Compositions – Miscellaneous
Reexamination Certificate
2000-05-22
2003-01-07
Warden, Jill (Department: 1743)
Compositions
Miscellaneous
C252S182290, C124S029000, C124S042000, C124S058000, C124S060000
Reexamination Certificate
active
06503411
ABSTRACT:
FIELD OF THE INVENTION
This invention is concerned with compositions containing an amorphous phase which comprises a water-soluble or water-swellable material, in an undercooled amorphous form.
BACKGROUND OF THE INVENTION
A glass is defined as an undercooled liquid with a very high viscosity, that is to say at least 10
12
Pa.s.
Normally a glass presents the appearance of a homogeneous, transparent, brittle solid which can be ground or milled to a powder. In a glass, diffusive processes take place at extremely low rates, such as microns per year. Diffusian-limited chemical or biochemical changes including more than one reacting moiety are severely inhibited.
Above a temperature known as the glass transition temperature T
g
, the viscosity drops rapidly and the glass turns into a rubber (which is also an undercooled liquid), then into a deformable plastic which at even higher temperatures turns into a mobile fluid. This invention is concerned with glass forming substances which are hydrophilic and water-soluble or water-swellable so that the water will act as a plasticiser. Many hydrophilic materials, both of a monomeric and a polymeric nature either exist as, or can be converted into, amorphous states which exhibit the glass/rubber transitions characteristic of amorphous macromolecules. They have well defined glass transition temperatures T
g
which depend on the molecular weight and a molecular complexity of the glass forming substance. T
g
is depressed by the addition of diluents. Water is the universal plasticiser for all such hydrophilic materials. Therefore, the glass/rubber transition temperature is adjustable by the addition of water or an aqueous solution.
It is well known to incorporate some form of sugar into a pharmaceutical composition as an excipient. It is also well known to incorporate sugars into compositions containing unstable biological materials which are converted from dilute aqueous solution into dry products by removal of upwards of 99% of water by freeze-drying or evaporative drying from a liquid state.
European Patent 383569 (Inventors: Franks and Hatley) teaches that a variety of carbohydrates are able to stabilize bioproducts against deterioration during drying and thereafter, provided that the preparations are dried to a low residual moisture content, typically 2% by weight, so as to render them into amorphous glasses, with glass transition temperatures lying well above the maximum temperature to which the dried product will be exposed during distribution and storage. It is demonstrated that the glass state ensures long-term stability of so-called labile products, such as isolated enzymes.
When a crystallizable water-soluble material such as a carbohydrate forms an amorphous glass (below the glass transition temperature) or rubber (somewhat above the glass transition temperature) which in either case includes some moisture, the composition is both an undercooled liquid and a supersaturated solution. That is to say it is cooled below the temperature at which crystallization could begin and contains a higher concentration of crystallizable material than a saturated solution. In terms of thermodynamics, such as amorphous composition is a non-equilibrium state with respect to the equilibrium solid, i.e. the crystalline solid state.
An amorphous glassy material, e.g. a glassy carbohydrate therefore relies for its apparent long-term existence on the low probability of crystallization and low rate of crystallization. The actual glass temperature of a mixture depends, among other factors, on the details of its chemical composition and any residual moisture content, with water acting as a plasticiser, depressing the glass temperature. If at any time the glass temperature is exceeded, either by exposure to heat or in consequence of the inadvertent migration of moisture into the product, a carbohydrate excipient may become liable to irreversible phase separation by crystallization. If crystallization occurs, any residual amorphous phase will then be composed of the other components and the moisture, resulting in a major depression of the glass temperature.
Thus, a freeze-dried wholly amorphous preparation, containing 2% of a calcitonin gene-related protein, 95% lactose excipient and 3% residual moisture was found to have a glass temperature of 40° C. When the preparation was heated above this temperature, the lactose crystallised irruptively, leaving a solution phase composed of 40% protein and 60% water. The resulting preparation now exhibited a glass temperature (of the solution phase) lying below −40° C. and had lost its chemical stability at ambient temperature, and its biological activity.
SUMMARY OF THE INVENTION
This invention employs the crystallization of certain sugars from an amorphous solid preparation to raise the glass temperature of the preparation and, hence, to enhance the useful storage stability of the preparation.
The present invention requires a sugar that is able to crystallise in a hydrated form, with water molecules included in the crystalline lattice as so-called water of crystallization. In general such crystalline forms will contain a stoichiometric amount of water, so that the ratio of water molecules to sugar molecules in such crystals will have constant values.
We have appreciated that such crystallization can be utilised to abstract water from an amorphous phase, which is the remainder of the composition and moreover do so to an extent which will raise the glass transition temperature of that phase.
Accordingly, this invention provides the use of a sugar, which is capable of existing as a crystalline hydrate, in a composition having an amorphous undercooled phase containing a water-soluble or water-swellable substance in an amorphous form and also containing moisture, as an agent to dehydrate the amorphous phase by crystallization therefrom, and thereby enhance the glass transition temperature of the residual amorphous phase.
This sugar, capable of crystallizing as a hydrate will be referred to as a “hydratable sugar”. It may serve to raise the glass transition temperature by 5° C. or more, possibly 10° C. or more.
When crystallization occurs, any moisture which is not taken up into the crystals becomes part of the residual amorphous phase. Consequently the amount of hydratable sugar in the composition should be large enough to abstract a high proportion of the water, and thereby achieve a residual amorphous phase with a raised glass temperature compared to that of the composition before crystallization.
The amount of hydratable sugar may be adequate to take all the water into crystals of the hydrate. Alternatively a small amount of water may remain in the residual amorphous phase, but it will generally be required that the amount of this sugar in relation to the total water content of the composition is such that the water content (if any) of the amorphous phase expressed as a percentage by weight of that phase is a smaller percentage than the total water content of the whole composition expressed as a percentage by weight of that whole composition.
Expressed algebraically, such a composition has a total mass m and a total water content w. After crystallization of the sugar, the residual amorphous phase has a mass m′ and this phase has a water content w′ which, as a percentage of the amorphous phase is
w
′
m
′
×
100
%
This percentage is less than
w
m
×
100
%
which is the total water content as a percentage of the total composition.
A suitable minimum quantity of hydratable sugar to incorporate in a formulation can be found by calculation from an estimate of the water content before crystallization and the ratio of sugar to water in the crystalline hydrate. If the water content of the composition before crystallization is too high it may be necessary to reduce this by more effective drying of the composition.
Preferably the amount of hydratable sugar exceeds the amount which would theoretically be required to take up all the moisture from the composit
Aldous Barry John
Auffret Anthony
Franks Felix
Cagan Felissa H.
Cross LaToya I.
Evans Susan T.
Inhale Therapeutic Systems Inc.
Warden Jill
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