| KR20000075940A (en) | 2000-12-26 |
| HUP0001515A3 (en) | 2000-10-30 |
| ID23531A (en) | 2000-04-27 |
| IL131703A0 (en) | 2001-03-19 |
| ZA982117B (en) | 1998-09-14 |
| CO4940404A1 (en) | 2000-07-24 |
| HUP0001515A2 (en) | 2000-09-28 |
| AU6729398A (en) | 1998-10-12 |
| GB2337703A (en) | 1999-12-01 |
| RU2185188C2 (en) | 2002-07-20 |
| WO1998041225A1 (en) | 1998-09-24 |
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