Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-05-18
2001-06-05
Leary, Louise N. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S002600, C514S053000
Reexamination Certificate
active
06242423
ABSTRACT:
The invention relates to the pharmaceutical and medical field and is aimed at providing a fake version of a medicinal product in its usual pharmaceutical form, but not containing the active principle.
The invention applies most particularly to lyophilized pharmaceutical forms simulating medicinal products containing peptides or proteins obtained by extraction, from animal or human biological fluids, by genetic recombination, by synthesis or modified by directed chemical reactions or by genomic remodeling or by gene transfer.
These decoys can then be used for controlled double-blind clinical studies.
The placing of medicinal products on the market is conditioned by the results obtained by these products in controlled clinical studies, in which the experimenter proposes to measure the therapeutic effects of the active principles under study, relative to a control substance containing no active principle, known as a placebo. This artifice avoids the influence of uncontrollable factors associated with the subjectivity of the observations or the patient's condition. In these studies, a placebo should be offered whose appearance, consistency and observable properties are as close as possible to those of the real medicinal product. The manufacture of such placebos poses great difficulties when the substance to be studied is in the pharmaceutical form of a lyophilizate and when it contains active principles of protein or polypeptide nature.
Specifically, proteins or polypeptides have an amphiphilic nature and modify the surface tension of water, the usual solvent, thus leading to the formation of a layer of foam during the reconstitution of the medicinal product. Furthermore, the macromolecular structure of proteins or peptides gives the lyophilizate a behavior which is visualized in the form of a “cake” of dry, more or less thick substance, enclosed in the bottle. The placebo should contain no active principle; only the usual excipients of the medicinal product under study are permitted, accompanied, where appropriate, by one or more other inert substances.
Hitherto, the difficulties were solved by adding an inert macromolecule such as human albumin or injectable gelatin. The potential risks outlined recently, during the outbreak of neurodegenerative diseases in cattle and due to transmissible agents whose nature is still unknown, have led to these inert macromolecular substances no longer being tolerated in the manufacture of placebo, so that the receiver of the placebo does not incur an unevaluable risk.
There is therefore, in the current state of the art, no means for formulating a fake version of a medicinal product free of active principle of protein or polypeptide nature, which indiscernibly resembles the product containing the active principle.
To overcome this difficulty, it has been found that the consistency of the “cake” of lyophilizate of real product can be limited by lyophilizing a solution of the usual excipient(s) for the product (sugars, mineral salts, amino acids in amorphous form in the solid state) in the presence of an amino acid or a saccharide which is readily crystallizable, added in amounts such that the placebo composition reconstituted after lyophilization remains compatible with the isotonicity required for parenteral, intramuscular or subcutaneous injection or other application (percutaneous or ocular application).
The invention thus relates to a lyophilized pharmaceutical composition intended to imitate a medicinal product, based in particular on proteins or peptides, which is free of medicinal product, and which can serve as a placebo, characterized in that it comprises the usual excipient for said medicinal product, one or more alcohol-sugars in crystalline form and/or one [lacuna] more amino acids in crystalline form.
Generally, the usual excipient for the protein or polypeptide principle is a sugar chosen in particular from the group consisting of oligosaccharides, disaccharides and monosaccharides. Among the preferred monosaccharides are glucose or fructose, alone or as a mixture. Among the preferred disaccharides are sucrose, maltose or lactose, alone or as a mixture.
The usual excipient can also be an alkali metal or alkaline-earth metal salt or mixture of such salts (calcium or sodium citrate, phosphate, glutamate or acetate), one or more amino acids in amorphous form in the solid state, the addition of a suitable amount of crystallizable amino acids making the mixture crystalline in the lyophilized product according to the invention. In the case of placebo medicinal products simulating medicinal products containing peptides or polypeptides, the excipient should comprise no peptide or polypeptide.
The behavior of the dried product can be improved with excipients of high molecular mass: dextran, hydroxyethyl starch, polyethylene glycol, cyclodextrin, which are readily lyophilizable, but which require an addition of salts in order to maintain the osmolarity within acceptable values for parenteral use (particularly when it is a matter of injecting a large volume, from about 50 to 100 ml).
Preferably, the composition has an osmolarity of between 250 and 650 milliosmoles after reconstitution in solution form.
One preparation process consists in mixing together the various ingredients in solution and then in lyophilizing the solution obtained. During the preparation of the solution, the sugars or amino acids are “crystallizable”, and this term will be used hereinbelow in this context. The term “crystalline” or “in crystalline form” is reserved for the finished lyophilized product.
Among the preferred crystallizable alcoholsugars are mannitol, sorbitol or a mixture thereof.
Among the preferred crystallizable amino acids are glycine, alanine, valine, leucine, lysine, glutamic acid, aspartic acid, arginine and histidine. These alcohol-sugars or amino acids crystallize readily during freezing of the starting solution, making it possible to obtain the lyophilized composition.
Furthermore, according to one preferred embodiment of the invention, the presence of nonionic surfactant which is compatible with parenteral use, in small amounts, gives the reconstituted placebo a foaming behavior which is comparable to that of the real product.
Among the nonionic surfactants which are mentioned are polysorbate, octoxynol, polyoxyethylenic alcohols or polyoxyethylenic esters of fatty acids. Mention is made in particular of Tween® 80.
Finally, in order to simulate the colloidal aspect of the real protein solution, it has been found that the controlled addition of a pharmaceutically acceptable metabolizable oil, or of an emulsified hydrolipidic compound, in small amounts gives a Tyndall effect which is comparable to that of the real product.
The expression “Tyndall effect” means the scattering of white light in the solution of macromolecules due to the light/protein interaction, giving this type of solution the “colloidal” aspect, which is a reflection of its polydispersity. Among the pharmaceutically acceptable oils which are mentioned are olive oil, corn oil, sunflower oil, soybean oil, castor oil, squalene or &agr;-tocopherol. These oils are compatible with the parenteral route.
A typical emulsion of injectable lipids for parenteral administration can also be used (Intralipide®).
Certain proteins at high concentration have a slightly yellow to brown color. The placebos obtained according to the invention can simulate this color by addition of pharmaceutically acceptable colorants or by adding specific mixtures obtained by the Maillard reaction between a reducing sugar and an amino acid. Depending on the sugar and the amino acid chosen, the shades range from pale yellow to dark brown.
The compositions below are given from the process of preparation in solution (which step will be followed by the lyophilization). The proportions of the dried composition can readily be deduced from the solutions.
According to one preferred embodiment, the composition is characterized in that it can be obtained from a starting solution comprising, as a percentage by weigh
Bardat Annie
Schmitthauesler Roland
Foley & Lardner
Laboratoire Francais du Fractionnement et des Biotechnologies
Leary Louise N.
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