CYCLOSPORIN FORMULATION

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: CYCLOSPORIN FORMULATION 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 water- insoluble pharmaceutically active material; a C 8 - C 2 o 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 hydrophihc 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 hydrophihc 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-A-0760237. 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, suφrisingly, 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 hydrophihc 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) a water-insoluble pharmaceutically active material; b) one or more propylene glycol esters of a fatty acid; c) surfactant; and either d) a hydrophihc 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 hydrophihc phase, and then mixing the preconcentrate with the hydrophihc 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 hydrophihc 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 C 8 - C 20 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, polyoxyethylene-sorbitan 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 hydrophihc 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 118:436. 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 -1 0% Oil phase 20-80% 30-60% 25-40% Surfactant 20-40%o 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 known by those skilled in the art of formulation, so further details are considered unnecessary. 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. D- to 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 Examples of compositions comprising a blend of preconcentrate and solid carrier are: Example 1 Imusporin-25 Component mg/capsule Cyclosporin USP 25 Glyceryl Monolinoleate (Maisine 33-1) 17.25 Propylene glycol monocaprylate 17.25 (Capryol 90) Polyoxyl 35 Castor Oil NF (Cremophor 50.00 EL) Colloidal silicon dioxide 52.50 Crospovidone USP (P VP CL-M) 13.00 Net Fill Wt/cap (mg) 175.00 Example 2 Imusporin-50 Component mg/capsule Cyclosporin USP 50.00 Glyceryl Monolinoleate (Maisine 33-1) 34.50 Propylene glycol monocaprylate 34.50 (Capryol 90) Polyoxyl 35 Castor Oil NF (Cremophor 100.00 EL) Colloidal silicon dioxide 105.00 Crospovidone USP (PVP CL-M) 26.00 Net Fill Wt/cap (mg) 350.00 Example 3 Imusporin-100 Component mg/capsule Cyclosporin USP 100.00 Glyceryl Monolinoleate (Maisine 33-1) 69.00 Propylene glycol monocaprylate 69.00 (Capryol 90) Polyoxyl 35 Castor Oil NF (Cremophor 200.00 EL) Colloidal silicon dioxide 210.00 Crospovidone USP (PVP CL-M) 52.00 Net Fill Wt/cap (mg) 700.00 The blended preparations were made as follows: 1 Mix Maisine 35-1, Capryol 90 and Cremophor EL in a clean jacketed vessel. 2 Add Cyclosporin to the above vessel under stirring, continue stirring for about 70-75 mins. If required, heat the blend to not more than 50°C till the drug dissolves completely. 4 Cool the above blend to room temperature and strain through 150#. 5 Sift Aerosil and Crospovidone through 20# and 40# respectively. Mix in a suitable mixer. 6 Adsorb the above blend (step 4) over the mixture of Aerosil and Crospovidone. 7 Pass the powder blend of Cyclosporin through 20#. 8 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. Examples 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-in- water emulsions. The procedure was: (a) 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. (b) add the surfactant with stirring. (c) add the hydrophilic phase ; with stirring (d) add the alpho tocopherol and mix thoroughly. Example 4 Preparation of microemulsion for administration in Soft Gelatin capsules: Component mg/capsule Capryol 90 130 Castor oil 130 Polyoxyl-40 hydrogenated 400 Castor oil - α-tocopherol 10 Propylene gl ycol 200 Cyclosporin A 100 Example 5 Preparation of microemulsion for administration as oral solution: Component mg/capsule Capryol 90 150 Maisine 125 Polysorbate-80 49 (Tween 80) α-tocopherol 10 Transcutol 225 Cyclosporin A 100 Example 6 Preparation of microemulsion for administration as oral solution Component mg/capsule Capryol 90 275 Polyoxyl-40 hydrogenated castor oil 425 α-tocopherol 10 Propylene glycol 225 Cyclosporin A 100 Example 7 Preparation of microemulsion for administration as oral solution: Component % Capryol 90 130 Lauroglycol 90 130 Polysorbate 80 (Tween 80) 400 α-tocopherol 10 Propylene glycol 200 Cyclosporin A 100 Example 8 Preparation of microemulsion for administration as oral solution: Component mg/capsule Capryol 90 14 Maisine 15 Polyoxyl-40 hydrogenated castor oil 45 α-tocopherol 1 Transcutol 25 Cyclosporin A 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 RT (25°C ± 2°C). Ref 40°C-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 lOOmg 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: 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) 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. 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 3, 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 Cι 2 to C ! 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 1 :0.5 to 1 :5.0. 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 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 1 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.

Inventors: HAMIED YUSUF KHWAJA, MALHOTRA GEENA, NAYAK VINAY G, HAMIED, YUSUF, KHWAJA, MALHOTRA, GEENA, NAYAK, VINAY, G.
Applicants: CIPLA LTD, HAMIED YUSUF KHWAJA, MALHOTRA GEENA, NAYAK VINAY G, WAIN CHRISTOPHER PAUL, CIPLA LIMITED, HAMIED, YUSUF, KHWAJA, MALHOTRA, GEENA, NAYAK, VINAY, G., WAIN, CHRISTOPHER, PAUL
Application year: 2000
Main classification: A61K9
IPC codes: A61K9, A61K38