RETIGABINE POLYMORPHIC FORMS

INTRODUCTION

Aspects of the present application relate to polymorphic forms of retigabine which are useful in making pharmaceutically acceptable dosage forms, and processes for their preparation.

The drug compound having the adopted name retigabine, has a chemical name 2-amino-4-(4-fluorobenzylamino)-1-ethoxycarbonyl-aminobenzene, and is represented by structure of formula (I).

U.S. Patent No. 5,384,330 discloses retigabine and its pharmaceutically acceptable salts. In addition, it discloses their properties as anti-epileptic, muscle relaxing, fever reducing and peripheral analgesic agent or anti convulsive. U.S. Patent No. 6,538,151 discloses modification A, modification B and modification C of the formula (I) (retigabine) and process for the preparation thereof. Modification A of formula (I) was characterized by an X-ray powder diffraction pattern, reflections not coinciding with the reflections of the other two modifications being observed, inter alia, at 6.97°, 18.02°, and 19.94° 2-theta; modification B of formula (I) was characterized by an X-ray powder diffraction pattern, reflections not coinciding with the reflections of the other two modifications being observed, inter alia, at 15.00°, 19.29°, and 19.58° 2-theta; modification C of formula (I) was characterized by an X-ray powder diffraction pattern, reflections not coinciding with the reflections of the other two modifications being observed, inter alia, at 9.70° and 21.74° 2-theta.

International Application Publication No. WO 2010/105823 A1 discloses retigabine in non-crystalline form together with a surface stabilizer in the form of a stable intermediate and process for the preparation thereof. International Application Publication No. WO 2011/039369 A1 discloses a stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier.

The occurrence of different polymorphs is possible for some compounds. A single compound may give rise to a variety of solids having distinct physical properties. This variation in solid forms may be significant and may result in differences with respect to bioavailability, stability, and other differences for formulated pharmaceutical products. Because polymorphic forms can vary in their physical properties, regulatory authorities require that efforts shall be made to identify all polymorphic forms, e.g., crystalline, amorphous, solvated, etc., of new drug substances.

The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no "standard" procedures that can be used to prepare polymorphic forms of a substance. However, new forms of a pharmaceutical^ useful compound may provide an opportunity to improve the performance characteristics of pharmaceutical products. Further, discovery of additional polymorphic forms, including solvate polymorphs, may help in the identification of the polymorphic content of a batch of an active pharmaceutical ingredient. For example, in some cases, different forms of the same drug can exhibit very different solubility and different dissolution rates. The discovery of new polymorphic forms enlarges selection of materials with which formulation scientists can design a pharmaceutical^ acceptable dosage form of a drug with a targeted release profile or other desired characteristics. Therefore, there remains a need for preparing new and stable polymorphic forms of retigabine.

SUMMARY OF THE INVENTION

In an aspect, the present application provides crystalline Form I of retigabine characterized by its powder X-ray diffraction (PXRD) pattern having two or more peaks at about 4.8, 9.7, and 19.6 ± 0.2 degrees 2-theta.

In an aspect, the present application provides crystalline Form I of retigabine further characterized by the powder X-ray diffraction pattern having one or more additional peaks at about 14.6 and 20.5 ± 0.2 degrees 2-theta.

In an aspect, the present application provides a process for the preparation of crystalline Form I of retigabine, comprising:

a) providing a solution of retigabine in a solvent comprising methanol; and

b) isolating the crystalline Form I of retigabine.

ln an aspect, the application provides crystalline Form II of retigabine characterized by its powder X-ray diffraction (PXRD) pattern having two or more peaks at about 8.4, 9.4, 10.4, 18.1, 23.6, 24.2, 26.4, 28.9, 29.5, and 31.0 ± 0.2 degrees 2-theta.

In an aspect, the present invention provides crystalline Form II of retigabine further characterized by the powder X-ray diffraction pattern having one or more additional peaks at about 13.8, 16.6, 22.1, and 25.4 ± 0.2 degrees 2-theta.

In an aspect, the present invention provides crystalline Form II of retigabine further characterized by the powder X-ray diffraction pattern having one or more additional peaks at about 21.1 and 25.0 ± 0.2 degrees 2-theta.

In an aspect, the present application provides a process for the preparation of crystalline Form II of retigabine, comprising:

a) providing a solution of retigabine in a solvent comprising formamide; and
b) isolating the crystalline Form II of retigabine.

In an aspect, the present application provides pharmaceutical formulations comprising crystalline polymorphic forms of retigabine, together with one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION

In an aspect, the present application provides crystalline Form I of retigabine characterized by its powder X-ray diffraction (PXRD) pattern having two or more peaks at about 4.8, 9.7, and 19.6 ± 0.2 degrees 2-theta.

In an aspect, the present invention provides crystalline Form I of retigabine further characterized by the powder X-ray diffraction pattern having one or more additional peaks at about 14.6 and 20.5 + 0.2 degrees 2-theta.

In an aspect, the present application provides a process for the preparation of crystalline Form I of retigabine, comprising:

a) providing a solution of retigabine in a solvent comprising methanol; and

b) isolating the crystalline Form I of retigabine. Providing a solution in step a) includes:

i) direct use of a reaction mixture containing retigabine that is obtained in the course of its synthesis that comprises methanol, or by adding methanol to a reaction mixture; or

ii) dissolving retigabine in a solvent comprising methanol.

Any physical form of retigabine may be utilized for providing the solution of retigabine in step a). The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of retigabine is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

Step b) involves isolation of crystalline Form I of retigabine from the solution obtained in step a). Isolation of crystalline Form I of retigabine in step b) may involve methods including removal of solvent (by techniques known in the art e.g. evaporation, distillation or the like) cooling, concentrating the mass, adding an anti-solvent, extraction with a solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation. Suitable temperatures for isolation may be less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, less than about 5°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperatures.

The crystalline Form I of retigabine may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the retigabine is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.

In an aspect, the application provides crystalline Form II of retigabine characterized by its powder X-ray diffraction (PXRD) pattern having two or more peaks at about 8.4, 9.4, 10.4, 18.1, 23.6, 24.2, 26.4, 28.9, 29.5, and 31.0 ± 0.2 degrees 2-theta.

In an aspect, the present invention provides crystalline Form II of retigabine further characterized by the powder X-ray diffraction pattern having one or more additional peaks at about 13.8, 16.6, 22.1, and 25.4 ± 0.2 degrees 2-theta.

In an aspect, the present invention provides crystalline Form II of retigabine further characterized by the powder X-ray diffraction pattern having one or more additional peaks at about 21.1 and 25.0 + 0.2 degrees 2-theta.

In an aspect, the present application provides a process for the preparation of crystalline Form II of retigabine, comprising:

a) providing a solution of retigabine in a solvent comprising formamide;
and

b) isolating the crystalline Form II of retigabine.

Providing a solution in step a) includes:

i) direct use of a reaction mixture containing retigabine that is obtained in the course of its synthesis that comprises formamide, or by adding formamide to a reaction mixture; or
ii) dissolving retigabine in a solvent comprising formamide, including mixtures of formamide with other solvents.

Any physical form of retigabine may be utilized for providing the solution of retigabine in step a). The dissolution temperatures may range from about 0°C to about the reflux temperature, or less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures, depending on the solvent used for dissolution, as long as a clear solution of retigabine is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material.

Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques.under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

Step b) involves isolation of crystalline Form II of retigabine from the solution obtained in step a). Isolation of crystalline Form II of retigabine in step b) may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, adding an anti-solvent, extraction with a solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation. Suitable temperatures for isolation may be less than about 80°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, less than about 5°C, less than about 0°C, less than about -10°C, less than about -20°C, less than about -40°C or any other suitable temperatures.

Optionally, isolation may be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which retigabine is less soluble or poorly soluble. Suitable anti-solvents that may be used include, but are not limited to: aliphatic or alicyclic hydrocarbon solvent; substituted hydrocarbon solvent such as nitromethane; aromatic hydrocarbon solvent; or any mixtures thereof. The crystalline Form II of retigabine may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The crystalline polymorphic forms of retigabine as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, these crystals may be washed with a solvent or a mixture of solvents to wash out the impurities.

The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the retigabine is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.

In an aspect, the present application provides pharmaceutical formulations comprising crystalline polymorphic forms of retigabine, together with one or more pharmaceutically acceptable excipients. Retigabine together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

Crystalline forms are characterized by scattering techniques, e.g., x-ray powder diffraction pattern, by spectroscopic methods, e.g., infra-red, 13C nuclear magnetic resonance spectroscopy, and by thermal techniques, e.g., differential scanning calorimetry or differential thermal analysis. The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. For a discussion of these techniques see J. Haleblian, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblian and W. McCrone, J. Pharm. Sci. 1969 58:911-929. Crystal forms of the application can be further processed to modulate particle size. For example, the crystal forms of the application can be milled to reduce average crystal size and/or to prepare a sample suitable for manipulation and formulation.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. As used herein, "consisting essentially of means that the invention may include ingredients in addition to those recited in the claim, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed invention. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

Generally, a diffraction angle (29) in powder X-ray diffractometry may have an error in the range of ±.0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ±.0.2°. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ±.0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (29 ±.0.2°) of 7.9°" means "having a diffraction peak at a diffraction angle (29) of 7.7° to 8.1°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the XRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of XRD is meant to encompass that peak assignments can vary by plus or minus about 0.2.degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not. All PXRD data reported herein are obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer or a PANalytical X-ray Diffractometer, using copper Ka radiation.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise. The term "anti-solvent" refers to a liquid that, when combined with a solution of retigabine, reduces solubility of the retigabine in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching and/or concentrating. Celite® is flux-calcined diatomaceous earth. Celite® is a registered trademark of World Minerals Inc. Hyflow is flux-calcined diatomaceous earth treated with sodium carbonate. Hyflo Super Cel™ is a registered trademark of the Manville Corp. Polymorphs are different solids having the same molecular structure, yet having distinct physical properties when compared to other polymorphs of the same structure.

An "aliphatic or alicyclic hydrocarbon solvent" refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvent include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, Cs-Csaliphatic hydrocarbons, ligroin, petroleum ethers, or mixtures thereof.

"Aromatic hydrocarbon solvent" refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has at least one 6-carbon ring containing three double bonds. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of an aromatic hydrocarbon solvent include, but are not limited to, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-Cioaromatic hydrocarbons, or mixtures thereof.

An "ether solvent" is an organic solvent containing an oxygen atom -O-bonded to two other carbon atoms. "Ether solvents" include but are not limited to diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran,1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6ethers, or the like.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES
EXAMPLE 1: Preparation of crystalline Form I of retigabine. Retigabine (100 mg) is dissolved in methanol (1.8 mL) and stirred for 10 minutes. The solution is transferred into a beaker and kept for slow evaporation at room temperature (28 ± 2°C) for 3 days to afford the title compound.

The Powder X-ray diffraction (PXRD) pattern of Form I of retigabine obtained in above example is in accordance with Figure 1.

EXAMPLE 2: Preparation of crystalline Form II of retigabine. Retigabine (0.5 g) and formamide (10 mL) are charged into flask and heated to 80°C. The obtained clear solution is cooled to -40°C by crash cooling and maintained at -40°C for 30 minutes. The obtained solid is collected by filtration under reduced pressure and dried in air tray dryer at 50°C to afford 300 mg of the title compound.

The Powder X-ray diffraction (PXRD) pattern of Form II of retigabine obtained in above example is in accordance with Figure 2.

EXAMPLE 3: Preparation of crystalline Form II of retigabine. Retigabine (2.0 g) and formamide (40 ml_) are charged into flask and heated to 80°C. The obtained clear solution is cooled to -40°C by crash cooling and maintained at -40°C for 5 minutes. The obtained solid is collected by filtration under reduced pressure and dried in air tray dryer at 50°C to afford 2.1 g of the title compound.

The Powder X-ray diffraction (PXRD) pattern of Form II of retigabine obtained in above example is in accordance with Figure 2.

EXAMPLE 4: Preparation of crystalline Form II of retigabine. Retigabine (1.0 g) and formamide (25 mL) are charged into flask and covered with aluminium foil. The resultant reaction mixture is stirred at 28°C for 25 hours, the separated solid collected by filtration under reduced pressure, and dried at 50°C to afford 0.34 g of the title compound.

The Powder X-ray diffraction (PXRD) pattern of Form II of retigabine obtained in above example is in accordance with Figure 2.

We Claim:

1. A crystalline Form I of retigabine, which shows the X-ray powder diffraction pattern of figure 1, having two or more characteristic peaks at reflection angle 26 at about 4.8, 9.7 and 19.6 ± 0.2° 20.

2. A crystalline Form I of retigabine according to claim 1 characterized by the powder X-ray diffraction pattern having one or more additional peaks at reflection angle 26 at about 14.6 and 20.5 ± 0.2° 26.

3. A process for preparing crystalline Form I of retigabine according to claim 1 or 2, wherein retigabine is dissolved in methanol and the obtained solution is kept for the slow evaporation at room temperature.

4. A crystalline Form II of retigabine, which shows the X-ray powder diffraction pattern of figure 2, having two or more characteristic peaks at reflection angle 29 at about 8.4, 9.4, 10.4, 18.1, 23.6, 24.2, 26.4, 28.9, 29.5, and 31.0 ± 0.2° 20.

5. A crystalline Form II of retigabine according to claim 4 characterized by the powder X-ray diffraction pattern having one or more additional peaks at reflection angle 26 at about 13.8, 16.6, 22.1, and 25.4 ± 0.2° 26.

6. A process for preparing crystalline Form II of retigabine according to claim 4 or 5, wherein retigabine is dissolved in formamide and the obtained solution is subjected to crash cooling.

7. A process for preparing crystalline Form II of retigabine according to claim 6 wherein the retigabine solution is cooled to -40°C.

8. A process for preparing crystalline Form II of retigabine according to claim 4 or 5, wherein retigabine is suspended in formamide and the obtained suspension is stirred at room temperature.

9. A pharmaceutical composition comprising a crystalline Form I or crystalline Form II of retigabine according to the preceding claims together with one or more pharmaceutically acceptable excipients.