Use of sulfoalkyl ether cyclodextrin as a preservative

Abstract

A method of preserving formulations is provided. The method includes the step of including a derivatized cyclodextrin in a formulation capable of sustaining microbial growth. One embodiment of the formulation employs a sulfoalkyl ether cyclodextrin as a preservative and optionally as a solubilizing and complexing agent. A suitable cyclodextrin is the CAPTISOL” brand cyclodextrin (sulfobutyl ether R-cyclodextrin). Whether or not the formulation includes a conventional preservative, the formulation will remain preserved for at least a minimum predetermined period. Specific embodiments of the invention include a carrier, a derivatized cyclodextrin and optionally one or more active agents, one or more water activity-reducing agents, and / or one or more complexation-enhancing agents. The derivatized cyclodextrin reduces the water activity of the formulation. A liquid formulation can be lyophilized or otherwise dried to yield a solid formulation that is optionally reconstitutable.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a method of preserving a formulation by including a sufficient amount of derivatized cyclodextrin in the formulation, and also to preserved formulations containing a derivatized cyclodextrin at least as a preservative in the formulation. BACKGROUND OF THE INVENTION [0002] Preservation of formulations generally involves the use of chemical preservatives to maintain or reduce the amount or concentration of microbes in the formulation below a certain value. In the food, cosmetic and pharmaceutical industries, for example, conventional preservatives are included to inhibit the proliferation of or reduce the rate of proliferation of microbes in the respective products. [0003] Many compounds varying dramatically in structure are known to serve as conventional preservatives. Depending upon the intended application / use of a product, a particular preservative is generally preferred. For example, conventional preservatives for foo...

AI Technical Summary

Benefits of technology

[0033] The present invention seeks to overcome the disadvantages present in known formulations. As such, a derivatized cyclodextrin-based, e.g., sulfoalkyl ether cyclodextrin (SAE-CD)-based, preserved formulation is provided. The present formulation can include any known active agent. The formulation is preserved in terms of its ability to resist microbial contamination, i.e., it has a reduced potential for sustaining bacterial growth as compared to a similar formulation that excludes the SAE-CD and a conventional preservative. The present formulation may provide enhanced solubility and / or enhanced chemical, thermochemical, hydrolytic and / or photochemical stability of the active agent or other ingredients in the formulation. Moreover, the present formulation possesses other physicochemical advantages over other formulations.

[0034] The formulation of the invention includes underivatized cyclodextrin and / or derivatized cyclodextrin in an amount sufficient to reduce the water activity of the formulation to a value below which a target microbe will not be able to grow and / or will be killed. In the absence of a conventional preservative or other agent(s) that enhance(s) or improve(s) the biostatic or biocidal activity of the cyclodextrin, a formulation of the invention will have a water activity (aw) less than about 0.97±0.025. Another biostatic, biocidal, or water activity reducing-agent can be included in the formulation to provide further improved preserving capacity.

[0037] Specific embodiments of the invention include those wherein: 1) the active agent to SAE-CD molar ratio is less than one, about one or greater than one; 2) the SAE-CD is sulfobutyl ether 4-β-CD or sulfobutyl ether 7-β-CD; 3) the SAE-CD is a compound of the formula 1 or a mixture thereof; 4) the formulation further comprises a conventional preservative, an antioxidant, a buffering agent, an acidifying agent, a solubilizing agent, a complexation enhancing agent, saline, an electrolyte, another therapeutic agent, an alkalizing agent, a humectant or a combination thereof; 5) the SAE-CD is present in an amount sufficient to provide a clear solution; 6) the liquid formulation is lyophilized or otherwise dried to form a solid formulation for reconstitution; 7) the formulation comprises at least 4.8±0.5% wt. / vol of SAE-CD to provide biostasis; 8) the formulation comprises more than one active agent, wherein each active agent may or may not complex with the SAE-CD; 8) the formulation comprises an excess, on a molar basis, of SAE-CD; 9) the formulation comprises an excess, on a molar basis, of active agent; 10) the formulation has been purged with an inert gas to remove substantially all of the oxygen contained in the formulation; 11) the formulation further comprises one or more conventional preservatives; 12) at least one active agent present in the formulation has a greater binding with the SAE-CD than does a conventional preservative in the formulation; 13) the water activity of the formulation is less than about 0.97±0.025 as measured according to the procedures detailed herein; 14) the formulation further comprises a liquid carrier other than water; 15) the formulation is a liquid; 16) the formulation is a semi-solid; 17) the formulation is a solid; 18) the formulation has been prepared at a temperature at or above 5° C, at or above 25° C., at or above 35° C., at or above 45° C. or at or above 50° C.; 19) the formulation has been prepared at a temperature approximating ambient temperature; 20) the SAE-CD, or derivatized cyclodextrin, reduces the water activity of the formulation; 21) the formulation comprises at least 25.6±2.5% wt. / vol of SAE-CD to provide biocidal properties; 22) the SAE-CD is present in an amount sufficient to unmask the biocidal or biostatic properties of an active agent, which properties are masked when the active agent is present in another formulation.

[0046] Specific embodiments of the method include those wherein: 1) the formulation is an aqueous formulation and the SAE-CD is present in an amount of at least about 25 % wt. / vol of the formulation for biocidal activity and at least 4.8% w / v for biostasis; 2) the SAE-CD is present as an alkali metal salt; 3) the method further comprises the step of including one or more active agents in the formulation; 4) the method further comprises the step of including one or more conventional preservatives in the formulation; 5) the method further comprises the step of sterilizing the formulation after addition of the SAE-CD and prior to storage of the formulation; 6) the method further comprises the step of including one or more humectants in the formulation; 7) the method further comprises the step of reducing the water activity of the formulation by addition of the SAE-CD; 8) the method further comprises the step of including one or more water activity-reducing agents in the formulation; 9) the formulation has a pH in the range of about 1-11; 10) the water activity of the composition is less than about 0.99 as measured according to the procedures detailed herein; 11) the method further comprises the step of preparing the formulation at a temperature at or above 5° C., at or above 25° C., at or above 35° C., at or above 45° C. or at or above 50° C.; 12) the derivatized cyclodextrin is SAE-CD, HPCD, a water soluble derivatized cyclodextrin capable of reducing the water activity of the composition or a mixture thereof

[0047] The invention also provides a method of reducing the water activity of an aqueous composition, the method comprising the step of including a derivatized cyclodextrin in the aqueous composition at a concentration sufficient to reduce the water activity.

Problems solved by technology

Some pharmaceutical formulations, especially those formulations comprising a medium that sustains microbial growth, are particularly prone to contamination by microbes.

In particular, albumin-based and lipid-based formulations are particularly prone to contamination by microbes and always require a conventional preservative in order to maintain an acceptable shelf life.

Lipid-based emulsion formulations are typically problematic with regard to microbial growth, not only because the lipid components can readily support the growth, but because 0.22 μm or smaller “sterilizing” filters cannot be used.

When cyclodextrin formulations are administered by injection into the blood stream, the complex rapidly dissociates due to the effects of dilution and non-specific binding of the drug to blood and tissue components.

The underivatized parent cyclodextrins are known to interact with human tissues and extract cholesterol and other membrane components, particularly upon accumulation in the kidney tubule cells, leading to toxic and sometimes fatal renal effects.

However, the HP-β-CD still possesses toxicity that the SBE-CD does not.

While CAPTISOL® cyclodextrin is a relatively new but known cyclodextrin, its use as a preservative has not previously been evaluated.

If the formulation being tested induces a significant amount of hemolysis, that formulation will generally be considered unsuitable for administration to a subject.

Cyclodextrins, however, are not generally known for their ability to preserve formulations.

However, since many of the preservatives are poorly soluble in aqueous systems, the complexation can assist in providing constant levels of the preservative in the formulation.

The affect that a cyclodextrin has on the preserving capacity of a known preservative is relatively unpredictable.

In other words, water is still present, however, it is just not readily available to be used for biological processes.

Although artisans have recognized that poly(vinylpyrrolidone) (PVP) and poly (ethylene glycols) can have an impact on the water activity of aqueous solutions, no work has been done to evaluate their water activity in combination with cyclodextrins, or their potential use as a preservative.

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