WO2006000913A1

WO2006000913A1 - Method for sterile filtration of viscous pharmaceutical compositions

Info

Publication number: WO2006000913A1
Application number: PCT/IB2005/002076
Authority: WO
Inventors: Julieanne Patricia Sees
Original assignee: Pfizer Products Inc.
Priority date: 2004-06-23
Filing date: 2005-06-13
Publication date: 2006-01-05

Abstract

The invention is directed to a method of using a volatile co-solvent to lower the viscosity of pharmaceutical compositions, for example those comprising a ziprasidone: sulfonyl butyl ether cyclodextrin complex, so as to facilitate sterile filtration, without permanently altering the properties of the pharmaceutical composition or its active ingredient. After the filtration the co-solvent is removed by evaporation. The invention also covers a mixture comprising ziprasidone or pharmaceutically acceptable salt thereof complexed with cyclodextrin in water containing from 1 to 30% ethanol by volume.

Description

METHOD FOR STERILE FILTRATION OF VISCOUS PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION This invention relates to a method of carrying out a sterile filtration on a viscous pharmaceutical formulation. The method involves reducing the viscosity of the formulation by adding a co-solvent to the formulation; sterile filtration; and removal of the co-solvent. The method is especially useful for those formulations whose viscosity make filtration difficult. The method is useful also when the active ingredient of the composition is complexed with a cyclodextrin. BACKGROUND OF THE INVENTION Drug sterility is crucial in the pharmaceutical industry. Production of a sterile pharmaceutical product is often a technically challenging task. Five techniques are currently in common use for pharmaceutical formulations: wet steam (autoclaving), dry heat, irradiation, ethylene oxide treatment, and sterile filtration. All of these methods have deficiencies or limitations. Because the first two methods involve a high heat, only thermally stable materials or products can be sterilized by these methods. Additionally, in the case of a viscous pharmaceutical formulation, heat often alters the physical attributes of the formulation by altering flocculation, sedimentation, and re-dispersion characteristics of any suspended particles. In many cases heat affects the homogeneity or uniformity of the final product either by catalyzing the formation of loose agglomerations called "curds," or, if the curds become compacted and fuse, "cakes" of suspended particles are produced. Curds and cakes hamper the caregiver's ability to re-suspend the product easily and to provide uniform dosing. The radiation technique is less commonly used today because of possible degradative impact on the pharmaceutical components, as well as concerns for human exposure to radiation. Currently, only packaging components, such as plastic and paper sheets, bottles, and caps, are sterilized by this method. The ethylene oxide method has been a widely used method for viscous pharmaceutical formulation products where product or components are degraded by heat treatment. However, this technique requires the elimination of residual ethylene oxide from the product, and this removal is difficult and time-consuming. Most products sterilized by this method were introduced in the market decades ago; current stringent regulatory requirements for nearly zero ethylene oxide residue would probably prevent the introduction of such products today. The sterile filtration method avoids the principal disadvantages of the other sterilization methods. This method involves passage through a membrane of sufficiently small pore size to retain bacteria. Such membranes typically have pore sizes in the sub- micron range. The standard size for this purpose is 0.22 μm. Filtration through a membrane of this diameter causes minimal degradation of most pharmaceutical products, including those that are highly sensitive to heat or radiation treatments. Moreover, filtration is technically easy and leaves no residue requiring removal. As a result, the sterile filtration method has been widely applied to pharmaceutical solutions. A significant drawback of the sterile filtration method, well known in the art, is that this technique cannot be utilized for higher viscosity solutions, since these do not pass easily through the standard 0.22 μm filter. Therefore, sterile filtration has heretofore not been available in the case of viscous solutions. Depot formulations, whose typically high viscosity has made filtration through the standard 0.22 μm filter impracticable, have until now required alternative methods of sterilization. The development of a sterile filtration method for depot formulations fills a long-felt need in the art. The present invention overcomes the shortcomings of the prior art need for a method of sterile filtration of viscous solutions. The invention is directed to a method for sterilizing pharmaceutical formulations that have until now been too viscous for sterile filtration. The present invention has surprisingly determined that a volatile solvent can be added to a viscous solution, filtered, followed by removal of the solvent while retaining the constituency of the composition and complexes therein. The present method was developed for a depot formulation, such as a ziprasidone:SBECD depot formulation, with the objectives of i) reducing the viscosity of the solution sufficiently to allow sterile filtration and ii) allowing generation of the solution with a ziprasidone: SBECD complex in the same form as before addition of the co-solvent. The ziprasidone depot formulation is a complex of ziprasidone or a ziprasidone salt with a cyclodextrin, such as sulfonyl butyl ether cyclodextrin (SBECD) or hydroxypropyl β cyclodextrin (HPBCD). Such complexes were disclosed by Kim et al., U.S. Patent No. 6,232,304, issued May 15, 2001 , and U.S. Patent No. 6,399,777, issued June 4, 2002, which are hereby incorporated by reference in their respective entireties. Hereinafter, compositions of matter comprising a cyclodextrin and a drug or salt thereof are denoted analogously to "ziprasidone:SBECD." SUMMARY OF THE INVENTION This invention is directed to a method for sterilizing a viscous liquid pharmaceutical formulation by adding a volatile co-solvent to the viscous pharmaceutical formulation in an amount sufficient to reduce the viscosity sufficiently for the resulting solution to pass through a filter; filtering the resulting solution through a membrane designed to retain bacteria; and removing the volatile co-solvent. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the results of circular dichroism measurements on solutions of the ziprasidone: SBECD complex before addition of ethanol and after ethanol had been added and then evaporated. The black spectrum represents a continuous scan from 380 nm to 270 nm of a ziprasidone:SBECD solution while the gray spectrum reflects the scan of the solution with an addition of 30% v/v ethanol, which was then removed by evaporation. Upon testing, solutions of ziprasidone:SBECD were diluted with water to yield a 0.6 mM ziprasidone:SBECD solution. DETAILED DESCRIPTION OF THE INVENTION This invention is directed to a method for sterilizing a viscous pharmaceutical formulation, comprising adding a volatile co-solvent to a viscous solution in sufficient amount to reduce the viscosity of the solution so that the solution can be passed through a membrane filter designed to retain bacteria; filtering the resulting solution through the membrane filter to produce a filtrate; and removing the volatile co-solvent from the resulting filtrate. As used herein, the term "viscous" refers to a solution or dispersion in which the internal resistance to flow is so high that filtration is difficult or impossible. The viscosity can be as high as 105 centipoise (cp) or higher. In one embodiment the viscosity is at least about 90 to about 95 cp. In another embodiment the viscosity is at least about 40 cp. In still another embodiment the viscosity is at least above the viscosity of water, i.e., above about 1.0 cp. As used herein, the term "pharmaceutical formulation" is a pharmaceutical composition comprising a drug as an active component and, optionally, a pharmaceutical carrier. The pharmaceutical composition is in liquid form. The pharmaceutical composition contains a predetermined amount of the drug. The preferred drug is an aryl heterocyclic compound, as defined in copending application serial no. 60/421 ,295 filed October 25, 2002 entitled "DEPOT FORMULATION IN THE FORM OF A SUSPENSION", the contents of which are incorporated herein by reference. In a preferred embodiment, the drug has the structure:

or one of its pharmaceutically acceptable salts; wherein Ar is benzoisothiazolyl or an oxide or dioxide thereof, each optionally substituted by halo, trifluoromethyl, lower alkoxy, cyano or nitro, n is 1 or 2; and X and Y together with the phenyl to which they are attached form benzothiazolyl, 2- aminobenzothiazolyl, benzoisothiazolyl, indazolyl, 3-hydroxyindazolyl, indolyl, oxindolyl, benzoxazolyl, 2-aminobenzoxazolyl, benzothiazolyl, benzimidazolonyl or benzothiazolyl which groups may be unsubstituted or substituted by one to three substituents selected from the group consisting of halo, lower alkyl, lower alkoxy amino, lower alkylamino, di-lower alkylamino, trifluoromethyl, and hydroxy. Preferably, the aryl heterocyclic compound is an arylpiperazinyl-ethylene (or butylene)-heterocyclic compound. Representative examples are found in U.S. Patent No. 4,831 ,031 , which is incorporated herein by reference. The most preferred drug is ziprasidone or a pharmaceutically acceptable salt thereof. The heterocyclic compound can be present as the free base or it may be present as a pharmaceutically acceptable salt. The salts can be anhydrous or in the form of one or more solvates, such as hydrates or mixtures thereof. The drug including its salts can be present in various polymorphic forms. Examples of salts include hydrochloride, tosylate, tartrate, napsylate, besylate, aspartate, and especially the mesylate form. As used herein, a "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. The pharmaceutical composition used for sterilization is associated with a pharmaceutically acceptable liquid vehicle or diluent. Once sterilized, the pharmaceutical composition can be administered orally or parenterally, including intravenously or intramuscularly. Alternatively, it can be subjected to further processing such as lyophilization. Suitable pharmaceutical carriers include pharmaceutically acceptable aqueous solutions or organic solvents. When aqueous suspensions or elixirs are desired for oral administration, the drug can be combined with various sweetening or flavoring agents, coloring matter, or dyes and, if desired, emulsifying or suspending agents, together with diluents, such as water, ethanol, propylene glycol, glycerin or combinations thereof. When capsules or tablets are desired for oral administration, the lyophilized drug can be combined with suitable carriers, excipients, and the like. For parenteral administration, a solution or suspension of the drug in vegetable oil, such as sesame or peanut oil or aqueous propylene glycol or aqueous solutions is preferred. Such aqueous solution should be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose solution. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The aqueous media employed are all readily available by standard techniques known to those skilled in the art. Some drugs, such as ziprasidone, are poorly soluble in a liquid pharmaceutical carrier. In accordance with the present invention, such drugs can be associated with a solubilizer. For example, ziprasidone is preferably solubilized by complexation with a cyclodextrin. Another drug that is solubilized by complexation with a cyclodextrin is voriconazole. Voriconazole is described in U.S. Patent No. 6,583,136, incorporated herein by reference, and its complexation with cyclodextrins is described in U.S. Patent No. 6,387,906, incorporated herein by reference. The preferred solubilizer is a cyclodextrin. Cyclodextrins are cyclic oligosaccharides with hydroxyl groups on the outer surface and a void cavity in the center. The outer surface is usually hydrophilic; hence, cyclodextrins are soluble in water. On the other hand, the cavity is typically hydrophobic. Cyclodextrins have the ability to form complexes with guest molecules, such as ziprasidone. Cyclodextrins contemplated by the invention include, without limitation, the following: α, β, γ-cyclodextrins, methylated cyclodextrins, hydroxypropyl-β-cyclodextrin (HPBCD), hydroxyethyl-β-cyclodextrin (HEBCD), branched cyclodextrins, and sulfoalkyl ether cyclodextrins, such as sulfobutyl ether-β-cyclodextrins, dihydropropyl cyclodextrins, and sulfoalkyl ether cyclodextrins, such as sulfobutyl ether-β-cyclodextrin (SBECD). The cyclodextrins can be unsubstituted or substituted in whole or in part as known in the art; mixtures of cyclodextrins are also useable in accordance with the present invention. The preferred cyclodextrins for the depot formulation of the invention include γ-cyclodextrin, HPBCD, SBECD or mixtures thereof; SBECD being most preferred. In the first step of the present invention, the viscous pharmaceutical composition is mixed with a co-solvent in sufficient quantities to reduce the viscosity so that it can pass through a filter having a pore size as low as about 0.45 μm. More preferably the viscosity is sufficiently reduced to pass through a filter with pore size as low as about 0.22 μm. Such filters are available from numerous vendors, for example Whatman Ltd. of Kent, UK and Clifton, NJ and Millipore, Inc. of Billerica, MA. Alternatively, passage through a filter with pore size of less than about 0.12 μm is contemplated. The co-solvent must be one that does not react with any component of the pharmaceutical carrier and one in which the pharmaceutical composition is soluble. Preferably the co-solvent is both readily obtainable in substantially pure form and of low toxicity. Preferably the co-solvent is ethanol. Most preferably the co-solvent is 95% ethanol, which contains 5% water by volume. The amount of co-solvent added to the pharmaceutical composition is such as to be effective in reducing the viscosity of the pharmaceutical composition sufficiently to facilitate filtration through a sterilizing membrane. Preferably, the amount of co-solvent added is sufficient to reduce the viscosity of the pharmaceutical formulation to a value ranging from about 5 cp to about 130 cp and more preferably from about 15 cp to about 60 cp and most preferably from about 30 cp to about 50 cp. It is preferred that the resultant concentration of the co-solvent in the solution comprising the co-solvent and pharmaceutical composition be in the range of about 1% to about 45% by volume. It is more preferred that the concentration of the co-solvent be in the range of about 5% to about 35% by volume. Most preferably, the concentration of the co-solvent is in the range of about 10% to about 30% by volume. In another embodiment, the co-solvent is isopropanol. In the second step of the present invention, once the viscosity is reduced, the solution is passed through an anti-microbial sterilizing filtration apparatus used to remove bacteria from solution. The size of the pores of the filter must be large enough to permit the passage of the pharmaceutical composition but small enough to prevent the passage of bacteria. The filter used is an anti-microbial or antibacterial filter known in the art which is impermeable to contaminants and bacteria and viruses that may be present in the pharmaceutical formulation but permeable to the remainder of the components therein. Preferably such filter is formed from a thin sheet of microporous filtration material. Preferably, the filtration material is a sterilizable grade having a uniform pore size of about 0.22 μm or less. Typical filtration materials made of mixed esters of cellulose of this grade are approximately 80% porous, have a bubble point of approximately 55 psi, are autoclavable and have a water flow rate of about 15 ml/min per square centimeter of filtration area at 25⁰C with a differential pressure of about 10 psi. A typical thickness for such a filter sheet is about 150 to about 200 μm. When properly supported this grade of filtration can withstand high pressure differential. Although a pore size of 0.22 μm is preferred, smaller pore sizes will also sterilize the flow being filtered but with correspondingly higher applied pressure differentials and reduced flow rate. An example of a filtration apparatus that may be used in the process of the present invention is described in U.S. Patent No. 4,101 ,423, the contents of which are incorporated by reference herein. In the third step of this invention, the co-solvent is removed from the solution, preferably by a technique known to one of ordinary skill in the art. The most preferred technique is by evaporation. After sterilization, the pharmaceutical formulation is charged into a container. The container can be subsequently enclosed for packaging, such as vial, ampoule, bottle and the like to make a filling solution. As used herein, the term "filling solution" or fill solution or a synonym thereof is a solution of the pharmaceutical formulation described hereinabove administered with water or another carrier containing saline or dextrose placed into the container. The container can be a bottle, ampoule or vial or any other container used for parenteral administration of the drug. For example, the pharmaceutical formulation can consist of a sterile ampoule or vial or bottle containing the drug in a known weight amount and mixed together with sufficient sterile dextrose or sodium chloride so that on dissolution in sterile water, a sterile solution of the active ingredient is associated with isotonic dextrose or saline solution. The pharmaceutical formulation is preferably freeze-dried. In a preferred embodiment, the container contains a predetermined amount of the sterile filtered pharmaceutical formulation as prepared hereinabove. Particularly convenient containers of such compositions are ampoules or vials containing from about 2 to 100 mg and preferably from about 40 to 80 mg of sterile active ingredient, optionally mixed with sterile dextrose or sodium chloride in an amount calculated to provide a solution for injection containing up to about 5% w/v of dextrose and/or up to about 0.9% w/v sodium chloride after dilution with sterile water. In one embodiment, a solution of ziprasidone:SBECD is sterilized by addition of up to about 30% v/v ethanol, followed by sterile filtration through a 0.22 μm filter, followed by evaporation of the ethanol from the filtrate. In another embodiment of the invention, a solution of ziprasidone: SBECD in sterile water or saline solution suitable for injection is diluted by addition of up to about 30% v/v ethanol, followed by sterile filtration through a 0.22 μm filter, followed by evaporation of the ethanol from the filtrate. In another embodiment of the invention, a solution of ziprasidone: SBECD in sterile water or saline solution suitable for injection is diluted by addition of up to about 30% v/v ethanol, followed by sterile filtration through a 0.45 μm filter, followed by evaporation of the ethanol from the filtrate. In another embodiment of the invention, a viscous pharmaceutical formulation of a medicament other than ziprasidone is sterilized by dilution by addition of up to about 30% v/v ethanol, followed by sterile filtration through a 0.22 μm filter, followed by evaporation of the ethanol from the filtrate. In another embodiment of the invention, a viscous pharmaceutical formulation of a medicament other than ziprasidone is sterilized by dilution by addition of up to about 30% v/v isopropanol, followed by sterile filtration through a 0.22 μm filter, followed by evaporation of the ethanol from the filtrate. As used herein, a depot formulation is a long-acting drug delivery system, as is well known in the pharmaceutical arts. A depot formulation is especially formulated to provide slow absorption of a drug; such formulations often maintain steady therapeutic levels for several days to several weeks. Depot formulations reduce patient decision-making and, consequently, also reduce the risk of non-compliance. Depot formulations are particularly well-suited for the administration of antipsychotic drugs to psychiatric patients. As used herein, a suspension is a system in which very small particles are more or less uniformly distributed throughout a liquid medium. Such distribution can be effected through various means, including mild agitation, sonication, and vortexing, among numerous methods. In the context of the present invention, a suspension includes a viscous pharmaceutical solution or formulation. As used herein, a volatile co-solvent is a liquid that is miscible with water and that is readily removable by evaporation under conditions of temperature and pressure that do not significantly affect the other components of the particular mixture. As used herein, the concentration unit "mgA/ml" refers to the number of milligrams of active ingredient per milliliter of solution or other liquid formulation, e.g. suspension. In particular, when associated with ziprasidone, a pharmaceutically acceptable salt of ziprasidone, or a complex of ziprasidone with a cyclodextrin, e.g. SBECD, "mgA/ml" refers to the mass in milligrams of ziprasidone free base per milliliter of solution. As used herein, ziprasidone:SBECD denotes a composition of matter comprising sulfonyl butyl ether-β-cyclodextrin and ziprasidone or salt thereof. As used herein, "ziprasidone:HPBCD" denotes a composition of matter comprising hydroxypropyl β- cyclodextrin and ziprasidone or salt thereof. As used herein, sterilization refers to the removal of viable forms of microorganisms. In accordance with the present invention, a solution was prepared containing ziprasidone mesylate, 80 mgA/mL, and 56% sulfonyl butyl ether cyclodextrin (SBECD) in sterile water for injection (B.Braun Medical Inc. catalog #NDC926409200-55). Ethanol was added in amounts up to 30% by volume to determine effects on viscosity and filtration feasibility. The density of the solution of the ziprasidone:SBECD, determined by pycnometry, was 1.297+ 0.0904 g/mL. The glass transition temperature of the pre-lyophilization solution of ziprasidone:SBECD was evaluated using Differential Scanning Calorimetry (DSC), with heating and cooling rates set at 5°C/min. The viscosity of the pre-lyophilization solution of ziprasidone:SBECD was determined using Advanced Rheometry. A continuous ramp test of shear stress from 0.1 Pa to 100.0 Pa at 25°C was performed on the pre-lyophilization solution of ziprasidone:SBECD and on the pre-lyophilization solution + 30% ethanol by volume. The ellipticity and absorbance of the pre-lyophilization solution of Ziprasidone:SBECD were determined using Circular Dichroism. A continuous scanning mode of 200 nm/min from 380 nm to 270 nm at 25⁰C was performed in a 5.00 mm cuvette on the pre-lyophilization solution and on the pre-lyophilization solution to which ethanol had been added and then evaporated. Evaporation of the co-solvent was performed on a standard laboratory rotary evaporator ("rotovap") apparatus after freezing of the suspension with an acetone-dry ice bath. The sample remained submerged in the bath during evaporation of co-solvent. The viscosity of the solution before addition of the ethanol was 95 cp. The viscosity of the 30% ethanol solution was 43 cp. The above-preferred embodiments and examples were provided to illustrate the scope and spirit of the present invention. These embodiments and examples will make apparent to those skilled in the art other embodiments and examples. These other embodiments and examples are within the contemplation of the present invention.

Claims

WHAT IS CLAIMED IS: 1. A method for sterilizing a viscous liquid pharmaceutical formulation, comprising a pharmaceutically effective amount of a drug, comprising: adding a volatile co-solvent to said viscous pharmaceutical formulation to reduce the viscosity sufficiently to pass through a membrane designed to retain bacteria; filtering the solution resulting from step i) through a membrane designed to retain bacteria; and removing the volatile co-solvent by evaporation. 2. The method of Claim 1 , further comprising a pharmaceutical carrier. 3. The method of Claim 1 or Claim 2, wherein the volatile co-solvent is ethanol. 4. The method of Claim 1 or Claim 2, further comprising a solubilizing agent. 5. The method according to Claim 4, wherein the solubilizing agent is a cyclodextrin. 6. The method of Claims 1 , 2 or 3, wherein the amount of added co-solvent is from about 1 % to about 30% by volume of the solution of (i). 7. The method of Claim 1 or Claim 2, wherein the membrane pore size of the membrane designed to retain bacteria is from about 0.1 μm to about 0.45 μm. 8. A mixture comprising a solution of ziprasidone or pharmaceutically acceptable salt thereof complexed with cyclodextrin in water containing from about 1 to about 30% ethanol by volume. 9. The mixture according to Claim 8, wherein the complex is ziprasidone:SBECD. 10. The mixture according to Claim 8, wherein the complex is ziprasidone:HPBCD. 11. The mixture according to Claim 8, wherein the ziprasidone salt is selected from the group consisting of the tosylate, napsylate, besylate, aspartate, hydrochloride tartrate, esylate and mesylate.