Solid mixtures of cyclodextrins prepared via meltextrusion

Details Solid mixtures of cyclodextrins prepared via meltextrusion Solid mixtures of cyclodextrins prepared via meltextrusion

1998-05-20

2002-04-02

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Matrices

C424S489000, C424S464000

Reexamination Certificate

active

06365188

ABSTRACT:

CROSS REFERENCE TO RELATED APPLICATIONS
This application is a National Stage application under 35 U.S.C. 371 of PCT/EP96/05118 filed Nov. 20, 1996, which claims priority from EP95.203.219.1, filed Nov. 23, 1995.
The present invention involves a process for preparing solid mixtures by melt-extrusion comprising one or more active ingredients, preferably one or more practically insoluble active ingredients and one or more cyclodextrins. The invention further concerns pharmaceutical compositions comprising the above mixture.
WO 94/11031, published on May 5, 1994, discloses a method of manufacturing a high-quality enclosure compound using extrusion techniques. In this document the extrusion of cyclodextrins together with an active ingredient is mentioned. However, the document discloses the use of a wet mixture (i.e. including water or another solvent) to feed into the extruder. French patent application 2,705,677 published on Dec. 2, 1994 describes micro-granules obtained by extrusion-spheronisation containing a cyclodextrin. The extrusion-spheronisation technique is the combination of an agglomeration technique, i.e. extrusion, and a shaping technique, i.e. the spheronisation. Said patent application actually teaches the formation of microgranulates containing &bgr;-cyclodextrin (Kleptose®) and microcrystalline cellulose (Avicel®) and as active ingredients ketoprofen and paracetamol. The extrusion technique used in the above-mentioned patent application consists in preforming a humid mass by forcing said human mass through a nozzle thus forming long strands of extruded material. The document does not mention melt-extrusion at all.
EP 0,665,009, published as international application on Apr. 24, 1994, discloses a method of dislocating the crystalline condition of crystalline medicine by extruding said crystalline material as such, i.e. without any excipient such as cyclodextrins. In J. Pharm. Pharmacolog., vol 44, No 2, pages 73-8, Uekama et al show how amorphous nifedipine powders were prepared by spray-drying with hydroxypropyl-&bgr;-cyclodextrins. The document does not mention melt-extrusion.
In Pharm. Weekbl. Sci. Ed., 1988, vol 10, No 2, page(s) 80-85, Van Doorne et al, the complex formation between &bgr;-cyclodextrins and six antimicotic imidazole derivatives was studied. In said study gels and creams comprising antimicotics were prepared whereby a 1.8% solution of &bgr;-cyclodextrin was added instead of purified water. There is no mentioning of extrusion at all. In J. Antimicrob. Chemother., 1993, vol 32, No 3, pages 459-463, Hostetler et al describe the effect of hydroxypropyl-&bgr;-cyclodextrin on the efficacy of oral itraconazole in disseminated murine cryptococcosis. In said document the authors describe how itraconazole is solubilized in hydroxypropyl-&bgr;-cyclodextrin resulting in a 100 ml solution. There is no mentioning at all of an extrusion process. In Jpn. J. Med. Mycol., 1994, vol 35, No 3, page 263-267, Mikami et al describe the effect of carrier solvents on the efficacy of oral itraconazole therapy in aspergilossis in mice. Again this document discloses itraconazole being solubilized in hydroxypropyl-&bgr;-cyclodextrin. There is no mentioning of extrusion techniques.
In “Effect of 2-Hydroxypropyl-&bgr;-cyclodextrin on Crystallization and Polymorphic Transition of Nifedipine in Solid State”, Pharmaceutical research, vol 11, No 12, 1994, Uekama et al. describe a glassy mixture of 2-hydroxypropyl-&bgr;-cyclodextrin obtained by heating said mixture and immediately cooling said mixture to 0 degrees Celsius. There is no teaching that this mixture can be extruded.
U.S. Pat. No. 5,009,900 describe glassy matrices that are useful for introducing and/or retaining and/or stabilizing the volatile and/or labile components in cooked and uncooked food products. These glassy matrices comprise chemically modified starch having a dextrose equivalent not greater than about 2; maltodextrin, corn syrup solids or a polydextrose, and a mono- or disaccharide. The document does disclose extrusion to form glassy matrices. However, there is no specific mentioning of cyclodextrins and of therapeutically or pharmaceutically active ingredients.
None of the above mentioned documents disclose the present invention.
Although WO 94/11031 and French patent application 2,705,677 disclose extrusion of mixtures of cyclodextrins and actives ingredients, said documents do not mention the use of meltextrusion. The technique described in WO 94/11031 and French patent application 2,705,677 has a main disadvantage, that a humid mass needs to be prepared which requires adding to the cyclodextrin and the active ingredient a certain amount of water and in most cases others solvents such as ethanol or methanol. Removing the water and/or other solvents is often a troublesome production step, which often leads to irreproducibiity because not all of the solvent can be removed. Moreover, with practically insoluble active ingredients the amounts of water and/or adjuvant solvents needed make the above technique unpractical on a production scale. Another disadvantage of the technique described in the prior art is that the drying step can induce unwanted crystallization of the active ingredient.
These problems are solved in the present invention by the use of a melt-extrusion process to form solid mixtures comprising one or more cyclodextrins and insoluble active ingredients.
The present process is advantageously applicable when said active ingredient is sensitive to a solvent such as water or an organic solvent, because it does not require any solvent. The term “sensitive” used herein means that the active ingredient is readily (e.g. within about one hour) influenced by a solvent to such an extent that its physical, chemical and/or biological properties are substantially modified or changed.
The present process is further advantageous because it does not require a drying step, during which insoluble active ingredients often tend to crystallize.
The term “insoluble” hereinabove and hereinunder refers to three categories of compounds, i.e. the “very slightly soluble”, “practically insoluble” and “insoluble”.
The terms “very slightly soluble”, “practically insoluble” or “insoluble” are to be understood as defined in the United States Pharmacopeia 23, NF 18 (1995) page 7, i.e. a “very slightly soluble” compound requires from 1000 to 10,000 parts of solvent for 1 part of solute; a “practically insoluble” or “insoluble” compound requires more than 10,000 parts of solvent for 1 part of solute. The solute referred to in these cases are water or aqueous solutions.
Three examples of this type of insoluble compounds are: itraconazole, loviride and (±)-ethyl (R*,R*)-4-[5-[1-[1-[(4-chlorophenyl)hydroxymethyl]propyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]-2-pyridinyl]-1-piperazinecarboxylate (hereinafter referred to as compound 1).
Itraconazole is an art-known antifungal. Loviride is an art-known anti-retrovirally active compound, particularly useful in treating HIV-infected patients. (±)-Ethyl (R*,R*)-4-[5-[1-[1-[(4-chlorophenyl) hydroxymethyopyl]propyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol4-yl]-2-pyridinyl]-1-piperazinecarboxylate is described as compound No. 3, in WO 95/27704 published on Oct. 19, 1995.
The compounds that are suitable to be used in this technique are compounds that show no appreciable decomposition at the temperatures needed to melt and extrude the mixture of said one or more active ingredients with the cyclodextrin or cyclodextrins.
The term “active ingredient” further refers to compounds or mixtures of compounds which are pharmaceutically or therapeutically or cosmetically active for treating humans or animals.
The present invention provides a process for preparing a solid mixture comprising one or more cyclodextrins and an (insoluble) active ingredient, comprising a melt-extrusion step wherein one or more cyclodextrins are combined with the one or more active ingredients.
Melt-extrusion is a polymer extrusion t

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