Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2000-01-21
2002-02-12
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S484000, C424S400000, C514S772200
Reexamination Certificate
active
06346273
ABSTRACT:
The present invention concerns a process for solubilizing pharmaceutically active ingredients in water and in aqueous vehicles. More specifically, this invention relates to a working procedure by means of which it is possible to remarkably increase the water-solubility of pharmaceutically active organic compounds that are intrinsically sparingly or negligibly water-soluble, so as to obtain preparations stable in aqueous solution having therapeutically and commercially useful concentrations of active ingredient.
As it is known, the poor water-solubility that characterizes many pharmaceutically active substances often results in major difficulties in the formulation, particularly in the event that easily sterilizable and administrable homogeneous aqueous solutions are desired. This particularly occurs in the fields of liquid preparations for topical ophthalmic, rhinologic, otologic, gynecologic, dermatologic use and for use on the oral mucous membranes, but it may also occur in the field of compositions for systemic administration, in particular parenteral administration (i.e. injectable solutions).
Considering specifically the ophthalmic field, it is known that there are many active ingredients sparingly soluble in water which would be extremely advantageous and effective if they could be topically administered in the form of eye-drops, or the effectiveness or ease of application of which would be increased if the concentration of the existing preparations could be increased. By way of example, there may be cited antiglaucoma agents (forskolin, dapiprazole), anti-cataract agents (tolrestat), non-steroidal anti-inflammatory drugs (piroxicam), steroidal anti-inflammatory drugs (formocortal), glucoside vasoprotective agents (rutin), fluoro-quinolone antibacterial drugs (rufloxacin), antibiotics (amphotericin B). In all of the preceding cases, the water-solutility of the active ingredient is so slight that the marketing of ophthalmic solutions based on the said actives is made impossible or unprofitable, or that the concentrations of the producible preparations are drastically limited. For instance, toirestat has been shown to be remarkably active in inhibiting aldose reductase, and this makes it quite interesting as an anticataract agent. It would be extremely useful if tolrestat could be employed in topical ophthalmic preparations rather than by systemic administration, since this would considerably reduce its side effects. The latter, on thecontrary, are not totally negligible when the product is administered systemically. Moreover, a topical formulation would enhance the drug distribution in the ocular tissues. However, eye-drop forms of toirestat are not presently on the market, very likely owing to the fact that said active principle is practically insoluble in water (0.75 mg/100 g of water, at 20° C.).
Over the years, various methods for increasing the solubility, and accordingly increasing the ease of formulation and the bioavailability, of sparingly water-soluble drugs have been studied and proposed. All said methods can be classed into one or another of the following groups:
A) chemical modifications:
1) introduction of a ionic or ionizable group;
2) introduction of a group that lowers the melting point;
B) physico-chemical solubilization techniques:
1) micellar solubilization by means of surface-active agents;
2) complexation and formation of solid solutions and suspensions by means of polymers.
The transformation of the active ingredient into a ionic or ionizable derivative (as per A1 above) is a very common solubilization method (see, e.g., S. Yalkowsky e W. Morozowich, in: Drug Design, Vol. 9, E. J. Ariens Ed., Academic Press, New York, 1980; G. L. Amidon et at., in: Design of Biopharmaceutical Properties Through Prodrugs and Analogues, Am. Pharm. Msoc., Washington, 1977, p. 281; N. J. Harper, J. Med. Pharm. Chem., 1, 467 (1959)). If the drug has free hydroxy groups hemisuccinates, phosphates, dimethyl amino acetates, amino acid esters may be formed; if, on this other hand, a carboxy group is available, esters may be formed (with amino acids, choline, dimethyl annmino ethyl alcohol, etc.). The basis of this method lies in the relationship between solubility and pH for weak acids and bases. Said basis is valid only to the point where the total solubility approaches the solubility of the ionic species (i.e. salts) (see S. F. Kramer and G. L. Flynin, J. Pharm. Sci., 61,1896 (1972)).
The method of lowering the melting point (see A2 above) is based on the concept that, in order to be solubilized, the molecules have to league the crystal lattice. Any modification of the molecule that lowers the melting point, and thus reduces the energy of the crystal lattice, tends to increase the solubility thereof in any solvent (see, e.g., N. J. Harper, Progr. Drug Res., 4, 221 (1962)).
More than 3000 scientific publications had as their subject-matter, in the last twenty years, the micellar solubilization of drugs by means of surface-active agents (as per B1 above) (see, e.g., A. T. Florence, “Drug Solubillization in Surfactant Systems” in: “Techniques of Solubilization of Drugs”, S. H. Yalkowsky Ed., Vol. 12, Marcel Dekker,. New York, 1981, pp. 15-89; P. H. Elworthy et al., “Solubilization by SurfaceActive Agents”, Chapman and Hall, London, 1968).
This technique has some limiting factors, such as, for instance: 1) the limited solubilizing ability of the micelles; 2) the possible short term and long term toxicity of surfactants, and 3) the simultaneous solubilization of other components of the formulation, such as preservatives, flavoring agents and dyes, with resulting alteration of the stability and activity. Coming back to the example of tolrestat, the only possibility that appears to have been Found at an experimental level in order to administer the drug as eye-drops is to produce a suspension (1% by weight) of tolrestat in an aqueous solution containing a non-ionic surfactant, i.e. Tween 80 (or polysorbate 80). Such composition could be stored (at 4° C.) for a limited time only, and had to be resuspended by shaking it every time before use. It is apparent that such a solution cannot be proposed for developments at the industrial and commercial level.
The formation of complexes, solid solutions and solid dispersions by means of the use of suitable polymers (as per B2 above) is another class of widely employed methods for increasing the water-solubility of pharmaceutically active substances.
With respect to the formation of solid solutions and suspensions, it is known that in several cases it is possible to increase the solubility of a substance even by means of a simple physical mixture. In such a case the active ingredient is incorporated in a suitable hydrophilic carrier, which increases the solubility and the bioavailability thereof without any particular chemical bonds originating between the drug and the polymer matrix. The difference between a solid solution and a solid dispersion can be defined in terms of the form of the active ingredient in a solid solution the active is present in the amorphous molecular form, while in a dispersion said active is present in a crystalline form, as fine as possible.
Even more widespread and studied is the case where the interaction between polymer and drug is such as to give rise to a true complex, wherein chemical bonds of a noncovalent nature are involved. As complexing polymers employed in the pharmaceutical field there may be cited, inter alia, polyethylene glycols, polypropylene glycols, cyclodextrins, carboxymethylcellulose, polyvinylpyrrolidone (PVP) (see, e.g., T. Higuchi et al., J. Am. Pharm. Ass., Sci. Ed., 43, 393, 398, 456 (1954); ibid., 44, 668 (1955); ibid., 46, 458, 587 (1957); J. L. Lach et al., Drug Standards, 24, 11 (1956); M. Nakano et al., J. Pharm. Sci., 65, 709 (1976)).
Co-precipitation is one of the most widespread methods for the preparation of complexes with increased solubility. By this method the substance and the polymer are dissolved in an organic solvent in which they are both soluble, and the solution is the
Bianchini Pietro
Boldrini Enrico
Giannaccini Boris
Saettone Marco Fabrizio
Di Nola-Baron Liliana
Farmigea S.p.A.
Page Thurman K.
Samuels Gauthier & Stevens
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