1. A method of preparing a pharmaceutical cream formulated with 1-(2-methylpropyl)-1H imidazo4,5-cquinolin-4-amine (imiquimod) and minimizing formation of imiquimod impurities in the prepared pharmaceutical cream during storage of the prepared pharmaceutical cream prior to application of the prepared pharmaceutical cream to a dermal or mucosal surface to treat a dermal or mucosal associated condition, said method comprising:
(a) preparing a water phase preparation for formulating the prepared pharmaceutical cream, the water phase preparation comprising pharmaceutically acceptable excipients;
(b) preparing an oil phase preparation for formulating the prepared pharmaceutical cream, the oil phase preparation comprising imiquimod and a refined oleic acid component, wherein the refined oleic acid component contains at least about 80% oleic acid by weight as a fatty acid and has a peroxide value of no more than about 5 milliequivalents of oxygen per kilogram and contains less than about 1% by weight polar impurities at or prior to formulation;
(c) adding said water phase preparation to said oil phase preparation to form an emulsion;
(d) homogenizing the emulsion to formulate the prepared pharmaceutical cream;
(e) storing the prepared pharmaceutical cream for at least about four months prior to use of the pharmaceutical cream; and
(f) minimizing the formation of imiquimod impurities in the pharmaceutical cream during said storing of the pharmaceutical cream, as compared to an amount of imiquimod impurities formed in an identical pharmaceutical imiquimod cream but formulated with a compendial grade oleic acid component rather than the refined oleic acid component when the pharmaceutical cream and the identical pharmaceutical imiquimod cream are each stored under identical storage conditions, so that the formation of imiquimod impurities in the pharmaceutical cream is minimized and a therapeutically effective amount of imiquimod can be delivered from the pharmaceutical cream to treat the dermal or mucosal associated condition when the pharmaceutical cream is applied to a dermal or mucosal surface following said storing of the pharmaceutical cream.
2. The method of claim 1, wherein said pharmaceutical cream contains imiquimod impurities in an amount of no more than about 0.18% wt.wt. after storage of said pharmaceutical cream for about four months, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.
3. The method of claim 1, wherein said pharmaceutical cream contains imiquimod impurities in an amount of no more than about 0.29% wt.wt. after storage of said pharmaceutical cream for about four months, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.
4. The method of claim 1, wherein said pharmaceutical cream contains imiquimod impurities in an amount of no more than about 0.04% wt.wt. after storage of said pharmaceutical cream for about four months, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.
5. The method of claim 1, wherein said pharmaceutical cream further comprises an antioxidant selected from the group consisting of butylated hydroxyl toluene (BHT) and butylated hydroxyanisole (BHA).
6. The method of claim 1, wherein the imiquimod is present in an amount of not more than 10% by weight based on the total weight of said pharmaceutical cream and wherein the oleic acid component is present in an amount of no more than about 40% by weight based on the total weight of said pharmaceutical cream.
7. The method of claim 1, wherein the imiquimod is present in an amount of about 5% by weight based on the total weight of said pharmaceutical cream and wherein the oleic acid component is present in an amount of about 28% by weight based on the total weight of said pharmaceutical cream.
8. A method of claim 1, said method including the further step of:
forming a premix comprised of imiquimod and the oleic acid component before said preparing of the oil phase preparation.
9. A method of claim 8, said method including the further step of:
adding petrolatum, certyl alcohol, stearyl alcohol, polysorbate, sorbitan monostearate to the premix.
10. A method of claim 8, said method including the further step of:
adding BHA to the premix.
11. A method of claim 9, said method including the further steps of:
stirring the premix; and
heating the premix while said stirring to about 55\xb0 C.
12. A method of claim 10, said method including the further steps of:
stirring the premix; and
heating the premix while said stirring to about 55\xb0 C.
13. A method of claim 8, said method including the further step of:
adding benzyl alcohol to the oil phase preparation.
14. A method of claim 9, said method including the further step of:
adding benzyl alcohol to the oil phase preparation.
15. A method of claim 10, said method including the further step of:
adding benzyl alcohol to the oil phase preparation.
16. A method of claim 11, said method including the further step of:
adding benzyl alcohol to the oil phase preparation.
17. A method of claim 1, wherein said homogenizing was for about 5 minutes.
18. A method of claim 1, said method including the further steps of:
forming a paraben premix comprised of methyl hydroxybenzoate, propyl hydroxybenzoate and water before said preparing of the water phase preparation;
stiffing and heating the paraben premix until the methyl hydroxybenzoate and propyl hydroxybenzoate are dissolved in the water; and
cooling the heated and stirred paraben premix in which the methyl hydroxybenzoate and propyl hydroxybenzoate are dissolved.
19. A method of claim 18, said method including the further steps of:
adding glycerin to the cooled paraben premix; and
heating the cooled paraben premix mixed with glycerin to a temperature of about 55\xb0 C.
20. A method of claim 19, said method including the further steps of:
adding xanthan gum to the heated paraben premix mixed with glycerin; and
mixing and heating the heated paraben premix mixed with glycerin and xanthan gum until the xanthan gum is dispersed in the heated paraben premix mixed with glycerin and xanthan gum.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A stable aqueous dispersion comprising:
a multi-branched soil releasewetting agent having an oxygen-containing polyfunctional base compound and at least two surfactant branches attached thereto, wherein each surfactant branch includes at least one hydrophilic and at least one hydrophobic constituent, wherein the multi-branched soil releasewetting agent is in an amount of between 0.05 and 3% by weight of the aqueous dispersion;
particles selected from the group consisting of inorganic, organic, and polymeric particles having a size range between 50 nm and 45 \u03bcm,
wherein the particle dispersion is stabilized for at least 10 days at 40\xb0 C.
2. The stable particle dispersion of claim 1, wherein the multi-branched soil releasewetting agent comprises at least three surfactant branches attached thereto, wherein each surfactant branch includes at least one hydrophilic and at least one hydrophobic constituent.
3. The stable particle dispersion of claim 1, wherein the multi-branched soil releasewetting agent is selected from the group consisting of ethoxylated propoxylated triglyceride, ethoxylated propoxylated saccharide, and mixtures thereof.
4. The stable aqueous dispersion of claim 1, wherein the oxygen-containing polyfunctional base compound is selected from the group consisting of a polyol, a polycarboxylic acid, and a lactone.
5. The stable aqueous dispersion of claim 4, wherein the polyfunctional base compound is a polyol selected from the group consisting of sorbitol, xylitol, mannitol, pentaertythritol, sucrose, saccharose, galactose, leucrose, fructose, mannose, glucose, glycerol, glycerine and polyethylene glycol.
6. The stable aqueous dispersion of claim 1, wherein the viscosity of the aqueous dispersion at 25\xb0 C. with Brookfield RVT viscometer, spindle #2 and 50 RPM is between 50 and 800 cps.
7. The stable particle dispersion of claim 1, further comprising a gelling agent comprising tridecyl alcohol ethoxylate.
8. The stable aqueous dispersion of claim 7, wherein the multi-branched soil releasewetting agent is in an amount of between 0.05 and 3.0% by weight of the aqueous dispersion, the gelling agent is in an amount of between 0.05 and 3.0% by weight of the aqueous dispersion.
9. The stable aqueous dispersion of claim 1, wherein the particles are added in an amount of between 0.05 and 3.5% by weight of the aqueous dispersion.
10. The stable aqueous dispersion of claim 1, further comprising a fabric conditioning agent.
11. An enhanced fabric conditioner formulation comprising:
a fabric conditioning agent;
a multi-branched soil releasewetting agent having an oxygen-containing polyfunctional base compound and at least two surfactant branches attached thereto, wherein each surfactant branch includes at least one hydrophilic and at least one hydrophobic constituent, wherein the multi-branched soil releasewetting agent is in an amount of between 0.05 and 3% by weight of the fabric conditioner;
particles selected from the group consisting of inorganic, organic, and polymeric particles having a size range between 50 nm and 45 \u03bcm,
wherein the stable particle dispersion is stable for at least 10 days at 40\xb0 C.
12. The enhanced fabric conditioner of claim 11, wherein the multi-branched soil releasewetting agent is selected from the group consisting of ethoxylated propoxylated triglyceride, ethoxylated propoxylated saccharide, and mixtures thereof.
13. The enhanced fabric conditioner of claim 11, wherein the viscosity of the enhanced fabric conditioner at 25\xb0 C. with Brookfield RVT viscometer, spindle #2 and 50 RPM is between 50 and 800 cps.
14. The enhanced fabric conditioner of claim 11, further comprising a gelling agent comprising tridecyl alcohol ethoxylate.
15. The enhanced fabric conditioner of claim 14, wherein the multi-branched soil releasewetting agent is in an amount of between 0.05 and 3.0% by weight of the fabric conditioning agent, the gelling agent is in an amount of between 0.05 and 3.0% by weight of the fabric conditioning agent, and the viscosity at 25\xb0 C. with a Brookfield RVT viscometer, spindle #2 and 50 RPM is between 50 and 800 cps.
16. The enhanced fabric conditioner of claim 11, wherein the enhanced fabric conditioner is biodegradable.
17. The enhanced fabric conditioner of claim 11, wherein the particles are added in an amount of between 0.05 and 3.5% by weight of the fabric conditioning agent.
18. The process of applying enhanced fabric conditioner to a fabric comprising:
washing a fabric with a detergent and water;
adding an enhanced fabric conditioner formulation a rinse cycle, the enhanced fabric conditioner formulation comprising:
an aqueous solution, a fabric conditioning agent, a multi-branched soil releasewetting agent having an oxygen-containing polyfunctional base compound and at least two surfactant branches attached thereto, wherein each surfactant branch includes at least one hydrophilic and at least one hydrophobic constituent, and wherein the multi-branched soil releasewetting agent is in an amount of between 0.05 and 3% by weight of the fabric conditioner, particles selected from the group consisting of inorganic, organic, and polymeric particles having a size range between 50 nm and 45 \u03bcm, wherein the stable particle dispersion is stable for at least 10 days at 40\xb0 C.; and,
removing the water from the treated fabric.
19. The process of claim 18, wherein the dried treated fabric has a dynamic load of between 0.24 and 0.60 Newtons and a static load of between 0.20 and 0.50 Newtons as measured by the AATCC friction test method.
20. The process of claim 18, wherein the enhanced fabric conditioner formulation comprises a gelling agent comprising tridecyl alcohol ethoxylate.