PHARMACEUTICAL COMPOSITIONSThis invention relates to a preparation, for example a soft capsule, containing cyclosporin as an active ingredient. More specifically, the present invention relates to a soft capsule preparation containing cyclosporin as an active ingredient; propylene carbonate or polyethylene glycol, or its 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. Cyclosporin is a specific macromolecular cyclic peptide compound (molecular weight: 1202.64) consisting of 11 amino acids, which has a broad spectrum of useful pharmacological activities , particularly an immunosuppressive activity and an anti-inflammatory activity. Accordingly, cyclosporin has been used to suppress the inherent immune responses of the living body, which are caused by tissue and organ transplantation, for example transplantation of the heart, lung, liver, kidney, pancreas, bone marrow, skin, or cornea, and especially the transplantation of foreign tissues and organs. In addition, cyclosporine is useful for suppressing hematological disorders such as anemia.different autoimmune diseases such as systemic lupus erythematosus, idiopathic malabsorption syndrome, etc., and inflammatory diseases such as arthritis, rheumatoid disorders, etcetera. Cyclosporine is useful in the treatment of protozoal diseases, such as malaria, schistosomiasis, etc., and, moreover, it is also recently used in chemotherapy. Cyclosporine is highly lipophilic and hydrophobic. Accordingly, cyclosporin is sparingly soluble in water, and dissolves well in an organic solvent, such as methanol, ethanol, acetone, ether, chloroform, and the like. Due to the low water solubility of cyclosporin having the aforementioned properties, when cyclosporin is administered orally, its bioavailability is extremely low, and can be greatly influenced by the conditions of each individual patient. According to the above, it is very difficult to retain an effective therapeutic concentration. Moreover, cyclosporine can show considerable side effects such as nephrotoxicity. Accordingly, cyclosporin is very difficult to formulate in a preparation for oral administration, due to its low solubility in water. In accordance with the above, numerous studies have been conducted extensively to discover a suitable preparation for the effective oral administration of cyclosporin, which can provide an adequate uniform dosage and an appropriate bioavailability.
In the prior art, preparations suitable for oral administration of sparingly water-soluble cyclosporin have been normally formulated in the form of a pre-concentrate emulsion. A typical method using this combination is taught in U.S. Patent Number 4,388,307, which was issued on June 14, 1983. This patent discloses a liquid formulation of cyclosporin using ethanol. According to the method disclosed in this United States of America Patent Specification, cyclosporin is combined with a vehicle consisting of ethanol as a co-surfactant; olive oil as a vegetable oil, and a transesterification product of a natural vegetable oil triglyceride and a polyalkylene polyol as a surfactant to form the liquid formulation. However, the resulting liquid formulation is administered as an aqueous dilution which makes it very difficult to adapt the subject to its administration, and to provide a uniform dosage for oral administration. In order to mitigate the inconvenience of diluting the composition of liquid cyclosporin in water prior to oral administration, a liquid composition has been formulated in the form of a pre-concentrate emulsion, in a soft capsule preparation, which is now commercially available as Sandimmune (registered trademark). In this case, the cyclosporin soft capsule contains ethanol due to the solubility requirements of cyclosporin. However, since ethanol can permeate the gelatin shell of the capsule because it is volatile even at normal temperature, to prevent volatilization of the ethanol from the soft capsule preparations during storage and distribution, the soft capsule preparations are They can be wrapped in a special packaging material, such as an aluminum-aluminum blister pack. Recently it has been possible to develop a cyclosporin preparation having a stability during the storage period, and which also substantially does not provide changes in the biological availability and in their difference between individual subjects, in such a way that the biological effect of Cyclosporine One of the preparations developed for this purpose is disclosed in Korean Open Patent Publication Number 93-113. This preparation is marketed under the registered trademark Sandimmun Neoral. However, since this preparation also uses ethanol, it can have some drawbacks as in previous ethanol-containing preparations, in storage stability, and changes in the ethanol content. In accordance with the above, the present inventors have studied numerous combinations of different surfactants, oil components, co-surfactants, etc., to find a cyclosporin composition that is stable, and that provides a higher bioavailability and a lower difference in blood levels between individual subjects, than those of the above cyclosporin preparations, in view of their pharmacokinetic properties. As a result, we have identified that a certain cyclosporin composition, consisting of the components defined below, can satisfy the aforementioned requirements, and then the present invention was made. Accordingly, it is an aspect of the present invention to provide a composition suitable for formulating in soft capsules, which comprises cyclosporin as an active ingredient; a hydrophilic substance of polyethylene glycol, or a non-hydrophilic substance of propylene carbonate or its mixture; an oil component as defined below, and a surfactant. It is a further aspect of the present invention to provide a soft capsule preparation comprising a composition containing cyclosporin as an active ingredient; a hydrophilic substance of polyethylene glycol, or a non-hydrophilic substance of propylene carbonate or its 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 (if desired), and fatty acid monoglyceride as an oil component; and a surfactant having a HLB (Hydrophilic-Lipophilic Balance) value of from 8 to 17. In addition, it is another aspect of the present invention to provide a process for producing a soft gelatin capsule preparation as defined above. While the present invention is particularly described herein with respect to soft gelatin capsules, it should be appreciated that the invention covers the same composition that can be used as such, for example, as a beverage solution, for example as the SandimmunNeoral, or it can be in other dosage unit forms. In one aspect, the present invention relates to a capsule containing cyclosporin, which has a high storage stability, such that there is little variation of the composition over time, and has a higher bioavailability, and that it contains a composition which comprises cyclosporin as an active ingredient; a hydrophilic substance of polyethylene glycol, or a non-hydrophilic substance of propylene carbonate or its mixture as a second component; an oil component as defined below; and a surfactant. To formulate this composition containing cyclosporin in the soft capsule preparation, a gelatin shell must be used. However, when the soft capsule is formulated with the general capsule shell containing glycerin as a plasticizer, the soft capsule preparation has some drawbacks, because it can change the emulsified state of the pre-concentrate to emulsion due to the influx of glycerin into the the emulsion, and therefore, significantly lowers the solubility of cyclosporin, to result in the precipitation of cyclosporin from the emulsion. According to the foregoing, in the present invention a gelatin shell is preferably selected that uses a mixture of propylene glycol and polyethylene glycol, not glycerin, as a plasticizer, for the soft capsule shell, which can resolve the problem related to the influx of glycerin. However, when the capsule cover band containing propylene glycol and polyethylene glycol according to the present invention is prepared by means of a water cooling method which is conventionally used for a cooling drum, it is not removed. easily from the drum. This possibility of removing the capsule cover strip from the cooling drum can be improved by overcooling the cooling drum by continuously circulating a cooling water to reduce the temperature of the belt to about 17. ° C.
However, the capsule cover band that is cooled to a lower temperature may provide a low degree of seal during the encapsulation process, and may lower productivity. Accordingly, the process for the preparation of the gelatin cover band which does not contain glycerin plasticizer according to the present invention, adopts an air cooling method, instead of the previous water cooling method, wherein the band The capsule shell can be cooled to the optimum temperature by providing an air flow from a fan, and therefore, can be easily removed from the cooling drum, and furthermore, it is maintained at the optimum temperature of about 21 ° C to increase the degree of seal in the encapsulation process, and ensure high productivity. As mentioned above, the present products can be produced by using the glycerin-free gelatin capsule shell, and the application of the air-cooling method to the non-ethanol-containing composition as a volatile low-boiling solvent. , and therefore, has a high storage stability, such that there is little variation of the composition over time, and has a higher bioavailability. More specifically, the present invention relates to a cyclosporin preparation, which comprises a composition containing: 1) cyclosporin as an active ingredient; 2) polyethylene glycol or propylene carbonate or its mixture; 3) 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 4) a surfactant that has an HLB value (BalanceHydrophilic-Lipophilic) from 8 to 17, for example, in a gelatin shell containing polyethylene glycol and propylene glycol as a plasticizer. In another aspect, the present invention provides a cyclosporin preparation, which comprises a composition containing: 1) Cyclosporin as an active ingredient; and 2) propylene carbonate. In yet a further aspect of the present invention, this composition is free of polyethylene glycol. This composition, which is also a composition of the invention, may optionally further comprise any other component as described herein, if desired in the amounts described herein. Cyclosporin, which is used as the pharmaceutically active ingredient in the composition according to the present invention, is a cyclic peptide compound having useful immunosuppressive activity and an anti-inflammatory activity, as described above. Although cyclosporins A, B, C, D, G, and the like can be used as the cyclosporin component in the present invention, cyclosporin A is more preferred, since its clinical effectiveness and pharmacological properties are well established in this field. . As the second component in the composition according to the present invention, and which can act as a co-surfactant, propylene carbonate or polyethylene glycol, or its mixture can be used. Propylene carbonate, which has a high boiling point (about 242 ° C) is non-volatile, shows low hygroscopic property and permeability of the shell, and has a high solubility for cyclosporin, it can be used as the substance not hydrophilic Alternatively, polyethylene glycol, which has a high boiling point, is not volatile, does not pass through the gelatin shell of the soft capsule, and has a high solubility for cyclosporin, it can also be used as the hydrophilic substance . In the composition according to the present invention, although any liquid polyethylene glycol can be used, preferably polyethylene glycol (PEG) having a molecular weight of 200 to 600, particularly PEG 200 can be used. In the present invention, the mixture of non-hydrophilic substance and hydrophilic substance, as mentioned above, can also be used. When the mixture of polyethylene glycol and propylene carbonate is used as the component in the present invention, they can be combined in general in the ratio of 1: 0.1-5, preferably 1: 0.1-3, and more preferably 1 : 0.2-2, based on weight. In the present invention, the use of polyethylene glycol and propylene carbonate provides certain advantages. That is, the stability of the cyclosporin-containing composition is improved during storage, and therefore, the content of the components contained therein is maintained in a substantially uniform manner. In addition, the use of propylene carbonate can even increase the solubility of the active ingredient of cyclosporin, and inhibit the influx of water from the gelatin capsule shell into the composition, to provide a more stable composition. In the composition of the present invention, the second component is preferably used in the proportion of 0.1 to 10 parts by weight, more preferably 0.5 to 8 parts by weight, and most preferably 1 to 5 parts by weight, per 1 part. by weight of ciclosporin. The third component used in the emulsion pre-concentrate according to the present invention is an oil component. As the oil component in the present invention, one or a mixture of two or more selected from the group consisting of esterified fatty acid and primary alcohol, medium chain fatty acid triglycerides (when present) can be used., and fatty acid monoglycerides. The esterified fatty acid and primary alcohol compound that can be used in the present invention can include an esterified fatty acid compound having 8 to 20 carbon atoms, and primary alcohol having 2 to 3 carbon atoms, for example , isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate, etc., with an esterified compound of linoleic acid and ethanol being particularly preferred.
In addition, as the medium chain fatty acid triglyceride(when present), a saturated fatty acid triglyceride having from 8 to 10 carbon atoms may be used, a triglyceride of caprylic / capric acid being more preferably used as a vegetable oil triglyceride of saturated fatty acid. The fatty acid monoglyceride which can also be used as the oil component in the present invention includes a fatty acid monoglyceride having from 18 to 20 carbon atoms, particularly an oleic acid monoglyceride. In a microemulsion pre-concentrate according to the present invention, the oil component can be used in the proportion of 1 to 10 parts by weight, preferably 2 to 6 parts by weight, per part by weight of cyclosporin. Preferably, fatty acid monoglyceride and fatty acid ester are present as the oil component, for example, in the ratio of 1: 1 to 1: 2, for example 1: 1 to 1: 1.2. Optionally, caprylic / capric acid triglyceride is also present, for example, in a ratio to ethyl linoleate of 1: 0.1 to 0.2. In the oil mixture used as the oil component according to the present invention, the mixing ratio of fatty acid monoglyceride: an esterified fatty acid compound and primary alcohol: medium chain fatty acid triglyceride (when present) , can be in general in the scale of 1: 0.1-5: 0.1-10, preferably in the scale of 1: 0.1-3.0: 0.1-3.0, based on weight. The fourth component used in the composition according to the present invention is a surfactant. Suitable surfactants for use in the present invention include any of the pharmaceutically acceptable surfactants having an HLB (Hydrophilic-Lipophilic Balance) value of 8 to 17, which are capable of stably emulsifying the lipophilic portion of the composition comprising the oil component. containing cyclosporin, and the hydrophilic portion comprising the co-surfactant in water, to form a stable microemulsion. Examples of the preferred surfactant according to the present invention include polyoxyethylene products of hydrogenated vegetable oils, polyoxyethylene sorbitan fatty acid esters, and the like, for example, NIKKOL HCO-50, NIKKOL HCO-40, NIKKOL HCO-60, TWEEN 20, TWEEN 21, TWEEN 40, TWEEN 60, TWEEN 80, TWEEN 81, etcetera. Particularly preferably a hydrogenated polyoxyethylene castor oil (50) which is marketed under the trademark NIKKOL HCO-50 (NIKKO Chemical Co., Ltd.), and a polyoxyethylene sorbitan monolaurate (20) can be used. ) which is marketed under the trademark TWEEN 20 (ICI Chemicals), which has an acid value of less than 1, a saponification value of about 48-56, a hydroxyl value of about 45-55, and a pH value ( to 5 percent) of 4.5-7.0. The surfactant may include any of the above-mentioned surfactants alone, or preferably in a combination of two or more surfactants selected from the above surfactants. In the composition according to the present invention, the surfactants can be used in the proportion of 1 to 10 parts by weight, preferably in the proportion of 2 to 8 parts by weight, for one part by weight of cyclosporin. In addition, when the mixture of two surfactants, ie polyoxyethylene hydrogenated castor oil (50) and polyoxyethylene sorbitan monolaurate (20) is used in the composition of the present invention, the constitutional ratio of the hydrogenated castor oil of polyoxyethylene (50): polyoxyethylene sorbitan monolaurate (20), preferably it is in the scale of 1: 0.1-5, more preferably in the scale of 1: 0.5-4, based on weight. In the composition according to the present invention, the four components are preferably present in the proportion of cyclosporin: second component: oil component: surfactant = 1: 0.1-10: 1-10: 1-10, and more preferably in the proportion of cyclosporin: second component: oil component: surfactant = 1: 0.5-8: 2-6: 2.8, by weight. In addition to this composition, the compositions illustrated in the following examples may be mentioned as additional preferred compositions according to the present invention. For oral administration, the composition of the present invention, which contains the aforementioned components, can be formulated in the form of a soft capsule. Since the soft capsule preparation according to the present invention does not use ethanol as the volatile low-boiling solvent, it is pharmaceutically stable, and can establish the desired improvements, including the improvement of bioavailability.
However, it may be difficult to prepare in a reproducible manner as a conventional soft capsule shell by means of a conventional method for the preparation of soft capsules. When formulating the soft capsule with the conventional capsule shell containing glycerin as a plasticizer, the soft capsule thus prepared may have some drawbacks, in that the emulsified state of the pre-concentrate in emulsion may change due to the influx of glycerin into the emulsion, and consequently, the solubility of cyclosporin is lowered significantly, which may result in the precipitation of cyclosporin from the emulsion. According to the above, in another aspect of the present invention, it is found that, when the capsule shell is formulated by using a mixture of polyethylene glycol and propylene glycol, not glycerin, as a plasticizer, the Soft capsule preparation that is stable over a long period. Although any polyethylene glycol that can be made liquid as a plasticizer can be used, it is preferable to use polyethylene glycol having a molecular weight of 200 to 600. Particularly, polyethylene glycol 200 is preferably used. In the soft capsule shell of According to the present invention, the mixture of polyethylene glycol and propylene glycol is preferably used in the proportion of 0.1 to 0.5 parts by weight, more preferably 0.1 to 0.4 parts by weight, and most preferably 0.2 to 0.3 parts by weight. weight, with respect to a part by weight of gelatin used for the preparation of the capsule shell. In the mixture of polyethylene glycol and propylene glycol as the plasticizer, the propylene glycol is preferably combined in the proportion of 1 to 10 parts by weight, more preferably 3 to 8 parts by weight, and most preferably 3 to 6 parts by weight, with respect to one part by weight of polyethylene glycol. In order to increase the possibility of removal of the band from the soft capsule cover from the cooling drum, the process for preparing the band of the gelatin capsule cover according to the present invention adopts the method of cooling by air, instead of the cooling method with water. According to this method of air cooling, since the band of the capsule shell is not overheated, and can be easily removed from the cooling drum while maintaining the optimum temperature of about 21 ° C, the seal degree at the encapsulation process is high, to ensure high productivity, and therefore, the process can be conducted in an efficient manner. In the preparation of the soft capsule according to the present invention, a volume of air flow suitable for the cooling drum in order to cool the capsule shell, is preferably from 5 to 15 cubic meters / minute, more preferably about 10 cubic meters / minute. Since, as the second component in the present invention, propylene carbonate can be used alone or as a major component thereof, soft capsule preparations containing cyclosporin which are stable for a long time, can be formulated without using certain plasticizer in a gelatin shell, considering the solubility of cyclosporin and the stability of the soft capsule. In this gelatin shell, the plasticizer can be used without limitation, one or more selected from the group consisting of glycerin, sorbitol, hexanetriol, propylene carbonate, hexanoglycol, sorbitans, tetrahydrofuryl alcohol ether, diethylene glycol monoethyl ether , 1,3-dimethyl-2-imidazolidone, dimethylisosorbide, and the like. However, it should be understood that the plasticizer that can be used in the present invention is not restricted to those mentioned above. In the formulation of the composition according to the present invention in soft capsules, the preparation of the capsule may also contain, if necessary, pharmaceutically acceptable additives that are conventionally used in the preparation of soft capsules. These additives include, for example, lecithin, viscosity regulator, perfume (e.g., peppermint oil, etc.), antioxidant (e.g., tocopherol, Vitamin E, etc.), preservative (e.g., paraben, etc.), coloring agent , amino acids, etc. The soft capsule preparation according to the present invention can be prepared by uniformly mixing the co-surfactant, the oil component, and the surfactant, by dissolving the cyclosporin therein while stirring and gently heating to the temperature of about 60 ° C, and then formulating the resulting concentrate, with or without the aforementioned pharmaceutically acceptable additives conventionally used in the preparation of soft capsules, containing the gelatin shell polyethylene glycol and propylene glycol as the plasticizer, in a machine for the preparation of soft capsules, by means of the air-cooled method, to obtain the suitable and desired soft capsule of cyclosporin. The compositions and preparations of the present invention are useful for the same indications, and can be administered in the same manner and in the same dosage range as known cyclosporin compositions, if necessary by adjusting the dose based on conventional bioavailability assays. in animals, for example dogs, or in humans, for example, as described hereinafter. As far as the details of the compositions of any excipients or components are not specifically written herein, they are described in the literature, for example, H.P. Fiedler, Lexikon der Hilfsstoffe, Edito Cantor Verlag, Aulendorf, Germany, 4th. 1996 edition, Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, and The Pharmaceutical Society, London, 2nd. edition, 1994, and Korean Patent Application Number 94-29208 filed on September 11, 1994. The present invention will be illustrated more specifically by the following examples. However, it should be understood that the present invention is not limited by these examples in any way.
EXAMPLES Component Content (mg / Capsule) Cyclosporin 25 25 25 25 25 Polyethylene glycol 200 45 70 100 45 45 Propylene carbonate 25 50 25 25 Polyoxyethylene hydrogenated hydrocarbon oil (50) 35 35 35 50 35 Polyoxyethylene sorbitan monolaurate ( 20) 85 85 85 100 85 Ethyl Linoleate 40 40 40 40 80 Ca-proic / capric acid triglyceride 5 5 5 5 10Monoghcendo of oleic acid 35 35 35 35 70 Total 295 mg 295 mg 375 mg 325 mg 375 mg EXAMPLE fi. The soft capsule preparation was prepared from the composition of Example 1, using the following composition for the capsule shell, and then the change in property and condition of the content was visually observed due to the influence of glycerin.6. 1 (control group) Component Weight ratio gelatin 20 purified water 16 glycerin 96. 2 (test group) Component Weight ratio gelatin 20 purified water 16 propylene glycol 4 polyethylene glycol 200 1The observed results are described in the followingTable 1.
Table 1: Stability of the content of the capsule preparation according to the capsule shellComposition of Just after After After After After Defu ?. the capsule of the formula- 1 day 2 days 5 days 10 days < _3) ds laciónControl group + + + + + + + +Test groupNote: = the content is stable = bad emulsification ++ = slight precipitation +++ = precipitationAs can be seen from the result described in Table 1, the capsule preparation made using the composition of control group 6.1 containing glycerin as the plasticizer, causes some problems, including the formation of precipitation due to the influx of glycerin, while that the preparation of the capsule made using the composition of test group 6.2 which contains polyethylene glycol and propylene glycol as the plasticizer, maintains the stable condition.
EXAMPLE 7: The soft capsule preparation having the composition of Example 1, was made using the capsule shell composition of test group 6.2 used in Example 6 above, by the method of cooling with water (water temperature about 12 ° C), and the air cooling method (volume of air flow of approximately 10 cubic meters / minute), respectively. In each case, the possibility of removing the band from the capsule shell from the cooling drum was observed and compared. The observed result is described in the following Table 2.
Table 2 Possibility of removing the band from the gelatin cover from the cooling drum, depending on the cooling method (Unit: degrees of angle) Composition of Cooling Method- Cooling method-the cover. water. by air.
Example 6.2 > 100 degrees < 50 degrees (poor possibility (good removal possibility) of removal) As can be seen from the above result described in Table 2, the soft capsule preparation made by the air cooling method according to the present invention, shows a much better possibility of removal from the cooling drum, compared to that prepared by the water cooling method. Specifically, it is generally considered that, if the degrees of angle to remove the band from the gelatin shell from the cooling drum are about 70 or more, the possibility of removal is bad, and if the degrees of the angle to remove the band of the cover are in less than about 70, the possibility of removal is good. The soft capsule preparation made by the water cooling method is not removed in a satisfactory manner from the cooling drum, even when the preparation is removed at the angle of 100 degrees or more. Contrary to this, the soft capsule preparation made by the air cooling method according to the present invention, it can be easily removed from the cooling drum at the angle of 50 degrees and less, and therefore, can provide good sealing force and productivity. EXAMPLE 8: The bioavailability of the preparation made by encapsulating the composition of Example 1 with the gelatin shell having the composition of Example 6.2 was compared as the test preparation, with the bioavailability of the commercial product containing ethanol, the Capsule SANDIMWJN, as the control preparation, to estimate the influence of the cyclosporin preparation according to the present invention, on the bioavailability of cyclosporin and its difference between the respective subjects. In this experiment, both the test preparation and the control preparation were administered in an amount of 300 milligrams as cyclosporin per kilogram of rabbit. The rabbits were fed uniformly with the conventional rabbit feed composition, for 4 days or more under the same conditions in wire cages. When the oral preparation was administered, the rabbits were fasted for 48 hours in a steel-made restriction cage, during which the rabbits were allowed to freely take water. A Levin tube with a diameter of 5 millimeters by the depth of 30 centimeters was placed through the esophagus after the surface of the Levin tube was coated with Vaseline in order to reduce friction. Each of the test preparations and control preparation was emulsified with 50 milliliters of water, and then introduced into a syringe that was connected to the Levin tube. The veins of the rabbit's ear were dilated using xylene, and then blood was taken from the vein of each rabbit's ear before the test and after 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24 hours, by means of a disposable syringe treated with heparin. To 1 milliliter of blood thus obtained, 0.5 milliliters of a saturated aqueous solution of sodium chloride, and 2 milliliters of ether were added, and then the mixture was stirred for 5 minutes, and centrifuged at 5,000 rpm for 10 minutes to separate the supernatant (ether layer). One milliliter of the supernatant was collected, and then developed in an activated silica sep-pak® (Waters). The developed sep-pak was washed with 5 milliliters of normal hexane, and eluted with 2 milliliters of methanol. The eluate was evaporated to dryness in nitrogen gas under reduced pressure. The residue was analyzed by means of HPLC (High Performance Liquid Chromatography) [HPLC condition: column μ-Bondapak C18 (Waters), mobile phase CH3CN: MeOH; H20 - 55:15:30, detection at 210 nanometers, flow rate of 1.0 milliliter / minute, column temperature of 70 ° C, sensitivity of 0.01 Aufs. , injection volume of 100 microliters].
The results obtained from the test preparation and from the control preparation are illustrated in the following Table 3:Table 3: Bioavailability of the test preparation of the present invention and the commercial product (SANDIMMUN)Prep. of Control (A) Prep. test. (B)Parameter (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)0. 8 ± 0.3 37.5 6.0 _t 1.5 25.0 7.5 (μg.hr / ml)Note: AUC = Area under the blood concentration curve Cmax: = Maximum blood concentration of cyclic-porin M_tS.D. = Average value _t Standard Deviation CV = Proportion of the standard deviation to the average value. P (B / A) = Proportion of the average value of the test preparation to the average value of the control preparation.
As can be seen from the above Table, the test preparation shows higher values of AUC and Cmax which are about 4 times or more, and about 7 times or more, respectively, higher than those of the control preparation. In accordance with the foregoing, it can be identified that the bioavailability of the test preparation is increased significantly compared to that of the control preparation. In addition, the test preparation of the present invention exhibits an effect of decreasing the difference between the respective test subjects (CV%) by approximately 2 times or more in the AUC value, and by approximately 1.5 times in the Cma? Value. compared to the control preparation. Accordingly, it could be determined that, when the soft capsule preparation according to the present invention is administered orally, it shows the highest bioavailability of cyclosporin about 4 times higher than that of the commercial product containing ethanol, the Capsule SANDIMMUNR, and also a decrease in the difference between the bioavailabilities of ciclosporin in the respective subjects, and at the same time, remains stable without changes during long-term storage. Accordingly, it can be seen that the soft capsule preparation according to the present invention provides a significant improvement in the field of the preparation of soft capsules of cyclosporin.
EXAMPLE 9: Soft gels are made which contain: I II Cyclosporin A 25 mg 100 mg Polyethylene glycol 200 45 mg 180 mg Propylene carbonate 25 mg 100 mg Polyoxyethylene hydrogenated castor oil (50) 40 mg 160 mg Polysorbate 20 85 mg 340 mg Ethyl Linoleate 40 mg 160 mg Glyceryl mono-oleate 40 mg 160 mg Vitamin E 1 mg 4 mg Total 301 mg 1204 mjEXAMPLES 10 11 12 13 14Component Content. me? / Cánsula. Cyclosporine 25 25 100 25 25 propylene carbonate 50 100 200 50 100 polyoxyethylene hydrogenated castor oil (50) 90 80 300 90 90 polyoxyethylene sorbitan monolaurate (20) 80 80 280 80 80 ethyl linoleate 40 30 150 - 40 triglyceride of ca-prilic / capric acid 5 10 20 5 5 oleic acid monoglyceride 35 50 120 35 35Labrafil - - 50 - - Total 325 mg 375 mg 1220 mg 285 mg 375rr EXAMPLES 15 16 17 18 Component Content (mg / Capsule)Cyclosporine 25 25 25 25 Polyethylene glycol 200 35 50 25 20 Propylene carbonate 45 100 45 80 Polyoxyethylene hydrogenated castor oil (50) 30 35 50 Polyoxyethylene sorbitan monolaurate (20) 80 90 75 85 Ethyl linoleate 35 40 40 80 caprylic / capric acid triglyceride 5 5 5 10 monoglyceride of oleic acid 3 355 30 35 85 Total »90 mg 375 mg 300 mg 420 mgEXAMPLE 19: The bioavailability of the soft capsule preparation made from the composition of Example 10 was compared according to a conventional manner as the test preparation, with the bioavailability of the commercial product containing ethanol, the SANDIMMUN Capsule, as the control preparation, to estimate the influence of the cyclosporin preparation according to the present invention, on the bioavailability of cyclosporin and its difference between respective subjects. The experimental protocol was the same as in Example 8 described.
The results obtained from the test preparation and the control preparation are illustrated in the following Table 4:Table 4: Bioavailability of the test preparation of the present invention and the commercial product (SANDIMMUNR)Control Prep. (A) Prep. test. (B) Parameter (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)0. 8 _h 0.3 37.5 6.2 ± 1.5 24.2 7.7 (μg.hr / ml)Note: AUC = Area under the blood concentration curve c Maximum blood concentration of ciclosporin M ± S,. D. = Average value ± Deviation Standard CV = Proportion of the standard deviation to the average value. P (B / A) = Proportion of the average value of the test preparation to the average value of the control preparation.
As can be seen from the Table above, the test preparation shows the highest values of AUC and Cma? which are about 4 times or more, and about 7 times or more, respectively, higher than those of the control preparation. In accordance with the foregoing, it can be identified that the bioavailability of the test preparation is increased significantly compared to that of the control preparation. In addition, the test preparation of the present invention exhibits an effect of decreasing the difference between the respective test subjects (CV%) by approximately 2 times or more in the AUC value, and by approximately 1.5 times in the Cmax value, in comparison with the control preparation. In accordance with the foregoing, it could be determined that, when the soft capsule preparation is administered according to the present invention orally, it shows the highest bioavailability of cyclosporin approximately 4 times higher than that of the above commercial product containing ethanol, the Capsule SANDIMMUNR, and also a decrease in the difference between the bioavailabilities of ciclosporin in the respective subjects, and at the same time, remains stable without changes during long-term storage. Therefore, it can be seen that the soft capsule preparation according to the present invention provides a significant improvement in the field of the preparation of soft capsules of cyclosporin.