Pump systems and methods for storing and dispensing a plurality of precisely measured unit-doses of imiquimod cream

Abstract

The present invention is directed to airless storage and dispensing systems that include a pump or dispensing package pre-filled with a topical semi-solid imiquimod pharmaceutical formulation (pump systems) and methods for storing and dispensing from the pump systems a plurality of precisely measured and uniform unit doses of a topical semi-solid imiquimod pharmaceutical formulation, and more particularly to pump systems, pre-filled with a topical imiquimod pharmaceutical cream and methods for delivering multiple precisely measured unit doses of a topical imiquimod pharmaceutical cream, and methods for using a controlled delivery pump system to store and dispense a plurality of consistent and precisely measured unit doses of a topical imiquimod pharmaceutical cream for use in topically treating a dermal and mucosal-associated condition, such as, external genital warts and/or perianal warts (EGWs), actinic keratosis or actinic keratoses (AK or AKs) and superficial basal cell carcinoma (sBCC).

Claims

1. A system for treating a subject diagnosed with a dermal and/or mucosal-associated condition, said system comprising: a dispensing device that includes: a lower subassembly that has a tubular body portion that defines an elongated interior fluid storage chamber into which a take-up piston element is slidably disposed; and an upper subassembly mounted upon the lower subassembly and including a dispensing head and an airless pumping mechanism, the dispensing head having an internal fluid passage formed therein which terminates in a self-closing outlet, the dispensing head also including and a finger-operated actuator which is operatively associated with the airless pumping mechanism; and an imiquimod cream formulation disposed at least partially within the fluid storage chamber defined in the tubular body portion of the lower subassembly of the dispensing package, and wherein operation of the finger-operated actuator causes the airless pumping mechanism to withdraw a portion of the imiquimod cream formulation from within the interior chamber and to dispense the imiquimod cream formulation into the internal fluid passage formed in the dispensing head wherein the pressure of dispensed cream causes the self-closing outlet to open thereby discharging a predefined effective unit dose amount of imiquimod cream from the dispensing package.

2. The system of claim 1, wherein the imiquimod cream formulation contains imiquimod in an amount by weight of between 1% and 10% w/w.

3. The system of claim 1, wherein the imiquimod cream formulation contains imiquimod in an amount by weight of between 1% and 5% w/w.

4. The system of claim 1, wherein the imiquimod cream formulation contains imiquimod in an amount by weight selected from a group consisting of 2.5%, 3.75% and 5% w/w.

5. The system of claim 1, wherein the fluid storage chamber is adapted and configured for storing about 7.5 grams of imiquimod cream formulation.

6. The system of claim 1, wherein the take-up piston is disposed within the tubular body portion so as to partially define the fluid storage chamber, wherein the take-up position moves axially towards the pumping device when the pumping device is manually operated, so as to reduce the volume of the fluid storage chamber by an amount which is equivalent to the volume of imiquimod cream formulation dispensed from the dispensing package.

7. The system of claim 1, wherein upon each operation of the pumping device an amount of the imiquimod cream formulation which is within about 15% of the predefined unit dose amount is discharged from the dispensing device.

8. The system of claim 1, wherein after multiple operations of the pumping device, the overall average of the dose value is within about 10% of the predefined unit dose amount.

9. The system of claim 1, wherein the predefined unit dose amount is about 240 mg.

10. The system of claim 1, wherein no more than 5 manual actuations of the pumping mechanism are required in order to prime the pumping mechanism, and start observing the discharging of imiquimod cream formulation from the self-closing discharge orifice.

11. The system of claim 1, wherein about 85% of the imiquimod cream formulation contained within the internal fluid passage of the dispensing head following an application remains in the internal fluid passage during storage.

12. The system of claim 1, wherein the dermal and/or mucosal-associated condition comprises any of: external genital warts, perianal warts, actinic keratosis, and superficial basal cell carcinoma.

13. The system of claim 1, wherein the dispensing package is configured so that a single actuation dispenses the predefined unit dose amount.

14. The system of claim 1, further comprising: a cap for sealing the self-closing outlet.

15. An airless pump pre-filled with an imiquimod cream for treating a subject diagnosed with a dermal and/or mucosal-associated condition with predefined single unit-dose amounts of the imiquimod cream dispensed from the pump, said airless pump comprising: a dispensing device that includes: a lower subassembly that has a tubular body portion that defines an elongated interior fluid storage chamber into which a take-up piston element is slidably disposed; and an upper subassembly mounted upon the lower subassembly and including a dispensing head and an airless pumping mechanism, the dispensing head having an internal fluid passage formed therein which terminates in a self-closing outlet, the dispensing head also including and a finger-operated actuator which is operatively associated with the airless pumping mechanism; and between about 5 grams and about 30 grams of the imiquimod cream disposed at least partially within the fluid storage chamber defined in the tubular body portion of the lower subassembly of the dispensing package, wherein operation of the finger-operated actuator causes the airless pumping mechanism to withdraw a portion of the imiquimod cream from within the interior chamber and to dispense the imiquimod cream formulation into the internal fluid passage formed in the dispensing head, wherein the pressure of the dispensed imiquimod cream causes the self-closing outlet to open thereby discharging the predefined single unit-dose amount of the imiquimod cream from the dispensing package, wherein the take-up piston is disposed within the tubular body portion so as to partially define the fluid storage chamber, wherein the take-up position moves axially towards the pumping mechanism when the pumping mechanism is manually operated, so as to reduce the volume of the fluid storage chamber by an amount which is equivalent to the volume occupied by the predefined single effective unit-dose amount of the imiquimod cream dispensed from the dispensing package.

16. The airless pump of claim 15, wherein the predefined single unit-dose amount is about 240 mg and the imiquimod cream comprises any of a 2.5% imiquimod cream, a 3.75% imiquimod cream, a 5% imiquimod cream.

17. The airless pump of claim 15, wherein the pump is configured to dispense at least about 85% of the single unit dose amount during each said pumping step during treatment.

18. The airless pump of claim 15, wherein the dispensing device is adapted to dispense a single product stored therein, the single product comprising the imiquimod formulation.

19. The airless pump of claim 15, wherein the dispensing device is adapted to protect a remaining imiquimod formulation remaining within the dispensing device after each actuation from air contact, oxidation, degradation and contamination such that subsequent actuations of the dispensing device each dispense a subsequent effective unit-dose amount.

20. The airless pump of claim 15, wherein the dispensing device is configured such that repeated actuations consistently and repeatedly dispense the effective unit-dose amount upon each actuation during treatment.

21. The airless pump of claim 15, wherein the dispensing device is pre-filled with a pre-fill amount corresponding to the treatment regimen such that repeated actuations of the dispensing device deliver a predefined number of single unit-dose amounts effective to treat the dermal and/or mucosal condition in accordance with the effective treatment regimen.

22. The airless pump of claim 15, wherein the dispensing device is configured such that a substantial portion of the imiquimod formulation drawn into the dispensing duct upon each actuation remains within the dispensing duct after actuation so that a uniform and consistent amount unit-dose of the imiquimod formulation is dispensed per each subsequent actuation.

23. The airless pump of claim 15, wherein the dispensing device is configured such that about 85% or more of the imiquimod formulation drawn into the dispensing duct upon each actuation remains within the dispensing duct after actuation so that a uniform and consistent amount unit-dose of the imiquimod formulation is dispensed per each subsequent actuation.

24. The airless pump of claim 15, wherein the dispensing device is configured such that an amount of the imiquimod formulation dispensed per one actuation is the same upon each subsequent actuation when actuating the dispensing device during treatment.

25. The airless pump of claim 15, wherein the dispensing device is configured so as to not be readily disassemblable by the patient so that a remaining amount of imiquimod formulation remaining with the dispensing duct after each actuation remains effective and to avoid exposing the patient to excess imiquimod formulation.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) So that those having ordinary skill in the art to which the present invention pertains will more readily understand how to employ the pump systems and methods of the present invention, embodiments thereof will be described in more detail herein below with reference to the drawings, wherein:

(2) FIG. 1 is a perspective view of a dispensing package which has been constructed in accordance with a preferred embodiment of the present invention;

(3) FIG. 2 is a cross-sectional view of a lower or first subassembly of the dispensing package of FIG. 1, which includes a hollow body along with the take-up piston and base closure member;

(4) FIG. 3 is a partial cross-sectional view of an upper or second subassembly of the dispensing package of FIG. 1, which includes a dispensing head, a finger-operable pump, a holding member and a cap;

(5) FIG. 4 provides a side elevational view of the finger-operable pump of the upper subassembly, and a cross-sectional view of an o-ring gasket and the hollow body associated with the lower subassembly;

(6) FIG. 5 is a cross-sectional view of the dispensing head used in the dispensing package of FIG. 1, the dispensing head including a body portion and a shutter member;

(7) FIG. 6 is a cross-sectional view of the body portion of the dispensing head of FIG. 5;

(8) FIG. 7 is a perspective view taken from the rear side of the shutter member of the dispensing head of FIG. 5;

(9) FIG. 8 shows a study regarding the evolution of daily dispensed doses from 10 packagings over a six week cycle using an Albion 30 piston LDPE restitution 7.5 ml+EV09/240+Cocoon pre-filled with an imiquimod 3.75% cream (conditions are under vacuum) to simulate a patient's clinical treatment period of 222. In this study, a pump is first primed and then actuated once every day for 2 weeks, then left static for 2 weeks, and then again actuated once daily for 2 more weeks to examine dose amount dispensed following each actuation. This study involves three two cycles (222) and shows that each dose dispensed per single daily actuation during the first two week cycle and again during the third two week cycle was about 240 mg of imiquimod 3.75% cream. See also Attachment VI below.

(10) FIG. 9 shows a study regarding the evolution of daily dispensed doses from 10 packagings over a six week cycle using an Albion 30 piston LDPE restitution 15 ml+EV09/240+Cocoon pre-filled with an imiquimod 3.75% cream (conditions are under vacuum) to simulate a patient's clinical treatment period of 222. In this study, a pump is first primed and then actuated once every day for 2 weeks, then left static for 2 weeks, and then again actuated once daily for 2 more weeks to examine dose amount dispensed following each actuation. This study involves three two cycles (222) and shows that each dose dispensed per single daily actuation during the first two week cycle and again during the third two week cycle was about 240 mg of imiquimod 3.75% cream (see also Attachment VI below).

(11) FIG. 10 is a cross-sectional view of a further embodiment of a lower or first subassembly used in the dispensing package of the present invention, which includes a hollow body along with the take-up piston and base closure member (see also Attachment VII below); and

(12) FIG. 11 is a partial cross-sectional view of a further embodiment of an upper or second subassembly used in the dispensing package of the present invention, which includes a dispensing head, a finger-operable pump, a holding member and a cap (no compressed neck gasket) (see also Attachment VII below).

(13) FIG. 12 is a graphic representation of subject accountability (external genital warts).

(14) FIG. 13 is a perspective view of a proper methodology for utilizing the pump in accordance with the disclosure.

(15) These and other aspects of the subject invention will become more readily apparent to those having ordinary skill in the art from the following detailed description of the invention taken in conjunction with the drawings and examples.

DETAILED DESCRIPTION

(16) Disclosed herein are detailed descriptions of specific embodiments of the devices, systems and methods for storing and dispensing unit doses of a topical semi-sold imiquimod pharmaceutical formulation, such as an imiquimod cream. It will be understood that the disclosed embodiments are merely examples of the way in which certain aspects of the invention can be implemented and do not represent an exhaustive list of all of the ways the invention may be embodied. Indeed, it will be understood that the pump systems, devices, methods and package assemblies described herein may be embodied in various and alternative forms. The figures are not necessarily to scale and some features may be exaggerated or minimized to show details of particular components. Well-known components, materials or methods are not necessarily described in great detail in order to avoid obscuring the present disclosure. Any specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the invention.

(17) Thus, by way of illustrating and providing a more complete appreciation of the present invention and many of the attendant advantages thereof, the following detailed description and examples are given concerning the novel methods and compositions.

(18) Unless otherwise indicated, all numbers expressing quantities, ratios, and numerical properties of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term about.

(19) All parts, percentages, ratios, etc. herein are by weight unless indicated otherwise.

(20) As used herein, the singular forms a or an or the are used interchangeably and intended to include the plural forms as well and fall within each meaning, unless expressly stated otherwise. Also as used herein, at least one is intended to mean one or more of the listed elements. Singular word forms are intended to include plural word forms and are likewise used herein interchangeably where appropriate and fall within each meaning, unless expressly stated otherwise. Except where noted otherwise, capitalized and non-capitalized forms of all terms fall within each meaning.

(21) The compound imiquimod is a known antiviral agent that is also known to induce interferon biosynthesis. It can be prepared using the method disclosed in U.S. Pat. No. 4,689,338, the disclosure of which is incorporated herein by reference in its entirety. The compound can be used to treat dermal and/or mucosal-associated conditions, such as external genital and perianal warts (EGWs), actinic keratoses (AKs) or superficial basal cell carcinoma (sBCC). The amount of imiquimod present in a topical semi-solid imiquimod pharmaceutical formulation of the present invention will be an effective amount to treat a dermal and/or mucosal-associated condition, for example, (a) EGWs, (b) AKs or (c) sBCC, as described herein. An example of an effective amount of imiquimod in a formulation of the present invention is between about 1. percent and about 10 percent by weight based on the total weight of a formulation, more preferably between about 2.5% and 5%, and more preferably about 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75% and 5%, even more preferably between about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75% and 4.0%, and still even more preferably between about 2.5%, 2.75%, 3.0%, 3.25%, 3.5% and 3.75%. Imiquimod formulations of the present invention that contain about 2.5% imiquimod, about 3.75% imiquimod or about 5% imiquimod by weight based on the total weight of the formulations are most preferred.

(22) By the term bioequivalence or bioequivalent, as used herein, it refers to topical semi-solid imiquimod pharmaceutical formulations in which they are pharmaceutically equivalent and their bioavailabilities (rate and extent of absorption) after administration in the same molar dosage or amount are similar to such a degree that their therapeutic effects, as to safety and efficacy, are essentially the same. In other words, bioequivalence or bioequivalent means the absence of a significant difference in the rate and extent to which imiquimod becomes available from such formulations at the site of imiquimod action when administered at the same molar dose under similar conditions, e.g., the rate at which imiquimod can leave such a formulation and the rate at which imiquimod can either cross the stratum corneum and/or become available at the site of action to treat a dermal and/or mucosal-associated condition, e.g., EGWs, AKs or sBCC. In other words, there is a high degree of similarity in the bioavailabilities of two topical semi-solid imiquimod pharmaceutical formulations (of the same galenic form) from the same molar dose, that are unlikely to produce clinically relevant differences in therapeutic effects, or adverse reactions, or both. The terms bioequivalence, as well as pharmaceutical equivalence and therapeutic equivalence are also used herein as defined and/or used by (a) the FDA, (b) the Code of Federal Regulations (C.F.R.), Title 21, and/or (c) Health Canada.

(23) By the term bioavailability or bioavailable, as used herein, it means generally the rate and extent of absorption of imiquimod into the systemic circulation and, more specifically, the rate or measurements intended to reflect the rate and extent to which imiquimod becomes available at the site of action or is absorbed from a topical semi-solid imiquimod pharmaceutical formulation and becomes available at the site of action. In other words, and by way of example, the extent and rate of imiquimod absorption from a topical semi-solid imiquimod pharmaceutical formulation of the present invention as reflected by a time-concentration curve of imiquimod in systemic circulation.

(24) By pharmaceutical equivalence or pharmaceutically equivalent, as used herein, it refers to topical semi-solid imiquimod pharmaceutical formulations of the present invention that contain the same amount of imiquimod, in the same dosage forms, but not necessarily containing the same inactive ingredients, for the same route of administration and meeting the same or comparable compendia or other applicable standards of identity, strength, quality, and purity, including potency and, where applicable, content uniformity and/or stability.

(25) By therapeutic equivalence or therapeutically equivalent, it is meant herein to mean those topical semi-solid imiquimod pharmaceutical formulations which (a) will produce the same clinical effect and safety profile when practicing treatment regimens to treat a dermal and/or mucosal-associated condition, namely, EGWs, AKs or sBCC, in accordance with the present invention and (b) are pharmaceutical equivalents, e.g., they contain imiquimod in the same dosage form, they have the same route of administration; and they have the same imiquimod strength. In other words, therapeutic equivalence means that a chemical equivalent of a topical semi-solid imiquimod pharmaceutical formulation of the present invention (i.e., containing the same amount of imiquimod in the same dosage form) when administered to the same individuals in the same dosage regimen will provide essentially the same efficacy and toxicity.

(26) The topical semi-solid imiquimod pharmaceutical formulations, such as the topical imiquimod pharmaceutical creams, according to the present invention can be applied to any suitable location, for example, applied topically to dermal and/or mucosal surfaces. In the case of dermal application, for example, depending on the imiquimod concentration, formulation composition, and dermal surface, the therapeutic effect of imiquimod may extend only to the superficial layers of the dermal surface or to tissues below the dermal surface. Thus, another aspect of the present invention is directed to a method for the treatment of a dermal and/or mucosal-associated condition comprising applying to skin one of the imiquimod creams via a pump system of the present invention. As used herein, a dermal and/or mucosal-associated condition means an inflammatory, infectious, neoplastic or other condition that involves a dermal and/or mucosal surface or that is in sufficient proximity to a dermal and/or mucosal surface to be affected by a therapeutic agent topically applied to the surface. Examples of a dermal and/or mucosal-associated condition include warts, atopic dermatitis, postsurgical scars, lesions caused by a herpes virus, and epidermal neoplasias, such as for example actinic keratosis, pre-actinic keratosis lesions, malignant melanomas, basal cell carcinoma, and squamous cell carcinoma.

(27) In some embodiments, the topical semi-solid imiquimod pharmaceutical formulations, e.g., topical imiquimod pharmaceutical creams, are particularly advantageous for use with the pump systems of the present invention for dermal and/or mucosal application for a period of time sufficient to obtain a desired therapeutic effect without undesired systemic absorption of the imiquimod.

(28) In view of the above, it should be understood by those versed in this art that the present invention contemplates pump systems and methods for storing and dispensing consistent and uniform unit dose amounts of an effective topical semi-solid imiquimod pharmaceutical formulation, and more particularly to pump systems, pre-filled with any effective topical semi-solid imiquimod pharmaceutical formulation, and methods for delivering a precisely measured unit dose amount of any effective topical semi-solid imiquimod pharmaceutical formulation, and still more particularly to pump systems pre-filled with an effective topical semi-solid imiquimod pharmaceutical formulation, and methods for using a controlled delivery pump to store and dispense multiple unit doses of an effective topical semi-solid imiquimod pharmaceutical formulation for use in treating dermal and mucosal-associated conditions, such as, EGWs, AKs and sBCC. It should therefore be understood by those versed in this art that the present invention also contemplates pump systems pre-filled with an effective topical semi-solid imiquimod pharmaceutical formulation that is bioequivalent, pharmaceutically equivalent and/or therapeutically equivalent to, for example, Aldara (imiquimod) 5% cream, Zyclara (imiquimod) 3.75% cream or a 2.5% imiquimod cream or any imiquimod formulation set forth herein, or which meets or has the same imiquimod bioavailability as, for example, Aldara (imiquimod) 5% cream, Zyclara (imiquimod) 3.75% cream, or a 2.5% imiquimod cream or any other imiquimod formulation set forth herein, as defined by the FDA, the C.F.R. and/or Health Canada.

(29) For ease of description, the components of this invention are described in an upright operating position, and terms such as upper, lower, front, rear, horizontal, etc., are used with reference to this position. It will be understood, however, that the components of this invention may be manufactured, stored, transported, used and sold in an orientation other than the positions described herein.

(30) FIGs. illustrating the components show some mechanical elements that are known and will be recognized by one skilled in the art. The detailed descriptions of such elements are not necessary to an understanding of the invention, and accordingly, are herein presented only to the degree necessary to facilitate an understanding of the novel and unique features of the present invention.

(31) Referring now to FIG. 1, which illustrates a dispensing package which has been constructed in accordance with a preferred embodiment of the present invention and is designated generally by the reference numeral 10. As will be discussed herein below, package 10 is specially adapted for storing and dispensing unit doses of a topical semi-solid imiquimod pharmaceutical formulation, such as an imiquimod cream formulation.

(32) The dispensing package 10 includes a dispensing head 20 having a projecting, finger-operable pump 22 (see FIGS. 3 and 4) and an external actuator button or plunger 24. The pump 22 is a non-venting type that has a pump chamber in which is disposed a pressurizing piston that can be actuated by pressing down on plunger 24, so as to dispense a quantity of the fluid product from a dispensing orifice or self-closing slit 26, which will be described in greater detail herein below.

(33) An optional cover or cap 40 may be releasably mounted over dispensing head 20. The cap 40 is shown as molded from a substantially transparent material. However, in many applications, the cap 40 is preferably made from any suitable opaque material.

(34) The dispensing package 10 includes a tubular structure or hollow body 50 for containing the imiquimod cream. The hollow body 50 is illustrated in the figures as being made from a substantially transparent material, such as a transparent thermoplastic material. However, in many applications, the body is preferably made from any suitable opaque material.

(35) The body 50 most typically would have a circular, transverse cross section. However, the hollow body 50 may have an oval shape, or some other shape, wherein the internal, transverse cross section is substantially uniform along most of its length.

(36) As shown in FIG. 2, the bottom of the hollow body 50 has an open end which is normally closed by a base closure member 52, which defines one or more apertures 54. The closure member 52 has a transverse cross-section corresponding generally to the transverse cross section of the hollow body 50. The closure member 52 is typically secured to the bottom of the hollow member 50 by means of a snap-fit engagement, by adhesive, or by other suitable means. However, prior to securing the closure member 52 to the hollow body 50, a follower or take-up piston 60 is inserted into the lower, open end of the hollow body 50. The piston sealingly engages the interior surface of the hollow body 50 and is adapted to slidingly move axially upwardly in the hollow body 50. The piston 60 can thus function as a take-up piston for moving toward the pump 22 at the upper, discharge end of the hollow body 50.

(37) The take-up piston 60 moves toward the pump 22 at the discharge end of the body 50 in response to the discharge of any amount of fluid, such as imiquimod cream, from the body 50 so as to decrease the internal volume of the body 50 by an amount equal to the volume of the amount of fluid product which is discharged, i.e., the unit-dose amount. The movement of the piston 60 is effected by the atmospheric pressure of the ambient air which acts against the exterior, bottom surfaces of the piston 60. It will be appreciated that the vent passages 54 in the bottom end closure member 52 insure that the ambient atmosphere will be in continuous contact with the exterior of the piston 60 regardless of how far the piston 60 travels up in the hollow body 50.

(38) The particular design and configuration of the take-up piston 60 are matters of design choice consistent with the configuration used for the hollow body 50. Any suitable conventional or special piston design may be employed. The details of the design per se of such a piston 60 form no part of the present invention. It should be noted that the initial position of the piston within the hollow body 50 is dictated by the total amount of imiquimod cream to be supplied to the patient based on the anticipated dosing regimen. For example, if it is desired to dispense to the patient 15 g of imiquimod cream, the piston would be initially located lower than the setting for 7.5 g of cream.

(39) The upper, discharge end of the body 50 defines a reduced-diameter neck 56. The upper end of the neck defines an external, peripheral shoulder 58. The side of the neck defines an annular, outwardly open groove 59. The distal end of the neck 56 defines an upwardly projecting, annular rim 57 at the inside diameter of the shoulder 58. In a preferred embodiment, the hollow body 50 is injection molded from a suitable thermoplastic material.

(40) The hollow body 50, along with the take-up piston 60 and base closure member 52, may be characterized as the lower subassembly or first subassembly. However, in some applications, the base closure member 52 may be omitted altogether from the first, or lower, subassembly. In any event, after the lower subassembly has been assembled, it can be filled with the imiquimod cream, and then the additional package components, comprising an upper subassembly or second subassembly as described below, are installed on the filled, first subassembly.

(41) Referring now to FIG. 3, there is illustrated the second subassembly or upper subassembly, which is designed for being mounted to the lower subassembly and comprises at least three components; a finger operable pump 22, a dispensing head 20; and a holding member 70. The dispensing head 20 may be regarded as part of the pump 22. Additional components are also preferably included in the upper subassembly, and such additional components may include a gasket 80 (FIG. 4) and the cap or cover 40 (FIG. 3).

(42) The exterior of the pump 22 is designed to be mounted within the holding member 70, along with the gasket 80 if the gasket is employed. Specifically, the pump 22 has a radially extending mounting flange 28 (FIGS. 3 and 4). The pump 22 may also include one or more bosses or ribs (not shown) which are spaced above the pump flange 28 to define an annular recess between the flange 28 and the ribs and can be used to secure the pump 22 to the holding member 70.

(43) The internal pumping mechanism of the pump 22 may be of any appropriate conventional or special non-venting design. Typically, a conventional, non-venting pump (airless), such as the pump 22 illustrated in the figures, has an interior chamber (not visible) which has a check valve at the lower end and in which is disposed a pressurizing piston (not visible). The pressurizing piston is arranged to cooperate with a hollow stem 30 which extends out through the top of the body of the pump 22 and which is received within the pump actuator button 24.

(44) The stem 30 and the piston within the pump body can move downwardly together in the pump chamber, but the hollow stem 30 can also move for some distance separately relative to the piston, so as to establish communication through the hollow stem 30 between the pump chamber and the actuator button 24. One or more springs (not visible in the figures) act against the piston and/or stem 30 inside the pump body to bias the piston, stem 30, and actuator button 24 upwardly to an elevated rest position when finger pressure is released. As will be discussed in more detail herein below, when the actuator button 24 is pressed, an unit-dose amount of product is dispensed from the pump 22.

(45) One conventional non-venting pump that may be employed in accordance with the present invention is the pump designated EV09/240 and sold by Valois S.A., 50 Avenue de L'Europe, 78160 Marly le roi, France. It will be appreciated, however, that the detailed design and operation of the internal components of such a pump, which may be employed for the pump 22 described herein, form no part of the present invention.

(46) The holding member 70 includes a peripheral, convex shroud 72 providing a pleasing, external configuration. The bottom of the shroud 72 has a laterally projecting flange or shoulder 74. At four locations around the shroud 72 above the flange 74, there are small, outwardly projecting protuberances (not shown) which are adapted to establish a snap-fit engagement in an annular groove formed in the interior bottom of the cap or cover 40. The cap or cover 40 and/or the lower portion of the holding member shroud 72 are resiliently deflectable, so as to accommodate relative movement between the cap 40 and shroud 72 as the cap 40 is installed on the package. The cap 40 and/or shroud 72 deflect sufficiently so that the cap bead can be located below, and adjacent, the protuberances of the holding member shroud 72. This confronting relationship establishes the snap-fit engagement.

(47) Projecting downwardly from the shroud 72 of the holding member 70 is an annular sleeve 76. See FIG. 3. The sleeve 76 defines an opening, bore, or passage for accommodating the annular neck 56 of the hollow body 50 and for accommodating the upwardly projecting portion of the pump 22.

(48) An annular flange 78 extends radially inwardly from the holding member annular sleeve 76 for engaging the upper surface of the pump flange 28. See FIG. 3. The sleeve 76 also includes an inwardly extending bead 77 for being received in the annular groove 59 defined in the hollow body neck 50.

(49) Typically, the pump 22 is initially disposed in the holding member 70, along with the gasket 80, if employed. To this end, the installation is accomplished with the pump actuator 24 initially removed from the pump. Relative movement between the pump 22 and the holding member 77 is effected so as to introduce the pump into the holding member 70 from the bottom end of the holding member.

(50) As noted above, prior to mounting the two subassemblies together, the lower subassembly is filled with the topical semi-solid imiquimod pharmaceutical formulation, such as an imiquimod cream formulation. This can be conveniently done pursuant to a conventional or special filling process which is typically performed under vacuum. Preferably, vacuum (i.e., a reduced pressure) is created by a suitable vacuum system around the body 50. The air below the piston 60 within the body 50 is evacuated through the vent holes/apertures 54 in the base closure member 52 of the body 50. Then the fluid product is discharged from a filling machine into the hollow body 50 through the opening in the body neck 56. Next, with vacuum still enveloping the components, the upper subassembly (comprising the pump 22, holding member 70, gasket 80 if employed, and cap 40 if employed) is moved into position on the lower subassembly hollow body 50 so as to establish the snap-fit engagement between the hollow body 50 and holding member 70.

(51) The particular process and detailed operation of filling the body 50 and mounting the upper subassembly on the lower subassembly form no part of the present invention.

(52) When the two subassemblies are properly mounted together as shown in FIG. 1, the pump flange 28 urges the gasket 80 into sealing engagement with the upper end of the body neck rim 57. However, depending upon the materials employed in the construction of the pump 22 and/or body rim 57 or neck 56, the gasket 80 may either be omitted altogether or be included as a unitary part of either the pump flange 28 or the upper end of the body neck 56.

(53) The set of components provided according to the present invention can be readily manufactured from material which is compatible with the imiquimod cream. Provided below are the results of a stability studies which have been conducted to ensure certain polymeric materials are compatible with an imiquimod cream.

(54) The set of components can be readily assembled to provide a compact package which is clean, safe, reliable, simple and easy-to-use to dispense consistent and uniform unit-dose amounts of a topical semi-solid imiquimod pharmaceutical formulation, such as an imiquimod cream, to treat a dermal and/or mucosal-associated condition. Except for the removable cap 40, the components are not readily disassembled, and the completed package protects a topical semi-solid imiquimod pharmaceutical formulation from degradation, oxidation, and/or external contaminants.

(55) Referring now to FIG. 5, it provides a cross-sectional view of dispenser head 20. In the embodiment shown in the FIGs., the dispenser head 20 is made up of two component elements, namely a body 90, FIG. 6, and a shutter 100, FIG. 7. The two elements may be made by injecting suitable plastics materials into appropriate molds. The body 90 is preferably made of a plastics material that is harder or stiffer than the shutter 100.

(56) The body 90, which is preferably integrally molded in one piece, comprises a push top wall 92 which serves a pusher surface against which one or more fingers of one hand can be applied and can exert a pressing force. In this example, the top wall 92 has a complex shape that is both rounded and inclined. This is an ergonomic shape for the position of a finger with the tip phalanx of the finger placed on the highest portion of the top wall 92. In addition, the body 90 forms a peripheral side skirt 94 which extends from the top wall 92 downwards. The skirt 94 has a configuration that is also complex, but that is substantially cylindrical.

(57) Where the top wall 92 is at its highest, the skirt 94 forms a join surface 96 that is exactly plane in this example. The join surface 96 is provided with plurality of openings or slots, as is described below. Shutter 100, described below, is designed to be mounted on the body 90 at the join surface 96.

(58) The body 90 of dispensing head 20 internally defines a connection sleeve 98 serving to receive the top end of the hollow stem 30 of pump 22. The socket formed by the connection sleeve 98 may be of the force-fitting type or of the snap-fastening type. The rod-receiving socket is extended by a dispensing duct 114 which defines an axial inlet 116. This inlet is disposed on a vertical longitudinal axis Y which coincides with the axis of the dispenser member and of its actuating rod. Naturally, the inlet 116 is open facing downwards so as to communicate with the socket formed by the connection sleeve 98 in which the top end of the hollow stem 30 of pump 22 is to be engaged.

(59) In many cases, the body 90, and more generally the dispenser head 20, is mounted to rotate about said vertical axis Y. The dispensing duct 114 also forms a radial passageway 118 which opens out at the join surface 96 via an outlet 120. The outlet 120 and the passageway 118 that connects the inlet 116 to the outlet 120 extend along a dispensing or outlet axis X. The outlet axis X extends substantially perpendicularly to the vertical longitudinal axis Y. However, the axis X may extend slightly or significantly upwards or downwards relative to the axis Y.

(60) Join surface 96 includes a circular groove 124 which extends from the join surface 96 into the body 90 in substantially the same direction as the outlet axis X. The groove 124 thus forms a sort of annular trench whose depth extends horizontally.

(61) As explained below, the function of said groove 124 is to provide sealing with the shutter 100. The shutter 100 forms a dispensing spout 130 internally forming an outlet or dispensing chamber 132. The chamber 132 terminates at self-closing slit 26 that forms a dispensing orifice. The self-closing slit 28 has edges that are in touching leak-tight contact in the rest position, i.e., whenever the chamber 132 does not contain any fluid subjected to a pressure higher than a threshold pressure making it possible to separate the edges of the slit and thus to open the self-closing slit 28. In the embodiment shown in the FIGS., the bottom surface 134 of the dispensing chamber 132 is inclined upwards and thus constitutes a convergence wall suitable for directing the fluid under pressure towards the dispensing orifice.

(62) Fixing catches 125a and 125b extend from the rear of the shutter 100 and secure the shutter to the body 90 in snap-fit engagement. In the non-limiting embodiment, there are a bottom catch 125a and two side catches 125b. The three catches extend from the rear of the shutter 100 around the sealing lip 126.

(63) The shutter 100 is fitted to the body 90 by causing the catches 125A and 125b to penetrate into respective holding recesses formed in the body 90. When the shutter 100 is fitted to the body 90, the sealing lip 126 is caused to be pressed into the groove 124 so as to come into leak-tight contact with the two side walls of said groove, and advantageously also with the end-wall thereof. Leak-tight contact is thus obtained at three points that have very good sealing quality, since the lip is in tight-fitting engagement between the two facing side walls.

(64) Once the package is filled, the priming of the actuator allows the imiquimod product to fill into the pump 22 and the dispensing duct 114. Once the pump 22 is fully primed with imiquimod product, each additional actuation will cause a precise dosage amount of the imiquimod product to be dispensed. Moreover, each actuation causes the take-up piston 60 to rise until ultimately, the piston reaches the top of the package and empties and remaining product.

(65) A series of trials were conducted to determine the suitability of the dispensing device for use with topical imiquimod pharmaceutical cream. A series of pump systems were evaluated for 2.5%, 3.75% and 5% w/w imiquimod creams targeting a pump system that could deliver approximately 250 mg of the product per actuation mimicking the dosage/delivery of the commercially available single use 250 mg packets or sachets.

(66) Two pump system constructions were evaluated: Albion EV09/1500-30 mL (hereinafter Albion) and VP39/70 pl-15 mL Digital Actuator Nova Pump EV09/150 (Nova). Like the previously described dispensing package, the Albion pump system includes a tubular base member in which a topical imiquimod pharmaceutical cream is retained. The Nova pump system stores a topical imiquimod pharmaceutical cream in an aluminum pouch.

(67) One difference between these two pumps are how they are designed to operate and the product contact materials used to manufacture the respective pump components. In order to determine which, if either, pump design and product contact components are best suited for consistently and uniformly dispensing precise unit-dose amounts of the 2.5%, 3.75% and 5% w/w imiquimod pharmaceutical creams, even after use interruption and storage for a period of time, a series of performance tests, filling trials and stability studies are conducted.

(68) While the topical semi-solid imiquimod pharmaceutical formulations of the present invention can be formulated into any form known to the art, such as a cream, an ointment, a gel or a lotion, it should be understood that such semi-solids may be packaged into the multi-dose, pump systems of the present invention for treatment of a dermal and/or mucosal-associated condition, such as EGWs, AKs or sBCC. A packaged amount of a topical semi-solid imiquimod pharmaceutical formulation contemplated by the present invention includes any suitable packaged amount, for completing one or more treatment regimens for treating a dermal and/or mucosal-associated condition, such as EGWs, AKs or sBCC, such as an amount between about 5 grams and 30 about grams, more preferably about 5 grams, about 7.5 grams, about 10 grams, about 12.5 grams, about 15 grams, about 17.5 grams, about 20 grams, about 22.5 grams, about 25 grams, about 27.5 grams, about 30 grams or more, and more preferably about 7.5 grams and about 15 grams. An actuated unit-dose amount of a topical semi-solid imiquimod formulation that may be dispensed from a pump system of the present invention includes any effective unit-dose amount for treating a prescribed dermal and/or mucosal condition discussed herein above, such as an actuated unit dose amount of about 125 mg to about 500 mg or more, and preferably about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 240 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 500 mg or more, and more preferably about 240 mg or about 250 mg per actuation.

(69) As indicated herein above, the present invention also contemplates bioequivalent or interchangeable topical semi-solid imiquimod pharmaceutical formulations. By way of an example, bioequivalent or interchangeable dosage strength topical semi-solid imiquimod pharmaceutical formulations, as contemplated by the present invention, include topical semi-solid imiquimod pharmaceutical formulations that have respective comparable in-vivo serum profiles, i.e., wherein the in-vivo parameters are either the same or may vary up to about 25% or more, when such a 2.5%, 3.75% or 5% topical semi-solid imiquimod pharmaceutical formulation is topically administered daily to the same individual in the same dosage regimen in accordance with dosage regimens described herein to treat a dermal and/or mucosal-associated condition, such as external or perianal warts, actinic keratosis or superficial basal cell carcinoma. In other words, two or more topical semi-solid imiquimod pharmaceutical formulations having the same imiquimod concentration but different formulations will be considered bioequivalent or interchangeable if their respective in-vivo parameters are either the same or vary up to about 25% or more, when such topical semi-solid imiquimod pharmaceutical formulations are topically administered daily to an individual in the same dosage regimen in accordance with dosage regimens described herein to treat a dermal and/or mucosal-associated condition, such as EGWs, AKs or sBCC carcinoma.

(70) By way of an example, bioequivalent or interchangeable 3.75% dosage strength topical semi-solid imiquimod pharmaceutical formulations, as contemplated by the present invention, include topical semi-solid 3.75% imiquimod pharmaceutical formulations that have comparable in-vivo serum profiles, i.e., wherein the following in-vivo parameters are either the same or may vary up to about 25% or more, when approximately 500 mg of each such formulation (about 18.75 mg imiquimod) or less is applied daily for 21 days to an AK treatment area of about 200 cm2 on the face or balding scalp between about day 8 and day 14 and, selected from one or more of the following in-vivo serum profiles:

(71) (a) a Day 21 T.sub.max of from about 4 hours to about 16 hours and preferably a mean T.sub.max of about 7.4 hours with a standard deviation (SD) of about 3.5, a median T.sub.max of about 9 hours and a geometric mean T.sub.max of about 6.6 hours and a coefficient of variation (CV) of about 48%;

(72) (b) a Day 21 C.sub.max of from about 0.07 to about 0.6 ng/ml and preferably a mean C.sub.max of about 0.3 ng/ml with a standard deviation of about 0.16, a median C.sub.max of about 0.35 and a geometric mean C.sub.max of about 0.27 ng/ml and a coefficient of variation of about 49%;

(73) (c) a Day 21 T.sub.1/2 of from about 9.7 to about 84 hours and preferably a mean T.sub.1/2 of about 29.3 hours with a standard deviation of about 17, a median T.sub.1/2 of about 25.6 hours and a geometric mean T.sub.1/2 of about 26 hours and a coefficient of variation of about 58%;

(74) (d) a Day 21 AUC.sub.10-24 of from about 1.1 to about 12 ng.Math.hr/ml and preferably a mean AUC.sub.0-24 of about 6 ng.Math.hr/ml with a standard deviation of about 3, a median AUC.sub.0-24 of about 7 ng.Math.hr/ml and a geometric mean AUC.sub.0-24 of about 5 ng-hr/ml and a coefficient of variation of about 52%;

(75) (e) a Day 21 z of from about 0.008 hr.sup.1 to about 0.07 hr.sup.1 and preferably a mean z of about 0.03 hr.sup.1 with a standard deviation of about 0.01, a median z of about 25.6 hr.sup.1 and a geometric mean z of about 0.03 hr.sup.1 and a coefficient of variation of about 49%;

(76) (f) a Day 21 C.sub.min of from about 0.06 to about 0.4 and preferably a mean C.sub.min of about 0.20 with an SD of about 0.11, a median C.sub.min of about 0.19 and a geometric mean C.sub.min of about 0.17 and a coefficient of variation of about 55%;

(77) (g) at Day 14/7 (a ratio of the trough concentration at Day 14 over the trough concentration at Day 7), a trough concentration geometric mean ratio of about 1.09 with a 90% confidence interval (CI) within a range of between about 0.8 and about 1.5;

(78) (h) at Day 21/14 (a ratio of the trough concentration at Day 21 over the trough concentration at Day 14), a trough concentration geometric mean ratio of about 1.33 with a 90% confidence interval (CI) within a range of between about 0.9 and about 1.9;

(79) (i) at Day 22/21 (a ratio of the trough concentration at Day 22 over the trough concentration at Day 21) a trough concentration geometric mean ratio of about 0.93 with a 90% confidence interval (CI) within a range of between about 0.6 and about 1.3;

(80) (j) a mean peak imiquimod serum concentration of about 0.323 ng/ml at Day 21;

(81) (k) a Day 21 RAUC of from about 1 to about 7 and preferably a mean RAUC of about 4 with a standard deviation of about 2, a median RAUC of about 3.5 and a geometric mean RAUC of about 3.3 and a coefficient of variation of about 56%;

(82) (l) a Day 21 RC.sub.max of from about 0.5 to about 5 and preferably a mean RC.sub.max of about 3 with a standard deviation of about 1.5, a median RC.sub.max of about 2.7 and a geometric mean RC.sub.max of about 2.4 and a coefficient of variation of about 54%;

(83) (m) a Day 21 Lz.sub.eff of from about 0.006 hr.sup.1 to about 0.08 hr.sup.1 and preferably a mean Lz.sub.eff of about 0.02 hr.sup.1 with a standard deviation of about 0.02, a median Lz.sub.eff of about 0.01 hr.sup.1 and a geometric mean Lz.sub.eff of about 0.16 hr.sup.1 and a coefficient of variation of about 97%; and

(84) (n) a Day 21 T.sup.1/2.sub.eff of from about 8 hr to about 110 hr and preferably a mean T.sup.1/2.sub.eff of about 55 hr with a standard deviation of about 36, a median T.sup.1/2.sub.eff of about 50 hr and a geometric mean T.sup.1/2.sub.eff of about 42 hr.sup.1 and a coefficient of variation of about 66%.

(85) By way of another example, bioequivalent or interchangeable topical semi-solid 3.75% imiquimod pharmaceutical formulations contemplated by the present invention include topical semi-solid 3.75% imiquimod pharmaceutical formulations that, when approximately 250 mg of each such topical semi-solid imiquimod pharmaceutical formulation (about 9.375 mg imiquimod) or less is applied daily for 21 days to EGWs in the genital/perianal area with a total wart area of greater than or equal to 100 mm.sup.2, provide a comparable in-vivo serum profile selected from one or more of the following:

(86) (a) a Day 21 mean T.sub.max of about 9.7 hours with a standard deviation (SD) of about 4.0, a median T.sub.max of about 12 hours and a geometric mean T.sub.max of about 8.3 hours and a coefficient of variation (CV) of about 41%;

(87) (b) a Day 21 mean C.sub.max of about 0.488 ng/ml with a standard deviation of about 0.368, a median C.sub.max of about 0.45 and a geometric mean C.sub.max of about 0.39 ng/mL and a coefficient of variation of about 75%;

(88) (c) a Day 21 T.sub.1/2 of from about 6.8 to about 54 hours and preferably a mean T.sub.1/2 of about 24.1 hours with a standard deviation of about 12, a median T.sub.1/2 of about 22.8 hours and a geometric mean T.sub.1/2 of about 21 hours and a coefficient of variation of about 51%;

(89) (d) a Day 21 AUC.sub.0-24 of from about 1.9 to about 14 ng-hr/mL and preferably a mean AUC.sub.0-24 of about 6.8 ng.Math.hr/mL with a standard deviation of about 3.6, a median AUC.sub.0-24 of about 6.6 ng.Math.hr/mL, and a geometric mean AUC.sub.0-24 of about 5.8 ng-hr/mL and a coefficient of variation of about 53%;

(90) (e) a day 21 z of from about 0.013 hr.sup.1 to about 0.102 hr.sup.1 and preferably a mean z of about 0.037 hr.sup.1 with a standard deviation of about 0.02, a median z of about 0.03 hr.sup.1 and a geometric mean z of about 0.03 hr.sup.1 and a coefficient of variation of about 60%;

(91) (f) a Day 21 C.sub.min of from about 0.025 to about 0.47 and preferably a mean C.sub.min of about 0.158 with an SD of about 0.121, a median C.sub.min of about 0.14 and a geometric mean C.sub.min of about 0.11 and a coefficient of variation of about 77%;

(92) (g) at Day 14/7 (a ratio of the trough concentration at Day 14 over the trough concentration at Day 7), a trough concentration geometric mean ratio of about 1.13 with a 90% confidence interval (CI) within a range of between about 0.7 and about 1.7;

(93) (h) at Day 21/14 (a ratio of the trough concentration at Day 21 over the trough concentration at Day 14), a trough concentration geometric mean ratio of about 0.84 with a 90% confidence interval (CI) within a range of between about 0.5 and about 1.3;

(94) (i) at Day 22/21 (a ratio of the trough concentration at Day 22 over the trough concentration at Day 21) a trough concentration geometric mean ratio of about 1.12 with a 90% confidence interval (CI) within a range of between about 0.7 and about 1.6;

(95) (j) a mean peak imiquimod serum concentration of about 0.488 ng/mL at Day 21;

(96) (k) a Day 21 RAUC of from about 0.6 to about 7 and preferably a mean RAUC of about 2.2 with a standard deviation of about 1.8, a median RAUC of about 1.8 and a geometric mean RAUC of about 1.7 and a coefficient of variation of about 81%;

(97) (l) a Day 21 RC.sub.max of from about 0.5 to about 5 and preferably a mean RC.sub.max of about 2.3 with a standard deviation of about 1.6, a median RC.sub.max of about 1.7 and a geometric mean RC.sub.max of about 1.8 and a coefficient of variation of about 70%;

(98) (m) a Day 21 Lz.sub.eff of from about 0.006 hr.sup.1 to about 0.09 hr.sup.1 and preferably a mean Lz.sub.eff of about 0.04 hr.sup.1 with a standard deviation of about 0.03, a median Lz.sub.eff of about 0.03 hr.sup.1 and a geometric mean Lz.sub.eff of about 0.03 hr.sup.1 and a coefficient of variation of about 69%;

(99) (n) a Day 21 T.sup.1/2.sub.eff of from about 8 hr to about 111 hr and preferably a mean T.sup.1/2.sub.eff of about 31 hr with a standard deviation of about 30, a median T.sup.1/2.sub.eff of about 22 hr and a geometric mean T.sup.1/2.sub.eff of about 23 h.sup.1 and a coefficient of variation of about 97%;

(100) (o) a Day 21 C.sub.max in female patients about 61% higher in female subjects than in male subjects (0.676 versus 0.420 ng/mL) and total systemic exposure AUC 0-24 8% higher in female subjects than in male subjects (7.192 versus 6.651 ng-hr/mL) when data is not dose normalized;

(101) (p) a Day 21 C.sub.max in female patients about 35% higher than in male subjects (0.583 versus 0.431 ng/mL) and AUC 0-24 about 6% lower in female subjects than in male subjects (6.428 versus 6.858 ng-hr/mL) when using dose normalization to adjust for differences in dosage and reported without subjects who missed an application of study drug during the last week of dosing; and/or

(102) (q) a median T.sub.max occurring approximately twice as quickly in female subjects (about 6.50 hours) as in male subjects (about 12.0 hours).

(103) In accordance with the present invention, mean peak serum concentrations are achieved with the topical semi-solid imiquimod pharmaceutical formulations of the Examples (see also Attachments I-XV) when topically applied as discussed herein throughout. For example, a mean peak serum concentration of about 0.488 ng/mL is achieved with a 3.75% dosage strength imiquimod pharmaceutical formulation 202 of Example 21 after about 9.4 mg of imiquimod is applied to the affected treatment area each day for up to 8 weeks.

(104) Examples of various embodiments of the present invention will now be further illustrated with reference to the following examples. Thus, the following examples are provided to illustrate the present invention, but are not intended to be limiting thereof. Parts and percentages are by weight unless otherwise specified. Examples of topical imiquimod cream and ointment compositions contemplated by the present invention are described in U.S. Pat. No. 4,689,338 and U.S. Pat. No. 5,238,944, which are incorporated herein by reference in their entireties. Percent modifications for, e.g., imiquimod and vehicle, to generate imiquimod formulations as described herein are likewise contemplated by the present invention. In addition, the formulations described and disclosed in U.S. Pat. No. 7,655,672, U.S. Patent Publication No. 2007/0123558, Ser. No. 11/276,324, U.S. Patent Publication No. 2007/0264317, U.S. Ser. No. 11/433,471, U.S. Patent Publication No. 2007/0900550 and PCT Publication No. W02008098232 (A1), are also contemplated by the present invention and are incorporated herein by reference in their entireties.

EXAMPLE 1

Pump Performance Attribute Tests

(105) A series of pump performance attribute testing is conducted to assess the best pump design for, for example, by weight 2.5%, 3.75% and 5% w/w imiquimod creams, such as described in Examples 16 and 20. The performance attributes tests and respective acceptance criteria are described below.

(106) A. Priming:

(107) The purpose of this test is to determine the number of actuations necessary to start observing delivery of the product dispensed from the actuator. Additionally, the number of pump depressions, i.e., the number of depressions/actuations required until the first full dose is delivered is also monitored.

(108) Acceptance Criteria:

(109) The number of actuations to start observing delivery of the product dispensed from the actuator must be less than or equal to 5 actuations.

(110) B. Dosage Reproducibility:

(111) The purpose of this test is to measure the doses restituted by the pump and verify the consistency of the dose value with time. Pumps are actuated manually.

(112) Acceptance Criteria:

(113) For each pump, the average of 10 individual dose values must be within about 10% of the pumps nominal value of about 240 mg and each individual dose value must be within about 15% of the pump's nominal value of about 240 mg.

(114) C. Sealing Integrity Under Vacuum:

(115) The purpose of this test is to evaluate the sealing integrity of a specific pump and container configuration when placed under vacuum. The sealing integrity of a pump corresponds to its ability to retain the product in the container and play its role in the closure of the system. Unprimed pump samples are filled with the product to be tested, are positioned horizontally for about 20 minutes at room temperature in a vacuum chamber at about 24 Hg depression.

(116) Acceptance Criteria:

(117) There must be no visual sign of leakage.

(118) D. Weight Loss at Atmospheric Pressure:

(119) The purpose of this test is to evaluate the sealing integrity of each pump and container configuration stored under specific conditions. For this test, filled samples are weighed, stored at specific conditions and then weighed again to measure for any weight loss.

(120) Acceptance Criteria:

(121) Weight loss values must typically not exceed about 0.3% after 4 weeks at room temperature and about 1.0% after about 4 weeks at about 45 C. (based on the total weight of the package).

(122) E. Restitution Rate:

(123) The purpose of this test is to determine the portion of product delivered by a package after the pump can no longer dispense any product and compare it to the quantity of product used to fill the package.

(124) Acceptance Criteria:

(125) The restitution rates depend on the type of package and the type of filling (airless or atmospheric).

(126) F. Dose Through Life:

(127) This test measures the dose restituted by the pump/device mechanism during each actuation until the container is empty. Devices are manually actuated.

(128) Acceptance Criteria:

(129) The overall average of the dose value must be within about 10% of the pump's nominal dose value of about 240 mg of product. Each individual dose value must be within about 15% of the pump's nominal dose value. The pump is considered to have met the Dose through life criteria if it provides about 240 mg of product and if it meets restitution rate criteria.

(130) G. Loss of Prime:

(131) The purpose of this test is to evaluate the ability of a pump to retain its prime over a specific storage time. The loss of prime is defined as the amount of product that returns from the dose chamber back into the container after storage in an upright position. Shot weights are measured before and after storage to determine the loss of prime and the percentage of dose retained.

(132) Acceptance Criteria:

(133) The pump must retain its prime during storage. The percentage of dose retained (ratio of dose after storage to dose before storage) must be more than about 85% in order to deliver a consistent, uniform and effective dosage amount.

(134) H. Gasket Swelling:

(135) This test measures the change in thickness of the gasket following storage in contact with the product. Relevant sets of gaskets (two gaskets per set) with the same chemical composition and similar thickness are stored at about 45 C. for about 8 weeks containers filled with product to be tested. The samples are stored at about 45 C. at about 1, about 4 and about 8 weeks interval are tested for the thickness of the gaskets at about room temperature. Additionally, the following conditions are observed: gaskets' deformation and color change in product or gaskets; samples will be compared with a control sample.

(136) Acceptance Criteria:

(137) The swelling of the gasket should be not more than about 15%. Also there should be no shrinking and no discoloration of the gasket and the product.

(138) I. Migration:

(139) The purpose of this test is to check that the pigments in a colored plastic material do not migrate into the customer's formulation. After priming, samples will be stored at about 45 C. for about 1 week. On each day, two samples will be actuated and the dispensed bulk will be compared to the control sample. Additionally after about 4 weeks at about 45 C. all samples will be emptied and bulk will be compared to the control sample. The dispensed product will be examined and inspected for the presence of pigments that might have migrated from the actuator or for any color modification of the bulk when compared to the bulk dispensed by the control sample.

(140) Acceptance Criteria:

(141) It is considered that migration has occurred if the presence of colored pigments is observed in the tested product when compared to the product dispensed by the controlled samples.

(142) J. Corrosion of the Metal Components:

(143) The purpose of this test is to assess the compatibility between the active formulation and the pump metal components after being in contact for a specific period of time.

(144) Corrosion of the Pump Metal Components is defined as the oxidation of pump metal components when exposed to the active formulation. Relevant components (spring(s) and stainless steel ball) will be stored in containers in intimate contact with product, at ambient temperature and elevated temperature (about 45 C./75% RH). Components will be inspected at 3 days, 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks and 24 weeks. Components are inspected for oxidation on the pump metal components at each time point.

(145) Acceptance Criteria:

(146) The results are verified against the reference sample.

(147) K. Discoloration of Formulation:

(148) The purpose of this test is to assess the compatibility between the product and the pump components after being in contact with the product for a specific period of time. Discoloration of Formulation is defined as the change of color of active formulation when in contact with pump components for a specific amount of time. The components will be stored in containers at ambient temperature and elevated temperature (about 45 C./75% RH). Change of color in the active product will be examined at 3 days, 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks and about 24 weeks at Room Temperature and about 45 C./75% RH.

(149) Acceptance Criteria:

(150) The results are verified against the reference sample.

(151) L. Pouch Compatibility (Nova System Only):

(152) The purpose of this test is to verify the compatibility of a pouch foil material with the formulation after 4 weeks of aging at about 45 C. in terms of welding resistance and physical appearance. After aging, each sample will be cut into two 15 mm strip film and a total of 10 test strips is obtained. Strips will be measured for the split force using the dynamometer. Samples will be visually inspected to verify the absence of physical defects such as de-lamination, blistering or spotting.

(153) Acceptance Criteria:

(154) Pull force that is required to split the welded parts of the foil must be about 1.5 Kg minimum and no physical defects are observed after storage for about 4 weeks at 45 C.

EXAMPLE 2

Pump Filling Trials

(155) A series of pump filling trials were conducted at two different facilities. In both facilities the filling process and equipment were identical. In each process, the cream formulation is filled under vacuum into the container barrel using volumetric dose pumps. The barrel and the pump head or upper assembly with the actuator is joined (snapped on) to the pump body under vacuum. This packaging process enables delivery of a precise quantity of product by depression of the pump mechanism, avoiding any contact with air.

(156) The filling trials as well as any salient observations and conclusions for each trial are described below.

(157) A. Filling Trial #s F008-08 and F009-08 at Facility I

(158) Initial fill trials are conducted on the Albion pump system to determine the capability of the filling equipment to fill the creams and also the flowability of the cream during the filling process. The pump body and the stem are made of polybutylene terephthalate, the actuator is made of polypropylene homopolymer/low density polyethylene and the piston is made of high density polyethylene material.

(159) A fill weight of about 7.5 g and about 15 g are selected for these trial runs. These fill weights correspond to the quantity of cream necessary to provide a full course of therapy to the patient depending on which indication is being treated. The filling trial runs prove that Imiquimod cream about 2.5% w/w (Lot #GJB070) manufactured by 3M, Loughborough, UK, can successfully be packaged using the airless filling process per Valois filling parameters.

(160) The filling trials prove that the about 2.5% w/w cream can be successfully filled into the pumps. However, it is also noted that filling issues causing lower pump delivery values, i.e., shot weight, are caused by air bubbles entrapped in the bulk cream. This problem is corrected by avoiding introduction of air during the transfer of the product from the storage drum to the filling hopper.

(161) All performance tests and physical stability screening data support that the Albion Pump Model Albion 30 ml EV09/150 pl and VP39/70 l-15 ml Digital actuator can be successfully filled and warrant further development.

(162) B. Filling Trials #s 2027 Through 2324 at Facility II

(163) These series of trials focuses on selecting which Albion and/or Nova Pump Model to commercialize, pump fill overages that are required to ensure a about 7.5 gm and about 15 gm pump delivery, pump actuator size, use of a cocoon tip, and contact materials to be used in each respective pumps. In addition, several of the package presentations are placed on RT and accelerated conditions to help select the most compatible pump design for Imiquimod about 2.5%, about 3.75% and about 5% w/w cream.

(164) The trials and corresponding observations are discussed below:

(165) 1.) Filling #s 2022 (about 2.5%) and 2026 (about 3.75%)about 7.5 g Fill Weight.

(166) Albion 15 ml pump with standard actuator, standard piston and about 150 l dosing is filled with imiquimod cream about 2.5% w/w (lot #GJJ067) and imiquimod cream about 3.75% w/w (Lot #GJJ068). The piston is made of high density polyethylene and the position of the piston inside the pump is set to deliver about 7.5 g.

(167) The product-components compatibility are satisfactory but the weight loss for about 4 weeks at about RT and loss of prime at about 1 week are not acceptable in both trials.

(168) 2.) Filling #s 2023 about (2.5%) and 2027 (about 3.75%)about 15 g Fill Weight.

(169) Albion 15 ml pump with standard actuator, standard piston and about 150 l dosing is filled with imiquimod cream about 2.5% w/w (lot #GJJ067) and imiquimod cream about 3.75% w/w (Lot #GJJ068). The piston is made of high density polyethylene and the position of the piston inside the pump was set to deliver about 15 g.

(170) The product-components compatibility is satisfactory but loss of prime at about 2 weeks is not acceptable in both trials.

(171) 3.) Filling #s 2024 (about 2.5%)about 7.5 g Fill Weight.

(172) Nova 15 ml with aluminum pouch pack standard actuator about 150 l is filled with about 7.5 g of Imiquimod cream about 2.5% w/w (Lot #GJJ067).

(173) During the testing it is observed that the pouch material is delaminating and not suitable for this cream product. It is theorized that the high concentration (about 20%) of isostearic acid in the cream formulation causes the delamination of these pouches.

(174) 4.) Filling #s 2025 (about 2.5%)about 15 g Fill Weight.

(175) Nova 30 ml with aluminum pouch pack standard actuator about 150 l with pouch is filled with about 15 g of about 2.5% w/w of the cream (Lot #GJJ067).

(176) On testing, it is observed that the pouch material is delaminating and not suitable for this cream product.

(177) 5.) Filling #s 2028 (about 3.75%)about 7.5 g Fill Weight.

(178) Nova 15 ml with aluminum pouch pack standard actuator about 150 l with pouch is filled with about 7.5 g of about 3.75% of the cream (Lot #GJJ068).

(179) On testing it is observed that the pouch material is delaminating and not suitable for this cream product.

(180) 6.) Filling #2029 (about 3.75%)about 15 g Fill Weight.

(181) Nova 30 ml with aluminum pouch pack standard actuator about 150 l with pouch is filled with about 15 g of the cream (Lot #GJJ068).

(182) On testing, it is observed that the pouch material is delaminating and not suitable for this cream product.

(183) 7.) Filling #2060 (about 5.0%)about 7.5 g Fill Weight.

(184) Albion 15 ml piston pump with standard actuator dosage about 150 l with the position of the piston inside the pack set to deliver about 7.5 g is filled with Aldara Cream 5% w/w (lot #GJF033).

(185) The product-components compatibility is satisfactory but loss of prime at 2 week is not acceptable.

(186) 8.) Filling #2061 (about 5.0%)about 15 g Fill Weight.

(187) Albion 15 ml piston pump with standard actuator dosage about 150 l with the position of the piston inside the pack set to deliver about 15 g is filled with Aldara Cream about 5% w/w (lot #GJF033).

(188) The product-components compatibility is satisfactory but loss of prime at about 1 week is not acceptable.

(189) 9.) Filling #2062 (about 5%)about 7.5 g Fill Weight.

(190) Nova 15 ml with aluminum pouch pack standard actuator about 150 l with pouch is filled with about 7.5 g of Aldara Cream about 5% w/w (Lot #GJF033).

(191) Delamination of pouch material and loss of prime at about 2 weeks are not acceptable.

(192) 10.) Filling #2063 (about 5%)about 15 g Fill Weight.

(193) Nova 30 ml with aluminum pouch pack standard actuator about 150 l with pouch is filled with about 15 g of Aldara Cream about 5% w/w (Lot #GJF033).

(194) Delamination of pouch material and loss of prime at about 2 days are not acceptable.

(195) 11.) Filling #2084 (about 2.5%)about 15 g Fill Weight.

(196) Albion 15 ml EV09/240 l pump with standard actuator dosage about 240 l to deliver about 240 mg shot weight is filled with low strength Imiquimod cream about 2.5% w/w (Lot #GJJ067).

(197) All physical test results are acceptable but there is a trend for loss of prime to decrease. However at about 4 weeks, the loss of prime is about 85.2% which is at the lower limit (about 85.0%) of the specification for loss of prime.

(198) 12.) Filling #s 2085 (3.75%)about 15 g Fill Weight.

(199) Albion 15 ml EV09/about 240 l pump with standard actuator dosage about 240 l to deliver about 40 mg shot weight is filled with low strength Imiquimod cream about 3.75% w/w (lot #GJJ068).

(200) All the physical test results are acceptable; however loss of prime at 4 weeks testing is at about 78.2% which fails the acceptance criteria limit of about 85.0%.

(201) 13.) Filling #2103 (5%)about 15 g Fill Weight.

(202) Albion 15 ml EV09/about 240 l pump with standard actuator dosage about 240 l with the position of the piston inside the pack set to deliver about 15 g is filled with imiquimod cream about 5% w/w (lot #GJF033).

(203) All the physical test results are acceptable but loss of prime at about 4 weeks testing is at about 79.5% and fails the acceptance criteria limit of about 85.0%.

(204) Summary of Trials #s 2022-2103.

(205) Based on the results from trials #2022, 2023, 2024, 2025, 2026, 2027, 2028, 2029, 2060, 2061, 2062, 2063, 2084, 2085 and 2103, there is a potential for failure for loss of prime using the standard actuator. It is theorized that these failures are attributable to the possibility of drying of the cream at the exposed tip of actuator nozzle.

(206) To prevent the potential of drying of the cream and also protect the cream from the atmospheric environment, a pump with shutter or cocoon actuator is investigated. However, in order to utilize the cocoon actuator, the pump size is adjusted to from about 15 mL to about 30 mL.

(207) Pumps with a cocoon actuator in about 30 mL volume pump are subsequently tested. These pumps also utilize a piston made of low density polyethylene material (standard), while the pumps that are tested previously used high density polyethylene pistons. Initial tests are carried out with pumps with low density polyethylene pistons to check for performance of the pump with the cream.

(208) 14.) Filling #2274 (about 3.75%)about 7.5 g Fill Weight.

(209) Filling #2275 (about 3.75%)about 15 g fill weight.

(210) Albion 30 mL pump EV9/about 240 l equipped with a cocoon actuator dosage about 240 l with the piston made up of low density polyethylene are filled at about 7.5 g and about 15 g fill weights using Imiquimod cream about 3.75% w/w (Lot #GJJ068). The fill weights are determined to be about 10.5 grams with the restitution rate of about 7.5 g and about 18 g with the restitution rate of about 15 g as almost about 3 g of the cream is held back in the dosing chamber. All pumps have their piston moved to the position during the snapping of the actuator unit to avoid empty space on the top of the pump barrel.

(211) Once again, Study #s 2274 and 2275 utilizing pumps with standard piston made of low density polyethylene material, where as all previous studies are conducted using pistons made up of high density polyethylene material.

(212) All the physical test results are acceptable and loss prime at about 4 weeks testing is at about 95.8% and about 96.6% respectively thus possibly confirming the earlier theory that the failure for loss prime may be attributed to drying of the cream at nozzle tip once actuated. The use of the cocoon actuator or shutter surprisingly and unexpectedly, but successfully, corrected the loss of prime issue.

(213) 15.) Filling #2324 (about 3.75%)about 7.5 g Fill Weight.

(214) This study is initiated with Albion 30 mL Pump EV9/about 240 l and cocoon actuator with piston made of high density polyethylene material (the pump body and the stem are made of polybutylene terephthalate, the actuator is made of polypropylene homopolymer/low density polyethylene and the piston is made of high density polyethylene material). The pump is filled with Imiquimod cream about 3.75% w/w (lot #GJJ068). Based on evaluating the restitution rate, it is estimated that approximately 3 g of the cream is left in the pump chamber. As a result, a fill weight of about 10.5 g is required to meet about 7.5 g Label claim.

(215) The main goal of this study is to prove that the change of piston material from low density to high density polyethylene material does not affect the performance of the pump systems of the present invention.

EXAMPLE 3

Stress and Stability Testing Results

(216) A. Stress Testing/Stability Results

(217) Several observations are made during the stress testing of the about 2.5%, about 3.75% and about 5% w/w imiquimod creams filled in the above filling trials (#2022 to #2029).

(218) The observations are as follows:

(219) 1. Delamination is observed of the Nova laminated pouch material when it is stored at accelerated conditions (i.e. about 40 C.). This leads to discontinuing any further development work with this pump model.

(220) 2. Loss of prime in both Nova and Albion pump models is observed after one week of storage. This is surprisingly corrected by using the Albion pump with cocoon actuator.

(221) B. Stability Testing Results

(222) Several stability programs per ICH guidelines involving a series of pump options, components, fill weights and imiquimod creams are initiated.

(223) Table 2 illustrates the stability studies and the corresponding creams that are used, fill run number, lot number of bulk cream that is used, fill weight, pump model and packaging description.

(224) Described below is a summary of each of the stability studies that are conducted. The data collected for each stability study can be found in Attachments I-IV.

(225) TABLE-US-00002 TABLE 2 Table 2. Imiquimod Cream Stability Studies Imiquimod Bulk (IMQ) Fill Cream Stability Cream Run Lot Fill Package Study w/w # # Weight Pump Model Description GW 2.5% IMQ 2022 GJJ067 - 7.5 g Albion 7.5 g fill in 15 mL 805-01 2.5% EV09/150 - Albion pump with 1.5 mL 150 l actuator GW 2.5% IMQ 2023 GJJ067 - 15 g Albion 15 g fill in 15 mL 805-01 2.5% EV09/150 - Albion pump with 15 mL 150 l actuator GW 2.5% IMQ 2024 GJJ067 - 7.5 g Nova Pump 7.5 g fill in 15 mL 805-01 2.5% EV09/150 - Nova pump with 15 mL pouch 15 mL Aluminum pouch GW 2.5% IMQ 2025 GJJ067 - 15 G Nova Pump 15 g fill in 15 mL 805-01 2.5% EV09/150 - Nova pump with 30 mL 30 mL Aluminum pouch GW 3.75% IMQ 2026 GJJ068 - 7.5 g Albion 7.5 g fill in 15 mL 805-01 3.75% EV09/150 - Albion pump with 15 mL 150 l actuator GW 3.75% IMQ 2027 GJJ068 - 15 g Albion 15 g fill in 15 mL 805-01 3.75% EV09/150 - Albion pump with 15 mL 150 l actuator GW 3.75% IMQ 2028 GJJ068 - 7.5 g Nova Pump 7.5 g fill in 15 mL 805-01 3.75% EV09/150 - Nova pump with 15 mL pouch 15 mL Aluminum pouch GW 3.75% IMQ 2029 GJJ068 - 15 g Nova Pump 15 g fill in 15 mL 805-01 3.75% EV09/150 - Nova pump with 30 mL pouch 30 mL Aluminum pouch GW 5% Aldara 2080 GJF033 - 7.5 g Albion 7.5 g fill in 15 mL 906-01 5% EV09/150 - Albion pump with 15 mL 150 l actuator GW 5% Aldara 2081 GJF033 - 15 g Albion 15 g fill in 15 mL 906-01 5% EV09/150 - Albion pump with 15 mL 150 l actuator GW 5% Aldara 2082 GJF033 - 7.5 g Nova Pump 7.5 g fill in 15 mL 906-01 5% EV09/150 - Nova pump with 15 mL pouch 15 mL Aluminum pouch GW 5% Aldara 2083 GJF033 - 15 g Nova Pump 15 g fill in 15 mL 906-01 5% EV09/150 - Albion pump with 30 mL pouch 30 mL Aluminum pouch GW 2.5% IMQ 2084 GJJ067 - 15 g Albion 15 g fill in 15 mL 805-01 2.5% EV09/240 - Albion pump with 15 mL 240 l actuator GW 3.75% IMQ 2085 GJJ068 - 15 g Albion 15 g fill in 15 mL 907-01 3.75% EV09/240 - Albion pump with 15 mL 240 l actuator GW 5% Aldara 2103 GJF033 - 15 g Albion 15 g fill in 15 mL 907-01 5% EV09/240 - Albion pump with 15 mL 240 l actuator GW 3.75% IMQ 2274 GJJ068 - 7.5 g Albion 15 g fill in 30 mL 907-01 3.75% EV09/240 - Albion pump with 30 mL with 240 l cocoon cocoon actuator/PEBD piston GW 3.75% IMQ 2275 GJJ068 - 15 g Albion Albion EV09/240 - 921-01 3.75% EV09/240 - 30 mL with cocoon 30 mL with actuator/PEBD cocoon piston 15 g fill GW 3.75% IMQ 2324 GJJ068 - 7.5 g Albion Albion EV09/240 - 921-01 3.75% EV09/240 - 30 mL with cocoon 30 mL with actuator/PEHD cocoon piston 15 *The 2.5%, 3.75% and 5.0% imiquimod creams are isa cream formulation numbers 146, 202 and 16, respectively, and are the creams used in Examples 1-4, FIGS. 8 and 9 and Attachments I-XV, respectively.

(226) 1.) Stability Study GW 805-01-Summary.

(227) Several observation/conclusions can be drawn from this study.

(228) First, the delamination of the Nova pump pouch can be clearly viewed as early as about 2 months under accelerated conditions (about 40 C./75% RH).

(229) All other testing (imiquimod assay, viscosity, benzyl alcohol, methyl and propyl parabens, pH, and 4 hydroxy imiquimod) remain well within specification and within the trend that is observed in the stability data for each cream in the commercial sachets presentation. The n-oxide testing is not performed initially as the method is not developed, however the method is available for testing the samples that are stored for about 9 month period at about 25 C160 RH and no detectable levels of n-oxide are observed.

(230) This data can be seen in Attachment I.

(231) 2.) Stability Study GW 906-01-Summary.

(232) This study is conducted to determine the compatibility/stability of the Aldara about 5% w/w (imiquimod) cream formulation in both about 7.5 g and about 15 g fill weight in Albion and Nova pump systems. The stability of the formulations in both the Albion over about nine months and Nova pumps over about a three month period are consistent and passes all specifications. However, a notable difference in lower viscosities of the formulations at about T=0 and at subsequent time points can be observed which is due to the age (6 months) of the bulk cream that is used for filling trials. Furthermore, the internal surfaces of the pouch for the Nova pumps that is stored at about 40 C./75% RH are observed to delaminate after about 2 months at both fill volumes (about 7.5 and about 15 g), and are subsequently discontinued from testing after the about 3 month time point.

(233) The stability data up to and including about 9 months, indicates that the Albion pump at the fill volumes of about 7.5 and about 15 g with the Aldara about 5% w/w formulation is suitable for commercial use.

(234) Both fill volumes (about 7.5 and about 15 g) is stored in the Albion pumps at about 40 C. 175% RH for about 3 months passes the PET test for all organisms according to the European Pharmacopeia and for the organism E. coli, which is an additional requirement for the United States Pharmacopeia.

(235) All other testing (imiquimod assay, viscosity, benzyl alcohol, methyl and propyl parabens, pH, and 4 hydroxy imiquimod) remain well within specification and within the trend that is observed in the stability data for Aldara 5% w/w cream in the commercial sachets presentation.

(236) The samples are also analyzed using the n-oxide method following about 9 months storage at about 25 C./60% RH and no detectable levels of n-oxide are observed.

(237) This data is in Attachment II.

(238) 3.) Stability Study GW 907-01-Summary.

(239) The stability of the formulations in the Albion pump over about six months for all three concentrations of imiquimod (about 2.5%, about 3.75% and about 5% w/w) meet all specifications (imiquimod assay, viscosity, benzyl alcohol, methyl and propyl parabens, pH, and 4 hydroxy imiquimod) and compare well with the equivalent formulations that are stored in borosilicate glass vials over the same period of time. The results also demonstrate the same trends that are observed in the stability data for each cream in the commercial sachet presentation. However, a notable difference between the results in this study and those that are observed in other 2.5%, 3.75% and 5% w/w imiquimod creams. In the commercial sachet presentation are the lower viscosities of the formulations at about T=0 and the subsequent time points. This is the direct result of the age of the bulk cream (2 months) prior to filling.

(240) The samples are also analyzed using the n-oxide method following 9 months storage at about 25 C./60% RH and no detectable levels of n-oxide are observed.

(241) In addition, all the formulations that are stored in the Albion pumps at about 40 C./75 RH for about 3 months passes Preservative Efficacy Test (PET) for all organisms according to the European Pharmacopeia and for the organism E. coli which is an additional requirement for the United States Pharmacopeia. This data is in Attachment III.

(242) 4.) Stability Study GW 921-01-Summary.

(243) The stability of Imiquimod cream about 3.75% in Albion 30 mL EV09/about 240 l (the pump body and the stem are made of polybutylene terephthalate, the actuator is made of polypropylene homopolymer/low density polyethylene and the piston is made of high density polyethylene material). The pump is equipped with a cocoon actuator. The test results for samples that are stored for about 6 months at about 25 C./60% RH and about 40 C./75 RH meet all specifications (imiquimod assay, viscosity, benzyl alcohol, methyl and propyl parabens, pH, and 4 hydroxy imiquimod). In addition, the data compares well with the equivalent formulation that is stored in borosilicate glass vials over the same period of time and also within the trends that are observed in the stability data for each cream in the commercial sachet presentation. The data for top, middle and bottom samples that are taken for imiquimod, parabens indicate that the product is homogenous in the pump.

(244) All samples are also analyzed using the n-oxide method following 6 months storage at about 25 C./60% RH and about 40 C./75 RH. There are no detectable levels of n-oxide observed. This data is in Attachment IV.

EXAMPLE 4

Additional Studies Conducted

(245) A. USP Extractable Testing

(246) The pump delivery system, Albion 30 mL EV09/about 240 l is equipped with a cocoon actuator (pump body and the stem are made of polybutylene terephthalate, the actuator is made of polypropylene homopolymer/low density polyethylene and the piston is made of high density polyethylene material) that is selected for commercial use meets USP 32/NF 27 <661> Physicochemical Tests-Plastics, and USP <281> for Residue on Ignition.

(247) This report is provided in Attachment V.

(248) B. Patient in Use Test

(249) In addition to the tests discussed in this report, Albion 30 mL, EV09/about 240 l with cocoon actuator (the pump body and the stem are made of polybutylene terephthalate, the actuator is made of polypropylene homopolymer/low density polyethylene and the piston is made of high density polyethylene material) is tested to simulate the patient's clinical treatment period for 2 weeks on 2 weeks off and 2 weeks on. See FIGS. 8 and 9 and Attachment VI.

(250) In this study, the pump is primed and actuated once every day for 2 weeks and then left static for 2 weeks. At the end of 2 weeks of no pump actuation, the pump is again actuated for 2 more weeks to check if a consistent and uniform dosage amount of cream is available to patient for the treatment period. The results are acceptable as the pump provides approximately 240 mg cream for each daily application during all 4 weeks of the treatment. See FIGS. 8 and 9. The data is provided in the Attachment VI.

(251) C. Leak Test During Stability Study

(252) During the course of the stability studies (about 12 month time point for GW 805, 906, 907 and 9 months for GW 921), it is decided to place all pumps on their sides to monitor leaking and delivery performance.

(253) There is no leaking of the product from the pumps and all pumps delivery performance is acceptable.

(254) Based on the satisfactory physical, chemical and performance testing data, Albion 30 mL EV09/about 240 l cocoon actuator (the pump body and the stem are made of polybutylene terephthalate, the actuator is made of polypropylene homopolymer/low density polyethylene and the piston is made of high density polyethylene material) is remarkable and surprisingly acceptable and, therefore, selected for commercialization. In addition, the NDA registration stability batches using this pump filled at both about 7.5 g and about 15 g fill using 3.75% and 5% w/w imiquimod cream are manufactured and are placed on stability at 3M, Loughborough, UK. This pump system is covered under Valois's DMF number 18156 Albion 30 nil Piston Assembled Barrel+EV09/240 Pump+PR820 Cocoon Actuator+Cap. The pump parts, assembly and specifications are provided in Attachment VII. See also FIGS. 10 and 11.

EXAMPLE 5

Imiquimod Cream Formulation 5

(255) A cream according to the present invention is prepared from the following ingredients in Table 3.

(256) TABLE-US-00003 TABLE 3 Imiquimod Cream Formulation 5 Example 5 Example 5 Oil Phase % by Weight Amount 1-isobutyl-1H-imidazo[4,5- 1.0 40.0 g c]-quinolin-4-amine Isostearic acid 10.0 400.0 g Benzyl alcohol 2.0 80.0 g Cetyl alcohol 2.2 88.0 g Stearyl alcohol 3.1 124.0 g Polysorbate 60 2.55 102.0 g Sorbitan monostearate 0.45 18.0 g Aqueous Phase Glycerin 2.0 80.0 g Methylparaben 0.2 8.0 g Propylparaben 0.02 0.8 g Purified water 76.48 3059.2 g

(257) The materials listed above were combined according to the following procedure.

(258) The glycerin, methylparaben, propylparaben and water were weighed into a 4 liter glass beaker then heated on a hot plate with stirring until the parabens isostearic acid and 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine were weighed into an 8 liter stainless steel beaker and heated on a hot plate until the amine was in solution (the temperature reached 69 C.). The benzyl alcohol, cetyl alcohol, stearyl alcohol, polysorbate 60 and sorbitan monostearate were added to the isostearic acid solution and heated on a hot plate until all material was dissolved (the temperature reached 75 C.). With both phases at approximately the same temperature (65-75 C.), the water phase was added to the oil phase. The mixture was mixed with a homogenizer for 13 minutes then put into a cool water bath and mixed with a 3 inch propeller for 40 minutes (the temperature was 29 C.). The resulting cream was placed in glass jars.

EXAMPLES 6-13

Imiquimod Cream Formulations 6-13

(259) Using the general method of Example 5, the imiquimod cream formulations shown in Tables 4 and 5 are prepared.

(260) TABLE-US-00004 TABLE 4 Imiquimod Cream Formulations 6-9 % by Weight Exam- Exam- Exam- Exam- ple 6 ple 7 ple 8 ple 9 Oil Phase 1-isobutyl-1H-imidazo[4,5- 1.0 1.0 1.0 1.0 c]quinolin-4-amine Isostearic acid 10.0 10.0 5.0 5.0 Benzyl alcohol 2.0 Cetyl alcohol 1.7 Stearyl alcohol 2.3 Cetearyl alcohol 6.0 6.0 6.0 Polysorbate 60 2.55 2.55 2.55 2.55 Sorbitan monostearate 0.45 0.45 0.45 0.45 Brij 30.sup.a 10.0 Aqueous Phase Glycerin 2.0 2.0 2.0 2.0 Methylparaben 0.2 0.2 0.2 0.2 Propylparaben 0.02 0.02 0.02 0.02 Purified water 77.78 77.78 82.78 72.78 .sup.aBrij 30 (polyoxyethylene(4) lauryl ether) is available from ICI Americas, Inc.

(261) TABLE-US-00005 TABLE 5 Imiquimod Cream Formulations 10-13 % by Weight Exam- Exam- Exam- Exam- ple 10 ple 11 ple 12 ple 13 Oil Phase 1-isobutyl-1H-imidazo-[4,5- 1.0 1.0 1.0 1.0 c]quinolin-4-amine Isostearic acid 10.0 25.0 10.0 6.0 Benzyl alcohol 2.0 2.0 Cetyl alcohol 2.2 1.7 Stearyl alcohol 3.1 2.3 Cetearyl alcohol 6.0 6.0 Polysorbate 60 2.55 3.4 2.55 2.55 Sorbitan monostearate 0.45 0.6 0.45 0.45 Brij 30.sup.a 10.0 Aqueous Phase Glycerin 2.0 2.0 2.0 2.0 Methylparaben 0.2 0.2 0.2 0.2 Propylparaben 0.02 0.02 0.02 0.02 Purified water 67.78 60.48 79.78 79.78 .sup.aBrij 30 (polyoxyethylene(4) lauryl ether) is available from ICI Americas, Inc.

EXAMPLE 14

Imiquimod Cream Formulation 14

(262) A cream according to the present invention is prepared from the following ingredients in the following Table 6.

(263) TABLE-US-00006 TABLE 6 Imiquimod Cream Formulation 14 % by Weight Amount Oil Phase 1-isobutyl-1H-imidazo[4,5- 1.0 3.00 g c]quinolin-4-amine Isostearic acid 5.0 15.0 g White petrolatum 15.0 45.0 g Light mineral oil 12.8 38.4 g Aluminum stearate 8.0 24.0 g Cetyl alcohol 4.0 12.0 g Witconol 14.sup.a 3.0 9.00 g Acetylated lanolin 1.0 3.0 g Propylparaben 0.063 0.19 g Aqueous Phase Veegum K.sup.b 1.0 3.0 g Methylparaben 0.12 0.36 g Purified water 49.017 147.05 g .sup.aWitconol 14 (polyglyceryl4 oleate) is available from Witco Chemical Corp. Organics Division .sup.bVeegum K (colloidal magnesium aluminum silicate) is available from R. T. Vanderbilt Company Inc.

(264) The materials listed above were combined according to the following procedure: The 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and the isostearic acid were weighed into a glass jar and heated with occasional stirring until the amine was dissolved (the temperature reached 68 C.). To this solution was added, the petrolatum, mineral oil, aluminum stearate, cetyl alcohol, Witconol 14, acetylated lanoline and propylparaben. The mixture was heated to 75 C. In a separate beaker, the methylparaben and water were combined and heated until the paraben dissolved (the temperature reached 61 C.). The Veegum K was added to the aqueous solution and heated at 75 C. for 30 minutes while mixing with a homogenizer. With both phases at 75 C., the aqueous phase was slowly added to the oil phase while mixing with a homogenizer. Mixing was continued for 30 minutes while maintaining a temperature to about 80 C. The jar was then capped and the formulation was allowed to cool.

EXAMPLE 15

Imiquimod Ointment Formulation 15(a) and 15(b)

(265) An ointment according to the present invention is prepared from the ingredients in the following Table 7.

(266) TABLE-US-00007 TABLE 7 Imiquimod Ointment Formulation 15(a) Example 15(a) Example 15(a) % by Weight Amount 1-isobutyl-1H-imidazo [4,5- 1.0 0.20 g c]quinolin-4-Amine Isostearic acid 5.0 1.00 g Mineral oil 12.8 2.56 g White petrolatum 65.2 13.04 g Cetyl alcohol 4.0 0.80 g Acetylated lanolin 1.0 0.20 g Witconol 143.0 0.60 g Aluminum stearate 8.0 1.60 g

(267) The materials listed above are combined according to the following procedure.

(268) The 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and the isostearic acid were placed in a glass jar and heated with stirring until the amine was dissolved. The remaining ingredients were added and the resulting mixture was heated to 65 C. and then mixed while being allowed to cool to room temperature.

(269) Using the general procedure of Example 15, an ointment containing the ingredients in the following Table 8 is prepared.

(270) TABLE-US-00008 TABLE 8 Imiquimod Ointment Formulation 15(b) Example 15(b) Example 15(b) % by Weight Amount 1-isobutyl-1H-imidazo[4,5- 1.0 0.20 g c]quinolin-4-Amine Isostearic acid 6.0 1.20 g Polyethylene Glycol 400 55.8 11.16 g Polyethylene Glycol 3350 32.6 6.52 g Stearyl alcohol 4.6 0.92 g

EXAMPLES 16-18

Imiquimod Cream Formulations 16-18

(271) Creams of the present invention are prepared using the ingredients shown in Table 9. The Example 1 except that benzyl alcohol was used with the isostearic acid to dissolve the 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine.

(272) TABLE-US-00009 TABLE 9 Imiquimod Cream Formulations 16-18 Example 16 Example 17 Example 18 Amount % Amount % Amount % by Weight by Weight by Weight Oil Phase 1-isobutyl-1H-imidazo[4,5- 5.0 5.0 4.85 c]quinolin-4-amine Isostearic acid 25.0 25.0 24.3 Benzyl alcohol 2.0 2.0 1.94 Cetyl alcohol 2.2 2.2 1.16 Stearyl alcohol 3.1 3.1 1.75 Petrolatum 3.0 2.91 Polysorbate 60 3.4 3.4 4.13 Sorbitan monostearate 0.6 0.6 0.73 Stearic acid 9.71 Aqueous Phase Glycerin 2.0 2.0 1.94 Methylparaben 0.2 0.2 0.19 Propylparaben 0.02 0.02 0.02

EXAMPLES 19 and 20

Imiquimod Cream Formulations 19 and 20

(273) A cream according to the present invention is prepared from the ingredients in the following Table 10.

(274) TABLE-US-00010 TABLE 10 Imiquimod Cream Formulations 19 and 20 Example 19 Example 20 % by Weight % by Weight Amount Amount Oil Phase 1-isobutyl-1H-imidazo[4,5- 4.0 0.80 g c]quinolin-4-Amine Isostearic acid 20.0 4.00 g Benzyl alcohol 2.0 0.40 g Cetyl alcohol 2.2 0.49 g Stearyl alcohol 3.1 0.62 g Polysorbate 60 3.4 0.68 g Sorbitan monostearate 0.6 0.12 g Aqueous Phase 1-isobutyl-1H-imidazo[4,5- 1.0 0.2 g c]quinolin-4-amine Glycerin 2.0 0.4 g 85% Lactic acid 1.0 0.22 g Methylparaben 0.2 0.04 g Propylparaben 0.02 0.004 g Purified water 60.48 12.0 g

(275) The materials listed above are combined according to the following procedure: The isostearic acid and 0.8 g of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine or 1-(2-methylpropyl-1H-imidazo[4,5-c]quinolin-4-amine were combined in a glass jar and heated with stirring until the amine had dissolved. The remaining oil phase ingredients were added to this solution and the mixture was heated to about 70 C. The aqueous phase ingredients were weighed into a separate beaker and heated with stirring until the amine and the parabens had dissolved. With both phases at about 70 C., the water phase was added to the oil phase and mixed with a propeller until the mixture cooled to room temperature.

EXAMPLE 21

Imiquimod Cream Formulations 21-254

(276) Topical Imiquimod Pharmaceutical Cream Formulations

(277) TABLE-US-00011 TABLE 11 Lower Dosage Strength Imiquimod Cream Formulations 21-254 Excipients % w/w % w/w % w/w % w/w % w/w % w/w Formulation 21 22 23 24 25 26 Fatty acid* 15.00 15.00 15.00 20.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10 White petrolatum 1.00 3.00 2.00 3.00 6.00 3.00 Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00 Sorbitan Monostearate 0.60 0.60 0.60 0.60 1.00 1.00 Glycerin 2.00 2.00 5.00 2.00 5.00 3.00 Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75 Purified water 68.98 66.98 64.98 61.98 60.73 60.73 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.00 1.00 1.00 1.00 1.00 1.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 27 28 29 30 31 32 Fatty acid* 15.00 15.00 15.00 25.00 18.0 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40 Sorbitan Monostearate 0.60 0.60 1.00 0.50 1.00 0.60 Glycerin 2.00 5.00 5.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 66.98 60.98 60.98 57.08 58.98 55.78 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.00 1.00 1.00 1.00 1.00 1.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 33 34 35 36 37 38 Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40 Sorbitan Monostearate 0.60 0.2 0.60 0.60 0.60 0.60 Glycerin 2.00 3.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purified water 56.48 67.08 59.98 58.98 56.98 61.98 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.00 1.00 1.00 1.00 1.00 1.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 39 40 41 42 43 44 Fatty acid* 15.00 15.00 15.00 20.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10 White petrolatum 1.00 3.00 2.00 3.00 6.00 3.00 Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00 Sorbitan Monostearate 0.60 0.60 0.60 0.60 1.00 1.00 Glycerin 2.00 2.00 5.00 2.00 5.00 3.00 Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75 Purified water 68.73 66.73 64.73 61.73 60.48 60.48 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.25 1.25 1.25 1.25 1.25 1.25 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 45 46 47 48 49 50 Fatty acid* 15.00 15.00 15.00 25.00 18.0 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40 Sorbitan Monostearate 0.60 0.60 1.00 0.50 1.00 0.60 Glycerin 2.00 5.00 5.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 66.73 60.73 60.73 56.83 58.73 55.53 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.25 1.25 1.25 1.25 1.25 1.25 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 51 52 53 54 55 56 Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40 Sorbitan Monostearate 0.60 0.2 0.60 0.60 0.60 0.60 Glycerin 2.00 3.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purified water 56.23 66.83 59.73 58.73 56.73 61.73 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.25 1.25 1.25 1.25 1.25 1.25 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 57 58 59 60 61 62 Fatty acid* 15.00 15.00 15.00 20.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10 White petrolatum 1.00 3.00 2.00 3.00 6.00 3.00 Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00 Sorbitan Monostearate 0.60 0.60 0.60 0.60 1.00 1.00 Glycerin 2.00 2.00 5.00 2.00 5.00 3.00 Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75 Purified water 68.48 66.48 64.48 61.48 60.23 60.23 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.50 1.50 1.50 1.50 1.50 1.50 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 63 64 65 66 67 68 Fatty acid 15.00 15.00 15.00 25.00 18.0 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40 Sorbitan Monostearate 0.60 0.60 1.00 0.50 1.00 0.60 Glycerin 2.00 5.00 5.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 66.48 60.48 60.48 56.58 58.48 55.28 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.50 1.50 1.50 1.50 1.50 1.50 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 69 70 71 72 73 74 Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40 Sorbitan Monostearate 0.60 0.2 0.60 0.60 0.60 0.60 Glycerin 2.00 3.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purified water 55.98 66.58 59.48 58.48 56.48 61.48 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.50 1.50 1.50 1.50 1.50 1.50 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 75 76 77 78 79 80 Fatty acid* 15.00 15.00 15.00 20.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10 White petrolatum 1.00 3.00 2.00 3.00 6.00 3.00 Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00 Sorbitan Monostearate 0.60 0.60 0.60 0.60 1.00 1.00 Glycerin 2.00 2.00 5.00 2.00 5.00 3.00 Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75 Purified water 68.23 66.23 64.23 61.23 59.98 59.98 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.75 1.75 1.75 1.75 1.75 1.75 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 81 82 83 84 85 86 Fatty acid* 15.00 15.00 15.00 25.00 18.0 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40 Sorbitan Monostearate 0.60 0.60 1.00 0.50 1.00 0.60 Glycerin 2.00 5.00 5.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 66.23 60.23 60.23 56.33 58.23 55.03 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.75 1.75 1.75 1.75 1.75 1.75 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 87 88 89 90 91 92 Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40 Sorbitan Monostearate 0.60 0.2 0.60 0.60 0.60 0.60 Glycerin 2.00 3.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purified water 55.73 66.33 59.23 58.23 56.23 61.23 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 1.75 1.75 1.75 1.75 1.75 1.75 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 93 94 95 96 97 98 Fatty acid* 10.00 12.50 25.00 10.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.70 4.00 4.00 2.20 Stearyl alcohol 3.10 3.10 3.80 2.00 2.00 3.10 White petrolatum 5.00 5.00 3.00 3.40 2.80 3.00 Polysorbate 60 3.40 3.40 3.40 3.80 3.00 3.00 Sorbitan Monostearate 0.60 0.60 0.60 1.00 1.00 1.00 Glycerin 5.00 5.00 2.00 1.00 3.00 3.00 Xanthan gum 0.50 0.50 0.50 0.30 0.70 0.75 Purified water 65.98 63.48 54.78 70.28 64.28 59.73 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.00 2.00 2.00 2.00 2.00 2.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 99 100 101 102 103 104 Fatty acid* 10.00 12.50 25.00 10.00 15.00 25.00 Cetyl alcohol 2.20 2.20 2.70 4.00 4.00 2.70 Stearyl alcohol 3.10 3.10 3.80 2.00 2.00 3.80 White petrolatum 5.00 5.00 3.00 3.40 2.80 3.00 Polysorbate 60 3.40 3.40 3.40 3.80 3.00 3.40 Sorbitan Monostearate 0.60 0.60 0.60 1.00 1.00 0.60 Glycerin 5.00 5.00 2.00 1.00 3.00 2.00 Xanthan gum 0.50 0.50 0.50 0.30 0.70 0.50 Purified water 65.98 63.48 54.78 70.28 64.28 54.78 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.00 2.00 2.00 2.00 2.00 2.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 105 106 107 108 109 110 Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40 Sorbitan Monostearate 0.60 0.2 0.60 0.60 0.60 0.60 Glycerin 2.00 3.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purified water 55.48 66.08 58.98 57.98 55.98 60.98 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.00 2.00 2.00 2.00 2.00 2.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 111 112 113 114 115 116 Fatty acid* 15.00 12.50 25.00 15.00 10.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.00 2.00 2.20 Stearyl alcohol 3.10 3.10 3.10 2.00 2.40 3.10 White petrolatum 6.00 5.00 3.00 3.40 2.80 3.00 Polysorbate 60 3.00 3.00 3.40 3.80 3.80 3.00 Sorbitan Monostearate 1.00 1.00 0.60 0.20 1.00 1.00 Glycerin 5.00 5.00 2.00 3.00 3.00 3.00 Xanthan gum 1.00 0.50 1.00 0.30 0.30 0.75 Purified water 60.23 63.23 55.23 66.83 70.23 59.48 Benzyl alcohol 1.00 2.00 2.00 1.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.25 2.25 2.25 2.25 2.25 2.25 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 117 118 119 120 121 122 Fatty acid* 15.00 12.50 25.00 15.00 10.00 25.00 Cetyl alcohol 2.20 2.20 2.20 2.00 2.00 2.70 Stearyl alcohol 3.10 3.10 3.10 2.00 2.40 3.80 White petrolatum 6.00 5.00 3.00 3.40 2.80 3.00 Polysorbate 60 3.00 3.00 3.40 3.80 3.80 3.40 Sorbitan Monostearate 1.00 1.00 0.60 0.20 1.00 0.60 Glycerin 5.00 5.00 2.00 3.00 3.00 2.00 Xanthan gum 1.00 0.50 1.00 0.30 0.30 0.50 Purified water 60.23 63.23 55.23 66.83 70.23 54.53 Benzyl alcohol 1.00 2.00 2.00 1.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.25 2.25 2.25 2.25 2.25 2.25 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 123 124 125 126 127 128 Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40 Sorbitan Monostearate 0.60 0.2 0.60 0.60 0.60 0.60 Glycerin 2.00 3.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purified water 55.23 65.83 58.73 57.73 55.73 60.73 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.25 2.25 2.25 2.25 2.25 2.25 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 129 130 131 132 133 134 Fatty acid* 15.00 15.00 15.00 20.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10 White petrolatum 2.50 3.00 2.00 3.00 6.00 3.00 Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00 Sorbitan Monostearate 0.60 0.60 0.60 0.60 1.00 1.00 Glycerin 2.00 2.00 5.00 2.00 5.00 3.00 Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75 Purified water 65.98 65.48 63.48 60.48 59.23 59.23 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 135 136 137 138 139 140 Fatty acid* 15.00 15.00 15.00 25.00 18.0 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40 Sorbitan Monostearate 0.60 0.60 1.00 0.50 1.00 0.60 Glycerin 2.00 5.00 5.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 65.48 59.48 59.48 55.58 57.48 54.28 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 141 142 143 144 145 146 Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40 Sorbitan Monostearate 0.60 0.2 0.60 0.60 0.60 0.60 Glycerin 2.00 3.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purified water 54.98 65.58 58.48 57.48 55.48 60.48 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 147 148 149 150 151 152 Fatty acid* 15.00 18.00 15.00 20.00 12.50 20.00 Cetyl alcohol 2.00 2.00 2.00 2.00 2.20 2.20 Stearyl alcohol 2.00 2.00 2.40 2.40 3.10 3.10 White petrolatum 3.40 2.80 3.40 2.80 5.00 3.00 Polysorbate 60 3.00 3.80 3.00 3.00 3.40 3.00 Sorbitan Monostearate 1.00 1.00 0.20 0.20 0.60 1.00 Glycerin 3.00 2.00 1.00 3.00 6.00 3.00 Xanthan gum 0.30 0.70 0.70 0.30 0.50 0.75 Purified water 65.08 62.48 67.08 61.08 61.48 58.73 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.00 3.00 3.00 3.00 3.00 3.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 153 154 155 156 157 158 Fatty acid* 15.00 18.00 15.00 20.00 12.50 25.00 Cetyl alcohol 2.00 2.00 2.00 2.00 2.20 2.70 Stearyl alcohol 2.00 2.00 2.40 2.40 3.10 3.80 White petrolatum 3.40 2.80 3.40 2.80 5.00 3.00 Polysorbate 60 3.00 3.80 3.00 3.00 3.40 3.40 Sorbitan Monostearate 1.00 1.00 0.20 0.20 0.60 0.60 Glycerin 3.00 2.00 1.00 3.00 6.00 2.00 Xanthan gum 0.30 0.70 0.70 0.30 0.50 0.50 Purified water 65.08 62.48 67.08 61.08 61.48 53.78 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.00 3.00 3.00 3.00 3.00 3.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 159 160 161 162 163 164 Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40 Sorbitan Monostearate 0.60 0.2 0.60 0.60 0.60 0.60 Glycerin 2.00 3.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purified water 54.48 65.08 57.98 56.98 54.98 59.98 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.00 3.00 3.00 3.00 3.00 3.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 165 166 167 168 169 170 Fatty acid* 15.00 20.00 15.00 20.00 10.00 20.00 Cetyl alcohol 2.00 2.00 4.00 4.00 2.20 2.20 Stearyl alcohol 2.00 2.40 2.40 2.40 3.10 3.10 White petrolatum 3.40 2.80 2.50 3.40 5.00 3.00 Polysorbate 60 3.00 3.00 3.00 3.80 3.40 3.00 Sorbitan Monostearate 1.00 0.20 1.00 1.00 0.60 1.00 Glycerin 3.00 3.00 1.00 3.00 5.00 3.00 Xanthan gum 0.30 0.30 0.30 0.70 0.50 0.75 Purified water 64.83 60.83 65.33 57.23 64.73 58.48 Benzyl alcohol 2.00 2.00 2.00 1.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.25 3.25 3.25 3.25 3.25 3.25 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 171 172 173 174 175 176 Fatty acid* 15.00 20.00 15.00 20.00 10.00 25.00 Cetyl alcohol 2.00 2.00 4.00 4.00 2.20 2.70 Stearyl alcohol 2.00 2.40 2.40 2.40 3.10 3.80 White petrolatum 3.40 2.80 2.50 3.40 5.00 3.00 Polysorbate 60 3.00 3.00 3.00 3.80 3.40 3.40 Sorbitan Monostearate 1.00 0.20 1.00 1.00 0.60 0.60 Glycerin 3.00 3.00 1.00 3.00 5.00 2.00 Xanthan gum 0.30 0.30 0.30 0.70 0.50 0.50 Purified water 64.83 60.83 65.33 57.23 64.73 53.53 Benzyl alcohol 2.00 2.00 2.00 1.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.25 3.25 3.25 3.25 3.25 3.25 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 177 178 179 180 181 182 Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40 Sorbitan Monostearate 0.60 0.2 0.60 0.60 0.60 0.60 Glycerin 2.00 3.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purified water 54.23 64.83 59.98 56.73 54.73 59.73 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.25 3.25 3.25 3.25 3.25 3.25 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 183 184 185 186 187 188 Fatty acid* 15.00 10.00 12.50 19.00 20.00 20.00 Cetyl alcohol 2.00 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol 2.40 3.10 3.10 3.10 3.10 3.10 White petrolatum 3.40 5.00 5.00 3.00 3.00 3.00 Polysorbate 60 3.00 3.40 4.00 3.40 3.40 3.00 Sorbitan Monostearate 0.20 0.60 0.60 0.60 0.60 1.00 Glycerin 1.00 4.00 5.00 2.00 6.00 3.00 Xanthan gum 0.70 0.50 0.50 0.50 0.50 0.75 Purified water 66.58 65.48 61.38 60.48 56.48 58.23 Benzyl alcohol 2.00 2.00 2.00 2.00 1.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.50 3.50 3.50 3.50 3.50 3.50 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 189 190 191 192 193 194 Fatty acid* 15.00 10.00 12.50 19.00 20.00 25.00 Cetyl alcohol 2.00 2.20 2.20 2.20 2.20 2.70 Stearyl alcohol 2.40 3.10 3.10 3.10 3.10 3.80 White petrolatum 3.40 5.00 5.00 3.00 3.00 3.00 Polysorbate 60 3.00 3.40 4.00 3.40 3.40 3.40 Sorbitan Monostearate 0.20 0.60 0.60 0.60 0.60 0.60 Glycerin 1.00 4.00 5.00 2.00 6.00 2.00 Xanthan gum 0.70 0.50 0.50 0.50 0.50 0.50 Purified water 66.58 65.48 61.38 60.48 56.48 53.28 Benzyl alcohol 2.00 2.00 2.00 2.00 1.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.50 3.50 3.50 3.50 3.50 3.50 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 195 196 197 198 199 200 Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40 Sorbitan Monostearate 0.60 0.2 0.60 0.60 0.60 0.60 Glycerin 2.00 3.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purified water 53.98 64.58 57.48 56.48 54.48 59.48 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.50 3.50 3.50 3.50 3.50 3.50 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 201 202 203 204 205 206 Fatty acid* 20.00 20.00 25.00 18.75 20.00 21.25 Cetyl alcohol 4.00 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol 2.40 3.10 3.10 3.10 3.10 3.10 White petrolatum 2.80 3.00 3.00 5.00 5.00 3.75 Polysorbate 60 3.00 3.40 3.40 3.00 3.40 3.40 Sorbitan Monostearate 1.00 0.60 0.60 1.00 0.60 0.60 Glycerin 1.00 2.00 2.00 5.00 5.00 5.00 Xanthan gum 0.30 0.50 0.50 0.50 0.50 0.50 Purified water 64.53 59.23 54.23 55.48 54.23 54.23 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.75 3.75 3.75 3.75 3.75 3.75 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 207 208 209 210 211 212 Fatty acid* 20.00 20.00 20.00 25.00 18.75 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40 Sorbitan Monostearate 0.60 0.60 1.00 0.50 1.00 0.60 Glycerin 2.00 5.00 5.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 59.23 53.23 53.23 54.33 55.48 53.03 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.75 3.75 3.75 3.75 3.75 3.75 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 213 214 215 216 217 218 Fatty acid* 25.00 20.00 20.00 20.00 20.00 21.00 Cetyl alcohol 2.20 4.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.40 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 5.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40 Sorbitan Monostearate 0.60 1.00 0.60 0.60 0.60 0.60 Glycerin 2.00 3.00 2.00 5.00 5.00 5.00 Xanthan gum 1.00 0.70 0.50 0.50 0.50 0.50 Purified water 53.73 55.73 57.23 56.23 54.23 53.23 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.75 3.75 3.75 3.75 3.75 3.75 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 219 220 221 222 223 224 Fatty acid* 20.00 25.00 22.50 20.00 20.00 22.50 Cetyl alcohol 2.20 2.70 2.20 4.00 2.20 2.20 Stearyl alcohol 3.10 3.80 3.10 2.40 3.10 3.10 White petrolatum 6.00 3.00 3.00 3.40 5.00 4.00 Polysorbate 60 3.00 3.40 3.40 3.80 3.40 3.40 Sorbitan Monostearate 1.00 0.60 0.60 1.00 0.60 0.60 Glycerin 5.00 2.00 2.00 3.00 2.00 2.00 Xanthan gum 0.50 0.50 1.00 0.70 0.50 0.50 Purified water 52.98 52.78 55.98 55.48 56.98 55.48 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 4.00 4.00 4.00 4.00 4.00 4.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 225 226 227 228 229 230 Fatty acid* 20.00 25.00 22.50 20.00 20.00 22.50 Cetyl alcohol 2.20 2.70 2.20 4.00 2.20 2.20 Stearyl alcohol 3.10 3.80 3.10 2.40 3.10 3.10 White petrolatum 6.00 3.00 3.00 3.40 5.00 4.00 Polysorbate 60 3.00 3.40 3.40 3.80 3.40 3.40 Sorbitan Monostearate 1.00 0.60 0.60 1.00 0.60 0.60 Glycerin 5.00 2.00 2.00 3.00 2.00 2.00 Xanthan gum 0.50 0.50 1.00 0.70 0.50 0.50 Purified water 52.98 52.78 55.98 55.48 56.98 55.48 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 4.00 4.00 4.00 4.00 4.00 4.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 231 232 233 234 235 236 Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40 Sorbitan Monostearate 0.60 0.2 0.60 0.60 0.60 0.60 Glycerin 2.00 3.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purified water 53.48 64.08 56.98 55.98 53.98 58.98 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 4.00 4.00 4.00 4.00 4.00 4.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 237 238 239 240 241 242 Fatty acid* 15.00 15.00 15.00 20.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10 White petrolatum 1.00 3.00 2.00 3.00 6.00 3.00 Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00 Sorbitan Monostearate 0.60 0.60 0.60 0.60 1.00 1.00 Glycerin 2.00 2.00 5.00 2.00 5.00 3.00 Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75 Purified water 65.73 63.73 61.73 58.73 57.48 57.48 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 4.25 4.25 4.25 4.25 4.25 4.25 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 243 244 245 246 247 248 Fatty acid* 15.00 15.00 15.00 25.00 18.0 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40 Sorbitan Monostearate 0.60 0.60 1.00 0.50 1.00 0.60 Glycerin 2.00 5.00 5.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 63.73 57.73 57.73 53.83 55.73 52.53 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 4.25 4.25 4.25 4.25 4.25 4.25 Total 100.00 100.00 100.00 100.00 100.00 100.00 Formulation 249 250 251 252 253 254 Fatty acid* 25.00 15.00 20.00 20.00 20.0 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00 Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40 Sorbitan Monostearate 0.60 0.20 0.60 0.60 0.60 0.60 Glycerin 2.00 3.00 2.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purified water 53.23 63.83 56.73 55.73 53.73 58.73 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 4.25 4.25 4.25 4.25 4.25 4.25 Total 100.00 100.00 100.00 100.00 100.00 100.00 *The Fatty acid referenced in this Table 11 can be, for example, linoleic acid (la), stearic acid (sa), palmitic acid (pa), isostearic acid (isa), unrefined oleic acid, (uoa), refined oleic acid, such as super refined oleic acid (roa), or mixtures thereof.

(278) The materials listed below in this Example 21 are combined according to the following procedure to make cream formulations in the above Table 11 of this Example 21.

(279) The work area, all vessels and equipment is initially cleaned prior to commencing manufacture. A 2 L glass container and paddle stirrer blade are placed onto a balance and the weight is recorded. The paddle is then removed from the vessel. The isostearic acid and benzyl alcohol are weighed directly into the 2 L glass container. The imiquimod is then weighed into the 2 L glass container and a spatula is used to ensure the imiquimod is wetted with the isostearic acid and benzyl alcohol mixture. The 2 L container is then heated in a water bath to about 555 C. while stirring with a Heidolph mixer (Note: aluminum foil is placed around the top of the vessel and the paddle for the mixer, to limit evaporation). The solution is visually inspected to confirm the imiquimod has fully dissolved prior to mixing with cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60 and sorbitan monostearate.

(280) Cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60 and sorbitan monostearate are then weighed directly into the 2 L container and mixing is continued at about 555 C. until the oil phase is completely in solution. Separately, about 2 L of water are placed into a beaker and heated to 555 C. while stirring with a magnetic follower. Briefly, about 500 ml of the heated water is transferred into a 1 L beaker and placed into the water bath maintained at about 555 C.

(281) Half of the amount of glycerin required for the final formulation is then weighed into the beaker along with the total amount of methylparaben and propylparaben to the water (where both methyl and propyl paraben are weighed into weighing boats first, a pipette is used to remove a portion of the heated water to wash out the weighing boats to ensure total transfer of both the propyl- and methylparaben into the aqueous phase). The mixture is continuously stirred at about 555 C. (this is the aqueous phase).

(282) The remaining glycerin is then added to a 28 ml vial and the xanthan gum is added and mixed using a small overhead mixer (1KA-Werke Lab Egg) with paddle attachment for about 10 min.

(283) The glycerin and xanthan mixture are then added slowly into the vortex of the aqueous phase, and a further aliquot of about 20 ml of heated water is used to rinse the vessel out into the water phase to ensure complete transfer.

(284) The water phase is then heated and mixed at about 555 C. until the xanthan gum mixture is fully and evenly dispersed into the aqueous phase. The temperatures of both the water phase and oil phase are both maintained at about 555 C.

(285) The aqueous phase is then transferred into the oil phase and the speed of the Heidolph mixer is increased during addition. The mixture is then homogenized on high speed for about 3 min and transferred immediately back to the Heidolph mixture; however, the contents of the homogenized sample, about 2 L, are mixed at about room temperature and allowed to cool to about 35 C.

(286) The container and contents and the paddle from the overhead mixer are then re-weighed and the weight of the paddle and 2 L beaker, as determined above, are subtracted to determine the total weight of the formulation remaining.

(287) The total weight (about 1 kg) of the cream is then made up to weight with heated water (Note: water evaporated during heating, which needs to be corrected at this point). The mixture is then transferred back onto the Heidolph mixer at about room temperature and mixed until the temperature of the formulation is below about 28 C. The lid of the container is then placed onto the vessel and stored at room temperature.

(288) While the procedure above describes making an imiquimod cream using isostearic acid as the fatty acid, it is believed that this procedure may be applicable for preparing imiquimod creams based upon other fatty acids, such as those described in Table 11 above.

(289) The lower dosage strength formulations of this Example 21 are believed to be stable and consistent with the specifications for the commercially available Aldara (imiquimod) 5% cream. More preferably, low dosage formulations of this Example 21, especially as to those lower dosage strength formulations wherein the vehicle comprises an isostearic acid as the fatty acid, are believed to have the following:

(290) (1) Stability. The imiquimod formulations of the present invention, when they are measured on HPLC at 25 C./60% RH, 30 C./65% RH and 40 C./75% RH over, one, two, three and six months, demonstrate stability consistent with the Aldara 5% imiquimod cream;

(291) (2) Degradation Products. No degradation products are detected in the formulations of the present invention, at its current recommended storage temperatures of about 4-25 C. In addition, there are no degradation products detected at any of the temperatures or time points mentioned under Stability above, when analyzed at about 318 nm.

(292) (3) Homogeneity. The amount of imiquimod that is recovered from the formulations at any of the above-mentioned temperatures and time points is between about 90 to about 110% w/w thereby demonstrating good homogeneity;

(293) (4) Benzyl Alcohol Content. The formulations of the present invention are also within specifications for the Aldara (imiquimod) 5% cream, i.e., between 1.0% w/w and 2.1% w/w, at any of the above-mentioned temperatures and time points as to benzyl alcohol content.

(294) (5) Microscopic Stability. There is no change in the particle size and no crystals are detected in the formulations of the present invention when they are stored at 25 C./60% RH and analyzed over a six month period;

(295) (6) Macroscopic Stability. There are no obvious physical changes in the formulations of the present invention when they are stored at 25 C./60% RH and analyzed over a six month period;

(296) (7) Viscosity. The formulations of the present invention are within the range of the specifications for the Aldara (imiquimod) 5% cream, i.e., between 2000 cPs and 35,000 cPs, when they are stored at 25 C./60% RH and analyzed over a six month period; pH Stability. The formulations of the present invention are within the range of the specifications for the Aldara (imiquimod) 5% cream, i.e., between pH 4.0 and pH 5.5) when they are stored at 25 C./600% RH and analyzed over a six month period;

(297) (8) Preservative Efficacy Test (PET). The formulations of the present invention demonstrate sufficient reductions in colony forming unit counts for each of the organisms with which the formulations are inoculated, i.e., S. aureus, E. coli, Ps. Aeruginosa, C. albicans, and A. niger, at 2-8 C. and 40 C. over a 28 day test period and meet the requirements specified in both the USP and EP;

(298) (9) Imiquimod In vitro Release. The Aldara (imiquimod) 5% cream releases statistically significant (p<0.05) higher amounts of imiquimod over a 3 hour time period in comparison to the lower dosage strength formulations of the present invention through a synthetic membrane, e.g., Microporous polyethylene film 3M No. 9711 CoTran. There is no statistical difference (p<0.05) in the total cumulative amount of imiquimod that is released from any of the 3.75% w/w imiquimod formulations. There is no statistical difference (p<0.05) in the total cumulative amount of imiquimod that is released from any of the 2.5% w/w imiquimod formulations. The Aldara (imiquimod) 5% cream also statistically significantly (p<0.05) releases imiquimod at a faster rate over a 3 hour time period in comparison to the lower dosage strength formulations of the present invention through a synthetic membrane, e.g., Microporous polyethylene film 3M No. 9711 CoTran. There is no statistical difference (p<0.05) between the imiquimod release rates for any of the 3.75% w/w imiquimod formulations. There is no statistical difference (p<0.05) between the imiquimod release rates for any of the 2.5% w/w imiquimod formulations. Thus, the greater the amount of imiquimod in a formulation, the faster and greater the total amount of imiquimod that is released from such formulation that the amount and rate of release of imiquimod are concentration dependant and that the rates and amounts of release of imiquimod from the formulations of the present invention are linear and dose proportionate to the Aldara 5% imiquimod cream;

(299) (10) Imiquimod In vitro Skin Permeation (Franz Cell Study). With respect to statistical analyses, there is no statistical difference between the lower dosage strength formulations of the present invention and the Aldara (imiquimod) 5% cream as to the amount of imiquimod recovered from the receiver fluid, epidermis and dermis combined. Nonetheless, there is a statistically significant (p<0.05) dose proportionate difference between the amount of imiquimod recovered from each of the matrices with respect to the concentration of imiquimod in the lower dosage strength formulations of the present invention and the Aldara (imiquimod) 5% cream for both un-absorbed and stratum corneum. Thus there is a linear dose release between the amount of imiquimod that is applied and recovered in each of the matrices, i.e., receiver fluid, unabsorbed dose, stratum corneum, epidermis and dermis.

(300) ANOVA statistical analysis at 95% confidence level is used to analyze the stability data generated, including the data generated for the membrane and skin permeation experiments.

(301) It is also believed that the formulations of the present invention, including the formulations identified in this Example 21, have Hydrophilic-lipophilic balance (HLB) values between about 12 and 15, and more preferably between about 12.4 and about 13.4.

(302) The complete disclosures of the patents, patent documents, labels and publications cited herein, including U.S. Pat. No. 6,991,139 and Attachments I-XV, are incorporated herein by reference in their entireties as if each were individually reproduced and incorporated. In case of conflict, the present specification, including definitions, shall control. Various modifications and alterations to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. Illustrative embodiments and examples are provided as examples only and are not intended to limit the scope of the present invention. The scope of the invention is limited only by the claims set forth as follows.