Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-01-11
2003-08-26
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S428000, C424S429000, C424S400000, C424S401000
Reexamination Certificate
active
06610318
ABSTRACT:
This application is a 371 of PCT/EP96/00697 filed Feb. 20, 1996.
The invention relates to a sterile ophthalmic gel preparation that can be Applied in drop form, especially for use as an artificial tear fluid and for the treatment of “dry eye”, as well as to a method for the production of such a gel preparation.
It has been known for some time to use aqueous preparations to replace natural tear fluid and to treat “dry eye”, which aqueous preparations e.g. contain film-building materials based on polyvinylalcohol (PVOH), polyvinylpyrrolidone (PVP), cellulose derivatives or dextrane. An overview can e.g. be found in Sucker, Fuchs und Speiser, “Pharmazeutische Technologie” 1978. These are generally systems which only have one fluid or liquid phase, typically an aqueous solution of further components.
Where components are present which are difficult to dissolve in water or which are water-insoluble, these are suspended as solids, in finally divided form, in the aqueous phase.
In semisynthetic preparations, such as e.g. those based on cellulose derivatives or dextrane, production is made more difficult by the fact that such materials are difficult to obtain free of insoluble components. One therefore has to incur very high expenditure in preparing solutions from such preparations which do not lead to eye irritation caused by mechanical effects. Further, such preparations are very difficult to sterilize, since they can only with great difficulty, or not at all, be filtered to remove germs, and they can also not be autoclaved without deteriation in quality. Cellulose derivatives cannot be autoclaved without irreversible changes in viscosity. Dextrane preparations are partly decomposed by autoclaving.
Also polyvinylalcohol can only be sterilized by heating if a very pure hydrolized form is employed since otherwise the PVOH component is depolymerized. Since PVOH as well as PVP only provide relatively little thickening effect, rather high amounts of these components must be used to provide suitable viscosities. This leads to a very high load of the ophthalmological preparation with such materials, e.g. contents of more than 10% in the case of PVOH.
It is already known from DE 34 40 352 and DE 43 03 818, and also from U.S. Pat. No. 5,252,318, to use polyacrylic acid and its derivatives, such as e.g. Carbopole® 940 (obtainable from B. F. Goodrich Company) as the gel basis for sterile ophthalmic gel drop preparations. In U.S. Pat. No. 5,441,732, which was only published after the priority date of the instant application, a combination of two specific gel components is disclosed, one of which is gelled thermally, whereas the other is gelled by a change in pH. Various cellulose derivatives are described as the thermally reactive gel polymer, whereas polyacrylates, especially cross-linked polyadrylates, are mentioned as polymers gelling in dependance of the pH value. It appears that gel formation is intended to only occur in the eye, by the pH change after application to the eye. It is stated that these-polymer mixtures are to be used together with organic oils, wherein a multiplicity of active agents can be dissolved. Vitamine A is not mentioned.
With respect to compliance, non-irritation, shelf life etc., very high-standards must be met by ophthalmic preparations which are to be used as film-forming preparations or lubricating preparations. Especially where ophthalmic preparations must be used for any extended period of time, which e.g. is regularly the case in the treatment of “dry eye”, even a temporary irritation, such as a burning sensation in the eye is an extremely unpleasant sensation, and is detrimental to any extended therapeutical treatment. It is self-understood that in the application of such ophthalmic preparations, impaired sight, blurred view or other acute irritations cannot be accepted.
In “dry eye” treatment, the use of vitamine A, generally in the form of vitamine A palmitate, has proven to be effective. Thus, gel drop preparations on Carbopol basis have been-commercialized (after the priority date of the instant application), which besides other customary components contain vitamine A palmitate. These are one-phase gels with a continuous aqueous liquid phase, and without any hydrophobic second liquid phase. These products have a shelf life of about a year, when the vitamine A component is provided in an excess of 40%. As trials have shown, the vitamine A content decreases by about 20% over six months in these preparations, so that at a 40% excess dosage, the guaranteed minimum content is still present after one year.
Natural tear fluid comprises inter alia a fatty component which comprises triglycerides and phospholipides. It has already been tried (WO 94/05298), to use triglycerides in synthetic tear liquids, which was, however, only possible when an emulgator was added, and the overall preparation was in the form of an emulsion, for topical application to the eye. This has the disadvantage that desirable residual amounts of natural tear fluid in the eye are destroyed by the emulgator component.
It is an important object of this invention-to provide ophthalmic preparations, especially gel preparations, which show an improved shelf life, especially when containing sensitive substances such as vitamine A and its derivatives.
It is a further important object of the invention to provide such preparations which do not cause acute irritations and impaired vision, especially when formulated for increased shelf life.
It is a further very important object of this invention to provide such preparations which make it possible to use the preparation repeatedly over an extended time period, and/or enable extended duration in the eye after each individual application without causing incompatibilities, lack of compliance, irritation to the eye and other such problems. The invention is based on various surprising findings.
On the one hand, it has surprisingly been found that relatively fast decomposition of vitamine A and its derivatives, especially vitamine A palmitate, in artificial tear fluids and preparations for “dry eye” treatment can be dramatically reduced when the preparation is in the form of a two component system with one aqueous liquid phase and one hydrophobic liquid phase. Especially it is preferred herein that the preparation-has a continuous aqueousphase wherein the hydrophobic liquid oil phase is provided in the form of very finely divided droplets. There is no easy explanation for this fact. Most probably, oxygen and/or light are responsible for the decomposition of vitamine A, and with respect to both, it should not make any material difference whether the preparation comprises one or two separate liquid phases. One would rather expect an increased, sensitivity with respect to oxygen and/or light in a solution of the vitamine A component in the hydrophobic phase.
Possibly, the simultaneous use of antioxidants, especially vitamine E and its derivatives and most specifically vitamine E acetate has an influence in these preparations. In any case, vitamine A is preferably used with such antioxidants in the inventive preparations.
On the other hand, a further surprising effect of the invention is that it makes it possible to prepare preparations with an aqueous and a liquid hydrophobic phase which come very close to the composition of natural tear liquid, and especially have a corresponding content of triglycerides, without any necessity of at the same time using emulgators. This is possible since according to the invention, such preparations are in the form of gel drop preparations. In contrast to preparations without any gel basis, triglycerides can be provided in the inventive gel preparations in the form of very finely divided droplets also over very extended storage periods, with the droplets being sufficiently stable in the gel even in the absence of any emulgator. It is possible without any problems to prepare such preparations so that they are sterile, and the preparations are not irritating and perfectly acceptable.
The inventive preparations, including gel prep
Bellmann Gunther
Claus-Herz Gudrun
Reimer Hevia Cornelia
Bausch & Lomb Incorporated
Bennett Rachel M.
Page Thurman K.
Thomas John E.
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