CA2231404C - Novel cyclosporine preparation forms for oral administration of simple composition and high bio-availability, and process for producing them - Google Patents
Novel cyclosporine preparation forms for oral administration of simple composition and high bio-availability, and process for producing them Download PDFInfo
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- CA2231404C CA2231404C CA002231404A CA2231404A CA2231404C CA 2231404 C CA2231404 C CA 2231404C CA 002231404 A CA002231404 A CA 002231404A CA 2231404 A CA2231404 A CA 2231404A CA 2231404 C CA2231404 C CA 2231404C
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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
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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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
-
- 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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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
The invention relates to novel preparation forms of cyclosporine of simple composition and high bio-availability for oral administration, containing 0,5 to 2 parts by weight (p/wt) of one or more amorphous cyclosporine(s), preferably cyclosporine A and/or cyclosporine G and 6 to 9 p/wt of one or mone polyethylene glycol ester(s) of saturated C10 - C22 hydroxy fatty acids, especially SOLUTOL.RTM. HS 15, and 1-3 p/wt of one or more monovalent or multivalent alcohols, preferably ethan ol and propylene glycol. The medical form is produced by first dissolving the amorphous cyclosporing in ethanol and adding under agitation propylene glycol and SOLUTOL.RTM. until a clear, viscous solution is obtained, which is packed as a drinking solution or capsules in the prior art manner.
Description
.- , 21489-9411 Novel Cyclosporine Preparation Forms for Oral Administration of Simple Composition and High Bio-availability, and Process for Producing Them The invention concerns cyclosporine, in particular liquid preparation forms containing cyclosporine A, for oral administration.
Cyclosporines are neutral cyclic peptides which are produced in a microbic manner. The most important representative of the cyclosporines is cyclosporine A which is used in transplant medicine for suppressing organ rejection and in bone marrow transplants.
Cyclosporine A, its microbiological production as well as its isolation and cleaning until an amorphous, colorless powder is obtained is known from DE-PS 24 55 859.
Cyclosprine A is also increasingly used in the- treatment of autoimmune diseases, such as psoriasis, uveitis, nephrotic syndrome and other diseases.
Antiinflammatory and antiparasitic properties are described for cyclosporines.
Due to the hydrophobic character of cyclosporine, it is difficult to produce pharmaceutical preparations which result in a high bioavailability of the active substance. In particular, the known administration forms exhibit a very high inter and intraindividual variability of the pharmacokinetic .. parameters. With the same dosage, the cyclosporine blood level varies from patient to patient by up to 50 0. Even with one and the same patient, the resorption fluctuates considerably. However, immunosuppressive therapy is dependent on a very narrow therapeutic window between dosis-dependent side ef7Eects and rejection of the transplanted organ.
In particular, bad bioavailabilities can be traced back to the bad solubility of the cyclosporine when mixing the cyclosporines in administration forms with water.
Thus, t:here have been a great many attempts to solve these galenic problems.
As a result, known, commercially available administration forms use complicated systems consisting of lipophilic and hydrophilic solvents as well as dissolving intermediary detergents with which cyclosporines are dissolved and are to be maintained in the dissolved form in aqueous systems. They consist of at least 4 components, namely active substances, vegetab:Le oil, ethanol and a surfactant.
The use of oil and ethanol as a carrier medium in association with Co solvents is known from US Patent 4,388,307. According to this patent, conventioinal drinking solutions of cyclosporine contain olive oil, ethanol and as a surface-active substance Labrafil . However, this method for preparing medicines results in problems. Oils and surface-active carrier substances often have an unpleasant smell and/or taste. Moreover, oils with unsaturated fatty acids tend to become rancid.
Secondly, a relatively high ethanol content is required in prescriptions with oils. However, this high ethanol content results in difficulties when administering the preparations to children and also involves storage problems.
When fi:lling in capsules, to protect against evaporation, an increased expenditure is required during preparation by packing in aluminum blisters.
New administration forms according to the patent GB 2,222,770 include solution methods by producing microemulsions. These systems consist of 4 to 6 components which form a complicated system comprised of an active substance, a lipophilic, hydrophilic phase and a surface-active substance. Systems of this type contain an increased risk of a cross reaction as well as the risk that the patient cannot tolerate one of the substances used.
From DE-PS 39 24 207, a process for producing perorally administrable stable aqueous injection solutions is known for intraveiious administration, according to which a) 1 part by weight of cyclosporine b) 8 - 13 parts by weight of one or more monoesters of a saturat(ad hydroxy fatty acid or acids with polyethylene glycol and c) 1-:3 parts by weight of one or more of monovalent and/or multivalent alcohols are mixed.
Orally administrable forms of medicines are not produced and studied in this patent. If attempts are made to dilute these prescriptions with water, this results in the precipitation of cyclosporine and thus to a considerable reduction in bioavailability.
All commercially available administration forms contain oily, lipophi:Lic components (corn oil, core oil, corn oil mono-di-tri-glycerides) and one or more detergents as well as monovalcant or multivalent alcohols.
It can be seen in DE-OS 38 43 054 that orthorhombic crystalline forms such as CY-A/X-II and, above all, CY-A/X-III
are espiacially suitable for producing galenic forms. These formulations should contain cyclosporine in a stable and finely reduced form and/or have an improved stability or exhibit more advantageous releasing characteristics.
Preferably, these forms are applied in a topically dermal or topically opththalmic manner. The described manufacturing process for the solvate-free orthorhombic crystalline form using ultrasound is difficult to carry out on a technical scale.
Similarly, it is shown that cyclosporine in an amorphous form is less suitable for the production of administration forms.
Accordiiig to the invention, the aforementioned problems were solved thereby that it was surprisingly found that, in administration forms of cyclosporine for oral administration with a simple composition and high bioavailability in the form of a dr:inking solution or capsules, containing:
a) 0.5 to 2, preferably 1 part by weight, of one or more amorphous cyclosporine(s) as active substance b) 6 to 9, preferably 7.5 parts by weight, of one or more polyethylene glycol monoester of saturated C10 to C22 hydroxy fatty acids, preferably SOLUTOL HS15 c) 1 - 3, preferably 2 parts by weight of one or more monovalent or multivalent alcohols as Co solvent, preferably ethanol and propylene glycol, substantially increases the solubility of the cyclosporine(s), in particular in dilutions with water, while maintaining these special quantitative ratios.
- 4a -According to one aspect of the present invention, there is provided a pharmaceutical composition for oral administration comprising: a) 0.5 to 2 parts by weight of one or more amorphous cyclosporines; b) 6 to 9 parts by weight of one or more polyethylene glycol monoesters of saturated C10-C22 hydroxy fatty acids; and c) 1-3 parts by weight of one or more monovalent or multivalent alcohols as solvents.
According to another aspect of the present invention, there is provided a process for production of a composition as described herein, comprising: i) dissolving component a) in component c) while stirring the resulting solution at room temperature, and ii) while stirring the result of step i) at room temperature, adding component b).
In a preferred process, the cosolvents are ethanol and propylene glycol and component a) is first disolved in the ethanol and then the propylene glycol is then added while stirring at room temperature.
Cyclosporines are neutral cyclic peptides which are produced in a microbic manner. The most important representative of the cyclosporines is cyclosporine A which is used in transplant medicine for suppressing organ rejection and in bone marrow transplants.
Cyclosporine A, its microbiological production as well as its isolation and cleaning until an amorphous, colorless powder is obtained is known from DE-PS 24 55 859.
Cyclosprine A is also increasingly used in the- treatment of autoimmune diseases, such as psoriasis, uveitis, nephrotic syndrome and other diseases.
Antiinflammatory and antiparasitic properties are described for cyclosporines.
Due to the hydrophobic character of cyclosporine, it is difficult to produce pharmaceutical preparations which result in a high bioavailability of the active substance. In particular, the known administration forms exhibit a very high inter and intraindividual variability of the pharmacokinetic .. parameters. With the same dosage, the cyclosporine blood level varies from patient to patient by up to 50 0. Even with one and the same patient, the resorption fluctuates considerably. However, immunosuppressive therapy is dependent on a very narrow therapeutic window between dosis-dependent side ef7Eects and rejection of the transplanted organ.
In particular, bad bioavailabilities can be traced back to the bad solubility of the cyclosporine when mixing the cyclosporines in administration forms with water.
Thus, t:here have been a great many attempts to solve these galenic problems.
As a result, known, commercially available administration forms use complicated systems consisting of lipophilic and hydrophilic solvents as well as dissolving intermediary detergents with which cyclosporines are dissolved and are to be maintained in the dissolved form in aqueous systems. They consist of at least 4 components, namely active substances, vegetab:Le oil, ethanol and a surfactant.
The use of oil and ethanol as a carrier medium in association with Co solvents is known from US Patent 4,388,307. According to this patent, conventioinal drinking solutions of cyclosporine contain olive oil, ethanol and as a surface-active substance Labrafil . However, this method for preparing medicines results in problems. Oils and surface-active carrier substances often have an unpleasant smell and/or taste. Moreover, oils with unsaturated fatty acids tend to become rancid.
Secondly, a relatively high ethanol content is required in prescriptions with oils. However, this high ethanol content results in difficulties when administering the preparations to children and also involves storage problems.
When fi:lling in capsules, to protect against evaporation, an increased expenditure is required during preparation by packing in aluminum blisters.
New administration forms according to the patent GB 2,222,770 include solution methods by producing microemulsions. These systems consist of 4 to 6 components which form a complicated system comprised of an active substance, a lipophilic, hydrophilic phase and a surface-active substance. Systems of this type contain an increased risk of a cross reaction as well as the risk that the patient cannot tolerate one of the substances used.
From DE-PS 39 24 207, a process for producing perorally administrable stable aqueous injection solutions is known for intraveiious administration, according to which a) 1 part by weight of cyclosporine b) 8 - 13 parts by weight of one or more monoesters of a saturat(ad hydroxy fatty acid or acids with polyethylene glycol and c) 1-:3 parts by weight of one or more of monovalent and/or multivalent alcohols are mixed.
Orally administrable forms of medicines are not produced and studied in this patent. If attempts are made to dilute these prescriptions with water, this results in the precipitation of cyclosporine and thus to a considerable reduction in bioavailability.
All commercially available administration forms contain oily, lipophi:Lic components (corn oil, core oil, corn oil mono-di-tri-glycerides) and one or more detergents as well as monovalcant or multivalent alcohols.
It can be seen in DE-OS 38 43 054 that orthorhombic crystalline forms such as CY-A/X-II and, above all, CY-A/X-III
are espiacially suitable for producing galenic forms. These formulations should contain cyclosporine in a stable and finely reduced form and/or have an improved stability or exhibit more advantageous releasing characteristics.
Preferably, these forms are applied in a topically dermal or topically opththalmic manner. The described manufacturing process for the solvate-free orthorhombic crystalline form using ultrasound is difficult to carry out on a technical scale.
Similarly, it is shown that cyclosporine in an amorphous form is less suitable for the production of administration forms.
Accordiiig to the invention, the aforementioned problems were solved thereby that it was surprisingly found that, in administration forms of cyclosporine for oral administration with a simple composition and high bioavailability in the form of a dr:inking solution or capsules, containing:
a) 0.5 to 2, preferably 1 part by weight, of one or more amorphous cyclosporine(s) as active substance b) 6 to 9, preferably 7.5 parts by weight, of one or more polyethylene glycol monoester of saturated C10 to C22 hydroxy fatty acids, preferably SOLUTOL HS15 c) 1 - 3, preferably 2 parts by weight of one or more monovalent or multivalent alcohols as Co solvent, preferably ethanol and propylene glycol, substantially increases the solubility of the cyclosporine(s), in particular in dilutions with water, while maintaining these special quantitative ratios.
- 4a -According to one aspect of the present invention, there is provided a pharmaceutical composition for oral administration comprising: a) 0.5 to 2 parts by weight of one or more amorphous cyclosporines; b) 6 to 9 parts by weight of one or more polyethylene glycol monoesters of saturated C10-C22 hydroxy fatty acids; and c) 1-3 parts by weight of one or more monovalent or multivalent alcohols as solvents.
According to another aspect of the present invention, there is provided a process for production of a composition as described herein, comprising: i) dissolving component a) in component c) while stirring the resulting solution at room temperature, and ii) while stirring the result of step i) at room temperature, adding component b).
In a preferred process, the cosolvents are ethanol and propylene glycol and component a) is first disolved in the ethanol and then the propylene glycol is then added while stirring at room temperature.
This was not generally assumed since comparable administration forms orily use polyethylene glycol esters of fatty acids as additiorial dissolving intermediary between a hydrophobic and hydrophilic phase.
Thus, it was all the more surprising that a prescription of this type showed a bioequivalence vis-a-vis commercial products (see above).
In part:icular, it could not be foreseen that such a simple prescription could attain such a high bioavailability without lipophilic components.
Furtherniore, it was found that it was just the use of amorphous cyclosporine in an oral administration form results in especially good solution properties in recipes with a cyclosporine content of > 5 %, which are also preserved as a stable, clear solution in dilutions with water.
Thus, oral administration forms are the object of the invention which, as a drinking solution or packed in capsules, contain the following components in the following quantitative ratios:
a) 0.5 -- 2 parts by weight, preferably 1 part by weight, of one or more cyclosporines, in particular cyclosporine A or G, which is used in an amorphous form b) 6 - 9 parts by weight, preferably 7.5 parts by weight, of one or more polyethylene glycol monoesters with saturated C10 to C22 of hydroxy fatty acid components, bound in the molecule:, in particular SOLUTEL HS 15 c) 1 to 3 parts by weight, preferably 2 parts by weight, of one or miore monovalent or multivalent alcohols as Co solvent, preferably ethanol and propylene glycol.
In the manufacturing process, also according to the invention, it should be noted that the quantitative ratios are maintained and that.the cyclosporine, while being continuously stirred at room temperature, is first completely dissolved in ethanol and that, subsequently, also while being stirred continuously and also at room temperature, propylene glycol and Solutol HS 15 is added. The solutions produced according to this process contain 100 mg/ml active substance.
The product packaged in the form of a drinking solution or capsules is prepared in a known manner, e.g. in capsules at 100 mg each, 50 mg or 25 mg active substance.
The prociuction of the composition according to the invention is described in greater detail in the following examples:
Example 1 100 g amorphous cyclosporine A are dissolved in 127 ml ethanol while being stirred at room temperature. 96 ml propylene glycol are subsequently added under continuous stirring at room temperature. After the cyclosporine A has been clearly dissolved, 750 g Solutol HS 15 are added under continuous stirrinq. A clear, viscous solution results with a content of 100 mg/ml cyclosporine A.
Example 2 A cyclos-porine A solution, produced according to Example 1, is diluted with water in the ratio 1. 40. The resultant solutiori remains clear and stable over a period of several months.
Thus, it was all the more surprising that a prescription of this type showed a bioequivalence vis-a-vis commercial products (see above).
In part:icular, it could not be foreseen that such a simple prescription could attain such a high bioavailability without lipophilic components.
Furtherniore, it was found that it was just the use of amorphous cyclosporine in an oral administration form results in especially good solution properties in recipes with a cyclosporine content of > 5 %, which are also preserved as a stable, clear solution in dilutions with water.
Thus, oral administration forms are the object of the invention which, as a drinking solution or packed in capsules, contain the following components in the following quantitative ratios:
a) 0.5 -- 2 parts by weight, preferably 1 part by weight, of one or more cyclosporines, in particular cyclosporine A or G, which is used in an amorphous form b) 6 - 9 parts by weight, preferably 7.5 parts by weight, of one or more polyethylene glycol monoesters with saturated C10 to C22 of hydroxy fatty acid components, bound in the molecule:, in particular SOLUTEL HS 15 c) 1 to 3 parts by weight, preferably 2 parts by weight, of one or miore monovalent or multivalent alcohols as Co solvent, preferably ethanol and propylene glycol.
In the manufacturing process, also according to the invention, it should be noted that the quantitative ratios are maintained and that.the cyclosporine, while being continuously stirred at room temperature, is first completely dissolved in ethanol and that, subsequently, also while being stirred continuously and also at room temperature, propylene glycol and Solutol HS 15 is added. The solutions produced according to this process contain 100 mg/ml active substance.
The product packaged in the form of a drinking solution or capsules is prepared in a known manner, e.g. in capsules at 100 mg each, 50 mg or 25 mg active substance.
The prociuction of the composition according to the invention is described in greater detail in the following examples:
Example 1 100 g amorphous cyclosporine A are dissolved in 127 ml ethanol while being stirred at room temperature. 96 ml propylene glycol are subsequently added under continuous stirring at room temperature. After the cyclosporine A has been clearly dissolved, 750 g Solutol HS 15 are added under continuous stirrinq. A clear, viscous solution results with a content of 100 mg/ml cyclosporine A.
Example 2 A cyclos-porine A solution, produced according to Example 1, is diluted with water in the ratio 1. 40. The resultant solutiori remains clear and stable over a period of several months.
Claims (13)
1. A pharmaceutical composition for oral administration comprising:
a) 0.5 to 2 parts by weight of one or more amorphous cyclosporines;
b) 6 to 9 parts by weight of one or more polyethylene glycol monoesters of saturated C10-C22 hydroxy fatty acids; and c) 1-3 parts by weight of one or more monovalent or multivalent alcohols as solvents.
a) 0.5 to 2 parts by weight of one or more amorphous cyclosporines;
b) 6 to 9 parts by weight of one or more polyethylene glycol monoesters of saturated C10-C22 hydroxy fatty acids; and c) 1-3 parts by weight of one or more monovalent or multivalent alcohols as solvents.
2. A pharmaceutical composition according to claim 1, comprising 1 part by weight of component a).
3. A pharmaceutical composition according to claim 1 or 2, wherein the one or more amorphous cyclosporines are one or both of cyclosporine A and cyclosporine G.
4. A pharmaceutical composition according to any one of claims 1 to 3, comprising 7.5 parts by weight of component b).
5. A pharmaceutical composition according to any one of claims 1 to 4, wherein component b) comprises SOLUTOL.TM. HS15.
6. A pharmaceutical composition according to any one of claims 1 to 5, comprising 2 parts by weight of component c).
7. A pharmaceutical composition according to any one of claims 1 to 6, wherein component c) is ethanol and propylene glycol.
8. A pharmaceutical composition according to any one of claims 1 to 7 in the form of a drinking solution.
9. A pharmaceutical composition according to any one of claims 1 to 7 in the form of a capsule.
10. A process for production of a composition as defined in any one of claims 1 to 7, comprising:
i) dissolving component a) in component c) while stirring the resulting solution at room temperature, and ii) while stirring the result of step i) at room temperature, adding component b).
i) dissolving component a) in component c) while stirring the resulting solution at room temperature, and ii) while stirring the result of step i) at room temperature, adding component b).
11. A process according to claim 10, wherein component c) is ethanol and propylene glycol, and component a) is first dissolved in the ethanol and then the propylene glycol is added while stirring at room temperature.
12. A process according to claim 10 or 11 comprising placing the resulting composition in capsules.
13. A process according to claim 10 or 11 comprising packaging the resulting composition as a drinking solution.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4438861.6 | 1994-11-03 | ||
| DE4438861 | 1994-11-03 | ||
| PCT/DE1995/000951 WO1996014079A1 (en) | 1994-11-03 | 1995-07-19 | Novel cyclosporine preparation forms for oral administration of simple composition and high bio-availability, and process for producing them |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2231404A1 CA2231404A1 (en) | 1996-05-17 |
| CA2231404C true CA2231404C (en) | 2009-02-17 |
Family
ID=6532126
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002231404A Expired - Fee Related CA2231404C (en) | 1994-11-03 | 1995-07-19 | Novel cyclosporine preparation forms for oral administration of simple composition and high bio-availability, and process for producing them |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US6486124B2 (en) |
| EP (1) | EP0789580B1 (en) |
| JP (1) | JP3833248B2 (en) |
| KR (1) | KR970704464A (en) |
| CN (1) | CN1121238C (en) |
| AT (1) | ATE218359T1 (en) |
| AU (1) | AU715165B2 (en) |
| BG (1) | BG62955B1 (en) |
| BR (1) | BR9509550A (en) |
| CA (1) | CA2231404C (en) |
| CZ (1) | CZ287806B6 (en) |
| DE (2) | DE59510233D1 (en) |
| DK (1) | DK0789580T3 (en) |
| EE (1) | EE03425B1 (en) |
| ES (1) | ES2177652T3 (en) |
| FI (1) | FI118722B (en) |
| HU (1) | HUT77283A (en) |
| LT (1) | LT4306B (en) |
| LV (1) | LV11884B (en) |
| NO (1) | NO970741D0 (en) |
| PL (1) | PL183579B1 (en) |
| PT (1) | PT789580E (en) |
| RU (1) | RU2158601C2 (en) |
| SK (1) | SK164796A3 (en) |
| TR (1) | TR199501361A2 (en) |
| TW (1) | TW492876B (en) |
| WO (1) | WO1996014079A1 (en) |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2231404C (en) | 1994-11-03 | 2009-02-17 | Arzneimittelwerk Dresden Gmbh | Novel cyclosporine preparation forms for oral administration of simple composition and high bio-availability, and process for producing them |
| US5962019A (en) * | 1995-08-25 | 1999-10-05 | Sangstat Medical Corporation | Oral cyclosporin formulations |
| US5766629A (en) | 1995-08-25 | 1998-06-16 | Sangstat Medical Corporation | Oral cyclosporin formulations |
| US5834017A (en) * | 1995-08-25 | 1998-11-10 | Sangstat Medical Corporation | Oral cyclopsporin formulations |
| WO1997007787A1 (en) * | 1995-08-25 | 1997-03-06 | Sangstat Medical Corporation | Oral cyclosporin formulations |
| DE19544507B4 (en) * | 1995-11-29 | 2007-11-15 | Novartis Ag | Cyclosporin containing preparations |
| DE29824679U1 (en) * | 1997-01-30 | 2002-03-28 | Novartis Ag | Pharmaceutical compositions |
| AU762247B2 (en) * | 1997-01-30 | 2003-06-19 | Novartis Ag | Oil-free pharmaceutical compositions containing cyclosporin A |
| DE19821951A1 (en) * | 1998-05-15 | 1999-11-18 | Basf Ag | Orally administered solid or liquid cyclosporin compositions |
| AUPP627498A0 (en) | 1998-10-02 | 1998-10-22 | University Of Queensland, The | Novel peptides - i |
| US6656504B1 (en) * | 1999-09-09 | 2003-12-02 | Elan Pharma International Ltd. | Nanoparticulate compositions comprising amorphous cyclosporine and methods of making and using such compositions |
| US6506742B2 (en) | 1999-12-13 | 2003-01-14 | Ortho-Mcneil Pharmaceutical, Inc. | Soluble contraceptive liquid formulation |
| WO2004050688A1 (en) | 2002-12-02 | 2004-06-17 | Xenome Ltd | NOVEL χ-CONOTOXIN PEPTIDES (-II) |
| US7851444B2 (en) | 2002-12-02 | 2010-12-14 | Xenome Ltd. | χ-conotoxin peptides (-1) |
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1995
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- 1995-07-19 BR BR9509550A patent/BR9509550A/en not_active Application Discontinuation
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- 1995-07-19 HU HU9702144A patent/HUT77283A/en unknown
- 1995-07-19 KR KR1019970700361A patent/KR970704464A/en not_active Application Discontinuation
- 1995-07-19 AT AT95925707T patent/ATE218359T1/en not_active IP Right Cessation
- 1995-07-19 RU RU97108682/14A patent/RU2158601C2/en active
- 1995-07-19 DE DE59510233T patent/DE59510233D1/en not_active Expired - Fee Related
- 1995-07-19 CZ CZ19963616A patent/CZ287806B6/en not_active IP Right Cessation
- 1995-07-19 CN CN95196010A patent/CN1121238C/en not_active Expired - Fee Related
- 1995-07-19 WO PCT/DE1995/000951 patent/WO1996014079A1/en not_active Application Discontinuation
- 1995-07-19 EP EP95925707A patent/EP0789580B1/en not_active Expired - Lifetime
- 1995-07-19 DK DK95925707T patent/DK0789580T3/en active
- 1995-07-19 SK SK1647-96A patent/SK164796A3/en unknown
- 1995-07-19 JP JP51493496A patent/JP3833248B2/en not_active Expired - Fee Related
- 1995-07-19 PT PT95925707T patent/PT789580E/en unknown
- 1995-07-19 AU AU29751/95A patent/AU715165B2/en not_active Ceased
- 1995-07-19 ES ES95925707T patent/ES2177652T3/en not_active Expired - Lifetime
- 1995-08-08 TW TW084108225A patent/TW492876B/en active
- 1995-10-26 DE DE19539860A patent/DE19539860A1/en not_active Withdrawn
- 1995-11-02 TR TR95/01361A patent/TR199501361A2/en unknown
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1997
- 1997-01-06 BG BG101117A patent/BG62955B1/en unknown
- 1997-01-09 LT LT97-002A patent/LT4306B/en not_active IP Right Cessation
- 1997-02-14 FI FI970634A patent/FI118722B/en active IP Right Grant
- 1997-02-18 NO NO970741A patent/NO970741D0/en not_active Application Discontinuation
- 1997-05-14 LV LVP-97-94A patent/LV11884B/en unknown
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1998
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2001
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