HK1174850A

HK1174850A - Taxane pro-emulsion formulations and methods making and using the same

Info

Publication number: HK1174850A
Application number: HK13102155.2A
Authority: HK
Inventors: 锅田喜一郎
Original assignee: 帝国制药美国公司
Priority date: 2010-02-19
Filing date: 2011-02-18
Publication date: 2013-06-21

Description

Taxane pro-emulsion formulations and methods of making and using the same

Cross Reference to Related Applications

According to 35u.s.c. § 119(e), the present application claims priority from the filing date of U.S. provisional patent application serial No. 61/306,315, filed 2/19 2010; the disclosure of this application is incorporated herein by reference.

Introduction to

Taxanes (taxanes) constitute a family of natural diterpene compounds including paclitaxel. Paclitaxel and its semi-synthetic analogue docetaxel (docetaxel), originally isolated from the bark of the pacific yew tree (Taxus brevifolia), are two examples of taxane compounds. Taxanes are active agents that arrest cell growth by disrupting microtubules to terminate mitosis.

Taxanes are useful in the treatment of a variety of cancers and have been reported to have therapeutic utility in the treatment of some inflammatory diseases. For example, paclitaxel has been found to be active against ovarian and breast cancers as well as malignant melanoma, colon cancer, leukemia and lung cancer (see, e.g., Borman, Chemical & Engineering News, 1991, 9, 2, pp. 11-18; The Pharmacological Basis of Therapeutics (edited by Goodman Gilman et al), Pergamon Press, New York (1990), 1239: Suffness, anticancer Alkaloids, "The Alkaloids, Vol. XXV," Academic Press, Inc. (1985), Chapter 1, pp. 6-18: Rizzo et al, J.Pharm. & biomed. Anal.8 (2): 159-164(1990) and Biotechnology 9: 933 938 (1991).

Because of the poor solubility characteristics of taxane molecules in both aqueous and lipid carriers, it is difficult to formulate the taxane in a therapeutically effective carrier to enable the administration of the taxane.

SUMMARY

Taxane pro-emulsion (pro-emulsion) formulations are provided. The pre-emulsion formulation is a dry powder comprising a taxane, an oil, a surfactant, and a sugar alcohol. Methods of making and using the pro-emulsion formulations are also provided, as are kits comprising the pro-emulsion formulations.

Accordingly, some aspects of the present invention include a taxane pro-emulsion formulation, wherein the formulation comprises a dry powder comprising a taxane, an oil, a surfactant, and a sugar alcohol; wherein the dry powder is formulated to produce a clear (clear) emulsion having a particle size substantially the same as the particle size of the precursor emulsion of the dry powder upon combination with an aqueous medium. In some cases, the taxane is represented by the formula:

wherein:

R₃alkyl or phenyl of 1 to 6 carbons; r₄Alkyl of 1 to 6 carbons or phenyl. In some cases, the taxane is paclitaxel or docetaxel. In some cases, the oil is present in an amount of 0.1 to 10 wt%. In some embodiments, the oil is selected from soybean oil, tocopherols, and glycerol esters of medium chain fatty acids. In some cases, the surfactant is present in an amount of 10 to 70 wt%. The surfactants involved include nonionic surfactants such as polysorbate 80. In some cases, the pro-emulsion formulation comprises a non-aqueous solvent. When present, the non-aqueous solvent is present in an amount of 0.1 to 30 wt%. The non-aqueous solvent involved includes propylene glycol. In some cases, the sugar alcohol is present in an amount of 15 to 80 dry weight%. The sugar alcohol involved includes mannitol. In some cases, the pro-emulsion formulation further comprises an emulsification enhancer. The emulsification enhancer involved is oleic acid. In some cases, the particle size is 70nm or less, including 50nm or less.

Some embodiments of the present invention include taxane pro-emulsion formulations in dry powder form comprising a taxane (e.g., paclitaxel or docetaxel), soybean oil, polysorbate 80, propylene glycol, and mannitol; wherein the powder is formulated to produce a clear emulsion having a particle size substantially the same as the particle size of the precursor emulsion of the dry powder upon combination with an aqueous medium. In some cases, the soybean oil is present in an amount of 0.4 to 8 wt%. In some cases, polysorbate 80 is present in an amount of 30 to 60 wt%. In some cases, the propylene glycol is present in an amount of 0.1 to 15 wt%. In some cases, mannitol is present in an amount of 25 to 65 dry weight%. In some cases, the pro-emulsion formulation further comprises oleic acid.

Some aspects of the invention also include methods of administering a taxane to a subject. The methods comprise combining a taxane pro-emulsion formulation (e.g., as described above) with an aqueous medium to produce a clear taxane emulsion; and administering the taxane emulsion to the subject. In some cases, the method comprises storing the taxane pro-emulsion formulation for 1 day or longer prior to contacting the pro-emulsion formulation with the aqueous medium. In some cases, the subject suffers from a cell proliferative disorder.

Aspects of the invention also include clear taxane emulsion compositions. In some cases, the clear taxane emulsion composition comprises a taxane, an oil, a surfactant, a sugar alcohol, and water. In some cases, the taxane is represented by the formula:

wherein:

R₃alkyl or phenyl of 1 to 6 carbons; r₄Alkyl of 1 to 6 carbons or phenyl. In some cases, the taxane is taxaneAlcohol or docetaxel. In some cases, the oil is present in an amount of 0.0007 to 6 wt%. In some embodiments, the oil is selected from soybean oil, tocopherols, and glycerol esters of medium chain fatty acids. In some cases, the surfactant is present in an amount of 0.07 to 40 wt%. In some cases, the surfactant is a nonionic surfactant. In some cases, the nonionic surfactant is polysorbate 80. In some cases, the emulsion comprises a non-aqueous solvent. In some cases, the non-aqueous solvent is present in an amount of 0.1 to 17 wt%. In some cases, the non-aqueous solvent is propylene glycol. In some cases, the sugar alcohol is present in an amount of 0.1 to 45 dry weight%. In some cases, the sugar alcohol is mannitol. In some cases, the pro-emulsion formulation further includes an emulsification enhancer, such as oleic acid. In some cases, the emulsion has a particle size of 70nm or less, including 50nm or less.

Some aspects of the invention also include kits comprising: (a) a taxane pro-emulsion formulation in dry powder form comprising a taxane, an oil, a surfactant, and a sugar alcohol; wherein the dry powder is formulated to produce a clear emulsion having a particle size substantially the same as the particle size of the precursor emulsion of the dry powder upon combination with an aqueous medium, and (b) an aqueous medium, such as water. In some cases, the taxane is represented by the formula:

wherein:

R₃alkyl or phenyl of 1 to 6 carbons; r₄Alkyl of 1 to 6 carbons or phenyl. In some cases, the taxane is paclitaxel or docetaxel. In some cases, the presence of oilIn amounts of 0.0007 to 6 wt%. In some embodiments, the oil is selected from soybean oil, tocopherols, and glycerol esters of medium chain fatty acids. In some cases, the surfactant is present in an amount of 0.07 to 40 wt%. In some cases, the surfactant is a nonionic surfactant. In some cases, the nonionic surfactant is polysorbate 80. In some cases, the emulsion comprises a non-aqueous solvent. In some cases, the non-aqueous solvent is present in an amount of 0.1 to 17 wt%. In some cases, the non-aqueous solvent is propylene glycol. In some cases, the sugar alcohol is present in an amount of 0.1 to 45% dry weight. In some cases, the sugar alcohol is mannitol. In some cases, the pro-emulsion formulation further includes an emulsification enhancer, such as oleic acid. In some cases, the emulsion has a particle size of 70nm or less, including 50nm or less.

Detailed description of the invention

Taxane pro-emulsion formulations are provided. The pre-emulsion formulation is a dry powder comprising a taxane, an oil, a surfactant, and a sugar alcohol. Methods of making and using the pro-emulsion formulations are also provided, as are kits comprising the pro-emulsion formulations.

Before the present invention is described in greater detail, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

When a range of values is given, it is understood that the upper and lower limits of the range, and any other stated value or any intervening value between the stated values in the stated range (to the tenth of the minimum integer below the lower limit, unless the context clearly dictates otherwise), are encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where a stated range includes one or both of the endpoints, ranges excluding either or both of those included endpoints are also within the scope of the invention.

Some ranges set forth herein as numerical values are preceded by the term "about". The term "about" as used herein refers to the literal value of the exact numerical value followed, as well as values near or approximate to the value followed. In determining whether a number is near or similar to a specifically indicated number, the near or similar unspecified number may be a value that is substantially equivalent to the specifically indicated number in the context in which it appears.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials equivalent to those described herein can be used in the practice or testing of the present invention, representative illustrative methods and materials are described herein.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were individually indicated to be incorporated by reference and were set forth in its entirety herein to disclose and describe the methods and/or materials in connection with which the publications are cited. Citation of any publication prior to the filing date of this disclosure shall not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

It should be noted that, unless otherwise explicitly indicated, in this document and in the appended claims, no term in the plural is intended to be implied by the word. It is also noted that the claims may exclude any optional elements. Thus, this statement is intended to serve as antecedent basis for use of any exclusive terminology such as "solely," "only," etc. in connection with the recitation of claim elements or use of a "negative" limitation.

It will be apparent to those skilled in the art upon reading this disclosure that each of the individual embodiments described and illustrated herein has individual components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any described methods may be performed in the order of events, or in any other order that is logically permissible.

In the following section, the pro-emulsion formulations and emulsions prepared therefrom and methods of using them are first described in more detail, followed by methods of preparing the pro-emulsion formulations and emulsions, and kits that may include the formulations.

Taxane pro-emulsion formulations and emulsions prepared therefrom

Some aspects of the invention include taxane pro-emulsion formulations. Since the formulations are pro-emulsion formulations, they are dry compositions that form taxane emulsions upon combination with aqueous media. Emulsions prepared from pro-emulsion formulations are liquid preparations of a suspension of small particles (i.e., globules) of one liquid in a second liquid with which it cannot be mixed. In some embodiments, the emulsion product prepared from the pro-emulsion formulation of the invention is an oil and water emulsion. Since the formulations are emulsions, they are mixtures of two immiscible (e.g., unblendable) fluids, with one fluid (e.g., oil or water) (the dispersed phase) dispersed in the other fluid (e.g., the other of oil or water) (the continuous phase). The water present in the emulsion may be any conventional water, including deionized water, USP water for injection (WFI), and the like.

The emulsion product comprises a taxane, an oil, a surfactant, a non-aqueous solvent, a sugar alcohol, and water. In some embodiments, the emulsion product is clear. By clear is meant that the emulsion is translucent, if not a transparent liquid, i.e. the liquid is clear (pellucid). Thus, the emulsion is not cloudy, for example, not as cloudy as a suspension may appear. Additional detailed information regarding emulsion products that can be prepared from taxane pro-emulsion precursors is provided below.

As noted above, the taxane pro-emulsion precursor is a dry solid composition. The dry solid composition may take a number of different forms, such as a solid block or cake, or a particulate composition (i.e., a powder). For powdered embodiments, the particles forming the powder may vary in diameter, in some cases from 1 μm to 1cm in diameter, such as from 1 μm to 5mm, and including from 1 μm to 1 mm.

The dry pre-emulsion formulation of some embodiments of the invention comprises at least a taxane, an oil, a surfactant, and a sugar alcohol. The taxane is diterpenoid. In some cases, the taxane is a compound represented by the formula:

wherein:

R₃alkyl or phenyl of 1 to 6 carbons; and

R₄alkyl of 1 to 6 carbons or phenyl.

In some embodiments, the taxane is paclitaxel or docetaxel. Related taxanes also include, but are not limited to: 7-epitaxol, 7-acyltaxol, 10-deacylated taxol, 10-deacylated-7-epitaxol, 7-xylosyltaxol, 10-deacylated-7-glutaryl taxol, 7-N, N-dimethylglycyltaxol, 7-L-alanyltaxol, SB-T-1011, etc. The taxane may be present as the free base or as a salt.

The pro-emulsion formulation comprises an effective amount of one or more taxanes. An effective amount refers to a dosage sufficient to provide a desired result (e.g., inhibition of cell proliferation). The effective amount of taxane may vary depending on the particular taxane employed, and in some embodiments, the effective amount is from 0.05 to 5 wt%, such as from 0.1 to 3 wt%, and including from 0.3 to 2 wt%. In some embodiments, the pro-emulsion formulation comprises an effective amount of paclitaxel. In some embodiments, paclitaxel is present in the pro-emulsion formulation in an amount of 0.05 to 5 wt%, such as 0.1 to 2.5 wt%, and including 0.3 to 1.0 wt%. In some embodiments, the pre-emulsion formulation comprises an effective amount of docetaxel. In some embodiments, docetaxel is present in the pre-emulsion formulation in an amount of 0.1 to 5 wt%, such as 0.2 to 3 wt%, and including 0.5 to 2 wt%.

An oil component consisting of one or more oils is also present in the pro-emulsion formulation. The oils involved are physiologically acceptable and include, but are not limited to, simple lipids, derived lipids, complex lipids derived from natural vegetable oils and fats, animal oils and fats, and mineral oils, and mixtures thereof, wherein the oils may be natural or synthetic.

In some embodiments, the oil includes, but is not limited to, soybean oil, olive oil, sesame oil, castor oil, corn oil, peanut oil, safflower oil, grape seed oil, eucalyptus oil, medium chain fatty acid esters, short chain fatty acid esters, and the like. Animal oils and fats of interest include, but are not limited to, cod liver oil, seal oil, sardine oil, docosahexaenoic acid, and eicosapentaenoic acid. Reference to mineral oils includes, but is not limited to, liquid paraffin (e.g., oils derived from n-alkanes), naphthenic oils (e.g., naphthenic-based oils), and aromatic oils (e.g., aromatic-based oils). One of these oil types or a combination of more than one of these oil types may be used. For example, some embodiments of the emulsion formulations of the present invention include soybean oil, olive oil, sesame oil, or combinations thereof. Other embodiments include soybean oil, olive oil, or combinations thereof. Highly refined oils and fats are used in some embodiments.

The oils involved also include tocopherols. Tocopherols are a family of natural and synthetic compounds commonly known as tocols or vitamin E. Alpha-tocopherol is the most abundant and active form of this class of compounds, and it has the following chemical structure (scheme I):

other members of this class include alpha-, beta-, gamma-, and delta-tocotrienols, as well as alpha-tocopherol derivatives such as tocopherol acetate, tocopherol phosphate, tocopherol succinate, tocopherol nicotinate, and tocopherol linoleate. Any common tocopherol may be present as desired, including the specific tocopherols described above.

The oils involved also include polyol esters of medium chain fatty acids. The term "polyol esters of medium chain fatty acids" is intended to include esters and mixed esters of glycerol, propylene glycol or other open chain polyols such as polyethylene glycol reacted with medium chain fatty acids (e.g. wherein the acid has a chain length of 6 to 12 carbon atoms). In some cases, the polyol ester of a medium chain fatty acid is C₈-C₁₀The triglyceride or diglyceride of fatty acids may, for example, be a commercially available fraction from coconut oil. The commercial products of this description are sold under the trade names "Miglyol" and "Captex 300", which are described as having a C of about 68%₈Fatty acid (caprylic acid) triglyceride and about 28% C₁₀Fatty acid (capric acid) triglycerides, and lower levels of C₆And C₁₄Typical composition of fatty acid triglycerides.

In some cases, the amount of oil in the pro-emulsion formulation is 0.05 to 12 wt%, such as 0.1 to 10 wt%, and including 0.4 to 8 wt%.

In some embodiments of the pre-emulsion formulations of the present invention, one or more surfactants are also present. Reference to a surfactant includes any type of surfactant that may be used in pharmaceutical formulations, including, but not limited to, phospholipids, refined phospholipids, nonionic surfactants, or mixtures thereof. The refined phospholipid may include phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin having phosphatidylcholine as a main component. For example, refined phospholipids include egg yolk lecithin and soybean lecithin. Nonionic surfactants contemplated include, but are not limited to, polyethylene glycols, polyoxyalkylene copolymers, and sorbitan fatty acid esters. In some embodiments, the sorbitan fatty acid ester is a polyoxyethylene sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan tristearate (Tween 65); polyoxyethylene sorbitan trioleate (Tween 85); polyethylene glycol 400 monostearate; polysorbate 60; (Tween 60); polyoxyethylene monostearate (Myrj 49); polysorbate 80(Tween 80); polysorbate 40(Tween 40); and polysorbate 20(Tween 20)) or a sorbitan fatty acid ester (e.g., sorbitan trioleate (Span 85); sorbitan tristearate (Span 65); sorbitan sesquioleate (Arlacel 83); glycerol monostearate; sorbitan monooleate (Span 80); sorbitan monostearate (Span 60); sorbitan monopalmitate (Span 40); sorbitan monolaurate (Span 20)). The amount of surfactant in the pre-emulsion formulation may vary. In some cases, the amount of surfactant in the pro-emulsion formulation is 10 to 70 wt%, such as 20 to 65 wt%, and including 30 to 60 wt%. The combined ratio of oil and surfactant in the pro-emulsion formulations of the invention may vary, in some cases from 1/1000 to 1/2, such as 1/100 to 1/5.

The pre-emulsion formulation of the present invention also comprises one or more sugar alcohols (i.e. polyols). The polyols involved include, but are not limited to, d-sorbitol, xylitol, ribitol, arabitol, galactitol, iditol, mannitol, and the like. The amount of sugar alcohol present may vary, in some cases from 15 to 80 wt%, such as from 25 to 65 wt%.

In some cases, the pro-emulsion formulations of the present invention further comprise one or more non-aqueous solvents. Non-aqueous solvents of interest include, but are not limited to, propylene glycol, polypropylene glycol, polyethylene glycol (e.g., PEG300, 400, 600, etc.), glycerol, ethanol, triacetin, dimethyl isosorbide, tetraethylene glycol, propylene carbonate, water, dimethylacetamide, or mixtures thereof. The non-aqueous solvent can be present in various amounts, in some cases in an amount of 0.1 to 30 weight percent, such as 0.1 to 15 weight percent.

Some embodiments of the emulsion formulations of the present invention further comprise one or more emulsification enhancers. Any type of fatty acid useful in pharmaceutical formulations can be used as an emulsification enhancer. The fatty acids involved contain 6 to 22 carbons. Natural or synthetic, and saturated or unsaturated fatty acids may be used, including, but not limited to stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid, and the like. In some embodiments, the emulsion formulation comprises a refined fatty acid, such as oleic acid. When an emulsification enhancer is present, it can be included in varying amounts in the pre-emulsion formulation, in some cases 0.1 to 5 wt%, such as 0.1 to 3 wt%.

An aspect of some embodiments of the pre-emulsion formulation is that the pre-emulsion formulation is configured to produce an emulsion upon combination with an aqueous medium, the particle size of the emulsion being substantially the same as the particle size of the precursor emulsion of the dry powder. In these cases, the pro-emulsion formulation is prepared from a pro-emulsion (as described in detail below). In the precursor emulsion, the particle size of the precursor emulsion (referring to the size of the average diameter of the droplets (i.e., globules) of the dispersed phase in its dispersed phase) may vary, in some embodiments, the particle size is from 3 to 100nm, such as from 5 to 70nm, and including from 7 to 50 nm. The final emulsion is prepared after combining the pro-emulsion with an aqueous medium (e.g., water for injection, saline solution, etc.) and has a particle size substantially the same as the particle size of the precursor emulsion. Thus, any variation in particle size between the final emulsion and the precursor emulsion is a difference of 50nm or less, such as 20nm or less, including 10nm or less, for example 5nm or 3nm or less. In some cases, the particle size of the final emulsion is 3 to 70nm, such as 5 to 50nm, and including 7 to 30 nm. In some embodiments are contemplated emulsion products that are clear (e.g., as described above) and have a particle size of 70nm or less, such as 50nm or less, including 30nm or less.

Process for preparing taxane pro-emulsion formulations

Pre-emulsion formulations may be prepared from precursor emulsions. The precursor emulsion can be prepared as follows: the ingredients of the pro-emulsion formulation (e.g., as described above) are combined with an amount of aqueous medium (e.g., water) under conditions sufficient to produce a precursor emulsion, and the water is then separated from the precursor emulsion to produce the desired pro-emulsion (e.g., as described above).

The precursor emulsion formulation may be prepared according to any suitable protocol. Thus, the ingredients of the desired pro-emulsion formulation may be combined with an aqueous medium (e.g., water) under conditions sufficient to produce the desired precursor emulsion. Thus, an amount of the taxane component, the oil component, the surfactant component, the non-aqueous solvent component, and the sugar alcohol component can be combined with water under conditions sufficient to produce a precursor emulsion. In the precursor emulsion, the amount of taxane (e.g., as described above) may vary, in some cases from 0.1 to 5, such as from 0.5 to 2 mg/ml. The amount of oil (e.g., as described above) may vary, in some cases from 0.1 to 100, such as from 1 to 10 mg/ml. The amount of surfactant (e.g., as described above) may vary, in some cases from 25 to 400, such as from 50 to 200 mg/ml. The amount of non-aqueous solvent (e.g., as described above) can vary, in some cases from 0.1 to 50, such as from 0.1 to 25 mg/ml. The amount of sugar alcohol (e.g., as described above) may vary, in some cases from 25 to 300, such as from 50 to 150 mg/ml.

The precursor emulsion can be prepared using any suitable protocol. The ingredients may be combined with the aqueous medium in any suitable order. Aqueous media of interest include, but are not limited to, deionized water, USP water for injection (WFI), and the like. Some of the ingredients may be combined with each other and then with the aqueous medium, or all of the ingredients may be combined at substantially the same time. Combining may include agitation, such as stirring, etc., in a variety of ways to produce the desired precursor emulsion. In some embodiments, the method of preparation comprises mixing the active agent, water, and oil, and emulsifying the mixture. For example, an injection solvent (e.g., WFI) may be added to a homogeneous mixture of suitable oils. Initially, the mixture can be roughly emulsified. For example, for coarse emulsification, a High speed mixer (Homomixer) (Mizuho Industrial co., Ltd.) or a High flexibility Disperser (High Flex Disperser) (SMT) may be used. At the coarse levelAfter emulsifying the mixture, the mixture can be finely emulsified, for example, by using a high pressure emulsifier. For fine emulsification, high pressure homogenizers such as Gaulin homogenizers (APV-SMT) and microfluidizers (microfluidizers, Newton, Mass.) can be used. Furthermore, for fine emulsification, the emulsion formulation may be processed more than once using the emulsifying machine, for example 2 to 50 times, for example 5 to 20 times, with a pressure in the range of 500 to 850kg/cm². The preparation method can be carried out at room temperature or below. In some embodiments, the method of making comprises flushing the emulsifier with nitrogen. Specific examples of precursor emulsion preparation protocols are provided in the experimental section below.

After the precursor emulsion is prepared, water can be separated from the precursor emulsion to produce the desired pro-emulsion. Thus, the precursor emulsion can be dried to produce the desired pro-emulsion formulation. The precursor emulsion can be dried using any suitable protocol, including but not limited to evaporation, lyophilization, and the like. When evaporation is used, the precursor formulation can be maintained at an appropriate temperature for a sufficient period of time to produce the desired pre-emulsion formulation. In some cases, the precursor formulation is maintained at a temperature of 20 to 80 ℃, e.g., 40 to 60 ℃, for 10 to 120 minutes, e.g., 20 to 60 minutes, to produce the desired pre-emulsion.

In some cases, the precursor emulsion is dried to produce a bulk (bulk _ amount) pre-emulsion formulation. Once a bulk quantity of pro-emulsion formulations is produced, a dose amount from the bulk quantity can be obtained and combined with an aqueous medium to produce a dose of injectable final emulsion. When desired, bulk pro-emulsion formulations can be stored for a period of time before being dispensed into a single dose and used, where the storage time can vary, in some embodiments, from 5 minutes to 24 hours, such as from 5 minutes to 12 hours, and including from 5 minutes to 6 hours.

If desired, a quantity of the precursor emulsion may be loaded into a separate dosage container, such as a vial (visual), which holds the pre-emulsion and maintains its sterility during transport, storage and handling. Prior to or during the loading phase, the emulsion may be passed through a sub-micron sterile filter having a pore size sufficiently small to remove any bacteria or viruses. The term "vial" as used herein refers to a hard-walled container for holding a pre-emulsion formulation. In some cases, the vial is made of clear glass, which has several advantages, including visual inspection of the enclosed drug (to ensure it is still clean, in an un-caramelised, un-collapsed form when ready to use) and the container itself (to ensure it does not develop hairline cracks in one wall that could compromise or destroy the sterility of the enclosed drug). Various types of pharmaceutical vials are known. The single-compartment vial may be sealed with a rubber or plastic stopper that allows the hypodermic needle to pass through the rubber seal. Alternatively, the single-chamber vial may be made of a brittle and easily breakable material in a sealed bag that may contain an aqueous solution (e.g., saline or glucose solution, in an intravenous infusion bag); if such vials break, their contents are released into the still sealed bag for mixing. In yet another embodiment, a two-compartment vial or similar structure is used, such as described in published U.S. application publication 20030099674 and U.S. patent 4,781,354. After loading the precursor emulsion into the container, the precursor emulsion can be dried in the container to produce a pre-emulsion formulation present in the container (e.g., vial). If desired, the pre-emulsion formulation may be stored for an extended period of time prior to reconstitution and use, which may vary, in some embodiments 1 week or more, such as 1 month or more, including 3 or more, for example 6 months or more, including 1 year or more. When stored, any suitable storage conditions may be used.

Taxane emulsion formulation products and methods of use

After preparation of the pre-emulsion formulation (e.g., as described above), a dosage amount of the pre-emulsion can be combined with an aqueous medium to prepare an emulsion formulation product suitable for use when desired for administration to a subject. Dosage amounts of the pro-emulsion formulation may be combined with any suitable aqueous medium including, but not limited to, deionized water, USP water for injection (WFI), saline, and the like. The liquid-to-solid ratio used during preparation of the emulsion product may vary, in some embodiments from 0.5 to 300, such as from 1 to 200, and including from 2 to 150. In some cases, the dosage amount of the pro-emulsion formulation combined with the aqueous medium is 100 to 1200g, such as 300 to 600g, and the amount of the aqueous medium combined with the dosage amount is 100 to 1200ml, such as 250 to 600 ml.

If desired, the pre-emulsion formulation may be stored for a period of time prior to combining with the aqueous medium, which may vary, in some cases from 5 minutes to 24 hours, such as from 5 minutes to 12 hours, and including from 5 minutes to 6 hours. Although storage conditions may vary, in some cases, storage conditions are characterized by temperatures in the range of 5 to 60 ℃, such as 8 to 40 ℃. The activity of the taxane active agent is maintained during storage, thereby allowing stable storage of the pre-emulsion formulation. Thus, the activity of the taxane active agent in the emulsion product reconstituted after storage is substantially the same as the activity of the precursor emulsion prior to drying, for example as measured by HPLC as summarized in the following table, wherein the magnitude of any activity difference may be 15% or less, such as 10% or less, including 5% or less.

The binding protocol may vary, wherein agitation may be used, e.g., by stirring, by kneading a bag containing the emulsion and the aqueous medium, etc.

The taxane emulsion formulation product produced by reconstitution of the pro-emulsion formulation with an aqueous medium may have a physiologically acceptable pH. In some embodiments, the pH of the emulsion formulation is from 2.5 to 8, such as from 3 to 7, including from 3.5 to 6. The taxane emulsion formulation product is a clear formulation. The concentration of the taxane in the emulsion product may vary, in some embodiments from 0.05 to 10mg/ml, such as 0.2 to 3 mg/ml.

Methods of using the taxane emulsion formulation include administering to a subject an effective amount of the taxane emulsion formulation to treat a target disorder in the subject. "treating" or "treatment" refers to at least inhibiting or ameliorating the symptoms associated with the condition in which the subject is suffering, wherein inhibiting or ameliorating is used in a broad sense to refer to at least reducing the extent of a parameter (e.g., symptoms) associated with the condition being treated (e.g., pain). Thus, treatment also includes situations where the condition is completely inhibited (e.g., prevented from occurring) or terminated (e.g., stopped) such that the subject no longer has the condition. Thus, treatment includes both prevention and modulation of the condition.

In practicing the methods, the emulsion formulations disclosed herein can be administered to a subject parenterally. "parenteral administration" refers to administration by a regimen in which an amount of the emulsion formulation is delivered to a subject (e.g., a patient suffering from post-operative pain) by a route other than the digestive tract. Examples of parenteral administration include, but are not limited to, intramuscular injection, intravenous injection, transdermal absorption, inhalation, and the like. In some embodiments, parenteral administration is by injection using an injection delivery device. The amount of emulsion formulation administered to a patient may vary depending on a number of factors, such as the specificity of the patient, the nature of the disorder, the nature of the taxane active agent, and the like. In some embodiments, the volume of the emulsion administered to a subject may be 100 to 1000ml, such as 200 to 600 ml. The time period over which the volume is administered may vary, being 0.5 to 6 hours, such as 1 to 3 hours. The dose administered to a subject in a given procedure may also vary, in some cases from 20 to 500mg/m²E.g. 50 to 300mg/m²。

In some cases, the individual administered the composition of the invention is an individual diagnosed as in need of the method of the invention. In some embodiments, the methods of the invention comprise a diagnostic step. Any suitable protocol may be used to diagnose an individual in need of the methods of the invention. Furthermore, it may be known that an individual is in need of the method of the invention prior to performing the method of the invention, e.g., they are suffering from a disease of interest (e.g., a cell proliferative disease). Any suitable diagnostic protocol may be used to diagnose or assess the condition of interest.

The methods of the invention may further comprise assessing the effectiveness of a treatment regimen comprising administering the taxane emulsion formulation. Any suitable protocol may be used to assess treatment effectiveness.

The taxane emulsion formulation of the present invention may be administered to a variety of different subjects. The objects involved include, but are not limited to: human and non-human mammals, including the orders carnivora (e.g., dogs and cats), rodents (e.g., mice, guinea pigs, and rats), lagomorpha (e.g., rabbits), and primates (e.g., humans, chimpanzees, and monkeys). In some embodiments, the subject (e.g., patient) is a human.

Utility of

The emulsion formulations and methods of the invention are useful in a variety of applications, including the treatment of subjects suffering from cell proliferative disorders. Cell proliferative disorders that can be treated with the compositions of the present invention include, but are not limited to, epithelial tumors of the brain, breast, lung, colon, prostate or ovary, myosarcoma, neuroblastoma or sarcoma, and leukemia or lymphoma. Specific diseases involved include, but are not limited to, human ovarian cancer, breast cancer, malignant lymphoma, lung cancer, melanoma, and kaposi's sarcoma.

Reagent kit

Kits for carrying out the above-described methods of the invention are also provided. For example, a kit for practicing the methods of the invention may comprise a pre-emulsion formulation in unit dosage form (e.g., vials) or in multiple dosage forms. Thus, in some embodiments, a kit may comprise one or more unit doses (e.g., vials) of a pre-emulsion formulation. The term "unit dose" as used herein refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of the pro-emulsion formulation of the invention calculated in an amount sufficient to produce the desired effect. The amount of a unit dose of the emulsion formulation of the present invention depends on a variety of factors, such as the particular active agent used, the effect to be achieved, and the pharmacokinetics associated with the active agent in the subject. In yet another embodiment, the kit may comprise one multi-dose amount of the emulsion formulation.

In some embodiments, the kit may further comprise an amount of an aqueous medium suitable for reconstitution of the taxane emulsion. The aqueous medium may be any conventional aqueous medium present in any suitable container (e.g., IV bag), as described above.

In addition to the above ingredients, the kits of the invention may contain instructions for carrying out the methods of the invention. These instructions may be present in the kits of the invention in a variety of forms, one or more of which may be present in the kit. One form of presentation is where the instructions may be as information printed on a suitable medium or substrate (e.g., one or more sheets of paper on which the information is printed), on the packaging of the kit, on package inserts, and the like. The instructions may reside on a computer-readable medium (e.g., a diskette, a CD, a DVD, etc.) having information recorded thereon. The instructions may reside on a website and the information may be obtained at different locations via the internet. May be in other suitable forms and may be included in a kit.

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to be exhaustive or to limit what the following examples are the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

Experiment of

A. Paclitaxel formulations

Composition (I)	Measurement of
		Paclitaxel	100mg
Polysorbate 80(Tween 80)	10000mg
		Propylene glycol	2000mg
Soybean oil	100mg
		Mannitol	10000mg
Diameter of precursor emulsion	11.7nm
		Diameter of final emulsion	17.0nm

In preparing a dry emulsion precursor formulation, 100mg of paclitaxel was combined with 2000mg of propylene glycol with ultrasonic heating to 50 ℃. The resulting mixture was combined with 10000mg of polysorbate 80 and 100mg of soybean oil, and heated with stirring. The resulting mixture was then stirred with a high speed stirrer (12000 rpm. times.15 minutes) while maintaining the temperature of the mixture at 60 ℃ and adding hot water (temperature 60 ℃) to increase the volume to 100 ml. 10000g of mannitol was then added and the mixture was stirred until the mannitol dissolved. 50ml of the resulting solution was placed in a vial and sealed with a cap. The vials were sterilized at 120 ℃ for 12 minutes and then cooled to room temperature. After sterilization, the liquid in the vial was removed with an evaporator to obtain a powder (50 ℃ C.. times.1 hour). The resulting powder is a dry paclitaxel emulsion precursor formulation.

At the time of use, the resulting powder is combined with water to obtain a clear emulsion solution suitable for injection.

The following additional formulations were also prepared using the above protocol.

B. Docetaxel formulations

In preparing a dry emulsion precursor formulation, 50mg docetaxel was combined with 120mg oleic acid, 500mg propylene glycol and 5000mg polysorbate 80 with sonication heating to 50 ℃. The resulting mixture was combined with 50mg of soybean oil, heated and stirred. The resulting mixture was then stirred with a high speed stirrer (11000 rpm. times.7 minutes) while maintaining the temperature of the mixture at 60 ℃ and adding hot water (temperature 60 ℃) to increase the volume to 50 ml. Then 5000g mannitol was added and the mixture was stirred until the mannitol dissolved. 10ml of the resulting solution was placed in a vial and sealed with a cap. The vials were sterilized at 120 ℃ for 12 minutes and then cooled to room temperature. After sterilization, the liquid in the vial was removed with an evaporator to obtain a powder (50 ℃ C.. times.1 hour). The resulting powder was a dry docetaxel emulsion precursor formulation.

C. Administration of

The following criteria are used to measure the response of a breast cancer patient to treatment with one embodiment of the present invention.

Partial Remission (PR): the sum of the products of all measurable lesion diameters decreased by more than 50% over at least one month.

Mild Relief (MR): the sum of the products of all measurable lesion diameters decreases by 25 to 50% over at least one month.

Disease Progression (PD): the sum of the products of any measurable lesion diameter increases by more than 25% over a chemotherapy cycle or any new lesions that are consistent with metastatic disease appear.

In using the above emulsion precursors, the dried emulsion precursor formulation is reconstituted in a suitable aqueous medium to provide a clear emulsion for injection. The clear emulsion provides a concentration sufficient to deliver 17.5 to 35mg of taxane per square meter (based on the body surface area of the patient) over a 6 hour period. The clear emulsion is formulated 30 to 60 minutes before the start of each infusion. Clear emulsions were formulated in polypropylene lined semi-solid containers of 500ml volume.

The container containing the clear emulsion was connected to an IV pump via polyethylene tubing. An In-Line Filter model Abbott #4525 (ivix-HP In Line Filter Set-SL, 15 ") having a pore size of 0.22 microns was then connected to the IV pump via a polyethylene Line. The connected in-line filter is then connected to the patient's central access device.

The clear emulsion was infused over a 6 hour period by IV pump control. This procedure was repeated 3 times for a total infusion of 18 hours. The final dose reached is 70 to 140mg/M²And/18 hours. This infusion process was repeated every 21 days, and the patient's response was monitored after two cycles. If the patient exhibits a toxic or allergic response to a dose of paclitaxel, the dose is reduced until tolerated. The cycle continues until the patient exhibits disease progression or stabilizes for 4-6 cycles. Using the above clear emulsion at 70 to 140mg/M every 21 days²After 18 hours of treatment of the patient, the patient's response was observed after two cycles.

Although the foregoing invention has been described by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this art that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Thus, the foregoing merely illustrates the principles of the invention. It will thus be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language used herein are principally intended to aid the reader in understanding the principles of the invention and the inventors' contribution to the art, and are to be construed as being without limitation. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Further, it is intended that such equivalents include both currently known equivalents as well as equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. Accordingly, the scope of the present invention is not intended to be limited by the exemplary embodiments shown and described herein. The scope and spirit of the present invention are indicated by the appended claims.

Claims

1. A taxane pro-emulsion formulation comprising:

a dry powder comprising:

a taxane;

an oil;

a surfactant; and

a sugar alcohol;

wherein the powder is formulated to produce a clear emulsion upon combination with an aqueous medium, the emulsion having a particle size substantially the same as the particle size of the precursor emulsion of the dry powder.

2. The pro-emulsion formulation according to claim 1, wherein the taxane is represented by the formula:

wherein:

R₃alkyl or phenyl of 1 to 6 carbons; and

R₄alkyl of 1 to 6 carbons or phenyl.

3. The pro-emulsion formulation of claim 2, wherein the taxane is paclitaxel or docetaxel.

4. The pro-emulsion formulation according to any one of claims 1 to 3, wherein the oil is selected from the group consisting of soybean oil, tocopherols and glycerol esters of medium chain fatty acids.

5. The pro-emulsion formulation according to any one of claims 1 to 4, wherein the surfactant is a nonionic surfactant.

6. The pro-emulsion formulation according to claim 5, wherein the non-ionic surfactant is polysorbate 80.

7. The pro-emulsion formulation according to any of the preceding claims, wherein the pro-emulsion formulation comprises a non-aqueous solvent.

8. The pro-emulsion formulation according to claim 7, wherein the non-aqueous solvent is propylene glycol.

9. The pro-emulsion formulation according to any of the preceding claims, wherein the sugar alcohol is mannitol.

10. The pro-emulsion formulation according to any of the preceding claims, wherein the pro-emulsion formulation further comprises an emulsification enhancer.

11. The pro-emulsion formulation according to claim 10, wherein the emulsification enhancer is oleic acid.

12. The pro-emulsion formulation according to any one of the preceding claims, wherein the particle size is 70nm or less.

13. A method of administering a taxane to a subject, the method comprising:

(a) combining a taxane pro-emulsion formulation according to any of the preceding claims with an aqueous medium to produce a clear taxane emulsion; and

(b) administering the taxane emulsion to the subject.

14. A clear taxane emulsion comprising produced by a method comprising combining the taxane pro-emulsion formulation of any of claims 1-12 with an aqueous medium.

15. A kit, comprising:

(a) a taxane pro-emulsion formulation according to any of claims 1 to 12; and

(b) an aqueous medium.