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GB2362573A - Cyclosporin formulation - Google Patents

Cyclosporin formulation Download PDF

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Publication number
GB2362573A
GB2362573A GB0012816A GB0012816A GB2362573A GB 2362573 A GB2362573 A GB 2362573A GB 0012816 A GB0012816 A GB 0012816A GB 0012816 A GB0012816 A GB 0012816A GB 2362573 A GB2362573 A GB 2362573A
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United Kingdom
Prior art keywords
component
preconcentrate
composition
composition according
solid
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.)
Withdrawn
Application number
GB0012816A
Other versions
GB0012816D0 (en
Inventor
Yusuf Khwaja Hamied
Geena Malhotra
Vinay G Nayak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cipla Ltd
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Cipla Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Cipla Ltd filed Critical Cipla Ltd
Priority to GB0012816A priority Critical patent/GB2362573A/en
Publication of GB0012816D0 publication Critical patent/GB0012816D0/en
Priority to PCT/GB2000/004143 priority patent/WO2001032142A1/en
Priority to AU10432/01A priority patent/AU1043201A/en
Priority to EP00971598A priority patent/EP1227793A1/en
Publication of GB2362573A publication Critical patent/GB2362573A/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K9/10—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
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

A pharmaceutical composition in the form of a preconcentrate mixed either with a liquid hydrophilic phase to form a stable oil-in-water microemulsion or with a solid carrier to form a stable, solid blend of carrier and preconcentrate, comprises a) a water-insoluble pharmaceutically active material; b) one or more propylene glycol esters of a fatty acid; c) surfactant; and either d) a hydrophilic phase, wherein component (a) has been wholly directly dissolved in component (b) and component (b) is dispersed as tiny particles in component (d); or e) a solid carrier. The composition is substantially free from ethanol.

Description

2362573 CYCLOSPORIN FORMULATION -1 This invention relates to improved
pharmaceutical compositions for the administration of water-insoluble pharmaceutically active substances especially, but not exclusively, cyclosporin.
In our European patent specification no. EP-A-0760237 there is described a pre-concentrate microemulsion composition comprising a waterinsoluble pharmaceutically active material; a Cg - C20 fatty acid mono-, di- or tri glyceride from a vegetable oil or any mixture of two or more thereof; and a phospholipid and another surfactant. A stable oil-in-water microemulsion can be formed by mixing the preconcentrate composition with a hydrophilic phase. Unlike prior art microemulsion compositions, the microemulsion compositions of EP 0760237 are made by directly dissolving the active material in the oil phase and then dispersing the oil phase in the hydrophilic phase. This has certain advantages. For example, in the case of cyclosporin microemulsions, it eliminates or vastly reduces the tendency for solid microfine cyclosporin to be precipitated during use of the microemulsions, a problem encountered with many of the prior art microemulsions.
Whilst the microemulsions disclosed in EP-A-0760237 are generally very satisfactory in many ways, we have found that there is an upper limit to the bioavailability of the active material in the compositions of EP-A0760237. We have now discovered that by judiciously alternating the components of the oil phase in the compositions of EP-A-0760237, the bioavailability of the active material can, surprisingly, be increased. The present compositions thus possess the advantages of the compositions of EP-A-0760237 together with, in addition, the advantage of increased bioavailability of the active material.
According to the present invention, there is provided a pharmaceutical composition in the form of a preconcentrate mixed either with a liquid hydrophilic phase to form a stable oil-in-water microemulsion or with a solid carrier to form a stable, solid blend of carrier and preconcentrate, which composition is substantially free from ethanol and comprises: a) b) c) a water-insoluble pharmaceutically active material; one or more propylene glycol esters of a fatty acid; surfactant; and either d) a hydrophilic phase, wherein component (a) has been wholly directly dissolved in component (b) and component (b) is dispersed as tiny particles in component (d); or e) a solid carrier.
There is also provided a process for making a composition according to the invention, which process comprises dissolving component (a) in component (b) optionally with component (c), and then mixing the resulting solution either with component (d) or with component (e), and component (c) if not included earlier. In the case of a microemulsion, the method of the invention thus comprises first forming a preconcentrate by directly dissolving component (a) in component (b), the preconcentrate also containing component (c) but being free from hydrophilic phase, and then mixing the preconcentrate with the hydrophilic phase, to form a stable oil-in water microemulsion, the composition being free from ethanol.
In the case of a solid composition, the method of the invention comprises first forming a preconcentrate by directly dissolving component (a) in component (b), the preconcentrate also containing component (c), and then mixing the preconcentrate with the solid carrier, to form a solid, table composition of preconcentrate and carrier, the composition being free from ethanol.
In its broadest aspect, the present invention therefore encompasses two different formulations, of the basic preconcentrate mixture. Both of these formulations possess the advantage of increased bioavailability of the active material.
Thus, in a first aspect, the invention provides a stable oil-in-water microemulsion composition wherein components (a) to (c) above have first been formed into a preconcentrate by wholly directly dissolving component (a) in component (b) optionally in the presence of component (c) (i.e. component (c) may be added later), and then mixing the preconcentrate with a hydrophilic phase. The microemulsion composition is generally liquid at room temperature and can, therefore, be advantageously provided in, for example, a soft gelatine capsule or as an oral solution such as an aqueous drink, for instance.
In a second aspect, the invention provides a stable, solid formulation comprising a blend of the basic preconcentrate mixture with a solid carrier. In this way, the preconcentrate mixture having increased bioavailability of the active material can, for example, be formulated into a free-flowing powder which, in turn can, for instance, be put into a hard gelatin capsule or compressed into a table. We generally prefer to formulate the composition of the invention in this way rather than as a microemulsion, since the solid formulation is simple to process and has excellent stability.
In the present invention, component (a) is a water insoluble pharmaceutically active material. The invention is particularly useful with the cyclosporins, e.g. cyclosporin A. dihydrocyclosporin C, cyclosporin D and dihydrocyclosporin D. It is also useful with other water-insoluble substances such as, for example, water-insoluble peptides, or water- insoluble antimicrobial or antineoplastic substances. Examples include desmopresin, calcitonin, insulin, lenprolide, erythropoetin, a cephalosporin, vincristine, vinblastine, taxol, etoposide or mixtures thereof.
In the compositions of the invention, component (a) is in solution in component (b). Component (b) can be a propylene glycol ester of a fatty acid or a mixture of any two or more such esters. The fatty acids may optionally be derived from a vegetable oil and are preferably C8 - C20 residues. Particular preferred compounds are propylene glycol monocaprylate (Caprgol 90) and propylene glycol monolaurate (Lauroglycol 90). We prefer to formulate the composition such that the weight ratio of component (a) to component (b) is from about 1: 1 to about 1: 10 but ratios outside this range can be used if desired.
These compounds, which increase the bioavailability of the active material can be used alone or in combination with one or more of the glycerides described in EP 0760237. For example, oleoyl macrogol-6 glycerides (Labrafil M 1944 CS), linoleoyl macrogol-6 glycerides (Labrafil M 2125 CS), and caprylocaproyl macrogol-8 glycerides (Labrasol) are particularly preferred compounds for use with the oils employed in the present invention.
Component (c) is a surfactant to provide the preconcentrate mixture and, where employed, the fully formed microemulsion with stability.. Those skilled in the art will be aware of many surfactants which can be used, but we prefer to use polyoxyl 40 hydrogenated castor oil, polyoxyethylenesorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate or polyoxyethylene sorbitan monostearate. If desired, the surfactant can be mixed with a phospholipid, such as lecithin. We prefer to use a weight ratio of component (a) to surfactant of about 1:1 to about 1:50, but ratios outside this range can also be employed if desired. When a phospholipid is included in the composition, we prefer to use a weight ratio of component (a) to phospholipid of about 1:05 to about 1:5.0, but, again, other ratios can be used.
In the case where the composition of the invention is provided as a microemulsion, component (d) is a hydrophilic phase. The preferred material is propylene glycol or diethylene glycol monoethyl ether (transcutol) but other substances can be used. Ethanol cannot be present. Water can of course also be present but it is not preferred. Despite the use of propylene glycol, component (a) remains wholly dissolved in the oil phase (component (b)).
Microemulsions are transparent due to the very small particle size of the dispersed phase, typically less than 200 nm. Such small droplets produce only weak scattering of visible light when compared with that from the coarse droplets (1 - 10 nm) of normal emulsions. An essential difference between microemulsions and emulsions is that microemulsions form spontaneously and, unlike emulsions. required little mechanical work in their formulation. General reviews on microemulsions are provided by Attwood D. et al J. Colloid Interface Sci 46:249 and Kahlweit M. et al J. Colloid Interface Sci 118:43 6.
The microemulsions can be formed by diluting with aqueous liquid (e.g. water, fruit juice, milk etc.) to form an oil-in-water microemulsion, e.g. for oral administration. This aids in ready absorption as the surface area of the fat globules is largely increased. The role played by bile salts in the initial step of fragmentation of fat globules, essential for fat digestion, is circumvented.
The rate determining factor for the absorption of drug in the vehicle is not the enzymatic metabolism of triglycerides but rests primarily in the breakdown of the fat globules into micro particles since the enzymes (lipases) act mainly at the surface of the fat globules.
In the microemulsions of the invention, the amounts of the components, in percent by weight, are as follows:
Component General Usual Preferred Active pharmaceutical 1-12% 2.5-10% 7-10% Oil phase 20-80% 30-60% 25-40% Surfactant 20-40% 25-60% 40-50% Hydrophilic phase 10-60% 20-50% 25-30% In the microemulsions, the weight percent of hydrophilic phase is generally up to about 75%, most usually from 15 to 50%, and preferably from 35 to 50%.
In the case where the composition of the present invention is provided as a blend of preconcentrate and solid carrier, component (e) is employed instead of component (d). Preferred solid carriers include colloidal silicon dioxide and polyvinyl pyrrolidone (cross Povidone) but other suitable inert solid substances can also be used, as will be clear to those skilled in the art. Typically, the solid carrier will be in the form of a dry powder. Generally, the preconcentrate mixture (comprising active material, oil and surfactant) is simply blended with the solid material such that the oily preconcentrate is absorbed by the material. Preferably, the blended mixture is provided in the form of a free-flowing powder. Such a powder can then be easily coated, for example, into a hard gelatin capsule or, alternatively, compressed into tablets, for instance. The technique of absorbing an oily phase (in this case an oily preconcentrate) on to a solid phase such as colloidal silicon dioxide followed by formulation into a final dosage form is a technique well knowp by those skilled in the art of formulation, so further details are considered unnece ssary.
Both the microemulsion and solid compositions can consist only of the components described, or they can contain other substances. For example, in order to prevent oxidation/ rancidification of the natural oils, an antioxidant, e.g. Elto copherol can be used. Propyl gallate may be used as an alternative.
In order that the invention may be more fully understood, the following examples are given by way of illustration only.
Examples 1-3 solid carrier are:
Ex"le 1 Imusporin-25 Component mglcapsule Cyclosporin USP 25 Glyceryl Monolinoleate (Maisine 33-1) 17.25 Propylene glycol monocaprylate (Capryol 90) Polyoxyl 35 Castor Oil NF (Cremophor EL) Colloidal silicon dioxide Crospovidone USP (PVP CL-M) Net Fill Wt/cap (mg) Examples of compositions comprising a blend of preconcentrate and 17.25 50.00 52.50 13.00 175.00 Ejam plc 2 Imusporin-50 Component mglcapsule Cyclosporin USP 50.00 Glyceryl Monolinoleate (Maisine 33-1) 34.50 Propylene glycol monocaprylate 34.50 (Capryol 90) Polyoxyl 3 5 Castor Oil NF (Cremophor EL) Colloidal silicon dioxide Crospovidone USP (PVP CL-M) Net Fill Wt/cap (mg) 100.00 105.00 26.00 350.00 Example 3
Imusporin- 100 Component Cyclosporin USP 100.00 Glyceryl Monolinoleate (Maisine 33-1) 69.00 Propylene glycol monocaprylate (Capryol 90) Polyoxyl 35 Castor Oil NF (Cremophor EL) Colloidal silicon dioxide Crospovidone USP (PVP CL-M) Net Fill Wt/cap (mg) 1 2 4 5 6 7 8 mg/capsule 69.00 200.00 210.00 52.00 700.00 The blended preparations were made as follows: Mix Maisine 3 5- 1, Capryol 90 and Cremophor EL in a clean jacketed vessel. Add Cyclosporin to the above vessel under stirring, continue stirring for about 70-75 mins. If required, heat the blend to not more than 50T till the drug dissolves completely. Cool the above blend to room temperature and strain through 150#. Sift Aerosil and Crospovidone through 20# and 40# respectively. Mix in a suitable mixer. Adsorb the above blend (step 4) over the mixture of Aerosil and Crospovidone. Pass the powder blend of Cyclosporin through 20#. Fill this blend in hard gelatin capsules or compressed with tablets.
The blends were then either fill into hard gelatin capsules or compressed into tablets.
Exgmples 4 - 8 Microemulsions of the invention were made of the compositions indicated, by dissolving the cyclosporin A in the oils and then forming the oil- inwater emulsions. The procedure was:
(a) (b) (c) (d) ExMle 4 dissolve the cyclosporin A in the mixture of oils with slight warming and under stirring to obtain a clear yellow liquid. Confirm the complete dissolution of the drug by microscopy. add the surfactant with stirring. add the hydrophilic phase with stirring add the alpho tocopherol and mix thoroughly.
Preparation of microemulsion for administration in Soft Gelatin capsules: Component Capryol 90 Castor oil Polyoxyl-40 hydrogenated Castor oil a-tocopherol Propylene glycol Cyclosporin A Example 5 mg/capsule 130 130 400 200 100 Preparation of microemulsion for administration as oral solution:
Component mglcapsule Capryol 90 150 Maisine 125 Polysorbate-80 (Tween 80) a-tocopherol Transcutol Cyclosporin A Example 6
425 225 100 Preparation of microemulsion for administration as oral solution Component Capryol 90 Polyoxyl-40 hydrogenated castor oil a-tocopherol Propylene glycol Cyclosporin A Exqmple 7 mg/capsule 275 425 10 225 100 Preparation of microemulsion for administration as oral solution:
Component Capryol 90 Lauroglycol 90 Polysorbate 80 (Tween 80) atocopherol Propylene glycol Cyclosporin A Ejample 8 130 400 10 100 Preparation of microemulsion for administration as oral solution:
Component Capryol 90 Maisine Polyoxyl-40 hydrogenated castor oil atocopherol Transcutol Cyclosporin A mg/capsule 14 15 45 1 10 The oral solution which is filled into bottles can be administered using a syringe or more preferably with the aid of a metered dose pump with a dropper actuator.
The compositions described in Examples 4 to 8 were subjected to stability examinations under accelerated conditions of temperature and humidity. The solutions were stored at kT (25'C 2'C). Ref 4TC-80% RH and 45'C, after filling into flint glass vials.
Simultaneously with the examination of solutions prepared according to the process of the invention, the stability of the commercially available Neoral capsules containing 10Orng cyclosporin A per capsule was also examined. It was observed from the above examination that the stability of solutions prepared according to the process of invention did not differ from the stability of the commercially available composition.

Claims (20)

CLAIMS:
1. A pharmaceutical composition in the form of a preconcentrate mixed either with a liquid hydrophilic phase to form a stable oil-in-water microemulsion or with a solid carrier to form a stable, solid blend of carrier and preconcentrate, which composition is substantially free from ethanol and comprises:
a) b) C) d) e) a water-insoluble pharmaceutically active material; one or more propylene glycol esters of a fatty acid; surfactant; and either a hydrophilic phase, wherein component (a) has been wholly directly dissolved in component (b) and component (b) is dispersed as tiny particles in component (d); or a solid carrier.
2. A composition according to claim 1, which composition is a microemulsion comprising components (a), (b), (c) and (d).
3. A composition according to claim 1, which composition is a blend of said preconcentrate and said solid carrier comprising components (a), (b), (c) and (e).
4. A composition according to claim 1, 2 or, wherein component (a) is a cyclosporin, or another water-insoluble peptide, or a water-insoluble antimicrobial or antineoplastic substance or mixtures thereof.
5. A composition according to claim 4, wherein component (a) is cyclosporin A, dihydrocyclosporin C, cyclosporin D or dihydrocyclosporin D, or desmopresin, calcitonin, insulin, leuprolide, erythropoetin, a cephalosporin, vincristine, vinblastine, taxol or etoposide or mixtures thereof.
6. A composition according to any preceding claim, wherein component (b) is a propylene glycol ester Of C 12 to C, 8 fatty acids.
7. A composition according to any preceding claim, wherein said surfactant is polyoxyl 40 hydrogenated castor oil, polyoxyethylene- sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate or polyoxyethylene-sorbitan monostearate or mixtures thereof.
8. A composition according to any preceding claim, wherein component (c) further comprises a phospholipid.
9. A composition according to any preceding claim, wherein the weight ratio of component (a) to component (b) is from 1: 1 to 1: 10.
10. A composition according to claim 8 or 9, wherein the weight ratio of component (a) to said phospholipid is from L0.5 to L5.0.
11. A composition according to any preceding claim, wherein the weight ratio of component (a) to said surfactant is from 1: 1 to 1: 5. 0.
12. A composition according to any of claims 1-9 and containing component (e), wherein component (e) is colloidal silicon dioxide, polyvinyl pyrrolidone or a mixture thereof
13. A soft gelatin capsule or oral administration fluid which comprises a composition as claimed in any of claims 1 to 11 F
14. A tablet or hard gelatin capsule which comprises a composition as claimed in any of claims 1 to 12 when in said solid form.
15. A process for making a composition according to claim 1, which comprises dissolving component (a) in component (b) optionally with component (c), and then mixing the resulting solution either with component (d) or with component (e) and component (c) if not included earlier.
16. A process according to claim 150, wherein a preconcentrate composition is mixed with component (d).
17. A process according to claim 15, wherein a preconcentrate composition is mixed with component (e).
18. A method of making a pharmaceutical composition according to any of claims I to 11, which method comprises first forming a preconcentrate by directly dissolving component (a) in component (b), the preconcentrate also containing component (c) but being free from hydrophilic phase, and then mixing the preconcentrate with the hydrophilic phase, to form said stable oil-in-water microemulsion, the composition being free from ethanol.
19. A method of making a pharmaceutical composition according to any of claims 1- 12, which method comprises first forming a preconcentrate by directly dissolving component (a) in component (b), the preconcentrate also containing component (c), and then mixing the preconcentrate with the solid carrier, to form a solid, stable composition if preconcentrated. and carrier, the composition being free from ethanol.
20. A pharmaceutical composition substantially as described in any one of Examples 1-8.
GB0012816A 1999-11-02 2000-05-25 Cyclosporin formulation Withdrawn GB2362573A (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
GB0012816A GB2362573A (en) 2000-05-25 2000-05-25 Cyclosporin formulation
PCT/GB2000/004143 WO2001032142A1 (en) 1999-11-02 2000-10-27 Cyclosporin formulation
AU10432/01A AU1043201A (en) 1999-11-02 2000-10-27 Cyclosporin formulation
EP00971598A EP1227793A1 (en) 1999-11-02 2000-10-27 Cyclosporin formulation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB0012816A GB2362573A (en) 2000-05-25 2000-05-25 Cyclosporin formulation

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Publication Number Publication Date
GB0012816D0 GB0012816D0 (en) 2000-07-19
GB2362573A true GB2362573A (en) 2001-11-28

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GB0012816A Withdrawn GB2362573A (en) 1999-11-02 2000-05-25 Cyclosporin formulation

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003053404A1 (en) * 2001-12-20 2003-07-03 Bernard Charles Sherman Pharmaceutical compositions comprising a cyclosporin, a hydrophilic surfactant and a lipophilic surfactant

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2222770A (en) * 1988-09-16 1990-03-21 Sandoz Ltd Cyclosporin emulsion compositions
GB2228198A (en) * 1989-02-20 1990-08-22 Sandoz Ltd Orally administrable cyclosporin solutions
WO1999044584A1 (en) * 1998-03-06 1999-09-10 Novartis Ag Emulsion preconcentrates containing cyclosporin or a macrolide
US5993858A (en) * 1996-06-14 1999-11-30 Port Systems L.L.C. Method and formulation for increasing the bioavailability of poorly water-soluble drugs
EP0985412A2 (en) * 1998-08-18 2000-03-15 Panacea Biotec Limited Cyclosporin compositions
WO2000033862A1 (en) * 1998-12-11 2000-06-15 Pharmasolutions, Inc. Self-emulsifying compositions for drugs poorly soluble in water

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2222770A (en) * 1988-09-16 1990-03-21 Sandoz Ltd Cyclosporin emulsion compositions
GB2228198A (en) * 1989-02-20 1990-08-22 Sandoz Ltd Orally administrable cyclosporin solutions
US5993858A (en) * 1996-06-14 1999-11-30 Port Systems L.L.C. Method and formulation for increasing the bioavailability of poorly water-soluble drugs
WO1999044584A1 (en) * 1998-03-06 1999-09-10 Novartis Ag Emulsion preconcentrates containing cyclosporin or a macrolide
EP0985412A2 (en) * 1998-08-18 2000-03-15 Panacea Biotec Limited Cyclosporin compositions
WO2000033862A1 (en) * 1998-12-11 2000-06-15 Pharmasolutions, Inc. Self-emulsifying compositions for drugs poorly soluble in water

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003053404A1 (en) * 2001-12-20 2003-07-03 Bernard Charles Sherman Pharmaceutical compositions comprising a cyclosporin, a hydrophilic surfactant and a lipophilic surfactant

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Publication number Publication date
GB0012816D0 (en) 2000-07-19

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