AU762963B2 - Cyclosporin solution - Google Patents
Cyclosporin solution Download PDFInfo
- Publication number
- AU762963B2 AU762963B2 AU30434/00A AU3043400A AU762963B2 AU 762963 B2 AU762963 B2 AU 762963B2 AU 30434/00 A AU30434/00 A AU 30434/00A AU 3043400 A AU3043400 A AU 3043400A AU 762963 B2 AU762963 B2 AU 762963B2
- Authority
- AU
- Australia
- Prior art keywords
- cyclosporin
- weight
- solution
- solution according
- dexpanthenol
- 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.)
- Ceased
Links
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 title claims abstract description 85
- 108010036949 Cyclosporine Proteins 0.000 title claims abstract description 84
- 229930105110 Cyclosporin A Natural products 0.000 title claims abstract description 80
- 229960001265 ciclosporin Drugs 0.000 title claims abstract description 79
- 229930182912 cyclosporin Natural products 0.000 title claims abstract description 57
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 claims abstract description 23
- 235000004866 D-panthenol Nutrition 0.000 claims abstract description 22
- 239000011703 D-panthenol Substances 0.000 claims abstract description 22
- 229960003949 dexpanthenol Drugs 0.000 claims abstract description 22
- 239000002736 nonionic surfactant Substances 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 27
- 239000003945 anionic surfactant Substances 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000002775 capsule Substances 0.000 claims description 15
- 239000003085 diluting agent Substances 0.000 claims description 15
- -1 glycerol-polyethylene Chemical group 0.000 claims description 10
- 239000007903 gelatin capsule Substances 0.000 claims description 8
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 7
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 7
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 7
- 229920000053 polysorbate 80 Polymers 0.000 claims description 7
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 7
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- 229940100688 oral solution Drugs 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 6
- 229940068968 polysorbate 80 Drugs 0.000 claims description 6
- 206010062016 Immunosuppression Diseases 0.000 claims description 5
- 230000001506 immunosuppresive effect Effects 0.000 claims description 5
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 10
- 238000001556 precipitation Methods 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 46
- 238000009472 formulation Methods 0.000 description 12
- 238000010521 absorption reaction Methods 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 239000008280 blood Substances 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
- 239000003995 emulsifying agent Substances 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- 239000004530 micro-emulsion Substances 0.000 description 4
- 229940063121 neoral Drugs 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- 108010036941 Cyclosporins Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 230000036765 blood level Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229940100242 glycol stearate Drugs 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229950008882 polysorbate Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 1
- 241001221554 Punia Species 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 150000003712 vitamin E derivatives Chemical class 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
-
- 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
Abstract
The invention relates to a cyclosporin solution which contains dexpanthenol as solubilizing agent and in water forms stable colloidal solutions which can be diluted with water to any volume without precipitation of the cyclosporin.
Description
Cyclosporin solution The present invention relates to a cyclosporin solution.
Cyclosporins are a known group of cyclic undecapeptides. Cyclosporin A (C 62
H
111
N
11 0 12 molecular weight 1202) is used as immunosuppressant pharmaceutical for the treatment of tissue rejection reactions or excessive immunological responses of the body and is commercially available for example as Sandimmun® and Neoral®. Besides cyclosporin A, a number of additional metabolites are known (cyclosporins which show a close relationship to cyclosporin A, both structurally and in some cases also in terms of effect.
The international nonproprietary name of a cyclosporin used for immunosuppression is ciclosporin.
It is additionally known that cyclosporin A has very poor solubility in water. This gives rise to problems in formulating pharmaceutical preparations of cyclosporin A which can be effectively and rapidly absorbed, because rapid and complete or virtually complete absorption of the active ingredient is an indispensible prerequisite for reliable efficacy for the vital indications such as suppression of tissue rejection after organ transplants. Numerous attempts have been made in the prior art to provide cyclosporin A in a formulation which can be absorbed effectively. Because of the great lipophilicity of cyclosporin A, pharmaceutical compositions have been formulated with conventional solid and liquid pharmaceutical carriers, but these often displayed disadvantages, such as inadequate adsorption (Cavanak and Sucker, Formulation of Dosage Forms, Prog. Allergy, 38, 65-72 (1986)), poor tolerability or physical instabilities such as crystallization of the active ingredient. It has also proved to be a disadvantage that the solubility of the active ingredient in the 2 preparation is often low (about which means that the amount taken for a daily dose of up to 1 g of cyclosporin A is up to 30 g of the formulation.
The patent DE 29 07 460 discloses, for improving the storage and absorption of cyclosporin A, the use of a carrier composed of a polyalkylene glycol triglyceride, of a fatty acid triglyceride and of a monoglyceride or diglyceride. The formulation is used as oral solution, injection solution or capsule contents. Ethanol can be added to promote solubility. The absorption of such as solution is relatively good, but it has the disadvantage that the blood level may vary greatly and depends on food intake.
An improved formulation is described in DE 39 30 928 as so-called microemulsion preconcentrate, which consists of a hydrophilic phase, a lipophilic phase and an emulsifier. The hydrophilic component may be C 1 or tetrahydrofurfuryl diether or a partial ether of low molecular weight mono- or polyoxyalkanediols or 1,2-propylene glycol. The lipophilic component may be a medium chain-length triglyceride. A polyethoxylated vegetable oil, for example, is provided as emulsifier.
In a comparative absorption study on beagle dogs there was found to be a 49% improvement in absorption compared with the formulation disclosed in DE 29 07 460.
DE 195 21 974 describes a solution of cyclosporin A in a mixture of an emulsifying vitamin E derivative, another emulsifier, such as a polyoxyethylene vegetable oil ester and ethanol. The formulation shows a profile of blood levels in beagle dogs comparable to the formulation of DE 39 30 928.
P:\WPDOCS\CRN\PniI\Spoci\76I 1370 mdcdpagmdm 391049 -3- WO 97/35603 describes a microdispersion comprising amorphous cyclosporin A, lower alkanols and polyoxyalkylene emulsifiers as cosolvents.
WO 97/07787 discloses a cyclosporin formulation which comprises an alkanol solvent with 2 to 3 carbon atoms and an emulsifier selected from polyoxyethylene alcohols and fatty acid monoesters of ethoxylated CI.
6 -polyols.
There continues to be a need for a reasonably priced, well tolerated and stable cyclosporin preparation which, in particular, is easy to produce, is readily miscible with water and forms a stable cyclosporin solution therein, which ensures good absorption of the cyclosporin on oral administration, and which can contain cyclosporin in high concentration.
The present invention provides a cyclosporin preparation which displays the aforementioned advantages.
20 It has now been found, surprisingly, that colloidal solutions which are stable in water and which can be diluted with water as desired without precipitation of cyclosporin are formed from a solution of cyclosporin in exclusively water-miscible excipients only in combination with dexpanthenol, an anionic surfactant and a nonionic surfactant or a mixture of nonionic surfactants.
Bioavailability investigations have shown good absorption of the active ingredient after oral administration.The cyclosporin solution according to the invention is able to take up a larger amount of active ingredient per ml of solution than known for 30 cyclosporin formulations in the prior art.
4 The present invention thus relates to a cyclosporin solution comprising dexpanthenol, an anionic surfactant and a nonionic surfactant or a mixture of nonionic surfactants.
Dexpanthenol is the short name for D-(+)-2,4-dihydroxy- N-(3-hydroxypropyl)-3,3-dimethylbutyramide.
The preferred cyclosporin is cyclosporin A.
The cyclosporin solution according to the invention may contain the active ingredient plus dexpanthenol, the anionic surfactant and the nonionic surfactant and, where appropriate, other pharmaceutically acceptable excipients in any desired amount as long as the amount of dexpanthenol, of the anionic surfactant and of the nonionic surfactant is sufficient to form a stable cyclosporin solution. The solution preferably comprises 0.2-2 parts by weight of dexpanthenol, 0.2-1 part by weight of anionic surfactant and 0.5-6 parts by weight of nonionic surfactant or a mixture of nonionic surfactants per part by weight of cyclosporin.
The cyclosporin solution according to the invention generally comprises 0.2-2, preferably 0.5-2, for example 0.7-1.3, parts by weight of dexpanthenol, 0.2-1, preferably 0.3-0.7, parts by weight of anionic surfactant and 0.5-6, preferably 3-5, parts by weight of nonionic surfactant or a mixture of nonionic surfactants per part by weight of cyclosporin.
The cyclosporin solution according to the invention may advantageously additionally comprise a diluent. The diluent reduces the viscosity of the solution. This had the advantage that when the solution is used to fill, for example, soft gelatin capsules, after intake of the capsule the contents escape very rapidly from the opening capsule, and thus good absorption of the active ingredient is ensured.
5 In the case of an oral solution which is diluted in water before administration so that its viscosity is reduced very greatly it is possible to dispense with addition of diluent.
If the solution according to the invention is to contain a diluent, the content thereof is advantageously 10-40% by weight, in particular about 20% by weight, based on the total weight of the solution. The preferred diluent is ethanol.
The anionic surfactant which can be used for the solution according to the invention is any conventional pharmaceutically acceptable anionic surfactant. It is also possible to use both an anionic surfactant alone or a mixture of two or more anionic surfactants.
Examples of anionic surfactants which can be used according to the invention are alkyl ether sulphates and alkane sulphonates. The preferred anionic surfactant is sodium lauryl sulphate.
The nonionic surfactant which can be used for the solution according to the invention is any conventional, pharmaceutically acceptable nonionic surfactant. It is also possible to use both a nonionic surfactant alone or mixed with other nonionic surfactants, and a mixture of nonionic surfactants is preferred. Examples of nonionic surfactants which can be used according to the invention are glycerolpolyethylene glycol oxystearate (for example Cremophor RH 40), ethoxylated hydrogenated castor oil and polysorbate 80, a polyoxyethylene (80) sorbitan monooleate which is obtainable under the proprietary name Tween 80. The preferred nonionic surfactants are polysorbate 80 and glyerol-polyethylene glycol oxystearate.
6 A preferred solution according to the invention consists of about 11% by weight of cyclosporin A, about 11% by weight of dexpanthenol, about 5.6% by weight of anionic surfactant, about 55.6% by weight of a mixture of nonionic surfactants, and about 16.8% by weight of diluent, in particular ethanol. This solution is particularly suitable for filling soft gelatin capsules because, owing to its low viscosity, it escapes very rapidly from the opening capsule and ensures good absorption of the active ingredient. Another preferred solution according to the invention consists of about 19-26% by weight of cyclosporin A, about 8-10% by weight of dexpanthenol, about 8-10% by weight of anionic surfactant, about 44-50% by weight of nonionic surfactant and about 12-14% by weight of a diluent.
The combination of dexpanthenol, an anionic surfactant and a nonionic surfactant as solvents for cyclosporin makes available a cyclosporin solution which is readily miscible with water to form a stable aqueous colloidal solution which can be diluted with water as desired without precipitation of cyclosporin. The solution according to the invention is not a microemulsion or microemulsion concentrate and consists exclusively of known pharmaceutical substances. It can be both used to fill capsules and administered in the form of a pleasant-tasting oral solution to the patient.
Compared with the prior art, it was possible owing to the combination of the substances mentioned to dispense with a lipophilic component, which is necessary to form a microemulsion. Completely unexepectedly, dexpanthenol in this case assumes the role of a solubilizer, although it is not a surfactant, resulting in a stable colloidal solution of the cyclosporin in the dissolving medium. The anionic and nonionic surfactants present in the formulation are unable, either alone or in combination, to dissolve the cyclosporin without precipitation.
The surprisingly good dissolving properties of dexpanthenol make it possible to increase the cyclosporin concentration in the solution according to the invention compared with the prior art, so that, for example, an increased concentration of active ingredient can be achieved in pharmaceuticals, or the amount of solution to be administered can be reduced.
It is thus possible to produce, for example, smaller capsules which can be taken more easily by the patient.
The present invention thus also relates to an oral pharmaceutical which comprises a cyclosporin solution described above.
Such a pharmaceutical preferably comprises capsules filled with the solution. Soft gelatin capsules are particularly preferred. On examination of the rate of dissolution in media of various pH values as are typical of the gastrointestinal tract, there was found to be substantially pH-independent release of active ingredient from the capsules.
In another embodiment, the pharmaceutical comprising the solution according to the invention is in the form of an oral solution which, besides the cyclosporin solution according to the invention, may contain other conventional, pharmaceutically acceptable additives and, for example, flavourings and colourings and which can be diluted, for example with water, to the required concentration before intake thereof. The cyclosporin solution according to the invention is thus also suitable for easy production of a stable aqueous pleasant-tasting oral solution which can easily be administered to the patient.
The necessary cyclosporin levels in the blood are reached very rapidly and reliably after administration of a pharmaceutical according to the invention, and the P:WPDOCS\CRN\PuniU\Sp.d\761 I370m.dedpl..d-3019193 -8uniformity of the levels in the blood is greater than after administration of the commercially available product Neoral®.
The described solution can be administered in the form of a diluted aqueous solution for intake or as a single-dose drug form, for example in the form of a capsule. A capsule may contain, for example, a single dose of 100 mg of cyclosporin.
A preferred embodiment of the pharmaceutical according to the invention accordingly comprises soft gelatin capsules which each contain a solution according to the invention composed of about 100 mg of cyclosporin A, about 100 mg of dexpanthenol, about 50 mg of sodium lauryl sulphate, about 100 mg of polysorbate 80, about 400 mg of glycerol-polyethylene glycol oxystearate and about 150 mg of ethanol.
The pharmaceutical according to the invention is particularly suitable for immunosuppression.
20 The present invention also provides the use of a cyclosporin
C
solution as described above for producing a stable aqueous colloidal cyclosporin solution, or for producing an oral Spharmaceutical for immunosuppression.
The following examples are intended to explain the present invention in detail.
Example 1 30 This example shows the production of a cyclosporin solution according to the invention and of a pharmaceutical according to the invention in the form of soft gelatin capsules.
Soft gelatin capsules with a filling of the following composition were produced: 9 Cyclosporin A 100 mg Dexpanthenol 100 mg Sodium lauryl sulphate (anionic 50 mg surfactant) Polysorbate 80 (nonionic 100 mg surfactant) Glycerol-polyethylene glycol 400 mg oxystearate (nonionic surfactant) Ethanol (diluent) 150 mg The cyclosporin A was dissolved in ethanol. Separately from this, sodium lauryl sulphate, dexpanthenol, polysorbate 80 and glycerol polyethylene glycol oxystearate were heated gently to produce a clear solution. The two solutions were mixed homogeneously and then used to fill soft gelatin capsules.
Example 2 An absorption study was carried out on six beagle dogs with the capsules produced in Example 1. Each dog was given a 100 mg cyclosporin A capsule in a crossover test comparing with Neoral® (composition: cyclosporin A, ethanol, glycerol, corn oil mono-di-tri-glycerides, propylene glycol, macrogol-glycerol hydroxystearate, alpha-tocopherol) and blood samples were taken after 1.0, 1.5 and 2.0 hours. The cyclosporin A levels in the samples of blood taken were determined using a commercially available enzyme immunoassay. The following table indicates in each case the means with standard deviations resulting from the curves of levels in the blood.
10 Table Product Level in the blood Standard deviation ng/ml ng/ml Neoral h 457.92 337.28 h 1222.83 406.48 h 1616.67 393.71 h 1432.33 243.08 Test formulation h 435.67 332.11 h 1201.5 328.79 h 1398.17 239.36 h 1170.67 111.88 The example shows that the necessary levels in the blood are reached very rapidly and reliably after administration of the cyclosporin solution according to the invention in the form of a capsule, and the uniformity of the levels in the blood is greater than after administration of the comparison product.
Example 3 A cyclosporin solution of the following composition was produced: Ingredients Ciclosporin A Dexpanthenol Sodium lauryl sulphate (anionic surfactant) Polysorbate Glycerol-polyethylene glycol stearate Diluent 175 mg 80 mg 80 mg 445 mg 120 mg (about (about (about (about (about 19.5%) 8.9%) 8.9%) 49.4%) 13.3%) Total 900 mg Total 900 mg 11 Example 4 A cyclosporin solution of the following composition was produced; Ingredients Ciclosporin A Dexpanthenol Sodium lauryl sulphate (anionic surfactant) Polysorbate Glycerol-polyethylene glycol stearate Diluent 228 mg 75 mg 75 mg 410 mg 112 mg (about (about 25.3%) 8.4%) (about 8.4%) (about (about 45.5%) 12.4%) Total 900 mg Total 900 mg P:\WPDOCS\CRN\Punia\Spcci\7611370mmndedpages.doc- -1lla- The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in Australia.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers or steps but not the exclusion of any other integer or group of integers or steps.
V
S
Claims (12)
1. Cyclosporin solution comprising dexpanthenol, an anionic surfactant and a nonionic surfactant or a mixture of nonionic surfactants.
2. Cyclosporin solution according to Claim 1, in which the cyclosporin is cyclosporin A.
3. Cyclosporin solution according to either of the preceding claims, where the solution comprises 0.2-2 parts by weight of dexpanthenol, 0.2-1 part by weight of anionic surfactant and 0.5-6 parts by weight of nonionic surfactant or a mixture of nonionic surfactants per part by weight of cyclosporin.
4. Cyclosporin solution according to any of the preceding claims, which additionally comprises a diluent. Cyclosporin solution according to Claim 4, in which the diluent content is 10-40% by weight based on the total weight of the solution.
6. Cyclosporin solution according to Claim 4 or 5, in which the diluent is ethanol.
7. Cyclosporin solution according to any of the preceding claims, in which the anionic surfactant is sodium lauryl sulphate.
8. Cyclosporin solution according to any of the preceding claims, in which the nonionic surfac- tants are polysorbate 80 and glycerol-polyethylene glycol oxystearate.
9. Cyclosporin solution according to any of Claims 4-8, consisting of about 11% by weight of P:%WPDOCS\CRN\Puniu\Fppei\7611I370=mdedp~.dm 10,04'01 -13- cyclosporin A, about 11% by weight of dexpanthenol, about 5.6% by weight of anionic surfactant, about 55.6% by weight of a mixture of nonionic surfactants and about
16.8% by weight of a diluent, in particular ethanol. Cyclosporin solution according to any of Claims 4-8, consisting of about 19-26% by weight of cyclosporin A, about 8-10% by weight of dexpanthenol, about 8-10% by weight of anionic surfactant, about 44-50% by weight of nonionic surfactant and about 12-14% by weight of a diluent. 11. Oral pharmaceutical comprising a solution according to any of Claims 1-10. 12. Pharmaceutical according to Claim 11, where the solution is used to fill capsules. 13. Pharmaceutical according to Claim 12, where the capsules 20 are soft gelatin capsules. 0 14. Pharmaceutical according to Claim 11, where the solution is in the form of an oral solution. 15. Use of a solution according to any of Claims 1-10 for producing a stable aqueous colloidal cyclosporin solution. 0* *0 16. Use of a solution according to any of Claims 1-10 for 30 producing an oral pharmaceutical for immunosuppression. 30 producing an oral pharmaceutical for immunosuppression.
17. Cyclosporin solution according to any one of Claims 1- P:\WPDOCS\CRN\P.ni.Spmci\76117 dd~.d 1-14 -14- substantially as described herein with reference to the Examples.
18. Oral pharmaceutical according to any one of Claims 11-14, substantially as described herein.
19. Use according to claim 15 or 16, substantially described herein. DATED this 30th day of April, 2003 RAT IOPHARM GMBH By its Patent Attorneys DAVIES COLLISON CAVE
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19859910 | 1998-12-23 | ||
| DE19859910A DE19859910C2 (en) | 1998-12-23 | 1998-12-23 | Oral medicine |
| PCT/EP1999/010358 WO2000038702A1 (en) | 1998-12-23 | 1999-12-23 | Cyclosporin solution |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU3043400A AU3043400A (en) | 2000-07-31 |
| AU762963B2 true AU762963B2 (en) | 2003-07-10 |
Family
ID=7892567
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU30434/00A Ceased AU762963B2 (en) | 1998-12-23 | 1999-12-23 | Cyclosporin solution |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP1140135B1 (en) |
| JP (1) | JP2002533401A (en) |
| AT (1) | ATE249834T1 (en) |
| AU (1) | AU762963B2 (en) |
| CA (1) | CA2355271A1 (en) |
| CZ (1) | CZ20012143A3 (en) |
| DE (2) | DE19859910C2 (en) |
| DK (1) | DK1140135T3 (en) |
| ES (1) | ES2203235T3 (en) |
| HK (1) | HK1037140A1 (en) |
| HU (1) | HUP0104623A3 (en) |
| NO (1) | NO20012932D0 (en) |
| PL (1) | PL348180A1 (en) |
| PT (1) | PT1140135E (en) |
| RU (1) | RU2216342C2 (en) |
| SK (1) | SK8702001A3 (en) |
| WO (1) | WO2000038702A1 (en) |
| ZA (1) | ZA200104828B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102008060549A1 (en) | 2008-12-04 | 2010-06-10 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Drug-peptide construct for extracellular accumulation |
| DE102009037551A1 (en) | 2009-08-17 | 2011-02-24 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Cyclosporin |
| DE102011111991A1 (en) | 2011-08-30 | 2013-02-28 | Lead Discovery Center Gmbh | New cyclosporin derivatives |
| US8957048B2 (en) | 2011-10-06 | 2015-02-17 | Allergan, Inc. | Compositions for the treatment of dry eye |
| US9907826B2 (en) | 2011-12-07 | 2018-03-06 | Allergan, Inc. | Efficient lipid delivery to human tear film using a salt-sensitive emulsion system |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8903804D0 (en) * | 1989-02-20 | 1989-04-05 | Sandoz Ltd | Improvements in or relating to organic compounds |
| US4996193A (en) * | 1989-03-03 | 1991-02-26 | The Regents Of The University Of California | Combined topical and systemic method of administration of cyclosporine |
| EP0813865B1 (en) * | 1993-04-20 | 2001-09-19 | Hexal Ag | Drug patch |
| US5603951A (en) * | 1994-11-09 | 1997-02-18 | Hanmi Pharm. Ind. Co., Ltd. | Cyclosporin-containing soft capsule compositions |
| US5798333A (en) * | 1996-09-17 | 1998-08-25 | Sherman; Bernard C. | Water-soluble concentrates containing cyclosporins |
| IL131609A0 (en) * | 1997-03-12 | 2001-01-28 | Abbott Lab | Hydrophilic binary systems for the administration of cyclosporine |
-
1998
- 1998-12-23 DE DE19859910A patent/DE19859910C2/en not_active Expired - Fee Related
-
1999
- 1999-12-23 AU AU30434/00A patent/AU762963B2/en not_active Ceased
- 1999-12-23 PT PT99964670T patent/PT1140135E/en unknown
- 1999-12-23 EP EP99964670A patent/EP1140135B1/en not_active Expired - Lifetime
- 1999-12-23 CZ CZ20012143A patent/CZ20012143A3/en unknown
- 1999-12-23 HU HU0104623A patent/HUP0104623A3/en unknown
- 1999-12-23 SK SK870-2001A patent/SK8702001A3/en unknown
- 1999-12-23 DK DK99964670T patent/DK1140135T3/en active
- 1999-12-23 CA CA002355271A patent/CA2355271A1/en not_active Abandoned
- 1999-12-23 RU RU2001120359/14A patent/RU2216342C2/en not_active IP Right Cessation
- 1999-12-23 ES ES99964670T patent/ES2203235T3/en not_active Expired - Lifetime
- 1999-12-23 WO PCT/EP1999/010358 patent/WO2000038702A1/en not_active Application Discontinuation
- 1999-12-23 DE DE59907058T patent/DE59907058D1/en not_active Expired - Fee Related
- 1999-12-23 JP JP2000590654A patent/JP2002533401A/en active Pending
- 1999-12-23 PL PL99348180A patent/PL348180A1/en unknown
- 1999-12-23 AT AT99964670T patent/ATE249834T1/en not_active IP Right Cessation
-
2001
- 2001-06-13 ZA ZA200104828A patent/ZA200104828B/en unknown
- 2001-06-13 NO NO20012932A patent/NO20012932D0/en not_active Application Discontinuation
- 2001-11-07 HK HK01107803A patent/HK1037140A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1140135A1 (en) | 2001-10-10 |
| AU3043400A (en) | 2000-07-31 |
| NO20012932L (en) | 2001-06-13 |
| CZ20012143A3 (en) | 2002-01-16 |
| JP2002533401A (en) | 2002-10-08 |
| HUP0104623A2 (en) | 2002-04-29 |
| DE19859910C2 (en) | 2001-03-22 |
| HUP0104623A3 (en) | 2002-08-28 |
| PT1140135E (en) | 2003-12-31 |
| RU2216342C2 (en) | 2003-11-20 |
| DE19859910A1 (en) | 2000-06-29 |
| NO20012932D0 (en) | 2001-06-13 |
| DE59907058D1 (en) | 2003-10-23 |
| ATE249834T1 (en) | 2003-10-15 |
| DK1140135T3 (en) | 2003-12-08 |
| HK1037140A1 (en) | 2002-02-01 |
| ES2203235T3 (en) | 2004-04-01 |
| PL348180A1 (en) | 2002-05-06 |
| EP1140135B1 (en) | 2003-09-17 |
| CA2355271A1 (en) | 2000-07-06 |
| ZA200104828B (en) | 2002-09-13 |
| WO2000038702A1 (en) | 2000-07-06 |
| SK8702001A3 (en) | 2002-01-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI116197B (en) | Process for the preparation of pharmaceutical compositions for poorly soluble active substances | |
| AU737053B2 (en) | Oil-free pharmaceutical compositions containing cyclosporin A | |
| EP1109532B1 (en) | Oral micro-emulsion composition of silybin | |
| KR0146671B1 (en) | Cyclosporin-containing powder composition | |
| AU630413B2 (en) | Pharmaceutical compositions comprising cyclosporin and a fatty acid saccharide monoester | |
| JP2001505928A (en) | Solid pharmaceutical composition comprising cyclosporin and an anionic surfactant | |
| CZ301382B6 (en) | Hydrophilic binary systems for administering cyclosporin | |
| NZ230660A (en) | Pharmaceutical compositions comprising cyclosporins in oil-in-water microemulsion pre-concentrate form | |
| EP0756489B1 (en) | Cyclosporin containing composition and process for the preparation thereof | |
| WO2006062334A1 (en) | Oral micro-emulsion composition comprising tacrolimus | |
| KR20000069688A (en) | Oral cyclosporin formulations | |
| JP2006206615A (en) | Pharmaceutical preparation comprising cyclosporin for oral administration | |
| KR20090131585A (en) | Self-microemulsified mastic composition and capsule containing the composition | |
| AU616049B2 (en) | Etoposide solutions | |
| JPH10509462A (en) | Oral cyclosporine preparation | |
| AU762963B2 (en) | Cyclosporin solution | |
| KR100308779B1 (en) | Novel compositions containing cyclosporin | |
| EP1151755B1 (en) | Pharmaceutical compositions comprising cyclosporin as active ingredient | |
| NO177484B (en) | Process for the preparation of a pharmaceutical composition in the form of soft capsules | |
| JP2006509785A (en) | Oral microemulsion composition of biphenyldimethyldicarboxylic acid | |
| KR100352089B1 (en) | Oral micro-emulsion composition comprising fenofibrate | |
| SK123299A3 (en) | Pharmaceutical compositions containing cyclosporin | |
| WO2004073693A1 (en) | Soft capsule containing cyclosporine and it's manufacturing process | |
| AP1040A (en) | A novel composition containing cyclosporin. | |
| KR0163210B1 (en) | Liquid composition comprising cyclosporin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) |