WO2012150891A1

WO2012150891A1 - Composition for administration of a pharmacologically or cosmetically active agent onto a surface of a living organism

Info

Publication number: WO2012150891A1
Application number: PCT/SE2012/000060
Authority: WO
Inventors: Anders Carlsson; Bengt Herslöf; Jan HOLMBÄCK
Original assignee: Lipidor Ab
Priority date: 2011-05-02
Filing date: 2012-04-30
Publication date: 2012-11-08

Abstract

A composition for topical administration comprises a volatile silicone oil of a boiling point above 180 °C, a pharmacologically or cosmetically active agent, and optionally a C₂ - C₄ aliphatic alcohol but which neither comprises lipid nor polymer silicone. The composition can be applied to a biological surface by spraying, dipping or brushing to form a layer of active agent on the surface. Also disclosed is a method of manufacture of the composition.

Description

COMPOSITION FOR ADMINISTRATION OF A PHARMACOLOGICALLY OR

COSMETICALLY ACTIVE AGENT ONTO A SURFACE OF A LIVING ORGANISM

FIELD OF THE INVENTION

The present invention relates to a composition for topical administration of a pharmacologically or cosmetically active agent onto a surface of a living organism, in particular onto a membrane, such as the skin or a mucous membrane. The present invention also relates to a method of manufacturing the composition.

BACKGROUND OF THE INVENTION

In the pharmaceutical and cosmetic fields there is a need for a method and a means for deposing pharmacologically or cosmetically active compounds onto a biological surface such as the skin or the surface of a wound including burns or physically otherwise compromised skin. The composition should be of low viscosity to facilitate delivery, in particular by spraying. The composition should furthermore allow to depose the active compound(s) in a manner so as to avoid permanent concurrent deposition of pharmaceutically or cosmetically acceptable constituents. The

composition should also be stable for storage, that is, have an acceptable shelf life of a year and even two years or more.

WO 01/87344 Al discloses a pharmaceutical or cosmetic composition comprising one or more pharmacologically or cosmetically active agent, one or more organosilicon compound based on oligomeric or polymeric diorganosiloxane, and one or more phospholipid. When applied to the skin, the composition of WO 01/87344 Al penetrates directly within a short period of time into the skin or into the external layers of plants treated with it, so that it cannot be rubbed off since it is rapidly absorbed into the interior of the body. For embodiments intended to be used topically in humans or animals the organosilicon compound of the composition has a boiling point varying between 15 °C and 150 °C at ambient pressure. OBJECTS OF THE INVENTION

It is an object of the invention to provide a composition of the aforementioned kind, which is easily applicable.

Another object of the invention is to provide such a composition that does not cause swelling when applied to the skin.

A further object of the invention is to provide such a composition that does not cause irritation nor give a burning feeling when applied on the skin.

An additional object of the invention is to provide such a composition that does not cause a cooling sensation when applied to the skin.

Further objects of the invention will be evident from the following summary of the invention, preferred embodiments thereof described in form of examples, as well as from the appended claims. SUMMARY OF THE INVENTION

The present invention is based on the insight that silicone oils of a boiling point of 180 °C or higher, in particular of a boiling point of 200 °C or higher but not exceeding 300 °C can be used as an evaporating component or, preferably, the major evaporating component of compositions for topical application comprising a pharmacologically or cosmetically active agent and optionally comprising lower alcohol. "Evaporating component" indicates the capacity of volatile silicone oils to evaporate, in spite of their high boiling point, within a short time upon application of the composition to the skin or other surface at ambient temperature or at a higher temperature. By their evaporation and the evaporation of the lower alcohol a layer of the agent is formed on the skin or other biological surface. The composition of the invention does neither comprise lipid nor polymer silicone.

According to the invention is disclosed a composition of the aforementioned kind, comprising or substantially consisting of volatile silicone oil, lower alcohol, and pharmacologically or cosmetically active agent. The composition of the invention does neither comprise polymer silicone nor lipid. A preferred biological surface is the skin or a mucous membrane such as the nasal or gastric mucous membrane. Another preferred surface is a plant surface, such as the surface of a grain or seed.

The present invention is based on the finding that a particular class of solvents, volatile silicone oils, optionally in combination with lower aliphatic alcohol, are particularly useful in formulating compositions of the aforementioned kind. After application onto a biological surface the composition of the invention forms an unstable layer from which the volatile silicone oil and, if present, the lower aliphatic alcohol, evaporates readily, leaving a layer of pharmacologically or cosmetically active agent on the surface. The low viscosity of the composition of the invention makes it particularly suitable for administration by spraying.

Silicone oils of personal care grade or pharmaceutical grade useful in the invention are known in the art. Examples of useful silicone oils include dekamethyl- cyclopentasiloxane (Dow Corning® 245 Fluid) and dodekamethylcyclohexasiloxane (Dow Corning ® 246 Fluid). While pentasiloxanes and hexasiloxanes are preferred, hepta- and octasiloxanes are also potentially useful. The silicone oils may be cyclic siloxanes, that is, cyclomethicones, or linear siloxanes, that is, dimethicones. The silicone oils of the invention can be used in pure form or in admixture. While permethyl substitution is preferred, one or more methyl groups of a siloxane can be substituted by lower alkyl, in particular by ethyl, propyl or isopropyl. Siloxanes partially or fully substituted by lower trifluoroalkyl, in particular trifluoromethyl and pentafluoroethyl, are also useful in the invention.

In addition to chemical inertness the usefulness of the silicone oil of the invention is determined by its volatility. In spite of its high boiling point above 180 °C, in particular above 200 °C, the silicone oil of the invention evaporates readily due to the low heat of vaporization of this class of compounds. In the invention a silicone oil having a heat of vaporization (kj/kg) at 25 °C of from about 100 kj/kg to about 300 kj/kg, more preferred of from about 120 kj/kg to about 200 kj/kg is particularly useful. Even more preferred is a silicone oil having a heat of vaporization of from 140 kj/kg to about l80 kJ/kg at 25 °C.

The silicone oil of the invention provides the composition of the invention with at least the following advantageous features: z) the formation of thermodynamically stable solutions; ii] the low viscosity of the solutions formed making them suitable for, e.g., spraying, dropping, painting or instilling.

The lower aliphatic alcohol of the invention is a C₂ to C4 alcohol or a mixture of such alcohols. Preferred examples of alcohols are ethanol and 2-propanol. Other useful alcohols are glycerol and 1,2-propanediol. The lower aliphatic alcohol can be comprised by the composition in an amount of up to 25 % or more and even up to 50 % or more. In general, it is advantageous to adjust the content of lower aliphatic alcohol in the composition to that required for dissolving the pharmacologically or cosmetically agent in the composition, that is, to keep the content of lower aliphatic alcohol in the composition as low as possible.

Solvents other than lower alcohols may also be used, such as dimethyl sulfoxide and N-methyl-2-pyrrolidone. In applications with less stringent

biocompatibility requirements solvents such chloroform, dichloromethane, pyridine, hexane, and methanol can be used.

The composition may further include additional components well known to a person skilled in the art, such as antioxidants, film forming agents, release modifiers and permeation enhancers.

The pharmacologically or cosmetically active agent or the protective agent can be incorporated in the composition in an amount of from 0 % to 2 % by weight or up to 5 % by weight or more.

The pharmacologically active agent for incorporation into the composition of the invention is preferably selected from the group consisting of: antimicrobial agent, antibiotic; antimycotic agent; antibacterial agent; antifungal agent; antiviral agent; antiseptic; anti-phlogistic; anti-pruritic agent; anti-psoriatic agent; antitussive agent; anti-alopecia agent; anti-acne agent; anti-inflammatory agent; antiulcer agent; local anaesthetic; immune response modifying agent.

In particular, the pharmacologically active agent of the invention is selected from: antibacterial agents, such as oxytetracycline, fusidic acid, gentamycine, mupirocin, retapamulin (and pharmaceutically acceptable salts and derivatives thereof); antimycotic agents, such as nystatin, clotrimazole, miconazole, econazole, ketoconazole, bifonazole, and combinations of imidazole and triazole derivatives, ciclopirox, terbinafine, fluconazole, and amorolfine (and pharmaceutically acceptable salts and derivatives thereof); antiviral agents, such as aciclovir, valaciclovir, penciclovir, famciclovir, foscarnet (sodium phosphoneformate hexahydrate) and docosanol (and pharmaceutically acceptable salts and derivatives thereof); antiseptics, such as chlorhexidine and hydrogen peroxide; anti-inflammatory agents

(glucocorticoids), such as hydrocortisone, clobetasone, triamcinolone, betamethasone, momethasone, and clobetasol (and pharmaceutically acceptable salts and derivatives thereof); antiphlogistics/analgesics (NSAID's), such as acetylsalicylic acid, diclofenac, and ibuprofen (and pharmaceutically acceptable salts and derivatives thereof);

antipruritic agents, such as glucocorticoids, for example, hydrocortisone, clobetasone, and betamethasone, and local anaesthetics, for example, lidocaine and prilocaine (and pharmaceutically acceptable salts and derivatives thereof); antipsoriatic agents, such as calcipotriol and cyclosporine A (and pharmaceutically acceptable salts and derivatives thereof); agents for treatment of eczema and atopic dermatitis: tacrolimus and pimecrolimus (and pharmaceutically acceptable salts and derivatives thereof);

antiglaucomateous agents, such as timolol, betaxolol, latanoprost, bimatoprost, and travoprost (and pharmaceutically acceptable salts and derivatives thereof); local anaesthetics, such as lidocaine, prilocaine, ropivacaine, mepivacaine, bupivacaine, levobupivacaine, benzocaine, and tetracaine (and pharmaceutically acceptable salts and derivatives thereof); agents for erectile dysfunction, such as alprostadil

(prostaglandin El) (and pharmaceutically acceptable salts and derivatives thereof); anti-dandruff agents, such as selenium sulphides, piroctone oleamine and

ketoconazole; anti-alopecia agents, such as minoxidil (and pharmaceutically acceptable salts and derivatives thereof); anti-acne agents, such as tretinoin (retinoic acid), adapalene, benzoyl peroxide, clindamycin, azelaic acid (and pharmaceutically acceptable salts and derivatives thereof); wound healing agents, such as fusidic acid (and pharmaceutically acceptable salts and derivatives thereof).

The cosmetically active agent for incorporation into the composition of the invention is preferably selected from the group consisting of: antiperspirant;

antisudoral agent; antidandruff agent; glidant; moisturizing agent.

The cosmetically active agent may also be a protective agent and is, as such, preferably selected from the group consisting of: insect repellent; UV absorbing agent; antifungal agent; antibacterial agent; antiviral agent.

Examples of other agents for incorporation into the composition of the invention are: insect repellents, such as N,N-diethyl-m-toluamide (DEET), icaridine, and ethyl butyl acetylaminopropionate (and salts and derivatives thereof); UV sunscreens, both physical and chemical, such as titanium dioxide, benzophenon-3, butyl methoxydibenzoylmethane, ethyl hexyl methoxycinnamate, and

4-aminobenzoic acid (PABA) (and salts and derivatives thereof); tanning agents, such as dihydroxyacetone.

antisudoral agent; antidandruff agent; glidant; moisturizing agent. Preferred

antidandruff agents include piroctone oleamine and ketoconazole.

In addition to the pharmacologically active agent, the cosmetically active agent or the protective agent the respective composition of the invention can contain a counterirritant, in particular one selected from methyl salicylate, capsaicin, camphor and menthol.

The pharmacologically or cosmetically active agent can be dissolved or dispersed in the silicone oil or the lower alcohol or the mixture of silicone oil and alcohol.

The composition of the invention can be applied to a dry or a humid biological surface by any suitable method, such as by spraying, dipping, brushing, dropping, rubbing in.

The invention will now be described in greater detail by reference to a number of examples.

DESCRIPTION OF PREFERRED EMBODIMENTS Materials

Table 1. Silicone oils used in the formulation experiments

Short Supplier, trade name Chemical name, CAS No. Lot No. name

DC 345 Dow Corning® 345 Dekamethylcyclopentasiloxane, 5627357

Fluid 541-02-6

DC 245 Dow Corning® 245 Dekamethylcyclopentasiloxane, 5480964

Fluid 541-02-6

DC 246 Dow Corning® 246 Dodekamethylcyclohexasiloxane, 5264620

Fluid 540-97-6 EXAMPLE 1. Local anaesthetic lidocaine composition

Ingredient % (w/w)

Lidocaine (Sigma L7757) 3.2

Absolute ethanol 22.0

Volatile silicone oil (DC 345] 74.8

A weighed amount of lidocaine was dissolved in absolute ethanol.

The solution was diluted with volatile silicone oil to obtain a colourless solutions, which was stored in an air-tight glass vials at room temperature. The appearance of the composition was unchanged for more than a month at room temperature. This indicates excellent physical stability.

EXAMPLE 2. Local anaesthetic benzocaine composition

Benzocaine was dissolved in absolute alcohol. The solution was diluted with the volatile silicone oil. The resulting colourless solution was stored in an air-tight glass vial at room temperature. Its appearance remained unchanged for more than a month at room temperature. This indicates excellent physical stability.

Ingredient % (w/w)

Benzocaine (Fluka 06952) 2.0

Absolute ethanol 23.0

Volatile silicone oil (DC 345) 75.0

EXAMPLE 3. Insect repellent N,N-diethyl-m-toluamide (DEET) composition

Ingredient % (w/w)

DEET (Aldrich D10,095-l) 5.0

Absolute ethanol 25.0

Volatile silicone oil (DC 345) 70.0 A pre-weighed amount of DEET was dissolved in absolute ethanol. The obtained clear solution was diluted with the volatile silicone oil. The resulting colourless solution was stored in an air-tight glass vial at room temperature. Its appearance remained unchanged for more than a month at room temperature. This indicates excellent physical stability.

EXAMPLE 4. Peptide hormone oxytocin compositions

Accurately weighed amounts of oxytocin (Sigma-Aldrich) were dissolved in mixtures of glycerol and ethanol at 40 °C under agitation. Silicone oil (DC 345) and optionally isopropanol was added and the respective mixture gently agitated at 40 °C until a homogenous, clear and colourless liquid was obtained (Table 2).

Table 2. Oxytocin compositions

* Concentration of oxytocin in % w/w of the non-volatile part of the composition (glycerol being considered as non-volatile)

EXAMPLE 5. Local anaesthetic lidocaine compositions

An accurately weighed amount of lidocaine was dissolved in absolute ethanol at 40 °C under agitation. Silicone oil (DC 345) and optionally isopropanol was added and the mixture was gently agitated at 40 °C until a homogenous, clear and colourless liquid was obtained (Table 3).

Table 3. Lidocaine compositions

Composition Lidocaine, % w/w DC 345, % w/w EtOH, % w/w

KL-LK-10 4.8 90.3 4.9

KL-LK-14 5.0 85.0 10.0

Claims

C l a i m s

1. Composition for topical administration comprising a pharmacologically or

cosmetically active agent, volatile silicone oil, optionally C₂ - C₄ aliphatic alcohol, wherein the silicone oil has a boiling point above 180 °C, in particular above 200 °C, with the proviso that the composition does neither comprise lipid nor polymer silicone.

2. The composition of claim 1, wherein the silicone oil has a heat of vaporization (kj/kg) at 25 °C of from about 100 kj/kg to about 300 kj/kg, in particular of from 120 kj/kg to 200 kj/kg, most particularly of from 140 kj/kg to 180 kj/kg.

3. The composition of claim 1 or 2, substantially consisting of volatile silicone oil, C₂ - C₄ aliphatic alcohol, optionally comprising water in an amount of 1 % by weight or less.

4. The composition of any of claims 1 to 3, wherein the volatile silicone oil

comprises one of dekamethylcyclopentasiloxane and

dodekamethylcyclohexasiloxane.

5. The composition of any of claims 1 to 3, wherein the volatile silicone oil

comprises one of heptasiloxane and octasiloxane.

6. The composition of any of claims 1 to 5, wherein the C₂ - C₄ aliphatic alcohol is selected from the group consisting of: ethanol, 2-propanol, 1,2-propanediol, glycerol, and their mixtures.

7. The composition of any of claims 1 to 6, optionally comprising less than 1 % by weight of water.

8. The composition of any of claims 1 to 7, wherein the pharmacologically active agent is selected from the group consisting of: antimicrobial agent, antibiotic; antimycotic agent; antibacterial agent; antifungal agent; antiviral agent;

antiseptic; anti-phlogistic; anti-pruritic agent; anti-psoriatic agent; antitussive agent; anti-alopecia agent; anti-acne agent; anti-inflammatory agent; anti-ulcer agent; local anaesthetic.

9. The composition of any of claims 1 to 7, wherein the cosmetically active agent is selected from the group consisting of: antiperspirant; antisudoral agent;

antidandruff agent; glidant; moisturizing agent.

10. The composition of any of claims 1 to 7, wherein the cosmetically active agent is a protective agent selected from the group consisting of: UV-absorbing agent, insect repellent, antibacterial agent, antifungal agent; antiviral agent, anti- nematode agent.

11. A method of forming a layer of a pharmacologically or cosmetically active agent on a biological surface comprising:

providing the composition of any of claims 1 to 12;

applying a desired amount of the composition to the surface so as to form a layer comprising agent, silicone oil and, optionally, C₂ - C₄ aliphatic alcohol; allowing the silicone oil and, if present, the C₂ - C₄ aliphatic alcohol to evaporate at the temperature of the surface to form a layer of the pharmacologically or cosmetically active agent on the surface.

12. The method of claim 11, wherein application is by spraying, dipping or

brushing.

13. The method of claim 11 or 12, wherein the temperature is from about 20 °C to about 45 °C.

14. Use of the composition of any of claims 1 to 10 for covering a surface of a

biological item of vegetable origin by a layer of pharmacologically or

cosmetically active agent.

15. The use of claim 14, wherein the item is one of seed, seedling, bedding plant, fruit.

16. A biological item of vegetable origin comprising a surface covered by a layer formed from the composition of any of claims 1 to 10.

17. The item of claim 16 in form of a seed, a seedling, a bedding plant or a fruit.