DESC:FIELD OF THE INVENTION
The present invention relates to an insect repellent composition and more particularly to a synergistic insect repellent composition, comprising N,N-diethyl-benzamide and p-menthane-3,8-diol.
BACKGROUND OF THE INVENTION
Mosquitoes thrive in an unhygienic environment, stagnant and polluted waters, sewage system and rain water puddles. They are known to spread diseases, such as Chikungunya, Malaria, Dengue, etc. Considering that millions of people die worldwide every year from malaria or mosquito transmitted diseases, it is difficult to ignore the fact that mosquito is a deadly, harmful insect.
To combat mosquitoes, a mosquito repellent is generally applied to the skin or clothes, because it not only offers protection from mosquito bites but is also relatively safe for application on a human body. Mosquito repellents are of two types, synthetic mosquito repellents, such as N,N-diethyl-m-toluamide (CAS-Number: 134-62-3), N,N-diethyl-benzamide (CAS-Number: 1696-17-9), and natural ingredient based mosquito repellents such as p-menthane-3,8-diol or PMD (CAS-Number: 42822-86-6), which is found in small quantities in the essential oil from the leaves of Eucalyptus citriodora, citronella oil, lemon grass oil, lemon eucalyptus oil, cinnamon oil etc. By far the best known and most widely used topical insect repellent is N,N-diethyl-m-toluamide (DEET).
Traditionally, insect repellents designed to be applied directly on humans (as opposed to area repellents, such as room foggers or candles) have been formulated using synthetic chemicals. The active ingredients in most insect repellents currently on the market today include DEET, which has been shown to be an effective repellent against biting insects. An insect repellent cream, Advanced Odomos, (12% N, N-diethyl-benzamide), developed by M/s. Balsara Home Products Ltd. (now Dabur India Limited, Sahibabad, UP) has been found to be effective against mosquitoes such as Anopheles quadrimaculatus, Anopheles albimanus, Aedes aegypti, etc.
Compositions useful as insect repellents should disperse easily onto the skin, adhere closely to the skin, resist penetration through the skin, and resist shedding with perspiration or rain. Unfortunately, most insect repellents do not fully satisfy these requirements in terms of durability and prolonged residence on the skin. Synthetic insect repellents, used alone or in combination with common cosmetic extenders, gradually penetrate into deep layers of the skin where their insect repelling activity is reduced. Various efforts have been made by a number of manufacturers to develop compositions comprising insect repellents either in combination or alone, but most have not proven their effectiveness.
US 5,698,209 discloses a composition containing a monoterpenediol selected from carane-3,4 diol and p-methane-3,8-cis-diol (Coolact® 38D) and a pyrethroid compound selected from phenothrin and permethrin as active ingredients. The composition purportedly exhibits a high arthropod repellency for a long period of time. Over the years, such synthetic chemicals have provided an effective means of pest control.
However, it has become increasingly apparent that the widespread use of synthetic chemicals as insect repellents and pesticides has caused detrimental environmental effects that are harmful to humans and other animals. For instance, the public has become concerned about the amount of residual chemicals that persist in food, ground water and the environment, and that are toxic, carcinogenic or otherwise incompatible to humans, domestic animals and/or fish. Moreover, some insects have even shown an ability to develop resistance to many commonly used synthetic chemicals. Further, although chemicals such as N,N-diethyl-m-toluamide and N,N-diethyl-benzamide are safe for application to animal skin at concentrations generally present in insect repellent products, they may be toxic at higher concentrations or on ingestion through the oral route.
Based on the above discussion, there is a need to substantially eliminate or reduce insect bites whilst lowering the concentrations of active ingredients in insect repellent compositions. However, despite the fact that currently available insect repellent compositions are good at repelling insects, the protection time, i.e. the time for which an insect repellent composition is effective, for the user, directly correlates with the concentration of the repellent. Inevitably, researchers are continually evaluating compounds to improve the activity of an insect repellent, i.e. active compound. These compounds are referred to as synergists, and an insect repellent composition containing a synergist is referred to as “a synergistic insect repellent composition”. The insect repellent activity of such a composition is greater than the sum of the activity of the repellent compound and the synergist, thereby precluding higher concentrations of the active compound, for prolonged protection time, for the user, in insect repellent compositions. Generally, synergists have essentially no repellent activity at the concentrations employed in the insect repellent compositions. Consequently, there exists a need for an insect repellent composition comprising an active insect repellent and a synergist.
SUMMARY OF THE INVENTION
The present invention is broadly directed towards a synergistic insect repellent composition with enhanced protection time for the user.
In accordance with an embodiment of the invention, there is provided a synergistic insect repellent composition, comprising N,N-diethyl benzamide, p-menthane-3,8-diol and excipients.
The mass ratio of N,N-diethyl benzamide and p-menthane-3,8-diol in the synergistic insect repellent composition ranges from 15:1 to 8:5 and is preferably 10:2.
In accordance with a further embodiment of the invention, N,N-diethyl benzamide is present in an amount in the range from 8 to 15% and p-menthane-3,8-diol is present in an amount in the range from 1 to 5%.
The synergistic insect repellent composition comprises excipients selected from the group consisting of an emulsifier, a preservative, a thickener, a humectant, a neutralizer, a fragrance, a diluent, a solvent and an emollient.
In accordance with another embodiment of the invention, the emulsifier is present in an amount of 0.01-18%, the preservative is present in an amount of 0.10-2.00%, the thickener is present in an amount of 0.10-2.00%, the humectant is present in an amount of 1.00-5.00%, the neutralizer is present in an amount of 0.01-2.00%, the fragrance is present in an amount in the range from 0.01-1.00%, the diluent is present in an amount of 25.00-70.00%, and the emollient is present in an amount of 0.1-11.00%.
The synergistic insect repellent composition may be in the form of a lotion, spray, cream, oil, ointment or gel.
DETAILED DESCRIPTION OF THE INVENTION
Discussed below are some representative embodiments of the present invention. The invention in its broader aspects is not limited to the specific details and representative methods. The illustrative examples are described in this section in connection with the embodiments and methods provided. The invention according to its various aspects is particularly pointed out and distinctly claimed in the appended claims read in view of this specification and appropriate equivalents.
It is to be noted that, as used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing “a compound” includes a mixture of two or more compounds. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. The terms “mosquito repellent” and “insect repellent” mean essentially the same thing and can be used interchangeably.
The expression of various quantities in terms of “% w/w” or “%” means the percentage by weight or composition unless otherwise specified.
An insect repellent (also commonly called "bug repellent”) is a substance applied to skin, clothing, or other surfaces which discourages insects from landing or climbing on that surface. Insect repellents help prevent and control the outbreak of insect-borne (and other arthropod-borne) diseases such as Malaria, Chikungunya, Lyme disease, Dengue fever, Bubonic plague, West Nile fever, etc. Pest animals commonly serving as vectors for disease include insects such as flea, fly, mosquito; and the arachnid tick.
Insect repellents based on amides are known to repel various species of mosquitoes (Mosquito Repellents: Alicyclic Amides as repellents for Aedes aegypti and Anopheles quadrimaculatus, McGovern et al, Mosquito News, September 1978, 347; Mosquito Repellents: Cyclohexanealkanoic carboxamides as repellents for Aedes aegypti, Anopheles quadrimaculatus and Anopheles albimanus, McGovern et al, Mosquito News, September 1980, 394).
N,N-Diethyl-meta-toluamide, also called DEET or diethyltoluamide, is the most common active ingredient in insect repellents. It is a clear, colourless to pale yellow oil intended to be applied to the skin or to clothing, and provides protection against mosquitoes, ticks, fleas, chiggers, leeches, and many biting insects. N,N-Diethylbenzamide is another active amide that is widely used in insect repellent compositions.
The amount of insect repellent, such as N,N-Diethylbenzamide, in a composition cannot be increased beyond a certain threshold. However, the effectiveness of an insect repellent composition can be increased, without increasing the concentration of the active ingredient, by adding certain ingredients called synergists.
Accordingly, the inventors of the present invention have prepared a synergistic insect repellent composition comprising N,N-diethyl benzamide, p-Menthane-3,8-diol (also known as para-menthane-3,8-diol, PMD, or menthoglycol) and excipients. PMD has an odour similar to menthol and has a cooling feel. There are eight possible isomers of PMD, and the exact composition is rarely specified and is commonly assumed to be a complex mixture.
The mass ratio of N,N-diethyl benzamide and p-menthane-3,8-diol in the synergistic insect repellent composition ranges from 15:1 to 8:5 and is preferably 10:2.
The composition of the present invention comprises N,N-diethyl benzamide in an amount in the range from 8 to 15% and p-menthane-3,8-diol in an amount in the range from 1 to 5%.
The synergistic insect repellent composition further comprises excipients selected from the group consisting of an emulsifier, a preservative, a thickener, a humectant, a neutralizer, a fragrance, a diluent, a solvent and an emollient.
An “emulsifier” is a detergent like substance that makes it possible for the components of said composition to mix with water. One class of emulsifiers are known as "surface active agents", or surfactants. Examples of emulsifiers include but are not limited to stearyl alcohol, glyceryl monostearate, stearic acid, polysorbate 80, polysorbate 60 and combinations thereof. In an embodiment, the emulsifier is present in an amount in the range from 0.01-18%.
A “preservative” is often added to a composition in order to prevent spoilage due to proliferation of microorganisms such as bacteria and fungi. Non-limiting examples of preservatives that can be used in the composition include propyl para hydroxyl benzoate, methyl para hydroxyl benzoate, and 2-phenoxy ethanol, each of which can be used individually or in combination, in an amount in the range from 0.10-2.00%.
A “thickener” is a substance which can increase the viscosity of a liquid without substantially changing its other properties. Hence, a thickener is added to adjust the viscosity of a composition to improve its storage and handling properties. Example of a thickener includes, but is not limited to polyacrylic acid. The thickener is present in an amount in the range from 0.10-2.00%.
A composition exposed to the environment soon hardens due to evaporation of water. Hence, in order to prevent the loss of water and hardening upon exposure to air, the composition of the present invention contains humectants selected from the group consisting of glycerine, sorbitol, polypropylene glycol and combinations thereof in the range from 1.00-5.00%.
Due to the presence of a thickener such as polyacrylic acid, the composition tends to have a low pH. Hence, a neutralizer is added to increase the pH and cause the dispersion to thicken and gel. Some neutralizing agents that can be used in the present invention include sodium hydroxide, potassium hydroxide, and triethanolamine. If inorganic bases are used to neutralize the solution, a stable water soluble gel is formed. If triethanolamine is used, the gel can tolerate high alcohol concentrations. In an embodiment, said composition comprises the neutralizer in an amount in the range from 0.01-2.00%.
It is desirable to have a fragrance in the synergistic insect repellent composition, which may be present in an amount in the range from 0.01-1.00%. Said composition may also contain a solvent such as isopropyl alcohol in an amount of 25.00-40.00%.
An “emollient” is a moisturizer which helps keep the skin moist by reducing water loss from the epidermis - the outer layer of skin. Emollients keep the skin moist and supple by providing a protective film. Accordingly, the composition contains Dimethicone Copolyol, glycerine or combinations thereof as emollients in an amount in the range from 0.1-11.00%.
The synergistic insect repellent composition of the present invention may be in the form of a lotion, spray, cream or gel.
The present invention is more particularly described in the following examples that are intended as illustrations only, since numerous modifications and variations within the scope of the present invention will be apparent to those of skill in the art. Unless otherwise noted, all parts, percentages and ratios reported in the following examples are on a weight basis and all reagents used in the examples were obtained or are available from the chemical suppliers.
Examples 1-7
Table 1 is a list of ingredients and their amounts present in the insect repellent composition in the form of a cream. The unit of each value is percent weight of the composition. Ingredients are combined and mixed by conventional means as known by one of ordinary skill in the art.

Table 1. Insect Repellent Cream
INGREDIENTS FUNCTION 1 2 3 4 5 6 7
N,N-diethyl-benzamide Active 12 10 0 0 6 2 0
N,N-diethyl-m-toluamide Active 0 0 0 12 0 0 10
p-menthane-3,8-diol Active 0 2 12 0 6 10 2
Glyceryl Monostearate Emulsifier 1.00-5.00.
Cetostearyl alcohol Emulsifier 1.00-5.00
Stearyl Alcohol Emulsifier 0.10-1.00
Polysorbate 60 Emulsifier 0.01-0.10
Propyl Para Hydroxy Benzoate Preservative 0.10-1.00
Methyl Para Hydroxy Benzoate Preservative 0.10-1.00
Polyacrylic Acid Thickener 0.10-1.00
Glycerine Humectant 1.00-3.00
Triethanolamine Neutraliser 0.01-1.00
Perfume Fragrance 0.01-1.00
D.M. Water Diluent q.s.
TOTAL 100
D.M. = Demineralized
q.s. = quantity sufficient

Example 8
Table 2 is a list of ingredients and their amounts present in the insect repellent composition in the form of a lotion. The unit of each value is percent weight of the composition. Ingredients are combined and mixed by conventional means as known by one of ordinary skill in the art.
Table 2. Insect Repellent Lotion
S. No. INGREDIENTS FUNCTION % w/w
1 Stearyl Alcohol Emulsifier 0.10 - 1.00
2 Glyceryl Monostearate Emulsifier 3.00 - 7.00
3 Stearic Acid Emulsifier 1.00 - 5.00
4 Polysorbate 80 Emulsifier 1.00 - 5.00
5 Propyl Para Hydroxy Benzoate Preservative 0.10 - 0.50
6 p-Menthane-3,8-diol Active Ingredient 2.00
7 N,N Diethylbenzamide Active Ingredient 10.00
8 Methyl Para Hydroxy Benzoate Preservative 0.10 - 0.50
9 Polyacrylic Acid Thickener 0.10 - 1.00
10 Glycerine Humectant 1.00 - 5.00
11 Potassium Hydroxide Neutraliser 0.01 – 1.00
12 Perfume Fragrance 0.10 - 1.00
13 D.M. Water Diluent qs to 100
TOTAL 100.00
D.M. = Demineralized
q.s. = quantity sufficient
Example 9
Table 3 is a list of ingredients and their amounts present in the insect repellent composition in the form of a spray. The unit of each value is percent weight of the composition. Ingredients are combined and mixed by conventional means as known by one of ordinary skill in the art.

Table 3. Insect Repellent Spray
S. No. INGREDIENTS FUNCTION % w/w
1 Isopropyl Alcohol Solvent 25.0 - 40.0
2 Dimethicone Copolyol Emolient 1.00 - 5.00
3 Glycerin Humectant 1.00 - 5.00
4 p-Menthane-3,8-diol Active Ingredient 2.00
5 N,N Diethylbenzamide Active Ingredient 10.00
6 2-Phenoxy Ethanol Preservative 0.10 - 0.50
7 Perfume Fragrance 0.10 - 1.00
8 D. M. Water Diluent qs to 100
TOTAL 100.00
D.M. = Demineralized
q.s. = quantity sufficient
Example 10
Table 4 is a list of ingredients and their amounts present in the insect repellent composition in the form of a gel. The unit of each value is percent weight of the composition. Ingredients are combined and mixed by conventional means as known by one of ordinary skill in the art.

Table 4. Insect Repellent Gel
S. No. INGREDIENTS FUNCTION % w/w
1 Carboxy Methyl Cellulose Thickener 0.10 - 1.00
2 Polyacrylic Acid Thickener 0.10 - 1.00
3 Polyethylene Glycol Emulsifier 1.00 - 5.00
4 Triethanolamine Neutraliser 0.10 - 2.00
6 2-phenoxy Ethanol Preservative 0.10 - 0.50
8 p-Menthane-3,8-diol Active Ingredient 2.00
9 N,N Diethylbenzamide Active Ingredient 10.00
10 Dimethicone copolyol Emolient 0.10 - 1.00
11 Glycerin Emolient 1.00 - 10.00
12 Perfume Fragrance 0.10 - 1.00
13 Di-sodium EDTA Chelating Agent 0.01 - 0.05
14 Colour Colour 0.00001 - 0.001
15 D M Water Diluent qs to 100
TOTAL 100.00
D.M. = Demineralized water
q.s. = quantity sufficient
Synergistic effect of the insect repellent compositions
The efficacy of the insect repellent compositions was evaluated on four volunteers. The skin on the back side of the palm was marked and cleaned with fresh water. After wiping the water, gloves were worn on both the hands. The marked portion of the back side of the palm was exposed by cutting open the glove over that area. After that, 50 mg of the insect repellent composition was applied as a thin and uniform film over the exposed portion in one hand, whereas the exposed area of the other hand served as untreated control. Thereafter, the control and test areas of the skin were exposed to 100±10 unfed (starved for 24 h) female mosquitoes (Aedes aegypti) in an observation chamber of volume 22” × 22” × 22”. Observations were made every hour, and the time after which the first bite occurred was recorded. The results of the experiments are illustrated in Table 5.
Table 5: Efficacy of Insect Repellent Compositions
Example 1 2 3 4 5 6 7
Protection time in h 4 6 3 4 3 3 5

Protection time = the time after which first mosquito bite occurred.
The effectiveness of the insect repellent compositions illustrated in table 1, in terms of the time after which the first mosquito (Aedes aegypti) bite occured, i.e. the protection time, is depicted in table 5. Example 1, comprising 12% N,N-diethyl-benzamide, was found to be effective upto 4 h; example 4, comprising 12% N,N-diethyl-m-toluamide, was effective upto 4 h; and example 3, comprising 12% p-menthane-3,8-diol, was effective upto 3 h. However, example 2 comprising a combination of 10% N,N-diethyl-benzamide and 2% p-menthane-3,8-diol was effective upto 6 h, which is two hours more than that observed with an equivalent amount of N,N-diethyl-benzamide, ie. 12%, present alone in example 1. Further, example 7 comprising a combination of 10% N,N-diethyl-m-toluamide and 2% p-menthane-3,8-diol was effective upto 5 h, and example 5, comprising N,N-diethyl-benzamide and p-menthane-3,8-diol at 6% each, were effective up to 3 h. Still further, example 6, comprising a combination of 2% N,N-diethyl-benzamide and 10% p-menthane-3,8-diol was effective only upto 3 h. From the experimental data, it is evident that the combination of N,N-diethyl benzamide and p-menthane-3,8-diol in example 2, i.e. in a ratio of 10:2 has a synergistic effect in repelling and preventing mosquito bites.
While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is thereof intended to cover in the appended claims such changes and modifications that are within the scope of the invention.

CLAIMS:
We claim:
1. A synergistic insect repellant composition, comprising N,N-diethyl benzamide, p-menthane-3,8-diol and excipients.
2. The synergistic insect repellent composition as claimed in claim 1, wherein the mass ratio of N,N-diethyl benzamide and p-menthane-3,8-diol is in the range from 15:1 to 8:5.
3. The synergistic insect repellent composition as claimed in claims 1 and 2, wherein the mass ratio of N,N-diethyl benzamide and p-menthane-3,8-diol is 10:2.
4. The synergistic insect repellent composition as claimed in claims 1 to 3, wherein N,N-diethyl benzamide is present in an amount in the range from 8 to 15% and p-menthane-3,8-diol is present in an amount in the range from 1 to 5%.
5. The synergistic insect repellent composition as claimed in claims 1 to 4, wherein the excipients are selected from the group consisting of an emulsifier, a preservative, a thickener, a humectant, a neutralizer, a fragrance, a diluent, a solvent and an emollient.
6. The synergistic insect repellent composition as claimed in claim 5, wherein the emulsifier is selected from the group consisting of stearyl alcohol, glyceryl monostearate, stearic acid, polysorbate 80, polysorbate 60 and combinations thereof, and present in an amount in the range from 0.01-18%.
7. The synergistic insect repellent composition as claimed in claim 5, wherein the preservative is selected from the group consisting of propyl para hydroxyl benzoate, methyl para hydroxyl benzoate, 2-phenoxy ethanol and combinations thereof, and present in an amount in the range from 0.10-2.00%.
8. The synergistic insect repellent composition as claimed in claim 5, wherein the thickener is polyacrylic acid and present in an amount in the range from 0.10-2.00%.
9. The synergistic insect repellent composition as claimed in claim 5, wherein the humectant is glycerine and present in an amount in the range from 1.00-5.00%.
10. The synergistic insect repellent composition as claimed in claim 5, wherein the neutralizer is triethanolamine, potassium hydroxide or combinations thereof and present in an amount in the range from 0.01-2.00%.
11. The synergistic insect repellent composition as claimed in claim 5, wherein the fragrance is present in an amount in the range from 0.01-1.00%.
12. The synergistic insect repellent composition as claimed in claim 5, wherein the diluent is water.
13. The synergistic insect repellent composition as claimed in claim 5, wherein the solvent is isopropyl alcohol and present in an amount in the range from 25.00-40.00%.
14. The synergistic insect repellent composition as claimed in claim 5, wherein the emollient is selected from the group consisting of Glycerine, Dimethicone Copolyol and combinations thereof, and present in an amount in the range from 0.1-11.00%.
15. The synergistic insect repellent composition as claimed in any of the claims 1 to 14, wherein the composition may be in the form of a lotion, spray, cream, paste or gel.