DESC:FIELD OF INVENTION:
The present invention relates to topical formulation more particularly topical lotion
comprising Dimetindene maleate.
BACKGROUND:
5 Dermatologic diseases relate to skin disorders. Skin conditions or dermatological
disorders afflict billions of people each day. These skin conditions may be acute
(lasting for just a few minutes to a few hours) or chronic conditions that may plague an
individual for days, months, years or even a lifetime. Some of the common and
frequently-occurring diseases seriously affecting people's health are dry, itchy skin that
10 leads to swelling, cracking or scaliness.
A multitude of different dermatological conditions exist and may be fungal, bacterial,
or viral based, or may be a non-infective, immunological response such as an
inflammatory response with or without an allergic component, or sunburn or may be
idiopathic. Accordingly, symptoms may vary and may range from mild itching, redness
15 and swelling to severe pustules and open sores and even in certain instances may lead
to debilitating manifestations such as disabling ulcerations. Regardless of the cause or
particular symptoms, dermatological disorders may substantially affect the quality of
an individual's life.
Dimetindene is a first generation selective H1 antagonist which binds to the histamine
20 H1 receptor and inhibit the interaction of histamine with histamine receptors.
3
Dimetindene is available orally and topically. It is marketed under the brand name
Fenistil which is used in the treatment of allergic conditions. Fenistil gel is used to
provide relief to itching, inflammation and pain associated with skin reactions like skin
rashes, hives, insect bites, sunburns and superficial burns.
5 Publication number WO9800168 discloses a lotion containing the fixed dose
combination of maleate salt of dimethindene and menthyl lactate for the treatment of
allergic and inflammatory skin diseases.
Publication number WO2004069338A1 discloses methods of treating allergic skin
conditions and disorders by combined administration of a histamine H1 receptor
10 antagonist and a histamine H3 receptor antagonist wherein the histamine HI receptor
antagonist and a histamine H3 receptor antagonist are present in a single dosage form
W. Englisch et. al., studied the efficacy and tolerability of dimethindene maleate (CAS
3614-69-5, DMM, Fenistil) as drops in the treatment of pruritus in children suffering
from chicken-pox. The study was conducted in a two different doses of dimethindene
15 maleate and placebo in 128 children, 1 to 6 years of age, were included in a double
blind, randomized, placebo controlled, multi-center clinical trial.
WO2020/194308 discloses a topical pharmaceutical composition comprising a
cannabinoid and an antihistamine for the treatment of pruritis. The composition may
be provided in a bottle for spraying onto an affected area.
4
Although there are several prior arts which discloses use of Dimetindene topically or
formulated with other active agents however there is no single prior art which discloses
the use of Dimethindene in lotion form.
Lotion as compared to gel easily spread over the large surface of outer most skin layer.
5 Dermatological conditions such as inflammation, skin rashes, itching, sun burn are not
limited to small surface and can affect larger area of skin, therefore in these conditions
the topical formulation needs to be spread little further across the affected skin.
Therefore, there is a need of different dosage form other than gel which can be easily
spread over to larger area of the affected skin, absorbed quickly and have enhanced
10 permeability across the skin.
The inventors of present study were able to formulate a topical formulation comprising
an antihistaminic agent which spread to cover the larger area of the affected skin, have
improved aesthetics, absorb quickly and have enhanced permeability.
15
SUMMARY OF THE INVENTION
The present invention provides a composition which is used to provide relief in itching
associated with skin reactions such as skin rashes, hives, dermatitis, insect bites,
sunburns and superficial burns affecting larger area of skin.
5
More particularly the composition comprises pharmacologically active compound
having a desired topical effect wherein the composition is applied topically onto the
affected area of skin.
In an embodiment the composition is a topical dosage form comprising a
5 pharmacologically active which can be easily applied to larger area of the affected skin
wherein the pharmacologically active compound comprises an anti-histaminic
compound, preferably Dimetindene or pharmaceutically acceptable salts thereof.
In further aspect the topical formulation comprises Dimetindene or pharmaceutically
acceptable salts thereof in lotion form wherein the composition reduces symptomatic
10 itching, inflammation associated with skin reactions such as sun burn, insect bites,
dermatitis, skin rashes, hives or superficial burns on an area of skin of a patient.
Detailed Description of the invention:
Those skilled in the art will be aware that the present disclosure is subject to variations
and modifications other than those specifically described. It is to be understood that the
15 present disclosure includes all such variations and modifications. The disclosure also
includes all such compositions, components of the composition, referred to or indicated
in this specification, individually or collectively and all combinations of any or more
of such components or composition.
Definitions
6
For convenience, before further description of the present disclosure, certain terms
employed in the specification, and examples are collected here. These definitions
should be read in the light of the remainder of the disclosure and understood as by a
person of skill in the art. The terms used herein have their meanings recognized and
5 known to those of skill in the art, however, for convenience and completeness,
particular terms and their meanings are set forth below.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at
least one) of the grammatical object of the article.
The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning
10 that additional elements may be included. It is not intended to be construed as “consists
of only”.
Throughout this specification, unless the context requires otherwise the word
“comprise”, and variations such as “comprises” and “comprising”, will be understood
to imply the inclusion of a stated element or step or group of element or steps but not
15 the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. “Including” and
“including but not limited to” are used interchangeably.
The term “aqueous lotion” or “aqueous based lotion” as used herein refers to a lotion
wherein water is used as the vehicle to prepare the lotion.
7
Unless defined otherwise, all technical and scientific terms used herein have the same
meaning as commonly understood by one of ordinary skill in the art to which this
disclosure belongs. Although any methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the disclosure, the preferred
5 methods, and materials are now described. All publications mentioned herein are
incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments
described herein, which are intended for the purposes of exemplification only.
Functionally equivalent products and processes are clearly within the scope of the
10 disclosure, as described herein.
The term “pharmaceutically or cosmetically/dermatologically acceptable excipient”
refers to inert substances other than active ingredients which are used in the preparation
of pharmaceutical or Cosmeceuticals composition. These ingredients are suitable for
use in contact with tissues (e.g., the skin or hair) without undue toxicity,
15 incompatibility, instability, irritation, allergic response, and the like.
The term “topical” refers to the drug delivery which is applied topically over skin to
provide topical therapeutics effects.
The present invention provides a composition comprising ant-histaminic agent for
topical treatment of itching as itching, inflammation and pain associated with skin
20 reactions like skin rashes, hives, insect bites, dermatitis, sunburns and superficial burns.
8
In one embodiment an anti-histamines or a pharmaceutically acceptable salt thereof are
selected from but not limited to brompheniramine, chlorpheniramine
debrompheniramine, dexchlorpheniramine, Dimetindene, doxylamine, trimeprazine,
phenindamine, ketotifen, hydroxyzine, tazifylline, temelastine, meclizine, acrivastine,
5 setastine, oxatomide, mequitazine, levocabastine, lodoxamide, rocastine,
phenindamine, azelastine, and ebastine, fexofenadine, loratadine, descarboethoxy
loratadine, astemizole, norastemizole, desmethylastemizole, cetirizine, acrivastine, and
temelastine, or a combination thereof.
In an embodiment, an anti-histaminic agent is Dimetindene or its pharmaceutically
10 acceptable salts thereof wherein maleate salt is being preferred.
In an embodiment the present invention provides a topical formulation comprising an
effective amount of Dimetindene or its pharmaceutically acceptable salts thereof.
In an another embodiment the present invention provides a dermatological formulation
comprising an effective amount of Dimetindene or its pharmaceutically acceptable
15 salts thereof applied topically on the skin surface.
In an another embodiment the topical formulation may be prepared in form of a lotion,
gel, cream or ointment. In a preferred embodiment the topical formulation is lotion.
In an embodiment the present invention provides a topical lotion comprising
Dimetindene or its pharmaceutically acceptable salts thereof which is easily applied
20 over larger area of the affected skin surface.
9
In an another embodiment the present invention provides a topical lotion comprises
Dimetindene maleate is in the form of an aqueous lotion.
In an embodiment the lotion may comprises alovera which help in moisturising the
skin and protect the skin from sunburn.
5 In an another embodiment alovera can be commercially available from a variety of
sources that manufacture bulk supplies of the aloe in liquid, gel or dry. The present
invention uses alovera in liquid form present in amount ranging from 0.5-5% w/v more
preferably 1% w/v.
In an another embodiment the topical lotion comprises an effective amount of
10 Dimetindene or its pharmaceutically acceptable salts thereof. In addition to the
Dimetindene as active agents, the composition of present invention may comprise one
or more dermatologically acceptable excipients, such as viscosity modifier, chelating
agents, buffers, preservatives, humectants, emollients, emulsifiers, solubilizer, antioxidant, emollient, preservative, pH adjusters, vehicle.
15 In an embodiment the topical lotion comprises solubilizer which helps in imparting
maximum drug diffusion across the skin, these solubilizer include, but are not limited
to, lauryl alcohol, polyoxyethylene ether, polyoxyethylene glycerol monostearate,
stearic acid ester oxygen poly hydrocarbon, vitamin E succinate polyethylene glycol
ester, sorbitan esters, polyoxyethylene castor oil, glycerol, propylene glycol, methyl
20 paraben, propyl paraben, ethanol more preferably propylene glycol.
10
In an another embodiment the solubilizer is propylene glycol and is present in an
amount ranging from 5-20 % w/v more preferably 10 % w/v.
In an embodiment the topical lotion comprises viscosity modifier selected from group
consisting of hydroxypropylcellulose, hydroxypropyl methylcellulose carrageenans,
5 microcrystalline cellulose, alginates, gellan gum, xanthan gum, veegum,
hydroxyethyethyl cellulose, carbomers and guar gum more preferably Carbomer.
In an another embodiment the viscosity modifier is carbomer and is present in an
amount ranging from 0.05 to 0.5% w/v of total weight of the composition more
preferably 0.2% w/v.
10 Exemplary chelating agents that can be used according to the invention is Disodium
EDTA present in an amount ranging from 0.05 to 0.5% more preferably 0.1% w/v.
In an another embodiment the present composition may comprises one or more
emulsifiers selected from group consisting of polyethylene glycol such as PEG-100
stearate, PEG-50 stearate and PEG-40 stearate, glyceryl stearate, stearic acid, sorbitan
15 tristearate, Glyceryl monostearate most preferably Stearic acid and Glyceryl
Monostearate.
In a preferred embodiment the emulsifiers are Stearic acid and Glyceryl Monostearate
and are present in an amount ranging from 1-3% w/v more preferably 1.5% w/v Stearic
acid and 2.0% w/v Glyceryl Monostearate.
11
In an another embodiment one or more anti-oxidants are present and is selected from
a-tocopherol, butylhydroxyanisole (BHA) or butylhydroxytoluene (BHT), superoxide
dismutase, ubiquinol, ascorbic acid, monothioglycerol, potassium metabisulfite,
sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
5 In an another embodiment anti-oxidant is a-tocopherol more preferably alphatocopherol acetate also known as vitamin E acetate present in an amount ranging 0.1-
1 wt% w/v more preferably 0.5 wt%
In an another embodiment the topical lotion further comprises Butylated
Hydroxytoluene present in an amount ranging from 0.05-0.5 wt% w/v more preferably
10 0.1 wt% w/v.
In an another embodiment the topical lotion further comprises emollient selected from
group consisting of but not limited to Decyl oleate, isopropyl palmitate, isostearyl
alcohol, castor oil, glyceryl stearate, octyl stearate, propylene glycol, isopropyl
myristate, dimethicone, octyl octanoate more preferably Isopropyl Myristate.
15 In an another embodiment the emollient is isopropyl myristate and is present in an
amount ranging from 1-5 wt% w/v more preferably 2.5 wt% w/v.
In an another embodiment the topical lotion further comprises Preservatives.
Preservatives are antimicrobial ingredients added to product formulations to maintain
the microbiological safety of the products by inhibiting the growth of and reducing the
20 amount of microbial contaminants. Preservatives include, but are not limited to, chloro-
12
m-cresol, citric acid, disodium edetate, ethoxylated alcohol, glycerin, 1,2,6-
hexanetriol, methylparaben, parabens, potassium, sorbate, propyl gallate, propylene
glycol, propyl paraben, sodium bisulfate, sodium citrate, butyl paraben, sodium
metabisulfite, chlorocresol, sorbic acid, tannic acid, zinc stearate, butylated
5 hydroxytoluene, butylated hydroxyanisole, benzoic acid, salicylic acid, propyl
paraben, dichlorobenzyl alcohol, formaldehyde, alpha-tocopherol, sodium ascorbate,
ascorbic acid, ascorbyl palmitate phenol, m-cresol, bisphenol, cetrimide, benzalkonium
chloride, sorbic acid, phenoxyethanol, and benzoyl peroxide more preferably
phenoxyethanol.
10 In an another embodiment the preservative is phenoxyethanol and is present in an
amount ranging from 0.5-5 %w/v more preferably 1% w/v.
In an another embodiment the topical lotion further comprises pH adjuster that help in
adjusting pH of the composition. Such agents include many pharmaceutically
acceptable acids, bases and buffers. Suitable acids may include one or more of
15 hydrochloric acid, phosphoric acid and lactic acid. Suitable bases may include one or
more of diethanolamine, triethanolamine and sodium hydroxide. Suitable buffers may
include phosphates, such as monobasic sodium phosphate, dibasic sodium phosphate,
lactates and citrates.
In a preferred embodiment pH adjuster is sodium hydroxide present in an amount
20 ranging from 0.05-1% w/v more preferably 0.2% w/v.
13
The present invention provides a topical lotion comprising following:
a) 0.1 % w/v Dimetindene Maleate as active ingredient and;
b) 10% w/v Propylene Glycol as solubilizer and;
5 c) 0.2% w/v Carbomer as viscosity modifier and;
d) 0.1% w/v Di-sodium EDTA as chelating agent and;
e) 1.5 % w/v stearic acid as emulsifier and;
f) 2% w/v Glyceryl monostearate as co-emulsifier and;
g) 0.5% w/v Vitamin E acetates as anti-oxidant and;
10 h) 0.1% w/v Butylated Hydroxytoluene as anti-oxidant and;
i) 2.5% w/v Isopropyl Myristate as Emollient and;
j) 1% w/v Phenoxyethanol as preservative and;
k) 1% w/v alovera juice as soothing agent and;
l) 0.2% w/v sodium hydroxide as pH adjuster
15 And water as a vehicle in sufficient amount.
In an another embodiment the present invention provides an aqueous lotion comprising
Dimetindene Maleate wherein the composition reduces symptomatic itching,
inflammation associated with skin reactions such as sun burn, insect bites, dermatitis,
skin rashes, hives or superficial burns on an area of skin of a patient.
14
In an another embodiment the present invention provides a process of preparation of
topical lotion by mixing active ingredients with dermatologically acceptable excipients
in aqueous carrier.
The present invention is further illustrated by the following examples that teach those
5 of ordinary skill in the art how to practice the invention. The following examples are
merely illustrative of the invention and disclose various beneficial properties of certain
embodiments of the invention. The following examples should not be construed as
limiting the invention as claimed:
Example-1
10 In one specific procedure, a lotion is prepared in accord with the present invention
utilizing the formulation of Table 1:
S.No. Ingredients %w/v Rationale
1 Dimetindene maleate 0.100 API
2 Propylene glycol 10.00 Solubilizer
3 Carbomer (980) 0.200 Viscosity Modifier
4 Di-sodium EDTA 0.100 Chelating Agent
5 Stearic Acid 1.500 Emulsifier
6 Glyceryl Monostearate 2.00 Co-Emulsifier
7 Vitamin E acetate 0.500 Anti-oxidant
8 Butylated Hydroxytoluene 0.100 Anti-oxidant
9 Isoproyl Myristate 2.500 Emollient
10 Phenoxyethanol 1.00 Preservative
11 Alovera juice 1.00 Soothing agent
12 Sodium Hydroxide 0.200 pH adjuster
13 Purified water q.s. to 100 vehicle
15
Example 2- Stability Study
The formulation as per example 1 was subjected to stability study under temperature
30°C±2°C and Relative humidity 75% ± 5%
Tests Acceptance
Criteria
Initial
Testing 3 Month 6 Month
Description
White to off white
colour lotion filled
in white HDPE
bottle with flip top
cap.
white colour
lotion filled
in white
HDPE bottle
with flip top
cap
white
colour
lotion filled
in white
HDPE
bottle with
flip top cap
white colour
lotion filled
in white
HDPE bottle
with flip top
cap
Identification
(by HPLC)
In the asaay, the
principle peak in
the chromatogram
obtained with the
test solution
correspond to the
peak in the
chromatogram
obtained with
standard solution
Complies Complies Complies
pH Between 5.50 to
7.50 6.75 6.63 6.70
Viscosity For record 11428 cps 14907 cps 9658 cps
Dimetindene
Maleate BP01% w/v
NLT 0.090% w/v
to NMT 0.110%
w/v (NLT 90% to
NMT 110% OF
label claimed
0.100% w/v
100%
0.0985%
w/v
98.50%
0.09872%
w/v 98.72%
,CLAIMS:We claim,
Claim 1- A topical pharmaceutical composition comprising Dimetindene maleate in
the amount of 0.1% and wherein the topical pharmaceutical composition is formulated
as a lotion.
5 Claim 2 – The topical pharmaceutical composition as claimed in claim 1, is a aqueous
based lotion.
Claim 3 - The topical pharmaceutical composition as claimed in claim 1 & 2, further
comprises pharmaceutically acceptable excipients selected from solubilizer, viscosity
modifier, chelating agent, emulsifier, co-emulsifier, anti-oxidant, emollient,
10 preservative or the combination thereof
Claim 4- The topical pharmaceutical composition as claimed in claim 3, wherein the
solubilizer is present in the amount of 8%-12% and wherein the solubilizer is propylene
glycol or the likes thereof.
Claim 5- The topical pharmaceutical composition as claimed in claim 3, wherein the
15 viscosity modifier is present in the amount of 0.1% to 0.4% and wherein the viscosity
modifier is Carbomer or the likes thereof.
Claim 6- The topical pharmaceutical composition as claimed in claim 3, wherein the
antioxidants are present in the amount 0.01% to 0.9% and wherein the antioxidant are
selected from vitamin E acetate and/or Butylated Hydroxytoluene or the likes thereof
20 Claim 7- The topical pharmaceutical composition as claimed in claim 3, wherein the
emulsifier and co-emulsifier are selected from stearic acid and/or glyceryl
monostearate, or the likes thereof and wherein the emulsifier and co-emulsifier are
present in the amount of 0.5% to 4%.
Claim 8- The topical pharmaceutical composition as claimed in claim 3, wherein the
25 preservative is present in the amount of 0.1 % to 10% and wherien the preservative is
Phenoxyethanol or the likes thereof.
Claim 9 – The topical pharmaceutical composition as claimed in claim 3, wherein the
soothing agent is present in the amount of 0.1% to 5% and wherein the soothing agent
is selected from aloevera or the likes thereof.
17
Claim 10 – The topical pharmaceutical composition as claimed in claim 3, wherein the
chelating agent is present in the amount of 0.1%, emollient is present in the amount of
2.5% and pH adjusting agent in the amount of 0.2%.