Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-01-22
2003-04-22
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S422000, C424S423000, C424S400000, C424S484000, C424S493000, C424S496000, C424S497000, C424S500000, C514S951000, C514S969000, C514S975000
Reexamination Certificate
active
06551619
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to particulate systems loaded with cyclosporin (also spelled “cyclosporine”) or cyclosporin derivatives of natural and/or synthetic origin, which said systems have improved biopharmaceutical properties for cyclosporins in vivo, improved quality (fineness and homogeneity of the particles, drug inclusion) and improved physical stability of the particulate formulation (no aggregation or gel formation).
2. Description of the Related Art
Cyclosporins are cyclic oligopeptides. They are a group of natural oligopeptides ranging from cyclosporin A to cyclosporin Z. Synthetic derivatives have also been described (SDZ IMM 125, the hydroxyethyl derivative of D-serine-8-cyclosporin).
Cyclosporin A is a lipophilic molecule consisting of 11 aminoacids. It is obtained by fermenting mushrooms. Its molecular weight is 1203.
Commercial products: Sandimmun®, Sandimmun Optoral® (outside Germany=Sandimmun Neoral®) [A. Meinzer, E. Müller, J. Vonderscher,
Perorale Mikroemulsionsformulierung—Sandimmun Optoral®/Neorale®,
in:
Pharmazeutische Technologie: Moderne Arzneiformen,
R. H. Müller and G. E. Hildebrand (eds.), Wissenschaftliche Verlagsgesellschaft Stuttgart, 169-177, 1998]. Cyclosporin A is preferably used as an immunosuppressant after organ transplants. Other fields of use are autoimmune diseases, psoriasis and diabetes. All the cyclosporins (both natural and synthetic) can be used in the present invention.
The cyclosporins are highly lipophilic substances and poorly soluble in water (e.g. cyclosporin A: <0.004% m/V in water at 25° C.). Their high lipophilia and very poor solubility in water constitute the main problems in producing a suitable pharmaceutical preparation. In view of their better solubility in fatty oils and alcohol, Sandimmun® was developed with these ingredient as solubility enhancers for oral use in the form of an emulsion concentrate. The said emulsion concentrate consists of 100 mg cyclosporin dissolved in 1 ml of a mixture of oil, ethanol and an emulsifier, namely macrogol glycerol trioleate linolate. The concentrate must be diluted before use, for example by stirring it with a spoon into cold milk, cocoa or fruit juice. This non-standardised, inefficient mixing procedure results in the formation of a coarse non-homogenous oil/water emulsion with a relatively large droplet size. Its bioavailability after oral administration varies in vivo, in extreme cases between 10 and 60% [T. Beveridge, A. Gratwohl, F. Michot et al.,
Curr. Ther. Res.,
30 (5), 1981].
In addition to the oral solution formulation, Sandimmun® is also available in capsule form. The capsules contain 25 mg/100 mg cyclosporin A dissolved in a mixture of oil, ethanol and emulsifier. In this case, the oily preparation is dispersed in the stomach by peristaltic movements. Here again, this is an inefficient oil dispersion procedure.
Alternatively, the oily phase loaded with cyclosporin A has been treated in further experiments with high-pressure homogenisation. This process produced a finer O/W emulsion [Dietl, H., Pharmaceutical preparation containing cyclosporin(s) for oral administration and process for producing same, U.S. Pat. No. 5,637,317, 1997]. However, this patent contains no data relating to the physical stability of the homogenised emulsion during storage, nor in vivo data demonstrating that the homogenisation process can lead to increased bioavailability. It is known that when cyclosporin is dispersed in the oily phase of an O/W emulsion it precipitates after a few days, forming large crystals in the emulsion by crystallisation of the drug, or the cyclosporin that has exited from the oily phase floats, forming an edge or film on the surface. This problem is known, for example, in the case of the Sandimmun® oral emulsion. It is also known that the incorporation of a drug into the oily phase of an O/W emulsion can reduce the physical stability of the said emulsion in view of its tendency to coalesce [S. S. Davis,
Pharmaceutical aspects of i.v. fat emulsions,
J. Hosp. Pharm., 32, 149-170, 1974]. The small size of the droplets is not the only critical factor that causes increased bioavailability of cyclosporin. Homogenisation of the emulsion alone does not automatically increase bioavailability, as normal cyclosporin A re-absorption is also largely influenced by the secretion of bile salts [A. Meinzer, E. Müller, J. Vonderscher,
Perorale Mikroemulsionsformulierung—Sandimmun Optoral™/Neoral™,
in:
Pharmazeutische Technologie: Moderne Arzneiformen,
R. H. Müller and G. E. Hildebrand (eds.), Wissenschaftliche Verlagsgesellschaft Stuttgart, 1998]. Apart from the extent of bile salt release, food intake also constitutes a significant factor during drug absorption which can influence the bioavailability of cyclosporin. The release of drugs from emulsions also depends on the coefficient of distribution. This influence is difficult to control in order to obtain protracted, non-variable blood levels. These disadvantages of O/W emulsions (ie. coarse emulsions) have already been described for other cyclosporin emulsions [e.g. A. Tibell et al.,
Cyclosporin A in fat emulsion carrier. Immunosuppressive effect in vitro, J. Immunolo.
35, 231-236, 1992].
The next stage of development was the replacement of the Sandimmun® coarse emulsion formulation with the Sandimmun Optoral® microemulsion. The result was that absorption of cyclosporin A became nearly independent of bile salt secretion [A. Meinzer, E. Müller, J. Vonderscher,
Perorale Mikroemulsionsformulierung—Sandimmun Optoral™/Neoral™,
in:
Pharmazeutische Tecnologie: Moderne Arzneiformen,
R. H. Müller and G. E. Hildebrand (eds.), Wissenschaftliche Verlagsgesellschaft Stuttgart, 176, 1998]. A microemulsion does not contain separate droplets, but is a “critical solution” [B. W. Müller,
Mikroemulsionen als neue Wirkstofftragersysteme,
in
Pharmazeutische Technologie: Moderne Arzneiformen,
R. H. Müller and G. E. Hildebrand (eds.), Wissenschaftliche Verlagsgesellschaft Stuttgart, 161-168, 1998; B. W. Müller, H. J. Franzky, C. J. Kölln, U.S. Pat. No. 4,719,239, 1988]. Oral administration of the cyclosporin A microemulsion reduces the variability of absorption, although it produces high initial blood level peaks, well above the limit of 1000 ng/ml (
FIG. 1
, right). The said blood level peaks must be eliminated in an optimised preparation.
There are no effective topical preparations with cyclosporin A designed for topical treatment (e.g. psoriasis). In the literature, cyclosporin is said to have a topical action in theory (Clinical Report, Servizio de Medicina, Hospital del Cobre, Rancagua. Chile,
Rev. Med. Chil.
1994, vol. 122; 1404-7]. However, its efficacy was only observed after six months' treatment; moreover, dimethyl sulphoxide had to be used as solvent at the concentration of 50%, which is unacceptable for a treatment like that of psoriasis. Theoretical therapeutic efficacy was also reported in another protocol (
Intralesional cyclosporine for psoriasis. Relationship of dose, tissue levels and efficacy.
J. Gajardo, J. Villaseca,
Arch. Dermatol.
1992, vol. 128; 786-790). Topical application had no effect in this case, which demonstrates the importance of a suitable pharmaceutical form. Intralesional injections were therefore performed, and demonstrated the theoretical efficacy of the substance, although its use proved totally impracticable for treatment purposes.
SUMMARY
The main technical and biopharmaceutical problems of cyclosporin A formulations at present are:
1. the pharmaceutical quality and physical stability of the preparation (e.g. coarse emulsion, formation of cyclosporin A crystals and coalescence),
2. high variability of blood levels,
3. blood level peaks substantially >1500 or >1200 or >1000 ng/ml, which cause toxic side effects of various kinds,
4. ineffective topical formulations.
The objective of this invention is to eliminate the above said problems
Müller Rainer Helmut
Penkler Lawrence John
Ravelli Vittorino
Runge Stephan Anton
Abelman ,Frayne & Schwab
Fubara Blessing M.
Page Thurman K.
Pharmatec International S.R.L.
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