WO2016133471A1

WO2016133471A1 - A topical composition comprising mupirocin and dexpanthenol

Info

Publication number: WO2016133471A1
Application number: PCT/TR2015/000057
Authority: WO
Inventors: Ersin Yildirim; Tolga Ramazan KARASU; Koray YILMAZ; Murat Muhibbi IŞIK; Derya AKSU; Mustafa Serkan SOLMAZ; Prabaharan RAMACHANDRAN
Original assignee: Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A. Ş.
Priority date: 2015-02-20
Filing date: 2015-02-20
Publication date: 2016-08-25

Abstract

The present invention relates to the topical pharmaceutical compositions containing mupirocin, dexpanthenol and pharmaceutically acceptable excipients.

Description

A TOPICAL COMPOSITION COMPRISING MUPIROCIN AND DEXPANTHENOL

Field of invention

The present invention relates to the topical pharmaceutical composition containing mupirocin antibiotic, dexpanthenol as cicatrizant.

Background of the invention

Topical preparations have been used for treating many diseases in many years. Combinations can also be used for topical preparations. Topical semi-solid dosage forms are normally presented in the form of creams, gels, ointments or pastes.

Transdermal drug delivery offers many potential advantages over conventional methods of drug administration. Topical formulations are applied directly to the skin. Advantages of this include a) increased dose of medication where it is needed, b) reduced side effects and toxicity to other organs.

The amount of the active ingredient that is absorbed through the skin depends on the following factors:

• Skin thickness,

• Skin barrier function,

• Skin hydration,

· Molecular size of the chemical,

• Whether the chemical is lipophilic,

• Chemical concentration,

• Other ingredients in the formulation may interact to increase or reduce potency or absorption rates.

Antibiotics are well known active agents used to treat infections and related diseases. Depending upon the antibiotic class, any one of a variety of mechanism of action is used to target and treat the infection.

Mupirocin is an antibiotic of the monoxycarbolic acid class. It was antibiotic from a strain of Pseudomonas fluorescens, developed by Beecham. It is a broad-spectrum antibiotic, which can be obtained by fermentation from Pseudomonas fluorescens.

Mupirocin is bacteriostatic at low concentrations and bactericidal at high concentrations.lt is used topically and is effective against Gram-positive bacteria, including methicillin-reststant Staphylococcus aureus (MRSA), which is a significant cause of death in hospitalized patients having received systemic antibiotic therapy.lt is used as a topical treatment for bacterial skin infections, e.g. furuncle, impetigo, open wounds. It is indicated for the topical treatment of impetigo due to Staphylococcus aureus and Streptococcus pyogenes.

Mupirocin helps by stopping the production of essential proteins needed by the bacteria to survive. It has shown excellent activity against gram-positive staphylococci and streptococci. l The antibiotic is used primarily for the treatment of primary and secondary skin disorders, nasal infections, and wound healing.

upirocin, chemical name is [2S-[2a(E),3b,4b,5a[2R*,3R*(1 R*,2R*)]]]-9-p-Methyl-1-oxo-4- [tetrahydro-3,4-dihydroxy-5-[[3-(2-hydroxy-1-methylpropyl)oxiranyl]methyl]-2H-pyran-2-yl]-2- butenyl]oxy]nonanoic acid.The compound having the figure 1 is known as mupirocin.

Figure 1 : Mupirocin

Crystalline mupirocin calcium, its properties and methods of preparation are described in detail in US patent No. 4,916,155. This patent emphasizes on the improved thermal stability of the crystalline dihydrate form of the calcium salt.

Topical antibacterial compositions comprising mupirocin mupirocin are marketed under the trade names Bactroban ^® Ointment, Bactroban ^® Nasal and Bactroban ^® Cream, by SmithKline Beecham. The first contains mupirocin, while the other two contain crystalline mupirocin calcium dihydrate. The formulation of Bactroban ^® Ointment is described in U.S Patent No. 4,524,075. The formulation of Bactroban ^® Nasal is described in U.S Patent No. 4,790,989. The cream base of Bactroban ^® Cream is described in world WO 95/10999 and U.S Patent No. 6,025,389.

U.S. Patent No. 6,025,389 discloses a pharmaceutical or veterinary composition containing about 2.4% by weight of mupirocin or a pharmaceutically acceptable salt thereof; about 50.9% by weight mineral oil USP; about 6% by weight polyethylene glycol monocetyl ether; about 3.5% by weight stearyl alcohol; about 3.5% by weight cetyl alcohol; about 0.5% by weight phenoxyethanol; about 1% by weight benzyl alcohol; about 0.2% by weight xanthan gum; and about 32% by weight purified water.

WO2009/047788 relates to a topical pharmaceutical composition, comprising mupirocin and beciomethasone, useful for the treatment of infected dermatoses caused by bacteria or for preventing secondary bacterial infections in patients of steroid responsive dermatoses.

WO/2012/052472 discloses a pharmaceutical or veterinary anhydrous topical gel composition of mupirocin.

EP1 174133A1 discloses topical compositions based in the use of a hydrophobic phase, in particular a composition comprising amorphous mupirocin calcium, a hydrophobic phase, and hexylene glycol as solvent.

WO200410988A1 discloses aqueous compositions of mupirocin with ethylcellulose as a rate modulating hydrophobic polymer.

Cicatrizant refers to agents including natural substances such as herbs, oils, or essences, or conventional pharmaceutical drugs, that promote healing of the skin by the formation of scar tissue. Panthenol is a member of cicatrizant group. Panthenol (pantothenol) is the alcohol analog of pantothenic acid (vitamin B₅). For topical applications is usually given panthenol in ointment form, even in ophthalmology. Only D-panthenol (dexpanthenol) is biologically active, however both forms have moisturizing properties.

Dexpanthenol can be used for mouth and throat disorders, pantothenic acid deficiency, eye disorders, wounds, burns, sensation of burning in feet, upper respiratory-tract disorders, skin disorders.A cream with dexpanthenol regularly can apply to the skin to improve the moisture content of dry skin significantly. Dexpanthenol cream can use for an emollient.

An ointment with dexpanthenol can prevent erythema due to UV light. Dexpanthenol ointment also can protect the lips against solar herpes, sun burns, mild burns, skin irritations, dry or cracked skin, cosmetic or shaving rashes, post chemical peeling treatment, post laser resurfacing treatment. Dexpanthenol is effective for preventing / treating nappy dermatitis in infants.

Panthenol, chemical name is 2,4-Dihydroxy-N-(3-hydroxypropyl)-3,3-dimethyibutanamide, is a cicatrizant. The compound having the figure 2 is known as panthenol.

Figure 2: Panthenol

EP0610655 describes to a sterile medicament for topical administration of dexpanthenol, containing a polyacrylate carrier to improve stability of active agent.

WO2005/063224 relates to a topical pharmaceutical preparation containing dimethyl sulfoxide and dexpanthenol, useful e.g. for treating inflammation, pain, rheumatic disease or neuralgia.

Summary of the invention

A topical pharmaceutical composition, characterized in that it comprises:

a) mupirocin base or pharmaceutically acceptable salt or ester thereof as antibiotic, b) dexpanthenol as cicatrizant,

in combination with pharmaceutically acceptable excipients.

The present invention relates to a topical pharmaceutical composition comprising mupirocin and dexpanthenol. Preferably, the composition comprises mupirocin in the range of about 1-5% w/w and dexpanthenol in the range of about 0.05— 10% w/w based on the total weight of the composition. For example, the composition may comprise about 2% w/w of mupirocin and about 5% w/w of dexpanthenol based on the total weight of the composition. The composition may further contain one or more pharmaceutically acceptable excipients. According to one embodiment, the composition further comprises poly (substituted or unsubstituted alkylene) glycol or a derivative thereof and a pharmaceutically acceptable carrier. The composition can be in the form of an ointment, cream, lotion, solution or gel. Suitable pharmaceutically acceptable excipients for the topical composition include, but are not limited to, solvents, vehicles, ointment/cream bases, emulsifiers, preservatives, buffers, emollients, humectants, surfactants, and transport enhancers or mixtures there of.

Detailed description of the invention

A topical pharmaceutical composition, characterized in that it comprises:

in combination with pharmaceutically acceptable excipients.

The term "mupirocin" as used herein includes mupirocin free base and/or its pharmaceutically acceptable salts or esters thereof.

Suitable pharmaceutically acceptable salts are well known in the art and include alkali metal salts such as sodium and lithium and alkaline earth metal salts such as calcium, of which the calcium salt is preferred, in particular the crystalline dihydrate form thereof described in EP 0 167 856-A (Beecham Group), as well as other metal salts, for instance silver, aluminium, ammonium and substituted ammonium salts. The salts may be anhydrous or may be in the form of pharmaceutically acceptable solvates, for instance alcoholates and, especially, hydrates. Preferred salts include the calcium, silver and lithium salts, in particular the calcium salt. In the case of the calcium salt of mupirocin, the crystalline salt, preferably the crystalline hydrated calcium salt, more preferably the crystalline dihydrate salt, is used. Mupirocin Calcium is the dihydrate crystalline calcium hemi-salt of the mupirocin. Suitable pharmaceutically acceptable esters are well known in the art and include lower alkyl esters, especially the methyl and ethyl esters. Mupirocin is used in preference to a salt or ester thereof.

The term "dexpanthenol" as used herein includes dexpanthenol free base and/or its pharmaceutically acceptable salts or esters thereof.

The present invention may be used for the treatment of infected dermatoses caused by bacteria. This includes the treatment of lesions like eczema, atopic dermatitis, allergic dermatitis, contact dermatitis, and psoriasis, (which are primarily inflammatory in nature and responsive to treatment with corticosteroids) that have been further infected by bacterial infection which signifies secondary bacterial infection. It may also be used for the prevention of steroid responsive dermatoses in patients who are at high risk of developing infection.The topical composition can be used to prevent the exacerbation of steroid-responsive dermatoses.

In one embodiment, pharmaceutical composition of present invention may further comprise corticosteroid. In this invention, the term "corticosteroid" means a compound including, but not limited to:hydrocortisone,cortisone, tixocortol, desonide, prednisolone, methylprednisolone, prednisone, triamcinolone, halometasone, fluocortolone, clobetasol, clobetasone, mometasone, amcinonide, budesonide, fluocinonide, fluocinolone, dexamethasone, betamethasone, halcinonide.prednicarbate, alclometasone, flupredntdene or a combination thereof and their pharmaceutically acceptable salts.

Formulations of the present invention may be produced by conventional pharmaceutical techniques. Thus, ointments and creams are conveniently prepared by melting and mixing together the solid or semi-solid vehicles, and stirring in the therapeutic agent and any other ingredients. The product is then slowly cooled and filled into containers such as collapsible metal or plastic tubes.

The term "composition" includes suitable dosage forms, such as ointments, creams, lotions, gels or solutions, and may contain appropriate conventional additives, such as preservatives, solvents and emollients, cream or ointment bases, viscosity modifiers, stiffening agents, emulsifiers, preservatives, buffers, vehicles and mixtures there of. Such carriers may comprise from about 1% to about 98% of the formulation.

The major subject of the present inventions are to provide a formulation which has resistant against physical and enviromental conditions and also have a high bioavailability.

Many challenges can be occured for topical formulations depending bioavailability and stability. Controlling of critical material attributes such as particle size and viscosity are very important to ensure formulation's target profile is achieved.

The present invention provides topical drug delivery systems which release a therapeutically effective amount of one or more active pharmaceutical ingredients to the site of absorption or action.

Another object of the present invention is to increase the rate of percutaneous penetration, thereby shortening the time period in which the active agents can show their effect.

The present invention showswell physical properties in the formulation depends on its solubility characteristics in appropriate excipients for topical formulations.lt shows good properties on rheology, particle or droplet size, pH, and visual appearance to provide basic physical stability. The present invention maybe used for relieving dry skin, preventing and treating sore nipples during breast-feeding, and promoting healing of burns and poorly-healing wounds. The present invention can be used for in the treatment of chronic wounds such as leg ulcers, decubitus ulcers.

The formulation of the present invention comprises mupirocin in combination with dexpanthenol. The formulations of the present invention are topical and may be in the form of an ointment, cream, liquid, lotion, or gel which can apply on affected skin surface.

The present invention relates to an easily applicable mupirocin and dexpanthenol combination, eliminating all problems and bringing additional advantages to the relevant prior art.

Another object of the present invention is to increase the rate of percutaneous penetration, thereby shortening the time period in which the active agents can show their effect. A safe and effective amount of a skin smoothing or skin healing active may be added to the present composition, preferably, more preferably from about 0.5% to about 10 %, by weight of the composition formed. Skin soothing or skin healing actives suitable for use herein include panthenoic acid derivatives (including panthenol, dexpanthenol, ethyl panthenol), aloe vera, allantoin, bisabolol, and dipotassium glycyrrhizinate.

According to the present invention, said novelty is realized with mupirocin or a pharmaceutically acceptable salt thereof together with dexpanthenol, wherein the amount of dexpanthenol makes up 1 to 10%, preferably 4 to 6%, and more preferably 5% of the total weight of composition, the formulation further comprising mupirocin and relevant excipients.

In one embodiment, corticosteroids can be incorporated into composition of present invention in an amount of 0.01 % to 1%.

The term "topical" as used herein is meant to encompass any condition, disease or disorder manifested on body surfaces such as the skin or mucousal membranes such as the vagina, anus, throat, eyes and ears, including any tissue covering a body of a mammalian subject consisting of the outer, thinner epidermis (epithelial tissue) and the inner, thicker dermis (connective tissue), that is anchored to the subcutaneous layer. It should be noted that a composition or kit of the invention is intended for dermatological use on any type of skin area, being an exterior exposed area (such as for example areas of the skin, scalp, hair, and nails), an interior skin area such as a mucosal membrane (such as for example mucosal membrane around on the nostrils, the lips, the ears, the genital area, and the anus) or any vicinal areas in close proximity with the treated skin or mucosal membrane areas wherein said composition and agents comprised in said composition may reach via any kind of diffusion mechanisms to a skin area or mucosal membrane.

Pharmaceutical composition of the present invention may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients comprise, but are not limited to, gelling agents, emulsifiers, preservatives, thickeners, plastizers, moisturizers, stabilizers, solubilizers, emollients, surfactants, aromatic agents, penetration enhancers, pH adjusters and the mixtures thereof.

Penetration enhancers can be selected from the group, but are not limited to, propylene glycol, calcium chelators such as EDTA, methylated P-cyclodextrin, and polycarboxylic acids; surfactants such as sodium lauryl sulfate, sodium dodecyl sulfate, carnitine, carnitine esters, and tween; bile salts such as sodium taurocholate; fatty acids such as oleic and linoleic acid; and non-surfactants such as dialkyl sulfoxides; E-flux inhibitors such as D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), and peppermint oil; chitosan and chitosan derivatives such as N-methyl chitosan, N-trimethyl chitosan, mono-N-carboxymethyl chitosan, quaternized chitosan derivatives; SNAC (N- (8-(2-hydroxybenzoyl) amino) caprylate) and SNAD (N-(10-(2-hydroxybenzoyl)amino)-decanoate); N-acylated non-alpha amino acids; Gelucire 44/14 or Vitamin E TPGS ; CARBOPOL® 934P; others known to those of ordinary skill in the art; and combinations thereof.

Gelling agents can be selected from the group, but are not limited to, acacia, alginic acid, bentonite, carbopols, carbomer 940, carbomer 941 , gelatin, carbomer copolymer, aluminum monostearat, dextrin, magnesium aluminum silicate, silicon dioxide, sodium alginate, triethanolamine, polyvinyl alcohol, pectin, methylcellulose, hydroxypropyl cellulose, aqueous thickening agents such as neutral, anionic-cationic polymers and other materials known to one of ordinary skill in the art and mixtures thereof.

pH adjusting agents can be selected from the group, but are not limited to, triethanolamine, triethylamine, diethylmethylamine, ethyldimethylamine, isopropyldimethylamine.one or more adipic acids, glycines, citric acids, calcium hydroxides, magnesium aluminometasilicates, buffers, typically Bronsted-Lowry and/or Lewis acids and/or bases, or any combinations thereofand other materials known to one of ordinary skill in the art.

Moisturizers can be selected from the group, but are not limited to, polyethylene glycol, propylene glycol, dipropylene glycol, 1 ,3-butylene glycol, glycerin, diglycerin, xylitol, maltitol, maltose, D-mannitol, glucose, fructose, sodium chondroitin sulfate, sodium hyaluronate, sodium lactate, glucosamine, cyclodextrin, cococaprylate/caprateand other materials known to one of ordinary skill in the art and mixtures thereof.

Emulsifiers can be selected from the group, but are not limited to, ceteth-20, laureth-3, glyceryl stearate, polyethylene glycol, macrogol cetostearyl ether, stearic acid, stearyl alcohol, polysorbate 60, Irish moss, Tween 80, sorbitol monostearate.glycol esters, fatty acids, fatty alcohols, fatty acid glycol esters, fatty esters, fatty ethers, esters of glycerin, esters of propylene glycol, fatty acid esters of polyethylene glycol, fatty acid esters of polypropylene glycol, esters of sorbitol, esters of sorbitan anhydrides, carboxylic acid copolymers, esters and ethers of glucose, ethoxylated ethers, ethoxylated alcohols, alkyl phosphates, polyoxyethylene fatty ether phosphates, fatty acid amides, acyl lactylates, soaps, polyethylene glycol 20 sorbitan monolaurate (polysorbate 20) , polyethylene glycol 5 soya sterol, steareth-2, steareth-20, steareth-21 , ceteareth-20, PPG-2 methyl glucose ether distearate, ceteth-10, polysorbate 80, cetyl phosphate, potassium cetyl phosphate, diethanol amine cetyl phosphate, polysorbate 60, glyceryl stearate, PEG-100 stearate, tragacanth gum, 10-30 alkyl acrylate crosspolymersand other materials known to one of ordinary skill in the art and mixtures thereof.

Emollients can be selected from the group, but are not limited to, liquid vaseline.paraffinum liquidum, petrolatum, proplylene glycol, fatty acid esters, mineral oil including dimethicone, waxes including white wax, spermacetic wax, squalene, cetearyl alcohol, cetostearyl alcohol, stearyl alcohol, 2-Octyldodecanol, mineral oil USP, light mineral oil NF, liquid paraffin BP, light liquid paraffin BP.candellilla wax, sweet almond oil, apricot oil, emu oil, argan oil, glycerin, coconut oil, grape seed oil, honey, lanolinand other materials known to one of ordinary skill in the art and mixtures thereof.

Surfactants can be selected from the group, but are not limited to, a polysorbate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, a polyoxyethylene fatty acid ester, Myrj 45, Myrj 49, Myrj 52 and Myrj 59; a polyoxyethylene alkylyl ether, polyoxyethylene cetyl ether, polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, a sucrose ester, a partial ester of sorbitol, sorbitan monolaurate, sorbitan monolaurate a monoglyceride, a diglyceride, isoceteth-20, a sucrose ester, or selected from the group consisting of steareth 2, glyceryl monostearate/PEG 100 stearate, Glyceryl Stearate, Steareth-21 , peg 40 stearate, polysorbate 60, polysorbate 80, sorbitan stearate, laureth 4, Sorbitan monooleate, ceteareth 20, steareth 20, ceteth 20, Macrogol Cetostearyl Ether, ceteth 2, PEG-30 Dipolyhydroxystearate, sucrose distearate, polyoxyethylene (100) stearate, PEG 100 stearate, laureth 4, cetomacrogol ether, cetearyl alcohol, cetearyl glucoside, oleyl alcohol, steareth-2, diisopropyl adipate, capric/caprilic triglicerides, polysorbate 20, montanov 68 (cetearyl alcohol (and) cetearyl glucoside.), sharonmix 824(a liquid blend of methyl paraben, ethyl paraben and propyl paraben - in phenoxyethanol), Simusol 165 (glyceryl stearate and PEG-100 stea rate), methyl glucose sequistearate, Peg 30 dipolyhydroxystearate, sucrose stearic acid esters, sorbitan laureth, sorbitan stearate and mixtures thereof.

Preservatives can be selected from the group, but not limited to, methylparaben and propylparaben and the salts thereof (e.g. sodium or potassium salts), sodium benzoate, diazolidinyi urea, phenoxyethanol, DMDM hydantoin, sorbic acid, benzyl alcohol, formaldehyde, triclosan.methylisothiazolinone, methylchloroisothiazolinone, caffeine, citric acid, benzoic acid, butylated hydroxytoluene, propylene glycol, organic acids, esters of parahydroxybenzoic acid(methyl, ethyl, propyl and butyl esters of parahydroxy benzoic acid, and their sodiumsalts etc), chloform,chlorocresol,phenoxyethanol,quaternary ammonium compoundsand butylated hydroxyanisole, and the mixtures thereof.

Aromatic agents can be selected from the group, but are not limited to, menthol, lavender, mint, cinnamon, chocolate, vanillin, and fruit extracts such as cherry, orange, strawberry, grape.fenouil oil, eucalyptus oil, carnation oil, ginger oil, sweet orange oil, and the mixtures thereof.

Solvents can be selected from the group, but not limited to, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, purified waterand other materials known to one of ordinary skill in the art and mixtures thereof.

Thickeners can be selected from the group, but not limited to, beeswax, cocoa butter, shea butter, woo! wax, cetyl alcohol, gum acacia, gum tragacanth, locust bean gum, guar gum, hydroxypropyl guar, xanthan gum, cellulose gum, sclerotium gum, carrageenan gum, karaya gum, cellulose gum, rosin, anionic polymers such as polyacrylic acid, carboxymethylcellulose, methylcellulose.hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, polyethylene glycol, acrylic acid polymers, PEG- 150 distearate, decyl alcohol, SMDI copolymer, faponite XLG, ethyl cellulose, natrosol and other materials known to one of ordinary skill in the art and mixtures thereof.

Plasticizers can be selected from the group, but not limited to, glycerol, propylene glycol or another glycol, peppermint oil, eucalyptol oil, geranyl acetate or geraniol, phthalate, sebacate and citrate esters, triacetin, sorbitol, sucrose, triethyl citrate, dibutyl phthalate and other materials known to one of ordinary skill in the art and mixtures thereof.

Claims

1. A topical pharmaceutical composition, characterized in that it comprises:

a) mupirocin base or pharmaceutically acceptable salt or ester thereof,

b) dexpanthenol,

in combination with pharmaceutically acceptable excipients.

2. A topical pharmaceutical composition according to claim 1 , wherein said composition comprising mupirocin base or pharmaceutically acceptable salts thereof in the range of 0.05-5% w/w based on the total weight of the composition.

3. A topical pharmaceutical composition according to claim 2, wherein said composition comprising mupirocin base or pharmaceutically acceptable salts thereof in the range of 2% w/w based on the total weight of the composition.

4. A topical pharmaceutical composition according to claims 1-3, wherein said composition comprising mupirocin calcium dihydrate.

5. A topical pharmaceutical composition according to claim 1 , wherein said composition comprising dexpanthenol in the range of 1-10 % w/w based on the total weight of the composition.

6. A topical pharmaceutical composition according to claim 5, wherein said composition comprising dexpanthenol in the range of 5 % w/w based on the total weight of the composition.

7. A process for preparing a topical composition according to any preceeding claims, comprising: i) melting and mixing together one or more solid or semi-solid vehicles; ii) adding mupirocin and dexpanthenol to the mixture of step (i) while stirring; and ii) mixing until the temperature of the composition drops.

8. A topical pharmaceutical composition according to any preceeding claims, wherein it may further comprise a corticosteroid selected from hydrocortisone, prednisolone, methylprednisolone, triamcinolone, halometasone, fluocortolone, clobetasol, clobetasone, mometasone, betamethasone, dexamethasone.

9. A topical pharmaceutical composition according to any preceeding claims, wherein said composition is an ointment, cream, lotion, solution or gel.

10. A topical pharmaceutical composition according to any preceeding claims, for use in the treatment of bacterial infection and infected dermatoses caused by bacteria.