Topical formulations for the prevention of sexually transmitted disease and methods of producing the same

[0001] The present invention relates to protective topical preparations for use in preventing the spread of sexually transmitted diseases (STDs); and especially unique topical formulations containing many film-forming excipients that work together to provide a barrier to inhibit the transmission of sexually transmitted diseases. BACKGROUND OF THE INVENTION [0002] Sexually transmitted diseases (STDs) are common, affect millions of people, and burden healthcare systems. Doctors have identified over 20 different sexually transmitted diseases, generally dividing into two groups, bacterial (e.g., gonorrhea, chlamydia and syphilis) and viral (human immunodeficiency virus (HIV), human papillomavirus (HPV) and hepatitis). Numerous diseases affect men, women and children from all walks of life, races and wealth. Despite years of research and educational programs, the spread of sexually transmitted diseases remains a global health threat. Although specific ways of transmitting disease may vary depending on the causative organism, sexually transmitted diseases are usually transmitted to uninfected through damaged or exposed skin or mucous membranes during sexual contact.

[0003] Some types of sexually transmitted diseases can be treated (e.g., antibiotic therapy of gonorrhea or chlamydia). However, most people who suffer from this type of sexually transmitted disease are unaware that they have the disease and therefore do not take the necessary treatment. In addition, due to the sociological impact and generally negative stigma associated with these diseases, people are reluctant to seek such treatment. Continuous emphasis on educating the public to use "mechanical barriers" such as condoms has helped reduce the incidence of most sexually transmitted infections, but more preventative methods are needed to prevent STDs.

[0004] Chemical active substances such as bactericides, antibacterials and spermicides, especially nonylphenoxypols (ethyleneoxy) -ethanol (also referred to as nonoxynol-9) have been used in topical formulations to effectively reduce the rate of STD transfer, especially when they are used in conjunction with prevention. However, many of these chemically active substances are irritants and have been shown to cause local irritation, inflammation and ulceration, which may actually promote the spread of sexually transmitted diseases. Thus, there is a need for topical formulations that do not cause irritation and help inhibit the spread of sexually transmitted diseases, particularly when used in combination with condoms and thus provide an additional degree of protection against infection in the event of damage to the condom.

Background Art [0005] Although there are many patents and publications regarding preparations containing chemical active substances such as bactericides, antibacterials, spermicides and drug delivery vehicles (liposomes, micelles), no prior art document discloses a composition containing non-irritating substances. which provide a physical barrier to the penetration of pathogens.

[0006] Patent application US 2003/0143189 A1 Askill et al. is directed to a method of treating skin damage by producing a polymer film over the damage to inhibit the proliferation of infectious agents into the damage. These compositions also contain one or more chemical agents.

[0007] US Patent 6835717 to Hildreth discloses a method of reducing the risk of sexually transmitted pathogens by contacting the pathogen with a composition that contains β-cyclodextrin.

[0008] US Patent No. 6,821,958 to Hershline discloses a method for preventing virus transmission using an alkyl sulfate dextrin sulfate derivative as a topical formulation.

[0009] In US Patent 6582711 Asmus et al. discloses an antibacterial hydro-alcoholic composition of a cationic polymeric thickener.

[0010] US Patent No. 6,355235 Cone et al. describes an antibody capable of sperm binding and a pharmaceutical carrier.

[0011] US Patent No. 6,328,991 Myhling discloses a chemical composition for preventing the spread of sexually transmitted diseases comprising nonylphenoxypoly- (ethyleneoxyl) -ethanol, benzalkonium chloride and iodopovidone.

[0012] US Patent 5439685 Augros describes the composition of the active agent against microorganisms responsible for sexually transmitted diseases together with a film-forming agent such as dimethylpolysiloxane and benzalkonium chloride as a spermicide.

[0013] Patent US 4952411 Fox, Jr. et al. describes a composition of silver sulfadiazine, alone or in combination with chlorhexidine or sodium deoxycholate (antibacterial agent and detergent).

[0014] Tennican et al., 1979 discuss the various effects of local or systemic administration of zinc on the virulence of genital herpes virus.

[0015] Eby, 1985 discusses the use of topically administered zinc in preventing recurrent herpes simplex infections; presents a literature review and proposed protocols ..

Summary of the Invention [0016] In a first aspect, the invention provides an oil-in-water formulation for inhibiting the spread of sexually transmitted pathogens, characterized in that it has improved skin protective properties consisting of a combination of:

(1) Dimethicone 20 in the range from 10.0 to 20.0% w / w;

(2) Dimethicone 12500, in the range from 3.0-10.0% w /;

(3) zinc oxide in the range of 1.0 to 8.0% w / w;

(4) mixtures of cetearyl alcohol and ceteareth-20 in the range of 6.0 to 10.0% w / w;

(5) glycerin, in the range of 2.0 to 10.0% w / w;

(6) ceteareth-12, in the range of 0.5 to 3.0% w / w;

(7) disodium acetate in the range of 0.01 to 0.1% w / w;

(8) a chelating compound in the range of 0.01 to 0.25% w / w;

(9) anhydrous lanolin, in the range of 0.5 to 3.0% w / w;

(10) cetostearyl alcohol, in the range of 1.0 to 5.0% w / w;

(11) cetyl alcohol, in the range of 1.0 to 5.0% w / w; and (12) enough deionized water to form a composition;

where contact with the skin causes the in situ protective layer of the skin, and sexually transmitted pathogens are viral pathogens. [0017] In a further aspect, the invention provides a method for producing an oil-in-water formulation consisting of:

the aqueous phase containing (in% w / w) (1) Deionized water (USP) in quantities sufficient to contain the ingredients 2-5;

(2) Disodium edetate 0.01-0.1 (3) Benzalkonium chloride 0.01-0.25 (4) zinc oxide 1.0-8.0 (5) Glycerin (USP) 2.0-10.0 and the oil phase containing (in% w / w) ( 6) Dimethikon 20 10.0-20.0 (7) Dimethikon 12500 3.0-10.0 (8) Cetearyl and / or Ceteareth-20 6.0-10.0 (9) Ceteareth-12 0.5-3.0 (10) Anhydrous Lanolin 0.5 -3.0 (11) cetostearyl alcohol 1.0-5.0 (12) Cetyl alcohol 1.0-5.0 wherein said oil-in-water formulation is prepared according to the following steps:

1. heating to 75 ° C dimethicone 20, dimethicone 12500, cetearyl alcohol, Ceteareth-20, Ceteareth-12, anhydrous lanolin, cetostearyl alcohol and cetyl alcohol to allow the materials to melt;

2. dissolving the dido edetate in deionized water;

3. Adding benzalkonium chloride to step 2;

4. heating step 3 to 75-78 ° C;

5. dispersing zinc oxide in glycerin to form a homogeneous dispersion;

6. slowly adding materials from stage 4 (water phase) to materials from stage 1 (oil phase) at high mixing speed and initiating cooling;

7. at a temperature of 60 ° C; adding the dispersion from step 5 to the materials from step 6;

8. at 50 ° C, reduction of mixing speed;

9. at 40 ° C, further reduction of mixing speed;

10. at 25 ° C mixing stops.

[0018] In a further aspect, the invention provides an oil-water formulation according to the invention for use in inhibiting the transmission of sexually transmitted pathogens, wherein the sexually transmitted pathogens are viral pathogens.

[0019] The object of the present invention is to provide non-irritating protective preparations to be used as an additive to prevent the spread of a wide range of sexually transmitted diseases. The products of the present invention may be formulated as a lotion, topical cream, solution, emulsion or the like and will be referred to as creams. The use of active antiviral / antimicrobial agents and film-forming excipients in the following preparations has demonstrated unique barrier properties that protect the skin with increased durability, which inhibit the transmission of pathogens "from skin to skin" and "from change to change" (e.g. viruses, bacteria, fungi, parasites, external parasites and mycoplasmas) associated with infectious diseases.

[0021] Skin protection products are regulated in CFR 21 part 347 "Non-prescription skin protection medical products for human use". The official description of skin protection products is "a medicinal product that temporarily protects damaged or exposed skin or mucous membranes from harmful or irritating stimuli and can help to bring relief" These provisions include ingredients used as well as the requirements for labeling of over-the-counter skin protection products. The active ingredients are officially classified as skin protection compositions as well as certain combinations of these compositions are listed in CFR 21 chapter. 347.10, reproduced in Table 1 below. According to the present invention, by the expression "a skin protection agent composition present in a concentration effective for the protection of the skin" is meant any of the following components in their designated concentration range:

Table 1:

<td colspan="2">This includes any of the following ingredients in the concentration range indicated:</td>

<td>Ingredient</td><td>Concentration</td>

<td>allantoin</td><td>0.5 to 2.0%</td>

<td>Aluminum hydroxide gel</td><td>0.15 to 5.0%</td>

<td>Calamine</td><td>1.0 to 25.0%</td>

<td>Cocoa butter</td><td>50.0 to 100.0%</td>

<td>Cod liver oil</td><td>5.0 to 13.56% (according to chapter 347.20 (a) (1) or (a) (2), provided that the product is marked so that the quantity used over a 24-hour period does not exceed 10,000 USP vitamin A units and 400 USP cholecalciferol units.</td>

<td>colloidal Porridge</td><td>0.007 minimum; 0.003 minimum, in combination with mineral oil, according to chapter 347.20 (a) (4).</td>

<td>dimethicone</td><td>1.0 to 30.0%</td>

<td>Glycerine</td><td>20.0 to 45.0%</td>

<td>Hard fat</td><td>50.0 to 100.0%</td>

<td>Kaolin</td><td>4.0 to 20.0%</td>

<td>Lanolin</td><td>12.5 to 50.0%</td>

<td>Mineral oil</td><td>50.0 to 100.0%; 30.0 to 35.0%, in combination with colloidal porridge, according to chapter 347.20 (a) (4).</td>

<td>Petrolatum</td><td>30.0 to 100.0%</td>

<td>Local starch</td><td>10.0 to 98.0%</td>

<td>White vaseline</td><td>30.0 to 100.0%</td>

<td>Zinc Acetate</td><td>0.1 to 2.0%</td>

<td>Zinc carbonate</td><td>0.2 to 2.0%</td>

<td>Zinc oxide</td><td>1.0 to 25.0%</td>

[0022] It has been found that the incorporation of at least one of the aforementioned compositions of skin protection agents given in Table 1, in combination with other film-forming excipients, in particular, film-forming emollients (for example, cetostearyl alcohol, cetyl alcohol), excipients silicone / skin protection agents (for example, polydimethylsiloxane derivatives of different viscosities, used alone or in combination, sold under names such as dimethicone 20 and dimethicone 12,500), emulsifying agents (e.g. selected from cetearyl alcohol (a mixture of fatty alcohols, usually cetyl and stearyl alcohols, polyoxyethylene ethers of a mixture of saturated high molecular weight fatty acids (mainly cetyl alcohol and stearyl alcohol, containing a number of ethylene oxide moieties in the polyoxyethylene chain equal to, for example 20, 12 or similar, referred to as Ceteareth -20, Ceteareth-12 or similar and / or mixtures thereof), humectants (e.g. glycerin and anhydrous lanolin) and chelating compounds (e.g. disodium edetate) in topical preparations result in a product that temporarily protects the surface of damaged or exposed skin and mucous membranes against harmful or irritating stimuli, thus preventing cross-contamination with pathogenic microorganisms, responsible for sexually transmitted diseases (for example, Herpes simplex type 1 and type 2 virus (HSV-1, HSV-2), human immunodeficiency virus (HIV) or similar), through skin or mucosal surfaces. In addition to the hydrophobic preparations that create the barrier, active substances that prevent the transmission of bacteria or viruses are included. The new formulation products of the present invention are stable, form a film or barrier on healthy or even damaged skin.

[0023] The hydrophobic parts of the exemplary formulations use film-forming auxiliaries, including the skin protection agents listed in Table 1, silicones and silicone derivatives or similar equivalents, and film-forming softeners. These ingredients are dispersed by emulsifiers throughout the entire continuous aqueous phase. They condense and spread on the skin as a result of body heat. They form a hydrophobic physical layer that remains on the surface of the skin (including mucous membranes) and forms a barrier that inhibits the penetration of liquids and pathogens, which are usually hydrophilic in nature. In conjunction with the consistent and careful use of condoms, the products of the invention help to stop the spread of sexually transmitted diseases and protect the skin from infection in the event of damage to the condom.

[0024] Accordingly, the object of the present invention is to provide various topical protective formulations used to prevent the spread of sexually transmitted diseases.

[0025] Another object of the present invention is to provide formulations that are compatible with condoms, which means that they do not damage latex and provide effective lubricating properties.

[0026] Still another object of the present invention is to provide skin protective formulations in which contact with the skin creates a hydrophobic protective layer for the skin surface.

[0027] Still another object of the present invention is to provide skin protective formulations in which contact with the skin creates a mechanical protective barrier for the surface layer of the skin.

[0028] Still another object of the present invention is to provide skin protective formulations in which contact with the skin causes the formation of a hydrophobic protective layer on the skin surface containing antiviral / antibacterial agents.

[0029] Still another object of the present invention is to provide finished formulations in the form of a cream, lotion, solution, emulsion or other surface-applied products.

[0030] Other objects and advantages of the present invention will become apparent from the following description, which illustrates, by way of illustration and example, some embodiments of the present invention.

Detailed description of the invention [0031] Zinc oxide is an inert, non-toxic chemical compound with the chemical formula ZnO. Zinc oxide can be used as a skin barrier. When applied to the skin, zinc oxide acts as a mechanical barrier that physically excludes isolates and protects the skin from contact with harmful stimuli. Zinc oxide is often used in the form of creams or lotions and provides a continuous barrier that also prevents the loss of active ingredients due to friction and abrasion. Because it is inert and non-toxic, and essentially insoluble in water, it can be applied to the skin as often as it may be needed. Although zinc oxide is a preferred skin protection composition of the invention, other suitable skin protection compositions can be used in an amount effective to provide skin protection as listed in Table 1 (e.g., dimethicone). [0032] Glycerin is a nonirritating humectant and film forming agent. It is also water soluble. In addition, glycerin is harmless to latex products and provides improved lubricating properties, which makes it a widely used basis for many products intended for use within the genitals. [0033] Lanolin is a humectant isolated from the wool of animals, such as sheep. It is a product of sebaceous glands and consists mainly of a mixture of cholesterol and esters of several fatty acids. It has many commercial applications, including in the medical and cosmetics industries.

[0034] Benzalkonium chloride is a quaternary ammonium compound. These compounds are a group of ammonium salts in which organic radicals have been substituted for all four hydrogen atoms of the original ammonium cation. Benzalkonium chloride has been reported to be an effective, wetting antiviral agent in preventing the transmission of viral diseases such as HIV and herpes simplex virus. Benzalkonium chloride is also listed in an FDA monograph on topical antimicrobial medicinal products as a first aid antiseptic. Although the use of benzalkonium chloride is preferred, it is believed that any other quaternary salt of the ammonium compound may be used without departing from the scope of the present invention, such as cetrimide (alkyl sulfate bromide).

[0035] The term "film-forming emollient" refers to any excipient suitable for cosmetic and pharmaceutical applications that forms a water impermeable film. According to the invention, the film-forming emollients are cetyl alcohol and cetostearyl alcohol. Cetyl alcohol (IUPAC name 1-hexadecanol) is a member of the alcohol class. It is a solid organic compound and belongs to the group consisting of fatty alcohols. Regardless of its use as an emollient, it is often used in the cosmetics industry as a surfactant in shampoos, emulsifiers and thickeners for the production of creams and lotions for the skin. Cetyl stearyl alcohol is a mixture of cetyl alcohol and stearyl alcohol, two fatty alcohols derived from plant sources.

[0036] The term "silicone-containing excipient" refers to any silicone or silicone derivative, including silicone-based skin protective agents, suitable for cosmetic and pharmaceutical applications, which acts as an emollient and creates a film impermeable to water, including silicone oils. In addition to creating a skin barrier, silicone oils and silicones are highly serous to the skin. As a result of this property, silicone oils and silicones are often used in topical preparations, such as creams and lotions, to improve the affinity of active ingredients on the skin.

[0037] After application of the topical formulation to the skin and removal of volatiles, the film resulting from the use of a silicone-containing excipient helps to keep the active ingredient in contact with the skin and prevents the loss of the active ingredient by abrasion. The ability to create hydrophobic films that can be easily applied and spread on the skin provides high resistance to washing and abrasion. The use of silicones in topical formulations is more desirable than petroleum based products because silicones do not exhibit the negative aesthetics of petroleum products and, unlike petroleum, are known to be compatible with the materials used to make condoms. According to one non-limiting embodiment, Dimethikon (preferably Dimethicone 20 cSt and Dimethikon 12,500 cSt) is preferred. Dimethicone is a very clean, non-volatile silicone oil that is colorless and odorless. It can be used as a lubricant and a protective emollient. [0038] Ceteareth-12 belongs to the family called INCI Ceteareth-n and refers to polyoxyethylene ethers of a mixture of saturated fatty alcohols of relatively high molecular weight. "N" means the average number of ethylene oxide moieties in the polyoxyethylene chain. Ceteareth12 is a non-toxic surfactant that is often used as an emulsifier in the cosmetics industry. A mixture of cetearyl alcohol and ceteareth-20 (Emulgade 1000NI, Cognis Corporation) is a non-ionic, self-emulsifying base commonly used in the production of oil / water creams and lotions.

[0039] Disodium edetate, having the chemical name disodium tetraacetate dihydrate (ethylene dinitrile), is also commonly known as EDTA disodium salt. It works chemically as a chelating compound, preventing components from binding to trace elements that may be present.

[0040] Excipients and antimicrobial and / or antiviral ingredients useful in the preparation of skin protective creams according to the present invention are described in the following non-limiting example.

Example 1 [0041] In formulating a portion of a skin protection cream according to the invention, the active ingredients and excipients useful for making this product resulted in a particularly effective product when the ingredients were used in the following approximate ranges

<td colspan="2">ACTIVE INGREDIENTS / EARNINGS</td><td>% Waqowv /</td>

<td colspan="2" rowspan="2"></td><td>RANGES</td>

<td></td>

<td>Water phase</td><td></td><td></td>

<td> (1)</td><td>Deionized water</td><td>qs</td>

<td> (2)</td><td>Disodium edetate</td><td> 0,01-0,1</td>

<td> (3)</td><td>Benzalkonium chloride</td><td> 0,01-0,25</td>

<td> (4)</td><td>Zinc oxide</td><td> 1,0-8,0</td>

<td> (5)</td><td>Glycerin (USP)</td><td> 2,0-10,0</td>

<td>Oil phase</td><td></td><td></td>

<td> (6)</td><td>Dimethicone 20</td><td> 10,0-20,0</td>

<td> (7)</td><td>Dimethicone 12500</td><td> 3,0-10,0</td>

<td> (8)</td><td>cetearyl alcohol and / or ceteareth-20</td><td> 6,0-10,0</td>

<td> (9)</td><td>Ceteareth-12</td><td> 0,5-3,0</td>

<td> (10)</td><td>Anhydrous lanolin</td><td> 0,5-3,0</td>

<td> (11)</td><td>Cetostearyl alcohol</td><td> 1,0-5,0</td>

<td> (12)</td><td>Cetyl alcohol</td><td> 1,0-5,0</td>

[0042] A preferred, although non-limiting method of producing a preparation consists of the steps of:

Procedure:

[0043]

1. Heat to 75 ° C dimethicone 20, dimethicone 12500, cetearyl alcohol and Ceteareth-20 (available as Emulgade 1000 NI from Cognis), ceteareth-12 (available as (Eumulgin B1 from Cognis), anhydrous lanolin, cetostearyl alcohol and cetyl alcohol, Allow materials to melt.

2. Dissolve disodium edetate in deionized water (USP).

3. Add benzalkonium chloride to step 2

4. Heating step 3 to 75-78 ° C.

5. Disperse zinc oxide in glycerin to form a homogeneous dispersion.

6. At high mixing speeds, slowly add materials from stage 4 (water phase) to materials from stage 1 (oil phase). Start cooling.

7. At 60 ° C, add the dispersion from step 5 to the materials from step 6 (emulsion).

8. At 50 ° C, reduce the mixing speed.

9. At 40 ° C, reduce the mixing speed again.

10. At 25 ° C stop mixing.

[0044] Without wishing to be bound by any particular theory, it is believed that film-forming excipients and the active substance form an inert, hydrophobic barrier layer that is also believed to interact with the skin, thereby having a stabilizing effect on the hydrophobic layer, which leads to increased product durability. The use of silicone-containing skin protection agents, e.g. dimethicone 20 and dimethicone 12500, or their equivalents, works in collaboration with at least one of the skin protection compositions as specified in CFR 21 chapter 347.10, e.g. zinc oxide, or others from Table 1, excipients and film-forming softeners and melted under the influence of body heat. This in turn creates a hydrophobic physical layer that provides a barrier that appears to inhibit the penetration of liquids and sexually transmitted pathogens (viral, bacterial), which are primarily hydrophilic in nature. This property helps protect you against infection during sexual contact with infected people.