TWI474841B - Preservative system for emulsion-based therapeutic topical formulations - Google Patents

Description

Emulsion-based treatment system for topical preparations

The present invention is generally directed to the field of formulation chemistry. More specifically, the present invention relates to an improved emulsion-based therapeutic topical formulation preservation system, in particular, an improved emulsion avermectin formulation preservation system. The invention further relates to a topical emulsion in which the aqueous phase is buffered within an acidic pH range, within the acidic pH range, the storage system provides a shelf life that is significantly longer than the same emulsion-based product without the buffer. And when the therapeutically active agent is avermectin, base-catalyzed isomerization is also inhibited.

Emulsions are useful as a vehicle for the local delivery of therapeutically active agents. An emulsion is a single fluid having a monolithic appearance formed by combining an oil phase with an aqueous phase, which has the advantage that several water-based or oil-based topical therapeutic compositions cannot provide. First, by combining the oil phase with the aqueous phase, the emulsion makes it possible to formulate hydrophilic and hydrophobic components in a single composition. Secondly, despite having an oil component, the emulsion still attracts consumer interest because it does not have the same greasy feel as a pure oil based formulation.

Again, and perhaps most importantly for topical therapy, the emulsion has a rheology in which it is stable at rest, but exhibits a decreasing viscosity when applied with increasing shear stress. This will facilitate topical application, but after application, the emulsion will no longer flow or drip and remain in the application area where a therapeutic treatment is desired.

This is particularly beneficial for the topical composition used to treat head lice. The product must be securely retained at the application site for a period of time effective for eradicating the head lice. Watery products quickly flow down the forehead and neck, making them uncomfortable and ineffective.

The emulsion should be stable to retain its desired rheological properties. The separation of the oil and water components will reduce the viscosity and produce a dripping, flowable product that has a greasy feel and does not remain in place when applied. Emulsion-based topical treatment products should remain stable for their intended life.

The therapeutically active agent must also remain stable. Abamectin is known to undergo base-catalyzed isomerization to form 2-epimer impurities which have substantially lower biological activity compared to the base product.

Moreover, a variety of oils and other emulsion components suitable for topical application serve as a nutritional matrix for microorganisms such as fungi and bacteria. If left unchecked, the growth of microorganisms in the formulation poses a risk of infection to patients who have been bitten by the head. Moreover, the microbial biomass produced has an unpleasant odor and appearance and may otherwise render the product unsuitable for skin contact. There is a need to improve the preservation system for emulsions.

The present invention provides topical formulations that are resistant to the growth of microorganisms, including bacteria, yeast, fungi, molds, and the like. The formulation generally comprises an effective amount of an insecticide dissolved in an oil phase comprising an aqueous miscible or water soluble surfactant, a suspending agent and a nonionic surfactant, and an aqueous phase comprising Including one or more preservatives and buffered to a pH at which the formulation is more resistant to microbial growth than the unbuffered or otherwise buffered equivalent of the aqueous phase. Degree, or otherwise microbicidal.

The insecticide preferably comprises avermectin, such as ivermectin, doramectin, selamectin or abamectin, or a combination thereof. Preferred is ivermectin. Insecticides may further include spinosyn, such as the Sbynoxin factors A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, and Y, or a combination thereof. Spinosad is a better Spoonosin. Ivermectin may be included at a concentration of from about 0.1% to about 1% by weight of the formulation. When ivermectin and spinosad are used, the combined concentration may range from about 0.1% to about 5% by weight of the formulation.

The pH is preferably buffered in the range of from about 4.5 to about 6.2. The buffering agent preferably or comprises citric acid and/or sodium citrate, which may be added at a concentration of from about 0.01% to about 0.1% citric acid and from about 1.0% to about 1.25% sodium citrate, by weight of the formulation.

The oil phase may comprise from 20% to 35% by weight of the formulation, and the suspending agent may comprise olive oil, shea butter or a combination thereof. Olive oil may comprise from 25% to 28% by weight of the formulation, and shea butter may comprise from 1% to 5% by weight of the formulation. The oil phase may comprise from 15% to 45% of a nonionic surfactant by weight of the formulation, and the nonionic surfactant may comprise oleyl alcohol, lanolin alcohol, sorbitan tristearyl Sorbitan tristearate, or a combination thereof. The oil phase may comprise from 10% to 20% water-miscible or water-soluble surfactant, and the water-miscible or water-soluble surfactant may comprise polysorbate 80, cetyl acetate, based on the weight of the formulation. Cetyl acetate, acetylated lanolin alcohol, or a combination thereof.

The formulation preferably includes a preservative such as methylparaben and propylparaben, which may be present in the formulation at a combined concentration of from 0.01% to 2% by weight of the formulation.

The formulation may include a conditioner such as cyclomethicone. The concentration of the conditioning agent can range from 1% to 5% by weight of the formulation.

The present invention also provides a method of enhancing the resistance of a topical emulsion to microbial growth comprising bacterial, fungal, mold and/or yeast growth. The method generally comprises buffering the aqueous phase of the emulsion to a pH at which the formulation is unbuffered or buffered to a more acidic, neutral or alkaline pH relative to the aqueous phase. In equivalent formulations, larger amounts of microbial growth are inhibited. The emulsion preferably comprises those emulsions described herein.

The emulsion can be buffered to a pH in the preferred range of from about 4.5 to about 6.2. The aqueous phase of the buffer may be buffered using an effective amount of citric acid and/or sodium citrate. Preferably, when a method using a formulation comprising ivermectin is employed, the pH also inhibits or alternatively inhibits the alkali catalyzed isomerization of ivermectin.

The invention also provides a method of treating a head lice infection caused by a susceptible or anti-treatment head lice, such as a human. Generally, the method comprises topically administering to the individual an effective amount of an emulsion described herein for a period of time sufficient to treat the head lice infection. Preferably, the individual is administered a single dose of the formulation topically. The period of time may range from about 1 minute to about 60 minutes, although shorter or longer periods of time may also be used. If multiple administrations are employed, the time interval between each administration is preferably from 5 to 9 days.

In the present specification and claims, various terms related to the systems, methods, and other aspects of the present invention are used. Unless otherwise stated, the terms will have their ordinary meanings in the art.

As used in the specification and the appended claims, the singular forms "

As used herein, the term "about" is intended to encompass a variation of ±20% or ±10%, more preferably ±5%, even more preferably ±1% and even more preferably ±0.1% from a specified value.

In accordance with the present invention, it has been observed that by buffering the aqueous phase to a pH of from about 4.5 to about pH 6.2, the antimicrobial properties of the emulsion will be enhanced. Accordingly, the present invention provides a topical emulsion comprising a preservative, wherein when the aqueous phase of the emulsion is buffered accordingly, the resistance of the formulation to microbial growth is unbuffered or buffered to a more acidic, neutral or relative to the aqueous phase. A similar formulation with an alkaline pH is enhanced. The invention also provides methods of enhancing the microbial resistance and/or antimicrobial properties of topical emulsions.

The topical preparation of the present invention may be an aqueous dispersion containing the oil phase of the therapeutically active ingredient. Depending on the rheological properties desired by the product blender, the aqueous dispersion can be prepared as a water-in-oil emulsion or an oil-in-water emulsion. Formulation technicians familiar with personal care products such as shampoo and hair conditioner will understand how to formulate the ingredients disclosed herein into a water-in-oil or oil-in-water emulsion.

The formulations of the invention are particularly suitable for topical application of therapeutically active ingredients which are hydrophobic and poorly water soluble. Accordingly, the therapeutically active ingredient is preferably dissolved in a suitable reagent to improve the stability of the active ingredient in water. These agents are preferably water soluble or water miscible and comprise, for example, a surfactant comprising a water soluble or water miscible surfactant. Water-soluble and water-miscible surfactants comprise a compound which will dissolve the therapeutically active ingredient and stabilize the active ingredient in water. A particularly preferred topical emulsion comprises an oil phase and an aqueous phase, wherein the active ingredient is dissolved in the oil phase. The oil phase preferably comprises three components: a solubilizer, a nonionic surfactant, and a suspending agent.

Active agent

The active agent is preferably a pesticide or an insecticide, and more preferably an insecticide capable of killing lice.

One aspect of the invention pertains to topical formulations of avermectin containing a medicament useful for treating or preventing head lice infection, wherein the infectious scorpion can be a susceptible or anti-therapeutic species of Pediculus humanus capitis . Anti-therapeutic varieties include those that are resistant to one or more pesticides/insecticides, particularly pesticides/insecticides that are typically prescribed for the treatment or treatment of sputum infections. Suitable avermectins include ivermectin, doramectin, serramycin, avermectin B _1a , avermectin B _1b , serramycin, eprinomectin And abamectin, of which ivermectin is especially good.

One or more avermectins may be present in the formulation at different concentrations, for example from about 0.005% to about 5% by weight of the formulation. For example, a formulation containing 1% avermectin will comprise 1 gram (gram, g) of avermectin per 100 milliliters (milliliter, ml) of formulation.

In some aspects, the concentration of avermectin is from about 0.1% to about 2% by weight of the formulation. In accordance with the present invention, it has been observed that 0.25%, 0.5%, and 1% of the ivermectin concentration promotes effective killing of the permethrin-resistant head lice. It may be used in the form of a mixture of more than 80% of 22,23-dihydroavermectin B _1a and less than 20% of 22,23-dihydroavericin B _1b , preferably at least 90% of 22,23 - Ivermectin in the form of a mixture of dihydroavermectin B _1a and less than 10% of 22,23-dihydroavermectin B _1b . For example, from about 0.05% to about 5%, from about 0.1% to about 2%, or from about 0.25% to about 1%, by weight of the avermectin, such as ivermectin, can be dissolved in the formulation.

The topical formulation can include a combination of at least one avermectin and at least one Spernomycin. The Spernosine may be present, for example, at a concentration of from about 0.005% to about 5% (weight/volume percent) by weight of the formulation. For example, from about 0.05% to about 5%, from about 0.1% to about 5%, from about 0.1% to about 2%, or from about 0.25% to about 1%, by weight of the Spernosin may be dissolved in the formulation.

Sbynosin includes (but is not limited to) individual Spanosin factors A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W or Y, and any combination thereof. The promise of killing is the combination of the Sbnosin factor Sbynosin A and the Spoonosin D. Among them, Spoonosin A accounts for about 85% and Spoonosin D accounts for about 15%. .

The combination of sibnoxin and avermectin may comprise from 0.01% to about 5% by weight of the formulation, preferably from about 0.1% to about 5% by weight, preferably from 0.25% to about 2% by weight, and more preferably It accounts for 0.5% to 3% by weight of the preparation.

More preferably, the insecticide or insecticide combination has dissolved and remains dissolved in the oil phase of the emulsion. Preferably, the active agent does not precipitate out of solution.

Solubilizers

The oil phase of the emulsion may include one or more solubilizers. The solubilizing agent can include a water soluble or water miscible surfactant, or a combination thereof. The water soluble or water miscible surfactant can comprise at least about 10% by weight of the formulation. In some aspects, the agent comprises from about 10% to about 50% by weight of the formulation, and in some aspects, the agent comprises from about 20% to about 50% by weight of the formulation. In a particularly preferred aspect, the agent will comprise from about 10% to about 20% by weight of the formulation.

Any suitable water soluble or water miscible surfactant can be used. Non-limiting examples include polysorbate 80, cetyl acetate and ethoxylated lanolin alcohol, or a combination thereof. Crodalan AWS is available from Croda Chemicals, Inc. and is a suitable reagent including polysorbate 80, cetyl acetate and ethoxylated lanolin alcohol.

From about 5% by weight to about 25% by weight, from about 10% by weight to about 15% by weight, and preferably from about 11.25% by weight to 13.5% by weight of polysorbate 80 may be present in the formulation, by weight of the formulation. Methyl cetyl acetate may be present in the formulation from about 0.5% to 10% by weight, from about 1% to about 4% by weight, and preferably from about 1.50% to 3.75% by weight, based on the weight of the formulation. From about 0.10% to about 3% by weight, from about 0.5% to about 1% by weight, and preferably from 0.15% to 0.75% by weight, based on the weight of the formulation, of ethoxylated lanolin alcohol may be present in the formulation.

In some aspects, the incorporation of a water soluble or water miscible surfactant onto the surface of the therapeutically active ingredient ensures that the active ingredient is stable in the aqueous environment of the emulsion. In some aspects of the invention, it may be utilized in the formulation in an amount less than 30% by weight, such as less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5%. A pharmaceutically acceptable diol to stabilize the therapeutically active ingredient. In some particularly preferred embodiments, the formulation does not comprise any glycol, especially propylene glycol or polyethylene glycol.

Suspending agent

The oil phase of the emulsion may include one or more suspending agents. In some aspects, a combination of fatty oils and/or fats can be used as a suspending agent. Examples of suspending agents include, without limitation, olive oil, shea butter, cocoa butter, vegetable oils, and the like. Olive oil is a triglyceride in which three fatty acids are linked to the main chain of glycerin, and shea oil is mainly made of palmitic acid, stearic acid, oleic acid, linoleic acid and arachidic fatty acid. Although these fatty acids have been used as "home remedy" to remove the head lice from the scalp, they do not kill the head lice. Both olive oil and shea oil are viscous materials that slow the movement of adult lice to remove it better. The combination of olive oil and shea oil is a preferred suspending agent.

In some aspects, the amount of olive oil present in the formulation is from about 20% to 30% and preferably from about 25% to 28% by weight (e.g., about 27.5% by weight), based on the weight of the formulation. The amount of shea butter present in the formulation may range from about 1% to about 5%, and preferably about 2% by weight, based on the weight of the formulation. Other known suspending agents which may be used in the formulations and related methods include, but are not limited to, coconut oil, palm oil, cottonseed oil, vegetable oil, soybean oil, olive oil, peanut oil, corn oil, sunflower oil, safflower oil, lotus Jojoba oil, canola oil, shea butter, cocoa butter, milk fat, amaranth oil, apricot oil, argan oil ), avocado oil, babassu oil, ben oil, alga-roba oil, coriander seed oil, flaxseed oil (false flax oil), grape seed oil, hemp oil, kapok seed oil, meadowfoam seed oil, okra seed oil, perilla seed Perilla seed oil, poppy seed oil, prune kernel oil, pumpkin seed oil, quinoa oil ramtil oil, rice bran oil , camellia oil, thistle oil, wheat germ oil, and combinations thereof. Fatty acid glycerides can be used and are known to be useful as skin moisturizers.

Nonionic surfactant

The oil phase of the emulsion can include one or more nonionic surfactants. Nonionic surfactants include compounds that act at the water-air and water-oil interfaces, thereby enhancing the wetting ability, emulsion stability, foaming ability, rheology, antistatic properties, lubricity, and surface conditioning properties of the emulsion. In some aspects of the invention, a fatty alcohol or a mixture of fatty alcohols can be used as the nonionic surfactant. In addition to additionally stabilizing the active ingredient, when the formulation is used in a final product such as shower gel or shampoo-conditioner, the nonionic surfactant acts in a variety of surface chemistries of the formulation. effect.

In addition to its surface-active properties, fatty alcohols are emollients that make the skin smoother, and they act at the water-air and water-oil interfaces, thereby enhancing the wetting ability, emulsion stability, and foaming ability of the formulation. , rheology, antistatic, lubricity and surface conditioning properties. Emollients include compounds that soften and smooth the skin by preventing the skin from losing moisture. Examples of suitable nonionic surfactants include, without limitation, oleyl alcohol, lanolin alcohol, sorbitan tristearate, beeswax, erucyl alcohol, ricinolyl alcohol, arachidyl Alcohol), capryl alcohol, capric alcohol, behenyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearic acid Stearyl alcohol, isostearyl alcohol, oleyl alcohol, palmitoleyl alcohol, linoleyl alcohol, 9E-eleidyl alcohol, 9E, 12E-eleidolinoleyl alcohol, linolenyl alcohol, 9E, 12E, 15E-elaidolinolenyl alcohol, and combinations thereof.

In some preferred aspects, the formulation comprises a combined concentration of from about 10% to about 35%, or preferably from about 15% to about 24%, and more preferably from about 18% to about 24% by weight of the formulation. % of nonionic surfactant. Nonionic surfactants preferably include oleyl alcohol, lanolin alcohol, and sorbitan tristearate. In some aspects, from about 5% to 15% by weight, and preferably from about 10% by weight, of oleyl alcohol may be present in the formulation, by weight of the formulation. From about 3% by weight to about 15% by weight, more preferably from about 5% by weight to 10% by weight, and more preferably about 8% by weight of lanolin alcohol may be present in the formulation. Sorbitan tristearate is commercially available as Glycomul TS (Lonza), or SPAN 65 sold by Merck Schuchardt OHG. Sorbitan tristearate is a low hydrophilic lipophilic balance (HLB) ester based surfactant and has many uses in the food and cosmetic industry. The chemical structure of sorbitan tristearate is defined by a five-membered cyclic ether having a hydroxyl group and three fatty acid side chains. From about 0.1% to about 3% by weight, preferably about 0.5% by weight, of sorbitan tristearate may be present in the formulation based on the weight of the formulation.

Conditioner

The polyoxyxides can be added to the formulation, and in some aspects, preferably added to the oil phase of the emulsion for use as a skin or hair conditioning agent. Conditioning agents can alter the texture, feel, and appearance of a person's hair. Other conditioning agents other than polyoxyxides can also be used. In some aspects, the polyoxyxene compound can be selected from the group consisting of volatile polyoxyxides, one of which is a cyclomethicone. Cyclomethanone can act as a conditioning agent in a formulation to be applied to the hair, such as shampoo-conditioner. It leaves the hair silky smooth and evaporates quickly, leaving very little residue. The formulation may comprise from about 1% to 5% by weight and preferably about 3% by weight, based on the weight of the formulation, of cyclomethoxane. Examples of useful conditioning agents include, but are not limited to, cyclomethoxane, dimethicone, hexamethyldisiloxane, octamethyltrisiloxane, Decamethyltetrasiloxane, dodecamethylpentasiloxane, polydimethylsiloxanes, and combinations thereof.

preservative

The formulation preferably includes a preservative to inhibit the growth of the microorganisms and/or to prevent chemical breakdown of the formulation. In some aspects, the preservative can be selected from the group of compounds in the paraben family. The paraben preferably comprises methyl p-hydroxybenzoate, propyl p-hydroxybenzoate or a combination thereof. The preservative is preferably water soluble and is preferably included in the aqueous phase of the emulsion.

In some aspects, the combined concentration of preservative in the formulation is from about 0.05% to about 2% by weight of the formulation. Molecular weight of p-hydroxybenzoate may be present in the formulation from about 0.01% to about 2%, preferably from about 0.1% to about 0.3%, and more preferably about 0.20% by weight, based on the weight of the formulation. From 0.01% by weight to about 1% by weight, and more preferably from about 0.01% by weight to about 0.5% by weight, more preferably from about 0.05% by weight to about 0.1% by weight, and still more preferably about 0.1% by weight of p-hydroxybenzene may be present in the formulation. Propyl formate. Other suitable preservatives include, but are not limited to, methylparaben, propylparaben, ethyl p-hydroxybenzoate, butyl paraben, isobutyl p-hydroxybenzoate, p-hydroxybenzene Isopropyl formate, benzyl p-hydroxybenzoate and salts thereof.

pH regulator and buffer

The pH of the formulation is preferably from about 1.0 to about 6.5. Preferably, the pH is between about 4.0 and about 6.5, the pH is preferably between about 4.5 and about 6.2, the pH is preferably between about 4.5 and about 6.0, and the pH is better between about 5.0 and about 6.0. And preferably the pH is between about 5.3 and about 5.8. Especially good for the pH of human skin. Buffers capable of buffering the aqueous phase to a pH between about 4.5 and about 6.2 are very common and are readily identified by those skilled in the art. Such buffers include, for example, citrate buffers, acetate buffers, phosphate buffers, tartrate buffers, fumarate buffers, dimethyl glutarate buffers, succinate buffers. Agents, phthalate buffers, maleate buffers, and mixtures thereof. The agent preferably comprises a biologically acceptable carboxylate capable of buffering the aqueous phase of the emulsion, non-limiting examples of which are described in the foregoing list.

A combination of citric acid and sodium citrate is preferred. The pH adjusting agent may be incorporated directly into the formulation in its solid form, or may be added as part of a liquid or solid buffer comprising a plurality of agents.

In some aspects, the formulation comprises from about 0.01% to 0.1% by weight, and preferably about 0.055% by weight, based on the weight of the formulation, of citric acid. In some aspects, from about 1% to about 1.25% by weight, based on the weight of the formulation, of sodium citrate, preferably about 1.099% by weight sodium citrate, is combined. The amount of citric acid and/or sodium citrate may vary depending on the desired pH to be achieved by the formulation. In a particularly preferred aspect, about 0.055% by weight citric acid is used in combination with about 1.099% by weight or about 1.1% by weight sodium citrate. These agents can provide antimicrobial activity by themselves independent of the preservative and, in some aspects, can be used in place of a separate preservative.

Sodium phosphate and/or sodium monohydrogen phosphate and sodium dihydrogen phosphate may also be used in combination with citric acid and/or sodium citrate. Other suitable buffers include those comprising acetic acid and/or sodium acetate.

In some aspects, when avermectin is used as a therapeutically active ingredient, a buffer can also be used to prevent isomerization of avermectin to the 2-epimer.

Other suitable preservatives include sodium benzoate, imidazolidinyl urea (such as the GERMALL preservative family, including GERMALL PLUS), sequestering agents (such as ethylenediamine tetraacetic acid), either alone or in combination with the free acid. , EDTA)) and related compounds at various stages of protonation, as well as citric acid and its sodium salt. Other suitable preservatives present in the formulation may be at a concentration ranging from about 0.01% to 2%, or from about 0.01% to about 0.5% by weight (e.g., 0.05% by weight), for example, from about 0.01% to about 2%.

Humectant

In some aspects, the formulation may further comprise a humectant. Humectants are hygroscopic materials intended to prevent the formulation from drying out during use and prior to rinsing from the skin, hair or scalp. Humectants can also act as moisturizers in shampoo and conditioner formulations. Humectants are generally molecules having a number of hydrophilic groups, such as hydroxyl groups, amines, carboxylic acid groups, and esters thereof, which enable the molecules to form hydrogen bonds with water molecules.

In some aspects, other components of the formulation have the dual function of acting as a humectant, such as many nonionic surfactants including, but not limited to, oleyl alcohol, lanolin alcohol, acetylated lanolin alcohol, and the like. . In another embodiment, the humectant is selected from the group consisting of glycerin, triacetin, sorbitol, xylitol, maltitol, polydextrose, quillaia, lactic acid, urea, and the like, and mixture.

water

The oil phase mixture in which the therapeutically active ingredient, suspending agent, solubilizing agent, and nonionic surfactant are dissolved may be dispersed in water or the water may be dispersed in the oil phase. In some aspects, the water is deionized. Water acts as a carrier and is licensed for use in any individual formulation. In the exemplary formulations, from about 30% to about 40%, preferably from about 30% to about 33%, and preferably about 32% by weight water may be present in the formulation, by weight of the formulation.

Adding an oil phase comprising a therapeutically active ingredient to deionized water produces a colloidal suspension of the active ingredient, wherein the micelles are formed around the active ingredient and arranged such that the hydrophilic head of the surfactant and the solvent water molecule Contact and contact the hydrophobic tail of the surfactant with the active ingredient. This formulation is particularly suitable for the delivery of therapeutic active ingredients in body washes and shampoo-conditioners, which, for shampoo-conditioners, make the product easy to wash off and flow, thereby leaving the hair in good condition.

The formulations of the present invention will be exemplified by, but not limited to, the topical emulsions disclosed in Table 1. The formulation has the same consistency as the shampoo-conditioner or ointment and includes at least an effective amount of the therapeutically active ingredient, as well as any combination and/or concentration that can be expected by those skilled in the art after reviewing this specification. Solvents, water, suspending agents, surfactants, polyoxyxides and preservatives.

The specific concentration of the therapeutically active ingredient shown in Table 1 was 0.50% (w/v). This range of concentrations is provided to illustrate the invention and is not to be construed as limiting the scope of the invention.

The components, known equivalent components, combinations of components, and individual concentrations can be readily adjusted to provide alternative formulations for use in the applications disclosed herein.

Thus, those skilled in the art will appreciate that the weight percent of any component can be adjusted to compensate for the active ingredient concentration, texture or rheology of the topical formulation, and whether it is formulated as a water-in-oil emulsion or an oil-in-water emulsion (eg, shampoo) The sperm, ointment, gel), and the components may be added at different concentrations, or may be omitted from the formulation or substituted with equivalent components, thereby providing a topical formulation similar to the exemplary topical formulations described herein.

Those skilled in the art will appreciate that other useful agents can be added to the formulations of the present invention. Such useful agents include, without limitation, vitamins, hair dyes, nutrients, antidandruff agents, and the like. Those skilled in the art will be able to suitably select useful agents or combinations thereof such that at least one useful agent does not eliminate useful aspects of the formulation.

The present invention also provides methods of enhancing the resistance of a topical emulsion, including the formulations described and/or exemplified herein, to microbial growth, or otherwise enhancing the antimicrobial properties of the formulation. The method generally comprises buffering the emulsion to a pH at which the preservative inhibits the growth of microorganisms in the formulation by an equivalent or equivalent formulation in which the pH is not buffered or buffered to a different pH. Big. The formulation exhibits strong resistance to growth by bacteria, yeast, fungi and molds.

The pH can be adjusted to an alkaline, neutral or acidic level depending on the formulation or depending on the particular preservative used. Preferably, the pH is buffered to an acidic pH. In some aspects, the aqueous phase is buffered to between about pH 4.5 and about pH 6.2, although higher or lower pH values can also be used. The aqueous phase can be buffered to between about pH 5 and about pH 6, or any other pH value described herein.

The method can include adding an effective amount of citric acid and/or sodium citrate to the aqueous phase of the emulsion. The effective amount can vary and is preferably sufficient to bring the aqueous phase of the formulation to a pH that enhances the overall antimicrobial efficacy of the formulation. By way of example, but not limitation, the aqueous phase can comprise from about 0.01% to about 0.1% citric acid and from about 1% to about 1.25% sodium citrate, by weight of the formulation. These agents can provide antimicrobial activity by themselves independent of the preservative and, in some aspects, can be used in place of the preservative.

In some aspects, the method is useful for inhibiting the isomerization of a base catalyzed active ingredient. Thus, the formulation can be buffered to inhibit isomerization of the active ingredient, such as avermectin. For example, when the formulation includes ivermectin, the method can include buffering the formulation to a pH sufficient to inhibit base-catalyzed isomerization of ivermectin. For composite liquids, such as the formulations described and exemplified herein, it is not previously known whether the pH of the buffered aqueous phase will affect the stability of the components of the oil phase, given that the oil phase component is transiently exposed to the aqueous phase. Since alkaline pH induces isomerization of avermectin (Pivnichny, JV et al. (1988) J. Agric. Food Chem. 36:826-8), it is now known that avermectin will be dissolved in Acidification of the pH of the aqueous phase of the emulsion in the oil phase will prevent or reduce isomerization of avermectin. Therefore, the aqueous phase is preferably buffered. The pH sufficient to inhibit the base-catalyzed isomerization of the active agent can vary depending on the particular active agent employed. For example, in the case of ivermectin, the aqueous phase is preferably buffered to a pH of from about pH 4.0 to about pH 6.5, including the pH values described and exemplified herein, and more preferably buffered to the pH of human skin.

For example, the oil phase and the aqueous phase can be separately prepared (e.g., by mixing the ingredients of the phases together) in any suitable manner in the art, followed by mixing the oil phase with the aqueous phase, To prepare a topical preparation. The various conditions (e.g., temperature, heating and cooling rates, and the like) used to mix the oil phase with the aqueous phase can be varied to ensure proper dispersion and stability of the resulting emulsion.

The invention further encompasses methods of preventing or eliminating head lice that are susceptible to infection or resistance to treatment. The resistance may be resistance to any head lice treatment currently marketed or otherwise known in the art, such as malathion resistance, lindane resistance, pyrethrum ( Pyrethrum) resistance or resistance to chlorpyrifos. The method utilizes a formulation comprising avermectin or avermectin and sibnoxin in a topical formulation, including any of the formulations described or exemplified herein.

In general, the method comprises topically administering to a subject in need of such treatment an effective amount of a topical emulsion comprising an aqueous phase buffered to enhance the antimicrobial properties of the preservative in the formulation or formulation for a period of time sufficient to treat and Good to eliminate the pH of the head lice infection time. It is especially preferred to administer a single dose of the preparation to the individual, but if necessary, multiple doses may be used, including 2, 3, 4 or more doses, depending on the individual or physician's discretion.

The formulation (which may be a shampoo-conditioner) may be used once or twice in about seven days (eg, on Day 1 and between Days 5 and 9), and 3 or 4 times. The administration was started on the first day, and then the second, third or fourth administration was carried out in the interval of about 5 days to about 9 days. At each administration, the formulation can be administered and maintained at the site of infection (such as the scalp) for from about 1 minute to about 60 minutes, or from about 3 minutes to about 30 minutes, followed by rinsing with warm water. The formulation may also be maintained at the site of infection (such as the scalp) for from about 5 minutes to about 20 minutes, and for about 10 minutes to about 15 minutes. It is especially good for about 10 minutes. It is preferred to formulate the shampoo-conditioner to keep the hair in good condition while removing the lice from the scalp.

The method can be applied to any animal, including companion animals and farm animals. The best for humans.

Administration can be altered by altering the concentration of avermectin or sibnoxin as described above, or by increasing the amount of topical formulation applied to the scalp of a human individual. Although ivermectin and a spinosad formulation are suitable for use in the practice of the present invention, other known avermectins other than ivermectin, as well as other known sinnoxins other than sinister, are also contemplated, and It can be used as an active ingredient component of the present invention.

Although the dosage range may vary, the single application amount (dosage) of the present invention containing ivermectin/sinolicide to the scalp may preferably range from about 1 milliliter (ml) to about 200 milliliters. In some preferred aspects, the dosage is from about 3 milliliters to about 75 milliliters, more preferably from about 50 milliliters to about 120 milliliters, and more preferably from about 100 milliliters to about 120 milliliters. The dosage can vary, for example, depending on the amount and/or length of the hair. Thus, for example, longer hair may require larger doses.

In some aspects, at least about 60 ml of the topical formulation is applied to saturate the roots as a whole and effectively cover the entire scalp area. Practitioners can alter the concentration of ivermectin and spinosad, and/or the volume of the topical formulation to manipulate the effective amount of ivermectin and spinosad to be administered to the individual.

Another aspect of the invention pertains to multiple administrations of the topical formulations of avermectin (in the presence or absence of a Sbnosin) or ivermectin (with or without a spinosa) based on the present invention. Multiple administrations may include at least one, two, three or four additional doses in addition to the initial dose, with one or possibly two additional doses being preferred.

It is known in the art that similar treatment regimens are currently available to treat not only head lice infections, but also pubic lice or body lice infections. Therefore, it is apparent that the avermectin-containing preparation of the present invention can not only effectively treat head lice, but also treat sputum and body sputum infections of the human body. The formulations of the invention are useful for the treatment of haze and/or body lice infections. The core component of the formulation can be modified to provide a formulation having the consistency of a cream rinse or lotion that can be applied to the affected area for a period of time desired for the treatment of the head, followed by Wash off. Multiple administrations may also occur as contemplated herein with respect to the treatment of head lice with the formulations disclosed herein.

The following examples are provided to describe the illustrative aspects of the invention in more detail. It is intended to illustrate and not to limit the invention.

Example 1

Ivermectin shampoo conditioner

A preparation comprising ivermectin and/or spinosad as a topical shampoo-conditioner can be prepared as follows to eliminate the anti-therapeutic forceps:

Ivermectin was weighed and pre-dissolved in a container containing a water-miscible surfactant (hereinafter, phase A), that is, 15.00% w/v polysorbate 80. While mixing, phase A was heated at a constant temperature of 65 ° C until ivermectin was completely dissolved in the surfactant. Subsequently, phase A is poured into a vessel containing phase B consisting of a suspending agent, a preservative, a nonionic surfactant, a humectant, and a conditioning agent.

Phase B consisted of 27.25% w/v olive oil, 2.00% w/v shea butter, 8.00% w/v lanolin alcohol, 3.00% w/v cyclomethicone, 0.50% w/v sorbitan Tristearate, 0.20% w/v methylparaben and 0.05% w/v propylparaben. While mixing, phase A and phase B were heated at a constant temperature of 85 ° C until all ingredients dissolved and/or melted. At the same time, phase C was heated at a constant temperature of 85 ° C, which consisted of water buffered with 0.055% w/v citric acid and 1.099 w/v sodium citrate. While vigorously mixing, phase A and phase B were slowly added to phase C. The mixing is continued at or near room temperature until a homogeneous and homogeneous mixture is formed, which is subsequently packaged.

Example 2

Ivermectin emulsion blending

Ivermectin was weighed and dissolved in a water miscible surfactant AWS grade Crodalan and oleyl alcohol, and the resulting solution (phase A) was heated to 60 to 65 °C. Combine the suspending agent, nonionic surfactant and conditioning agent (Phase B) and, while mixing, heat to 75 to 80 ° C and determine that all ingredients are dissolved, the suspending agent, nonionic surfactant and conditioning agent They are composed of: 27.25% w/v olive oil and 2.00% w/v shea butter, 8.00% w/v lanolin alcohol and 0.50% w/v sorbitan tristearate, and 3.00% w /v cyclomethicone. At the same time, phase C is thoroughly mixed and heated to 75 to 80 ° C. The phase C consists of water buffered with 0.055% w/v citric acid and 1.099% w/v sodium citrate, and methyl and hydroxybenzoate. Composition of propyl formate. Phase A is premixed with phase B, followed by phase C while vigorously mixing. Continue mixing until a homogeneous and homogeneous blend is formed. The mixture was allowed to cool to room temperature with continued mixing, after which the compounded formulation was packaged.

Example 3

USP Antimicrobial Utility Test

Preparation of a topical ivermectin emulsion comprising a solubilizing agent, a nonionic surfactant, and a suspending agent, and according to US Pharmacopoeia, USP, Chapter 31, Section 51 (2008) (incorporated herein by reference) , screening for antimicrobial efficacy. As shown in Table 2 below, 10 parts of an emulsion containing a paraben preservative or a paraben preservative with citric acid and sodium citrate was formulated. The control formulation did not contain citric acid or sodium citrate.

According to the USP, the compendial articles are divided into four categories, see Table 3. The criteria for the antimicrobial efficacy of these products vary with the route of administration.

The USP test requires the cultivation of the following microorganisms: Candida albicans (ATCC No. 10231), Aspergillus niger (ATCC No. 16404), Escherichia coil (ATCC No. 8739), Pseudomonas Auruginosa ) (ATCC No. 9027) and Staphylococcus aureus (ATCC No. 6538), and the microorganisms used in this test were not comparable to the original ATCC culture for more than 5 generations.

Each container is inoculated with a prepared and standardized organism and mixed. The volume of the suspension inoculum used is between 0.5% and 1.0% by volume of the formulation. After inoculation, the concentration of the test microorganism added to the preparation was between 1 x 10 ⁵ and 1 x 10 ⁶ colony-forming units (cfu) per ml of product.

The inoculated containers were incubated according to the conditions described in Table 4. Each container was sampled at the appropriate time intervals as described in Table 5 below. The number of cfu present in each test formulation at each applicable time interval was determined using a plate counting procedure. Using the calculated concentration of cfu per ml at the beginning of the test, the change in log ₁₀ value per ml of cfu concentration for each microorganism at the applicable test interval was calculated and the change was indicated by log reduction.

If the criteria described in Table 5 are met, the requirements for antimicrobial efficacy are met. No increase is defined as no more than 0.5 log10 units higher than previously measured.

The results of the USP antimicrobial efficacy test selected from the formulations of Table 2 are provided in Table 6 below. Since the "control" preparation (see Table 2) was stored for several months under controlled laboratory conditions, mold growth was observed, even in the absence of specific inoculum size, so it was determined that the preparation was not suitable for inoculation (data) Not shown). For Candida albicans, it was subsequently found that a small number of variants of the control formulation failed conventionally to pass the USP antimicrobial efficacy test. (Table 6: Ec = E. coli; Pa = Pseudomonas aeruginosa; Sa = Staphylococcus aureus; Ca = Candida albicans; An = Melanium).

TNTC: The number is too large to count

These data indicate that by dispersing the dispersed aqueous phase of the emulsion to a pH at which the preservation system inhibits the growth of microorganisms in the formulation more than the equivalent of the aqueous phase without buffering. Enhances the overall antimicrobial efficacy of the emulsion.

The invention is not limited to the above described and exemplified embodiments, and variations and modifications can be made within the scope and equivalents of the appended claims.

Claims (21)

A topical formulation for inhibiting the growth of microorganisms comprising an effective amount of avermectin dissolved in an oil phase comprising an aqueous miscible or water soluble surfactant, a suspending agent and a nonionic interface An active agent, wherein the water-miscible or water-soluble surfactant comprises polysorbate 80, cetyl acetate, acetamino lanolinol or a combination thereof; the suspending agent comprises olive oil, and the preparation is The olive oil is present in an amount of about 20% to 30% by weight; the nonionic surfactant includes oleyl alcohol, lanolin alcohol, sorbitan tristearate, beeswax, sinapyl alcohol, castor oil, arachidyl alcohol, Octanol, sterol, behenyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, palmitol alcohol, linoleyl alcohol, 9E-octadecen-1-ol, 9E, 12E-octadecadien-1-ol, linolenic alcohol, 9E, 12E, 15E-octadecaen-1-ol or a combination thereof; and the aqueous phase comprises one or more preservatives, wherein the preservative Selected from paraben derivatives, sodium benzoate, imidazolidinyl urea, sequestering agent, citric acid, sodium citrate In combination therewith, the aqueous phase was include citric acid and sodium citrate buffer solution buffered to a pH of between about 4.5 to about 6.2 in. The topical preparation according to claim 1, wherein the avermectin is ivermectin, doramectin, selamectin or abaconin ( Abamectin), or a combination thereof. The topical formulation of claim 1, wherein the aqueous phase comprises from about 0.01% to about 0.1% citric acid and from about 1.0% to about 1.25% sodium citrate, by weight of the formulation. The topical preparation of claim 1, wherein the preparation further comprises a suspension agent of shea butter. The topical formulation of claim 1, wherein the nonionic surfactant comprises oleyl alcohol, lanolin alcohol, sorbitan tristearate or a combination thereof. The topical formulation of claim 1, wherein the ivermectin is present at a concentration of from about 0.1% to about 1% by weight of the formulation. The topical formulation of claim 1, wherein the oil phase comprises from 20% to 35% of the suspending agent, by weight of the formulation. The topical formulation of claim 1, wherein the oil phase comprises from 10% to 20% by weight of the formulation of the water-miscible or water-soluble surfactant. The topical formulation of claim 1, wherein the oil phase comprises from 15% to 45% of the nonionic surfactant by weight of the formulation. The topical preparation of claim 4, wherein the suspending agent comprises from 25% to 28% by weight of the preparation of olive oil, and from 1% to 5% by weight of the preparation. Oil tree oil. The topical formulation of claim 1, wherein the preservative comprises a combination of methyl p-hydroxybenzoate and propyl p-hydroxybenzoate in a combined concentration of from 0.01% to 2% by weight of the formulation. The topical preparation of claim 1, further comprising a conditioning agent. The topical formulation of claim 12, wherein the conditioning agent comprises cyclomethicone at a concentration of from 1% to 5% by weight of the formulation. The topical formulation of claim 1, wherein the topical formulation is an emulsion suitable for topical administration. A method of enhancing the resistance of an emulsion formulation to microbial growth, comprising buffering an aqueous phase of the emulsion to a pH at which the formulation inhibits microbial growth by an amount greater than the aqueous phase The buffered equivalent preparation is large, wherein the preparation is a topical preparation as described in claim 1 of the patent application. The method of claim 15, wherein the aqueous phase comprises from about 0.01% to about 0.1% citric acid and from about 1% to about 1.25% sodium citrate, by weight of the formulation. The method of claim 15, wherein the emulsion comprises ivermectin and the pH inhibits base catalyzed isomerization of the ivermectin. A topical preparation suitable for treating head lice in an individual comprising an effective amount of an insecticide dissolved in an oil phase comprising an aqueous miscible or water soluble surfactant, a suspending agent and a nonionic interface, and an aqueous phase comprising an effective amount of an insecticide An active agent, and said aqueous phase comprises one or more preservatives, wherein said aqueous phase is buffered to a pH at which said formulation inhibits microbial growth by an amount that is unbuffered than said aqueous phase The equivalent preparation is large, and the preparation is a topical preparation as described in claim 1 of the patent application. a topical preparation as described in claim 18, which includes A single dose of the formulation is administered topically to the individual. The topical formulation of claim 18, which comprises administering the formulation to the individual locally for from about 1 minute to about 60 minutes. The topical preparation of claim 18, which comprises administering to the individual 2, 3 or 4 doses of the preparation, wherein the interval between each administration is 5 to 9 days. .