JP5784619B2 - Method for wetting powders containing benzoyl peroxide - Google Patents

Description

  The present invention relates to the field of formulating stable and fine particle dispersions of benzoyl peroxide.

  Benzoyl peroxide is widely used in dermatological pharmaceutical compositions. Many compositions in the treatment of acne vulgaris and erythematous acne include, for example, 2.5% to 10% benzoyl peroxide. The effect of benzoyl peroxide in the treatment of these and other dermatological diseases is its usefulness as a keratolytic agent, thereby increasing skin turnover and washing the pores. In addition, benzoyl peroxide has direct antimicrobial activity as well.

  A significant difficulty in obtaining a stable dispersion of benzoyl peroxide in an aqueous fluid is that benzoyl peroxide is an organic compound that is very hydrophobic and that it is not immediately wetted with water. This challenge has been addressed by one or more prior art techniques.

  Benzoyl peroxide can be dissolved in organic solvents, thus preparing a stable, uniform, cosmetically concise, and effective dispersion of benzoyl peroxide in topical administration to treat skin diseases Avoid challenges. Early products containing benzoyl peroxide in solution for topical use were gels in which benzoyl peroxide was dissolved in an organic solvent such as acetone or a combination of alcohol and acetone. While these products have proven effective, there have been several disadvantages including flammability, excessive dryness of the skin, and apparent skin irritation in many acne patients. More recent developments have used other organic solvents to solubilize benzoyl peroxide. However, these compositions do not solve the problem of severe skin irritation in a significant number of patients due to the bolus delivery challenge of benzoyl peroxide solubilized within the cutaneous sebaceous gland of the skin.

  For these and other reasons, including increased production of degraded products generated by solutions, suspensions of benzoyl peroxide are preferred over solutions. A microsuspension is a suspension containing atomized benzoyl peroxide, and for several reasons, including the following exemplary reasons, against a standard or non-microsuspension of benzoyl peroxide: Is preferred. First, the microsuspension provides effective delivery of fine particles of benzoyl peroxide within the funnel of the pilosebaceous gland. They then stay and then provide non-bolus delivery of the drug into sebum and sebaceous gland tissue. This delivery provides an appropriate balance of optimal effect and reduction of skin irritation response. Second, cosmetic simplicity and patient acceptance are improved by a smooth, uniform gel, cream, or lotion containing suspended benzoyl peroxide. In particular, in the treatment of facial skin diseases such as acne or erythematous acne, cosmetic simplicity is an important factor in obtaining good patient compliance with treatment instructions. In chronic diseases with ongoing local drug treatment, good patient complications are important in obtaining overall therapeutic success.

  Surfactants are often utilized as wetting agents to help disperse benzoyl peroxide in aqueous fluids and maintain benzoyl peroxide in suspension. However, surfactants often irritate damaged or diseased skin, and when applied repeatedly to intact skin, surfactants are usually as evidenced by increased trans-epidermal water loss from the skin. It is known to disrupt the skin-protecting function. Thus, in formulating pharmaceutical compositions, particularly pharmaceutical compositions that are routinely used for long periods of time to treat chronic skin conditions, the surfactant is minimal or no surfactant It is desirable. In order to promote the dispersion of benzoyl peroxide and to maintain benzoyl peroxide in suspension, atomization of benzoyl peroxide is often used sometimes with surfactants.

  Cox, US Pat. No. 3,535,422, discloses a stable emulsion containing benzoyl peroxide. Cox discloses two methods for obtaining an emulsion containing benzoyl peroxide in suspension. In the first method, Cox forms an emulsion containing up to 25% water, surfactant, and saturated organic compound softener. Dry atomized benzoyl peroxide is mixed into this emulsion to obtain the composition. In the second method, non-micronized benzoyl peroxide is utilized, and the crude crystals of benzoyl peroxide in the form of a water-wet powder package are prepared with pre-made surfactants and saturated organic compound softeners. Combined with an emulsion containing all the components of the composition. The resulting composition is then ground to obtain a composition comprising atomized benzoyl peroxide.

  Young, US Pat. No. 4,056,611 discloses a single phase composition comprising benzoyl peroxide in suspension. Young's composition includes an alcohol solvent, water, and a surfactant as necessary components. Like Cox, Young discloses that the composition can be made by utilizing dry atomized benzoyl peroxide crystals. Preferably, Young utilizes a crude crystal wet powder package of benzoyl peroxide, similar to Cox. This powder contains 70% benzoyl peroxide and 30% w / w water. All the components of the composition are mixed together, after which the mixture is ground to obtain a composition comprising benzoyl peroxide atomized in suspension. Further, Young discloses that the composition can advantageously include a suspending agent and a viscosity building (gelling) agent that maintains the benzoyl peroxide particles in suspension.

  The methods and compositions of Cox and Young have several disadvantages with respect to compositions containing benzoyl peroxide. Cox and Young both use surfactants and often irritate damaged or diseased skin. In addition, Cox and Young combine all ingredients of their compositions including coarse, non-micronized benzoyl peroxide together to form a mixture, followed by micronized benzoyl peroxide. It is disclosed to grind this mixture to obtain a composition. Young uses the mechanical crushing force used to atomize benzoyl peroxide as a gelling agent, even though it discloses that the gelling agent may be combined in the composition. It is well known that there is a tendency to break down the polymer produced. Thus, the grinding process results in a decrease in the ability of the gelling agent to provide the desired viscosity.

  Klein, US Pat. No. 4,387,107 discloses a gel composition comprising benzoyl peroxide. Klein avoids the problem of comminuting a composition containing benzoyl peroxide by using benzoyl peroxide that has been atomized beforehand before combining with the residue components. To make the Klein composition, water is combined with a gelling agent to make the first mixture. To this mixture are optionally added other ingredients such as alcohol excipients and perfumes and other therapeutic agents such as methyl salicylate. Finally, to obtain the composition, a second mixture comprising atomized benzoyl peroxide, a surfactant and water is added to the first mixture. Since atomized benzoyl peroxide is used, there is no need to pulverize the composition on an occasional basis. Therefore, the polymerization gelling agent does not collapse. However, the Klein method requires the use of pre-atomized benzoyl peroxide and the presence of a surfactant.

  The use of atomized benzoyl peroxide, as disclosed in Klein, offers advantages, particularly in the formulation of semi-solid compositions that contain one or more polymeric gelling agents. In contrast to non-micronized benzoyl peroxide, micronized benzoyl peroxide is immediately suspended in a hydrophilic fluid and such suspensions are similar suspensions made by non-micronized benzoyl peroxide. It is physically more stable than the liquid. However, atomized benzoyl peroxide is often difficult to obtain, especially as a pharmaceutical grade, and even though it can be obtained, atomized benzoyl peroxide is expensive.

  Thus, it is advantageous to be able to purchase non-micronized benzoyl peroxide that is readily available and less expensive than micronized benzoyl peroxide and that it can be micronized for use in the manufacture of pharmaceutical formulations. It is.

As disclosed in the Cox and Young patents, benzoyl peroxide in crystalline solids is stable at room temperature, but is flammable and may explode when exposed to temperatures associated with grinding. Therefore, dry grinding of benzoyl peroxide is not suitable. Rather, it is preferred to wet grind benzoyl peroxide to obtain benzoyl peroxide in atomized form. Benzoyl peroxide in the presence of water is utilized in a suitable wet milling process and is a very safe process in which the risk of ignition and explosion is minimized.
One difficulty faced in wet milling of benzoyl peroxide is that, as mentioned above, benzoyl peroxide is very hydrophobic and resists wetting with water. Furthermore, the strong attraction between the benzoyl peroxide particles gives rise to agglomeration problems that compromise the quality of the manufacturing process and the final pharmaceutical formulation. Surfactants were utilized as disclosed in the Cox, Young and Klein patents for this purpose and to maintain a stable non-agglomerated microsuspension of benzoyl peroxide. Is not preferred due to its tendency to irritate damaged or diseased skin. Thus, a method in which benzoyl peroxide can be immediately wetted and is suitably placed in a suspension, hydrophilic or aqueous fluid, preferably without the use of surfactants, is a great advantage.
Prior art document information related to the invention of this application includes the following (including documents cited in the international phase after the international filing date and documents cited when entering the country in other countries).
[Prior art documents]
[Patent Literature]

[Patent Document 1] US Pat. No. 5,733,886 [Patent Document 2] US Pat. No. 3,535,422 [Patent Document 3] US Pat. No. 4,056,611 [Patent Document 4] US Pat. No. 6,117,843 [Patent Document] [Patent Document 6] US Patent Application Publication No. 2009/0191245 [Patent Document 6] US Patent No. 4387107

  By combining benzoyl peroxide with a wetting fluid, preferably an aqueous base, with or without mechanical stirring, the benzoyl peroxide powder is immediately wetted, with minimal or non-agglomerated peroxidation. It was unexpectedly discovered that a benzoyl suspension was obtained. The wetting fluid, preferably an aqueous base, comprises a water-soluble organic solvent dissolved in a water-containing fluid at a concentration sufficient to reduce the surface tension to about 64 dynes / cm or less. It has further been discovered that this wetting can be obtained without the use of a wetting agent such as a surfactant.

  As used herein, the term “benzoyl peroxide powder” is intended to mean any particulate form of benzoyl peroxide. Examples of such particulate types include granules, crystals and amorphous powders, whether coarse, fine or ultrafine, such as nanoparticle powders.

  As used herein, “powder comprising benzoyl peroxide” means a powder comprising any particulate type of one or more materials other than benzoyl peroxide powder and benzoyl peroxide. For example, a powder comprising benzoyl peroxide can comprise particles of benzoyl peroxide and one or more other particles, wherein the concentration of particles other than benzoyl peroxide in the powder is 50% w / w Or less. The powder containing benzoyl peroxide is at a concentration of 50% to 100% benzoyl peroxide, for example 50% to 60%, 60% to 70%, 70% to 80%, 80% To 90%, or 90% to 100%.

  As used herein, the term “non-atomized” when used in reference to benzoyl peroxide powder means a powder in which the average benzoyl peroxide particles are 50 microns or larger in size. Conversely, when the term “atomization” is used with respect to benzoyl peroxide powder, the average benzoyl peroxide particles are 50 microns or less in size. Preferably, but not necessarily, the benzoyl peroxide particles in substantially all non-atomized powders are 150 microns or more.

  As used herein, the term “wet” refers to spraying a fluid onto and onto a powder and replacing the air adsorbed thereto, whereby the particles of the powder are individually and It means to be separately encased in a fluid. As is known in the art, a powder is considered wet when almost all of the particles are encased in the fluid, for example about 80% + / − 10% of the particles based on visual inspection and evaluation. It is. For example, contact of the powder with a suitable wetting fluid may result in complete wetting even if a small number of particles, typically less than about 20% +/− 10% of the particles are not wetted. It becomes as.

  As used herein, the term “mechanical agitation” means applying kinetic energy to a powder mixture in contact with the liquid to facilitate wetting of the powder mixture in the liquid. Examples of mechanical agitation include, but are not limited to, mixing, agitation, shearing, shaking, or coalescence. Other examples include sonication and vortexing.

  As used herein, the term “aqueous gel” for a pharmaceutical dosage form for topical application is a single phase semi-solid pharmaceutical agent having a carrier or carrier system that is gelled with a thickening agent such as a polymer. By shape, where most carriers or carrier systems are water, ie 50% w / w or more.

  As used herein, the term “aggregation” means a strong physical attraction between small solid particles, whereby a large number of particles are aggregated into a single large mass that appears as a single particle. The

  In one embodiment, the present invention is a method for obtaining a wet powder comprising benzoyl peroxide. In accordance with the method of the present invention, the powder is placed in contact with a liquid comprising water and a water-soluble organic solvent. This solvent is dissolved in the liquid at a concentration sufficient to reduce the surface tension to less than 64 dynes / cm at room temperature. In a preferred embodiment, the solvent is present in the liquid at a concentration sufficient to reduce the surface tension to less than 62 dynes / cm. In a more preferred embodiment, the solvent is present in the liquid at a concentration sufficient to reduce the surface tension to less than 61 dynes / cm. In the most preferred embodiment, the solvent is present in the liquid at a concentration sufficient to reduce the surface tension to less than 60 dynes / cm. For example, the solvent is present in the liquid at a concentration sufficient to reduce the surface tension to 55-60 dynes / cm or 50-55 dynes / cm or less.

  As described below, the method is described for reducing surface tension to less than 64 dynes / cm. As disclosed in the previous paragraph, the surface tension is preferably reduced to a value of less than 64 dynes / cm, such as 50-62 dynes / cm or less.

  Non-micronized benzoyl peroxide is readily available as hydrous benzoyl peroxide, USP, sometimes mistakenly referred to as “wet” benzoyl peroxide. Hydrous benzoyl peroxide contains at least 65.0% and no more than 82.0%, on average about 74% benzoyl peroxide and 26% water to reduce flammability and impact sensitivity. The benzoyl peroxide in the hydrous benzoyl peroxide is not wetted as a term used by those skilled in the art. Hydrous benzoyl peroxide is not a paste, and benzoyl peroxide in hydrous benzoyl peroxide is in a microcrystalline state and behaves as a free flowing powder. There is no chemical interaction between water molecules and benzoyl peroxide powder, and water does not wet the core or interior of the benzoyl peroxide powder. Thus, commercially available “wet” benzoyl peroxide is not wetted.

  It is understood that the benzoyl peroxide in the powder is atomized or non-atomized and therefore the description herein regarding the non-atomized powder is also applicable to the atomized powder. An example of a wet benzoyl peroxide powder is sold under the trade name Benox® (Syrgis Performance Initiators, Inc., Helena, Arkansas). Such a powder is not applicable to the wet embodiments of the present invention because the powder containing atomized benzoyl peroxide is already wetted. However, the use of a wet powder comprising atomized benzoyl peroxide is applicable to the other embodiments discussed below.

  According to the method of the present invention to obtain wet benzoyl peroxide powder, the powder containing benzoyl peroxide is placed in contact with a suitable wetting fluid, which reduces the surface tension of water and water to a desired level. And one or more water-soluble organic solvents having a mixing concentration sufficient to cause Preferably, the wetting fluid does not contain a surfactant. The powder and wetting fluid can be kept in contact with each other for a time sufficient for benzoyl peroxide to be wetted by the wetting fluid. If necessary or necessary, the powder and wetting fluid may be mechanically agitated to facilitate, accelerate or complete wetting.

Suitable organic solvents for the method of the present invention are those listed in US Pat. S. P. 23rd Ed. Are “very soluble”, “soluble” or “soluble” in water, as defined in.

Preferably, but not necessarily, the organic solvent is miscible in water. Examples that are miscible in water and suitable for the process of the invention are methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, cyclopentanol and cyclohexanol. C _1-6 alkanols such as: linear amides such as dimethylformamide or dimethylacetamide; ketones and ketone alcohols such as acetone, methyl ethyl ketone, cyclohexanone and diacetone alcohol; water miscible ethers such as tetrahydrofuran and dioxane; diols For example, pentane-1,5-diol, ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol and thiodiglycol, And oligoalkylene glycols and polyalkylene glycols such as diethylene glycol, triethylene glycol, polyethylene glycol and polypropylene glycol; triols such as glycerol and 1,2,6-hexanetriol; 2-methoxyethanol, 2- (2-methoxyethoxy ) Ethanol, 2- (2-ethoxyethoxy) -ethanol, 2- [2- (2-methoxyethoxy) ethoxy] ethanol, 2- [2- (2-ethoxyethoxy) -ethoxy] ethanol and ethylene glycol monoallyl ether Mono-C _1-4 alkyl ethers of diols having 2 to 12 carbon atoms such as: cyclic amides, preferably 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, Caprolactam and 1,3-dimethylimidazolidone; sugar esters such as dimethyl isosorbide; cyclic esters such as caprolactone; and sulfoxides such as dimethyl sulfoxide and sulfolane.

In addition, solvents suitable in the method of the present invention can be dissolved in water at a concentration sufficient to reduce the surface tension to less than about 64 dynes / cm at room temperature. As shown in Table 2, the surface tension of water slightly changes depending on the temperature change.

  Suitably, the method of the present invention for wetting benzoyl peroxide powder is carried out at about room temperature, i.e. 20C-30C. Although less preferred, the method of the present invention is carried out at a temperature below room temperature, i.e., 0C to 20C. Although not preferred, it is carried out at a temperature above room temperature, that is, 30 ° C to 50 ° C. Although not preferred, the method of the present invention may be carried out at high temperatures between 50 ° C and 100 ° C. Since one of the advantages of the present invention is that there is no need to apply heat, it is desirable to carry out the process of the present invention at or below room temperature. However, the optimum surface tension at wetting may be slightly higher than 64 dynes / cm when heat is applied and when the temperature is raised to said temperature.

  In addition to one or more water-soluble organic solvents, the wetting fluid may contain additional components that can be additional solvents. Such additional components are preferably liquid at the temperature at which the wetting procedure takes place, and are preferably soluble in the water-soluble organic solvent utilized. Optionally, the wetting fluid may include a liquid state solute as an additional wetting agent, film former, or deagglomerating agent.

  It has been surprisingly discovered that a wetting fluid, a liquid comprising water and one or more water-soluble organic solvents as described above, can wet benzoyl peroxide. The concentration of hydratable organic solvent in the wetting fluid will vary depending on factors such as the particular solvent used and the relative volume of the benzoyl peroxide powder and wetting fluid used. Generally, the concentration of the water-soluble organic solvent in the wetting fluid is 1% to 100% w / w. Preferably, the concentration is about 5% or more, more preferably about 10% or more, and most preferably at least about 15%. The term “about” in the preamble is intended to mean an amount that is rounded to the stated amount. Thus, about 5% means 4.5% or more, about 10% means 9.5% or more, and about 15% means 14.5% or more. Powders and wetting fluids may be mechanically agitated to facilitate, accelerate or complete wetting.

  In another embodiment, the invention is a wet benzoyl peroxide powder combined with a liquid comprising water and one or more water-soluble organic solvents as described above. Here, the concentration of the water-soluble organic solvent in the liquid is sufficient to reduce the surface tension at room temperature to less than 64 dynes / cm, as described above.

  In another embodiment, the present invention is wet benzoyl peroxide combined with a liquid comprising one or more water-soluble organic solvents as described above, wherein the concentration of the organic solvent or solvent in the liquid is at room temperature. The surface tension is sufficiently reduced to less than 64 dynes / cm.

  In another embodiment, the invention is a wet benzoyl peroxide powder combined with a liquid comprising one or more water-soluble organic solvents as described above, wherein the concentration of said organic solvent or solvent in the liquid is The surface tension is sufficiently reduced to less than 64 dynes / cm at room temperature. And as a result, the benzoyl peroxide powder is moistened so that during the manufacturing process of topical formulations or their compositions, the particles of benzoyl peroxide Reduce and control agglomeration.

  In another embodiment, the invention is a method for preparing micronized benzoyl peroxide, for example for use in the manufacture of a topical pharmaceutical formulation comprising benzoyl peroxide as an active ingredient. According to this embodiment of the present invention, the wetting fluid comprising a concentration of water-soluble organic solvent sufficient to reduce water and surface tension to less than 64 dynes / cm at room temperature comprises a powder comprising non-micronized benzoyl peroxide and Combined. The wetting fluid can wet most of the benzoyl peroxide particles in the powder. The wet benzoyl peroxide is then subjected to a suitable atomization procedure to obtain atomized benzoyl peroxide.

  In another embodiment, the invention is a suspension of benzoyl peroxide. According to this embodiment, the suspension is a single phase composition comprising benzoyl peroxide at a concentration of 1% to 30% w / w, preferably 10% or less, most preferably 5% or less. Benzoyl peroxide is suspended in a suspending fluid containing one or more water-soluble organic solvents at a concentration sufficient to reduce the surface tension to less than 64 dynes / cm at room temperature. The suspending fluid may contain only one or more organic solvents. Alternatively, the suspending fluid can include one or more excipients other than water soluble organic solvents that can reduce the surface tension to less than 64 dynes / cm at room temperature.

  It is preferred that the suspending fluid contains only one or more of the water-soluble organic solvents described above in addition to water. If shaping fluids other than water-soluble organic solvents are used that can reduce the surface tension of water to less than 64 dynes / cm at room temperature, such shaping fluids should be pharmaceutically acceptable. Yes and should be miscible with the one or more water-soluble solvents used. In addition, the concentration of one or more water-soluble organic solvents in the suspending fluid that can reduce the surface tension to less than 64 dynes / cm at room temperature is the absence of such shaping fluids other than water-soluble organic solvents. Below, it must be sufficient to wet the benzoyl peroxide powder that is bound immediately thereafter.

  The benzoyl peroxide in the suspension may be atomized or non-atomized. If the benzoyl peroxide is non-atomized, the suspension can be treated such that the benzoyl peroxide in the suspension is atomized. Suitable atomization processes include suspension grinding, grinding, crushing, cutting, impingement, cavitating, and shearing.

  When wetted and suspended according to the method of the present invention, the non-micronized benzoyl peroxide has a very low tendency to agglomerate at the liquid surface, and thus a small opening of a micronizing device such as a gorin mill (Delavan, WI). There is little or no problem with benzoyl peroxide particles adhering to the surface. Benzoyl peroxide, which has been wetted according to the method of the invention and then atomized, is maintained in a stable suspension and to a significant degree before being incorporated into a pharmaceutical formulation such as a gel, cream or lotion. Does not aggregate on the liquid surface. The stable microsuspension obtained according to the present invention thus results in good pharmaceutical homogeneity and optimal non-bolus delivery into the skin, especially to the follicular sebaceous gland, resulting in loss of effectiveness Minimize skin irritation.

  In another embodiment of the present invention, the present invention is a method for preparing micronized benzoyl peroxide, such as for use in manufacturing topical pharmaceutical formulations comprising benzoyl peroxide as an active ingredient. is there. According to this method, the benzoyl peroxide powder is wetted into a suspension as described above, after which the benzoyl peroxide suspension is appropriately atomized to obtain a suspension containing atomized benzoyl peroxide. Can be processed.

  In other embodiments, the present invention is a suspension comprising atomized benzoyl peroxide, which was atomized according to the method described above. The benzoyl peroxide atomization treatment and suspension of the present invention are useful in the manufacture of topical pharmaceutical products, particularly topical products that are semi-solid dosage forms, containing benzoyl peroxide as an active ingredient. The method of the present invention is suitable for optimal pharmacological acceptance without labeling “Shake well before use” in lotions and other pourable topical dosage forms, and for optimal drug delivery. Maintain dispersed, atomized benzoyl peroxide in a non-agglomerated state.

  In other embodiments, the present invention relates to benzoyl peroxide in a suspension comprising one or more water-soluble organic solvents that can reduce the surface tension of water to less than 64 dynes / cm at room temperature or in a bond. It is a pharmaceutical formulation containing. Therein, the concentration of water and water-soluble organic solvent in the pharmaceutical formulation is sufficient to wet the powder containing benzoyl peroxide at the concentration of benzoyl peroxide present in the formulation in the absence of all other liquid components of the formulation. It is enough. Preferably, the benzoyl peroxide is atomized. Preferably, benzoyl peroxide was atomized according to the present invention. If desired, one or more additional shaping fluids can be included as described above. The pharmaceutical formulation may further comprise excipients commonly used in pharmaceutical formulations such as wetting agents, emollients, pH stabilizers, chelating agents, film formers, preservatives and antioxidants.

  The concentration of benzoyl peroxide in the pharmaceutical preparation is preferably 1% to 10% w / w, the preferred concentration is 2% to 5%. If desired, additional agents useful in the treatment of skin diseases such as acne vulgaris or erythematous acne can be included in the formulation. Preferably, the additional anti-acne compound is dissolved in a solvent or a number of solvents and is therefore dissolved in the formulation.

  Such suitable anti-acne compounds are antibiotics. Suitable antibiotics include macrolide antibiotics such as erythromycin, azithromycin, clarithromycin, tilmicosin and tyrosine, and lincomycin antibiotics such as clindamycin and lincomycin. A particularly preferred antibiotic used in combination with benzoyl peroxide in the formulations of the present invention is clindamycin such as clindamycin hydrochloride or clindamycin phosphate. Additional topical anti-acne active ingredients that may be included in the formulations of the present invention include alpha-hydroxys such as salicylic acid, azelaic acid, sulfur, sulfacetamide, resorcinol, glycolic acid, with or without antibiotics. Includes acids, niacinamide, urea, and retinoids such as tretinoin, adapalene and tazarotene.

  When present in the formulations of the present invention, the additional anti-acne compound is preferably present at a concentration that produces a pronounced anti-acne effect in the absence of benzoyl peroxide. For example, when clindamycin is present in the formulations of the present invention, a concentration of clindamycin is preferably at least 0.5%, such as 1%. Concentrations lower than 0.5%, or higher than 1%, such as 2.5% to 5.0% or higher may be utilized in the formulation.

  Although not required, it is preferred that the formulation be present in a gel form, preferably an aqueous gel. Accordingly, the formulations of the present invention can include gelling agents or thickeners. Any gelling agent dispersible in water is suitable for use in epithelial tissues such as skin, forms an aqueous gel of substantially the same hardness, and is suitable for use in the compositions of the present invention . One suitable gelling agent is hydroxypropylcellulose, which is sold, for example, under the trademark KLUCEL® (Hercules Incorporated, Wilmington, Del.). Another suitable gelling agent is hydroxyethyl cellulose, which is sold, for example, under the trademark NATROSOL® (Hercules Incorporated). Other suitable gelling agents include carboxyvinyl polymers known as carbomers, such as CARBOPOL® 934, 940, 941, 980 and 981 (BF Goodrich Co., Ohio, USA, Akron), ETD 2020 ™, and ULTREZ® (Noveon, Inc., Cleveland, Ohio, USA). Further suitable gelling agents are polyvinyl alcohol, polyethylene oxide, propylene glycol alginate, methylcellulose, hydroxypropylmethylcellulose, and natural polymeric gums such as xanthan and carrageenan. The concentration of gelling agent in the composition can be varied by a number of factors including the desired viscosity of the gel composition. For example, the gel can be poured and dispensed from a bottle, such as a plastic squeeze bottle, or can be more viscous, preferably dispensed from a collapsible tube or jar.

  If desired, the formulations of the present invention can further comprise additional pharmaceutically acceptable excipients that are used topically in the formulations and are known to those skilled in the art. Such excipients include, for example, wetting agents, relaxation agents, pH stabilizers, chelating agents, film forming agents, permeation enhancers, preservatives and antioxidants.

  The semi-solid dosage form of the pharmaceutical formulation of the present invention may be in the form of an emulsion such as a cream or lotion. Preferably, such a cream or lotion is formulated without a low molecular weight surfactant, since the surfactant tends to irritate the skin or impair the skin protective function. Thus, the cream or lotion formulation of the present invention is a mild high molecular weight polymer emulsifier or a poloxamer that does not have deleterious effects on the skin, as disclosed in Dow, US Pat. No. 7,368,122. Manufactured with a low level of emulsifier.

  The invention is further described in the following non-limiting examples. In the following examples, the present invention is exemplified mainly by organic solvents that are miscible with water. However, it is understood that the examples are illustrative and, as noted above, the present invention may be practiced with water-soluble solvents that are not miscible with water.

Example 1 Wetting of Benzoyl Peroxide Powder Using Various Water Soluble Organic Solvents Wetness studies of benzoyl peroxide were conducted as follows. 1.5 grams of benzoyl peroxide powder was spread over the surface of four test fluids contained in a glass beaker having a diameter of about 5 cm. The four test fluids are 30 ml of purified water having a surface tension of 72.0 dynes / cm (Sample A), 30 ml of fluid consisting of 7.5% ethanol and 95% purified water having a surface tension of 51.4 dynes / cm. (Sample B), 30 ml of fluid consisting of 20% polyethylene glycol (PEG 200) and 80% purified water having a surface tension of 51.9 dynes / cm (Sample C), and 20% dimethyl isosorbide (DMI) and 50 30 ml of fluid consisting of 80% purified water having a surface tension of 1 dyne / cm (sample D). A 12 mm × 8 mm magnetic stir bar was placed at the bottom of each beaker. Each fluid had benzoyl peroxide powder on the surface and was stirred at 1200 rpm. After 5-10 minutes of stirring at room temperature, the samples were visually inspected for benzoyl peroxide wetness. There was little or no visual evidence of wetting in Sample A, and benzoyl peroxide wetting was insufficient. The benzoyl peroxide wetting in each of Samples B, C, and D was determined to be good by visual evidence of at least 90% wetting of the benzoyl peroxide powder.

Example 2 Effect of Various Solvents on Water Surface Tension The surface tension of water-containing fluids was determined before and after mixing with various water-soluble organic solvent concentrations in water. The study was performed at room temperature and the results are shown in Table 3. The value for surface tension is dynes / cm.

  As shown in Table 3, each tested organic solvent, with the exception of glycerin, reduced the surface tension of the water containing the fluid to less than 64 dynes / cm at room temperature. Ethanol, hexylene glycol, polyethylene glycol 400, and dimethyl isosorbide, respectively, are used in the methods of the present invention at concentrations of less than 5% w / w and higher, such as any concentration from 1% to 5%, for example. Suitable for. The data in Table 3 shows that propylene glycol is suitable at concentrations of about 7.5% and above. The data in Table 3 indicate that glycerin alone is not suitable in this method.

Example 3 Wetting of benzoyl peroxide powder with a fluid with propylene glycol and water to facilitate the preparation of a stable atomized suspension for use in the manufacture of 3.13% benzoyl peroxide topical gel The suspension is prepared with 24.8% w / w hydrous benzoyl peroxide utilizing a dispersion fluid containing 9.4% w / w propylene glycol and 90.6% w / w water. In a stainless steel tank, 36 kg of purified water and 3.75 kg of propylene glycol are combined. The bond was agitated by a propeller mixer to form a mixture. During mixing, 13.12 kg of hydrous benzoyl peroxide (74.5% benzoyl peroxide) was added. Mixing was continued at 1450 rpm for about 10 minutes to wet and disperse the benzoyl peroxide powder at room temperature and to obtain a benzoyl peroxide suspension.

  By visual inspection, the suspension had a uniformly wet benzoyl peroxide and appeared smooth and free of lumps. This suspension is passed through a gorin mill for atomization using a wet grinding method. The grinding process proceeded efficiently without problems (i.e. without boring) and a microsuspension was produced. This suspension has a short time before it is incorporated into a 3.13% benzoyl peroxide gel with the active topical benzoyl peroxide formulation raw material present as a stable microsuspension without the use of a final topical dosage form, surfactant. Set aside.

  This example shows that a concentration of about 9% propylene glycol in water is sufficient to provide wetting of the benzoyl peroxide powder.

  The above example shows that the hydrous benzoyl peroxide powder is easily wetted in water containing a water soluble organic solvent that can reduce the surface tension of the aqueous fluid to less than 64 dynes / cm. The wettability of benzoyl peroxide powder increases with increasing concentration of organic solvent and is further facilitated by mechanical stirring. Optionally, the benzoyl peroxide powder wetted according to the method of the present invention can be effectively and safely atomized by wet milling or other methods to produce a pharmaceutical formulation comprising atomized benzoyl peroxide. Can be done.

  Various modifications of the invention described above will be apparent to those skilled in the art. Such modifications are intended to fall within the scope of the following claims.

Claims (11)

A suspension of benzoyl peroxide having atomized benzoyl peroxide combined with an aqueous suspension fluid having water and one or more water-soluble organic solvents;
The benzoyl peroxide is in a concentration of 1% to 30%;
The one or more water-soluble organic solvents are selected from the group consisting of ethanol, propylene glycol, hexylene glycol, ethoxydiglycol, polyethylene glycol, propylene carbonate, isopropyl alcohol, polypropylene glycol, dimethyl isosorbide, and 1,3-propanediol. Is to be selected,
The concentration of the one or more water-soluble organic solvents in the suspending fluid is sufficient to reduce the surface tension of water to less than 62 dynes / cm at room temperature ;
The suspension all SANYO free of surfactants and gelling agents,
The benzoyl peroxide particles have an average size of 50 microns or less, and
The suspension is characterized by minimal or non-aggregation of the benzoyl peroxide,
Suspension of benzoyl peroxide. The benzoyl peroxide suspension of claim 1 , wherein the one or more water-soluble organic solvents are selected from the group consisting of propylene glycol and hexylene glycol. The benzoyl peroxide suspension according to claim 2 , wherein the water-soluble organic solvent is propylene glycol. The suspension of benzoyl peroxide according to claim 1, wherein the concentration of the water-soluble organic solvent in the suspension fluid is sufficient to reduce the surface tension of water to less than 61 dynes / cm at room temperature. A suspension of benzoyl peroxide. 5. The suspension of benzoyl peroxide according to claim 4 , wherein the concentration of the water-soluble organic solvent in the suspension fluid is sufficient to reduce the surface tension of water to less than 60 dynes / cm at room temperature. A suspension of benzoyl peroxide. 5. The suspension of benzoyl peroxide as claimed in claim 4 , wherein the concentration of the water-soluble organic solvent in the suspending fluid is sufficient to reduce the surface tension of water to 55-60 dynes / cm at room temperature. A suspension of benzoyl peroxide. 5. The suspension of benzoyl peroxide according to claim 4 , wherein the concentration of the water-soluble organic solvent in the suspension fluid is sufficient to reduce the surface tension of water to 50-55 dynes / cm at room temperature. A suspension of benzoyl peroxide. The suspension of benzoyl peroxide according to claim 4 , wherein the concentration of the water-soluble organic solvent in the suspension fluid is sufficient to reduce the surface tension of water to 50-62 dynes / cm at room temperature. A suspension of benzoyl peroxide. 5. The suspension of benzoyl peroxide according to claim 4 , wherein the concentration of the water-soluble organic solvent in the suspending fluid is sufficient to reduce the surface tension of water to less than about 50 dynes / cm at room temperature. A suspension of benzoyl peroxide. The suspension of benzoyl peroxide according to claim 1, wherein the aqueous suspending fluid comprises water and propylene glycol, the benzoyl peroxide being at a concentration of 1% to 30%, the concentration of the propylene glycol is a concentration sufficient to reduce the surface tension of water at room temperature to less than 50 dynes / cm, the suspension is one that does not contain a surfactant and a gelling agent, said peroxide The benzoyl peroxide suspension has an average size of 50 micron or less and the suspension is characterized by minimal or non-aggregation of the benzoyl peroxide. Liquid . Use of a suspension of benzoyl peroxide according to any of claims 1 to 10 for the manufacture of a topical pharmaceutical product having benzoyl peroxide as an active ingredient.