Title of Invention

A PHARMACEUTICAL OR COSMETIC COMPOSITION IN THE FORM OF MICRODROPLETS OF WATER INSOLUBLE LIQUID FOR TOPICAL APPLICATION

Abstract A pharmaceutical or cosmetic composition in the form of micro-droplets of water insoluble liquid for topical application, comprising from 1.0 to 5.0% by weight an active ingredient dispersed in the aqueous medium with oily excipient and/or solvent as a solid or liquid particles which are selected from diclofenac diethyl ammonium salt, fusidic acid, acyclovir, doxepin hydrochloride, diclofenac sodium and diclofenac potassium and pharmaceutically or cosmetically acceptable carriers selected from a non-ionic surfactant, skin penetration enhancers, antioxidants, chelating agent, inorganic thickening agent; wherein said composition is liquid & semisolid after adding gelling agent.
Full Text FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
& THE PATENS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]

A PHARMACEUTICAL OR COSMETIC
COMPOSITION IN THE FORM OF MICRO
DROPLETS OF WATER INSOLUBLE LIQUID
FOR TOPICAL APPLICATION

LAMAR INTERNATIONAL PVT. LTD., A COMPNAY INCORPORATED UNDER THE COMPANIES ACT 1956, WHOSE ADDRESS IS 31, KHIMAJI MEGHJI HOUSE, 3RD FLOOR, 11/15, ISSAJI STREET, VADGADI, MUMBAI - 400 003, IN THE STATE OF MAHARASHTRA WITHIN THE UNION OF INDIA.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.





The present invention relates to compositions and their method of preparation for topical applications.
More particularly, the invention relates to compositions for topical applications which can be used for pharmaceutical and/or cosmetic purposes.
Various types of compositions for topical applications are known.
It is an object of the present invention to suggest a novel type of composition for topical application, which can be used for pharmaceutical, medical and/or cosmetic purposes.
According to the present invention, there is provided a composition for topical applications which includes an active substance in the form of micro-droplets of water-insoluble liquid.
The composition may include an active substance with oily excipients and/or solvents in an aqueous medium.
The active substance may be a solid or liquid ingredient which is dispersed in the aqueous medium so as to form a suspension.
The composition may include a skin penetration enhancer as an excipient in the topical application.
The composition may include a non-ionic surfactant as one of the excipients. Examples of surfactant include a non-ionic alkylene oxide condensate of an organic compound, which contains one or more hydroxyl groups, such as an ethyoxylated and/or propoxylated alcohol or ester compound or mixtures thereof. The surfactant may be selected from any one of the following commercially known surfactants: Tyloxapol, Poloxamer 4070, Poloxamer 188, Polyoxyl 40 Stearate, Transcutol, Labrafac, Emulfor EL-620, Cremaphor, Polysorbate - 80, Polysorbate-20,

Tween, Pluronic F- 68. The above mentioned surfactants are by way of examples and other surfactants may also be used which are obvious to any person skilled in the art.
The composition may include preservatives and/or anti-oxidants such as thimerosal, chlorbutanol and methyl, ethyl, propyl and butyl parabens.
The anti-oxidant may be an oil phase anti-oxidant such as alpha-tocopherol or alpha-tocopherol succinate.
The composition may include a chelating agent of a polyamine carboxylic acid, such as ethylenediamine tetraacetic acid (EDTA) or a pharmaceutically accepted salt thereof.
The composition may be admixed with surfactants
The composition may be in semi-solid form.
The semi-solid form is obtained by the addition of gelling agents, such as carbopols, organic thickening agents like polyvinyl pyrrolidone (PVP), hydroxpropyl methyl cellulose (HPMC) polymer, cetostearyl alcohol other waxes capable of rigidifying, solidifying or increasing the viscosity of the aqueous dispersion.
The composition may also include inorganic thickening agents, such as fumed silica, alumina, clay or other similar colloidal particles to increase viscosity.
Compositions according to the present invention promote percutaneous penetration on topical application and local or transdermal effects.Thus the overall pharmacological effect, while using such a chemical enhancer in conjunction with such submicron chemical spheres, will be greater than either one of them alone.

The chemical skin penetration enhancers include examples such as decyl methyl sulfoxide (DMSO), N- dodecyl pyrrolidone, decanol, dodecanol or an organic acid such as oleic acid.
In contrast to the prior art, the present invention relates to oily spheres having an average diameter in the micron range, which are both physically and chemically distinct from the known art of liposome - type lipid vesicles and from the known art of micro - emulsion in which surfactants or synthetic emulsifiers comprise major proportion of the composition. In tenns of chemical composition, the particles are somewhat similar to the classical emulsions, but due to the finely divided particulate nature of compositions in accordance with the present invention, a significantly enhanced dermal penetration is achieved. These droplets thus can be termed as "micro-emulsion oil spheres"
Active ingredients not soluble in water may be dispersed in an aqueous medium as solid or liquid particles to form a suspension. One aspect of this invention relates to drugs or cosmetically active substances that are liquid at room temperature and may be dispersed as liquid, water insoluble droplets with the desired droplet size range. Otherwise, for drugs or cosmetics, which are solid at room temperature and in the shape of powder or crystals, mixtures with an oil are a preliminary required step in order to obtain oily droplets in aqueous suspension or may be an aqueous dispersion.
An emulsion is a dispersion of oil in water (o/w) and can be defined as macro-emulsion or a micro-emulsion. The term "micro" is used herein to mean a size of about 0.5u to lOu and preferably about 0.5u to 3u. Thus micro droplets of these sizes would be smaller than those of a classical macro-emulsion, which has a droplet size of about 1u, but generally larger

than those of a classical micro-emulsion, which for practical purposes, has droplet sizes of less than about 0.1u.
An oil-in-water emulsion is a dispersion of droplets or colloidal particles in an aqueous medium, with the colloidal particles having an oily core surrounded by an interfacial film of the surfactants
The surfactants chosen should preferably be non-ionic to minimize irritation, and one skilled in the art can conduct tests to routinely select specific surfactants for this purpose. Generally, the surfactant is a non-ionic alkylene group, for example ethoxylated and/or propoxylated alcohol or ester compound or mixture thereof are commonly available and are well known to those skilled in the art.
As mentioned above suitable surfactants include, but are not limited to TYLOXAPOL (chemical name : 4-(1,1,3,3-Tetramethylbutyl)phenol Polymer with Formaldehyde and Oxirane), POLOXAMER (synthetic copolymers of ethylene oxide and propylene oxide) 4070, POLOXAMER 188, POLYOXYL 40 Stearate (polyoxyethylene monostearate), TRANSCUTOL (Diethylene glycol monoethyl ether), LABRAFAC (caprylic/capric triglyceride polyethylene glycol-4 esters), EMULFOR EL-620 (polyoxyethylated castor oil), CREMAPHOR (Polyoxyl castor oil), POLYSORBATE - 80 and POLYSORBATE - 20 as well as various compounds sold under the name TWEEN (industrial name for polysorbate) (ICI American Inc., Wilmington, Delaware, USA). PLURONIC (2-methyloxirane; oxirane) F-68 (trade name of BASF, Ludwigshafen, Germany for a copolymer of polyoxyethylene and polyoxypropylene). At this time, PLURONIC F-68 and the POLOXAMER 188 are preferred. The TYLOXAPOL and TWEEN surfactants are also preferred as they are FDA (USA Federal Drug Agency) approved for human use.

As mentioned above the aqueous component will be the continuous phase of the emulsion and may be water, saline or any other suitable aqueous solution, which can yield an isotonic and pH controlled preparation.
The drug, cosmetic or active ingredient in accordance with the invention, alone or with oily excipients, is mixed with a sufficient amount of surfactants to allow dispersability within the desired size range in aqueous medium, in a form of stable micro size-range droplets. The drug with or without oily excipient, is vigorously mixed with an aqueous solution that may containing surfactants, to result in sub-micron droplets of the drug and the excipients.
If needed a high shear mixer and a high pressure homogenizer are employed to achieve the desired droplet size. Sonication is an alternative method to achieve the desired micro droplet size.
Highly efficient delivery of the micro droplets to the skin is obtained with a dosage form, which is semi-solid. To produce a semi-solid composition, many methods may be applied; addition of gelling agents, such as carbopols and adjusting to a desired pH, followed by addition of organic thickening agentSr like polyvinyl pyrrolidone (PVP) or a hydroxpropyl methyl cellulose (HPMC) polymer, or cetostearyl alcohol and other waxes that may rigidify, solidify or increase the viscosity of the aqueous dispersion to the desired consistency level.
Inorganic thickening agents, such as fumed silica (AEROSIL), alumina, clay or other similar colloidal particles can be used to increase the viscosity of the formulation. It is also possible to use oil concentration on the higher end of the disclosed range to achieve higher viscosity compositions. However, use of greater than 30% oil causes difficulty in the desired droplet size.

The composition in accordance with the invention provides micro spheres (or droplets) that are an insoluble assembly of unique entities dispersed in an aqueous phase with the aid of appropriate surfactants and the surfactant form a protective layer around the droplets thus enabling efficient dispersion and suspension of the oily phase in water. This layer is monolayer, polar by virtue of the surfactants.
Experiments carried out and measurements by means of laser diffraction (Mastersizer E) indicated that the droplet size in the compositions of the invention is in the size range of about 0.25 to about 2.0microns, Preferably, the size range is mainly in the 0.5 to I.Omicron (i.e. 100 to 300nm) range.
Compositions according to the invention for topical application a topical or systemic effect, contain, for example, as active ingredient: steroids or nonsteroidal anti-inflammatory drug, antibiotics, antifungals, antivirals, antihistamines, antineoplastics or local anaesthetics, and the like.
For cosmetic effects, the active ingredient might be a vitamin A, vitamin E, a polyunsaturated fatty acid such as eicosapentanoic acid, retinoids, carotenes and benzoyl peroxide.
Instead of viscous composition, the droplets of the invention can be topically and transdermally applied by an article, which includes the droplets, an active ingredient and a support for retaining the composition thereon. The support would include an adhesive for securing the article to the skin of a subject. A wide variety of active ingredients, including steroids such as estradiol, nicotine or nitroglycerine, can be administered by these articles, which would generally be in the form of an occlusive dressing or an adhesive patch.

DESCRIPTION OF EXAMPLES
Example 1: A cream containing 1.16% diclofenac diethyl ammonium salt-

Ingredients % by weight
Active ingredient
Carbomer 940
Chlorocresol 1.16
_100
0.12
0.05
1.00
0.10

Disodium EDTA


Benzyl alcohol


Sodium sulphite Transcutol



10.00

Cetomacrogol 1000 1.28
Liquid paraffin 5.00
Polysorbate 80 1.40 0,30 2.00
Lavender English


Triethanolamine
Isopropanol



15.00
Water to make 100.00
Chlorocresol and EDTA are dissolved in water. Carbomer is dispersed in the same. Isopropanol, Benzyl alcohol, liquid paraffin, Cetomacrogol 1000, polysorbate 80 and Lavender English are added under stirring in the specified order to form emulsion. Sodium sulphite dissolved in water and mixed with the emulsion mentioned above under fast stirring, this is followed by addition of Triethanolamine. The drug solution is transcutol is added to this under fast stirring. Water is added to make up volume. Example 2: A cream containing 2% of Fusidic acid ;

Ingredients :
Active ingredient
Carbomer 940 % by weight
2.00
8.00
Chlorocresol 0.12
Disodium EDTA 0.10
Cetomacrogol 1000 1.25
Cetostearyl alcohol 5.00


Active ingredient was dissolved in propylene glycol. Chlorocresol and Disodium EDTA were dissolved in water. Cetostearyl alcohol, Cetomacrogol 1000, Liquid paraffin, White soft paraffin, Glyceryl monostearate, Dimethicone 100 were melted. This was added to the aqueous phase and homogenized along with the drug solution. Temperature was bought down to 55 degree Celsius and SAPMG was added to the whole mixture congealed to room temperature.

Example 3; A cream containing 5% of Acyclovir

Ingredients % by weight
Active ingredient Propylene glycol Chlorocresol 5.00 8.00

0.12
Disodium EDTA 0.10
Cetomacrogol 1000 1.25
Cetostearyl alcohol 5.00
Glyceryl monostearate 7.00 2.00
Liquid paraffin


Dimethicone 100 4,00
Water to make 100.00
Active ingredient was dispersed in propylene glycol. Chlorocresol and Disodium EDTA were dissolved in water. Cetostearyl alcohol, Cetomacrogol 1000, Liquid paraffin. Glyceryl monostearate, Dimethicone

100 were melted. This was added to the aqueous phase and
homogenized along with the drug solution. Temperature was bought down
to 55 degree Celsius and the whole mixture congealed to room
temperature.
Example 4: A cream containing 5% of Doxepin hydrochloride

Ingredients % by weight
Active ingredient 5.00
Cetostearyl alcohol 6,00
Cetomacrogol 1000 3.00
Glyceryl monostearate 6.00
Myritol 318 10.00
Dimethicone 100 4.00
Carbopol 940 0.1
Disodium EDTA 0.1
Propylene glycol 8.00
Benzyl alcohol 1.00
Water to make 100.00
Disodium EDTA is dissolved in water, propylene glycol is added to this. Melt Cetomacrogol Glyceryl monostearate, cetyl alcohol, myritol, Dimethicone 100 and add to the aqueous phase under fast stirring and homogenise. Carbopol is hydrated with water. To this add the above emulsion and congealed to room temperature. Dissolve Doxepin HCI in the water and add to the cream under stirring.
Example 5: A cream containing Diclofenac free acid equivalent to 1% diclofenac sod.

Ingredients % by weight 1.16
Active ingredient


Carbopol 940 1.00
Chlorocresol 0.12
Disodium EDTA 0.05
Benzyl alcohol 1.00
10

Sod. Suphite 0.10
Transcutol 10.00
Glyceryl monostearate 1.28
Liquid paraffin 5.00
Polysorbate 80 1.40
Lavender English 0.30
Diethanolamine 2.00
Isopropanol 15.00
Water to make 100.00
Chiorocresol and Disodium EDTA are dissolved in water. Carbopol is dispersed in the same. Isopropanol, benzyl alcohol, liquid paraffin, Glyceryl monostearate, polysorbate 80 and lavender English are added under stirring in the specified order to form emulsion. Sod. Sulphite dissolved in water and mixed with the emulsion mentioned above under fast stirring, this is followed by addition of diethanolamine. The drug solution in transcutol is added to this under fast stirring. Water is added to make up volume. Example 6:A gel containing Diclofenac pot.

Ingredients % by weight
Active ingredient 1.16
Carbopol 940 1.00
Chiorocresol 0.12
Disodium EDTA 0.05
Benzyl alcohol 1.00
Sod. Suphite 0.10
Transcutol 10.00
Polysorbate 80 1.40
Lavender English 0.30
Triethanolamine 2.00
Isopropanol 15.00
Water to make 100.00
11

Chlorocresol and Disodium EDTA are dissolved in water. Carbopol is dispersed in the same. Isopropanol, benzyl alcohol, liquid paraffin, Glyceryl monostearate, polysorbate 80 and lavender English are added under stirring in the specified order to form emulsion. Sod. Sulphite dissolved in water and mixed with the emulsion mentioned above under fast stirring, this is followed by addition of triethanolamine. The drug solution in transcutol is added to this under fast stirring. Water is added to make up volume.
12

WE CLAIM
1. A pharmaceutical or cosmetic composition in the form of micro-droplets of water insoluble liquid for topical application, comprising from 1.0 to 5.0% by weight an active ingredient dispersed in the aqueous medium with oily excipient and/or solvent as a solid or liquid particles which are selected from diclofenac diethyl ammonium salt, fusidic acid, acyclovir, doxepin hydrochloride, diclofenac sodium and diclofenac potassium and pharmaceutically or cosmetically acceptable carriers selected from a non-ionic surfactant, skin penetration enhancers, antioxidants, chelating agent, inorganic thickening agent; wherein said composition is liquid & semisolid after adding gelling agent.
2. A composition as claimed in claim 1, wherein the surfactant is an non-ionic alkylene oxide condensate of an organic compound, and contains one or more hydroxyl groups, such as an ethyoxylated and / or propoxylated alcohol or ester compound or mixtures thereof.
3. A composition as claimed in claim 1, wherein the anti-oxidant is an oil phase anti-oxidant such as ά tocopherol or d tocopherol succinate
4. A composition as claimed in claim 1 wherein a chelating agent is such as ethylene diamine tetraacetic acid (EDTA) or a pharmaceutically accepted salt thereof.
5. A composition as claimed in claim 1, wherein the said semi solid form is obtained by the addition of gelling agents, such as corbopols.
13

organic thickening agents, polyvinyl pyrrolidone (PVP) or a hydroxypropyl methyl cellulose (HPMC) polymer, or cetostearyl alcohol and other waxes capable of rigidifying, solidifying or increasing the viscosity of the aqueous dispersion.
6. A composition as claimed in claim 1,wherein inorganic thickening agent isuch as fumed silica, alumina, clay or other similar colloidal particles to increase viscosity.
7. A composition as claimed claim 1, wherein the skin penetration enhancer includ^decyl methyl sulfoxide (DMSO), N-dodecyl pyrrolididone, decanol, dodecanol or an organic acid, such as oleic acid.
14
Dated this 28th day of December 1999


Documents:

974-bom-1999-cancelled pages(30-11-2005).pdf

974-bom-1999-claims(granted)-(30-11-2005).doc

974-bom-1999-claims(granted)-(30-11-2005).pdf

974-bom-1999-correspondence(30-11-2005).pdf

974-bom-1999-correspondence(ipo)-(30-11-2005).pdf

974-bom-1999-description(granted)-(30-11-2005).doc

974-bom-1999-form 1(28-12-1999).pdf

974-bom-1999-form 19(17-10-2003).pdf

974-bom-1999-form 2(granted)-(30-11-2005).doc

974-bom-1999-form 2(granted)-(30-11-2005).pdf

974-bom-1999-form 4(24-10-2005).pdf

974-bom-1999-form 5(28-12-1999).pdf

974-bom-1999-power of authority(28-12-1999).pdf


Patent Number 221180
Indian Patent Application Number 974/BOM/1999
PG Journal Number 43/2008
Publication Date 24-Oct-2008
Grant Date 18-Jun-2008
Date of Filing 28-Dec-1999
Name of Patentee L'AMAR INTERNATIONAL PVT. LTD.
Applicant Address 31 KHIMJI MEGHJI HOUSE, 3rd FLOOR,11/15, ISSAJI STREET, VADGADI, MUMBAI,
Inventors:
# Inventor's Name Inventor's Address
1 AMAR LULLA 31 KHIMJI MEGHJI HOUSE, 3rd FLOOR,11/15, ISSAJI STREET, VADGADI, MUMBAI-400 003.
PCT International Classification Number A61P39/06 A61K7/24
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA