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WO2011027246A1 - Crème contenant du nitrate de miconazole et biopolymère destiné au traitement de l'érythème fessier du nourrisson - Google Patents

Crème contenant du nitrate de miconazole et biopolymère destiné au traitement de l'érythème fessier du nourrisson Download PDF

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Publication number
WO2011027246A1
WO2011027246A1 PCT/IB2010/053598 IB2010053598W WO2011027246A1 WO 2011027246 A1 WO2011027246 A1 WO 2011027246A1 IB 2010053598 W IB2010053598 W IB 2010053598W WO 2011027246 A1 WO2011027246 A1 WO 2011027246A1
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Prior art keywords
cream
skin
chitosan
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amount
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Sulur Subramaniam Vanangamudi
Madhavan Srinivasan
Neelakandan Narayanan Chulliel
Kausik Ghosh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present invention relates to a composition for treating diaper rashes along with skin rejuvenation. More particularly, the present invention relates to a pharmaceutical cream comprising a biopolymer, and antidiaper rash active ingredient, Miconazole Nitrate.
  • Skin disorders can be broadly categorized as those arising from bacterial forms or fungi.
  • Antifungal or antibacterial compositions are traditionally applied as lotions, creams or ointments. Furthermore in many instances, it is difficult to ascertain whether the skin 15 condition is due to a bacterial agent or a fungus.
  • Diaper rash or nappy rash also known as “Diaper dermatitis” and “Napkin dermatitis”is a generic term applied to skin rashes in the diaper area that are caused by various skin disorders and/or irritants.
  • Irritant diaper dermatitis develops when skin is exposed to prolonged wetness, increased skin pH caused by urine and feces, and resulting breakdown of the stratum corneum, or outermost layer of the skin.
  • compositions use steroids, antibacterial agents or antifungal agents, (or a fixed dose combination of these) and focus on these pharmaceutically active ingredients.
  • the composition of such formulations is such as to enhance their physical/chemical/bio - release profile.
  • Many skin disorders caused by inflammation and bacterial attacks lead to itching and subsequent scratching, which, among other causes, can in turn lead to serious and complicated secondary infections.
  • the conventionally available treatments do not focus on skin healing or rejuvenation; normally these two aspects are left to heal naturally.
  • the word healing as related to compromised skin conditions are not only about prevention, control, elimination of the source cause such as bacteria or fungi but also to restore the skin to its pre-infection state.
  • the current approaches of skin treatment can be broadly categorized into two stages, a. healing b. restoration of skin to pre-ailment state.
  • the healing part comprises elimination, to the best possible extent, of the root cause of the disorder. This may be elimination of bacteria or fungi causing the infection through a suitable treatment of antibacterial or antifungal agents or reducing the inflammation through steroid treatment. While this treatment is under way, the ongoing compromised condition of the skin continues to be susceptible to secondary infections which can be of quite serious nature. In the case of scratched or wounded skin, it is important for blood clotting to occur quickly as it reduces chances of secondary infections.
  • the focus of such treatments, which are administered through creams, lotions, ointments is on the action of active pharmaceutical ingredients.
  • Cream bases or ointment bases are merely viewed as carriers to take APIs to the sites of disorder.
  • the aspect of restoring the skin back to its pre -disorder state is almost completely left to nature. Therefore one key drawback of the existing skin treatment approaches is that they run the risk of secondary infections due to slow blood clotting and wound healing process.
  • Topical skin formulations can deliver skin healing or regeneration beyond the activity of the main APIs such that the therapeutic outcome of the main APIs is enhanced.
  • biopolymers biologically active polymers
  • Patent applications EP2092935 and PCT/IN2008/000577 provide an insight into the typical way steroids such as Mometasone Furoate are used towards topical prescription derma products.
  • EP2092935 relates to aerosolized formulations for the treatment of asthma that contain mometasone furoate and formoterol fumarate and processes for preparing same.
  • EP2092935 claims novelty on the assertion that the aerosol suspension formulation is non-toxic, substantially free of CFCs, has improved stability, it is also easily manufacturable and is substantially free of a carrier and excipients. Further the applicant has also disclosed a process for the production of the formulation wherein dry powder of the active agents and the surfactant is mixed together and filled into a metered dose inhaler canister, followed by crimping the canister with a metering valve, and filling it with nonchlorofiuorocarbon propellant.
  • PCT/IN2008/000577 provides a treatment of inflammatory dermatoses associated with secondary bacterial infections using a combination therapy of a topical antibiotic and a topical steroid.
  • PCT/IN2008/000577 claims novelty over the existing prior art on the assertion that the applicant had found a combination which is very effective for the treatment of inflammatory dermatoses associated with secondary bacterial infections.
  • the applicant has disclosed 2 formulations of which the first formulation consists of a) 1% w/w - 5%w/w of fusidic acid; b) 0.05% w/w to 2%w/w of Mometasone furoate; and c) a pharmaceutically acceptable carrier.
  • PCT/GB2007/004373, US 6,899,897, US 6,080,744, US 6,537,970 are examples of typical usage of antifungals such as clotrimazole in prescription derma products.
  • PCT/GB2007/004373 provides medicaments and methods for the treatment of infections caused or contributed to by multi-drug resistant Staphylococcus species using effective amount of Clotrimazole, and its derivatives. It claims novelty on the assertion that the pharmaceutical composition according to the invention possesses ability of inhibiting methicillin resistant Staphylococcus species.
  • the composition described in the invention by the applicant is used for oral administration, it can be used topically at the site of an infection, or intravenously.
  • the said composition can also be used for sterilizing or cleaning solutions to decontaminate furniture, floors, equipment including for example specialized hospital equipment and/or surgical equipment
  • US 6,899,897 discloses a biological dressing comprising a sticky film of gum resin - benzoin, a pharmacologically active agent - clotrimazole is left on the skin or mucous membrane after the volatile solvent - ethanol has evaporated.
  • the composition further may include penetration enhancer. It claims novelty over the assertion that the dressing disclosed herewith is a clean and inexpensive vehicle/carrier of topically applied medications increasing the convenience and effectiveness of the treatment and decreasing the necessary time for the treatment. This is apparently associated with less waste and lower cost and improved treatment.
  • the film formed is apparently extends retention on the skin since it is resistant to water and abrasion by clothing.
  • US 6,537,970 deals with a composition comprising clindamycin and clotrimazole used for the treatment of vaginal infection. It claims novelty over the conventional therapy because of the unique combination of various mycotoxins present in the composition and synergetic effect of the same. It is also claimed that the said composition can be used for the treatment of bacterial infection, fungal infection and mixed infection. The treatment can also be carried out either orally or topically.
  • US 6,080,744 deals with a topical composition for medical, veterinary or dental use containing active antimycotic ingredients like, miconazole, clotrimazole, ketoconazole, nystatin, tolnaftate, propionic acid, sodium propionate, undecelynic acid and zinc undecelynate in a natural base such that the composition is capable of defeating a wide range of fungi and can clear topical fungal infection. It claims advantage over the existing prior art on the bases that the ingredients used in the composition is blended in natural - cream base, also it is effective over a wide range of mycological illnesses and helps in speedy recovery.
  • active antimycotic ingredients like, miconazole, clotrimazole, ketoconazole, nystatin, tolnaftate, propionic acid, sodium propionate, undecelynic acid and zinc undecelynate
  • active antimycotic ingredients like, miconazole, clotrimazole, ketoconazole, n
  • cream base which cream base provides therapeutical value complementary to that provided by the main APIs and serves the purpose over and above that of being a mere carrier or delivery mechanism.
  • Figure 1 Non-homogeneous nature of creams containing chitosan with non-compatible excipient such as carbomer
  • the present invention is directed to a composition for treating diaper rashes, along with skin rejuvenation containing a) a biopolymer in the form of Chitosan b) An active pharmaceutical ingredient (API), Miconazole Nitrate used in treating diaper rashes, c) A cream base containing primary and secondary emulsifiers, waxy materials, co- solvents, acids, preservatives, chelating agents, and humectants. d) Water The active ingredients, namely chitosan, Miconazole Nitrate are incorporated in cream base for use in treating diaper rashes due to allergy & itching, & wounds on human skin involving contacting human skin with the above identified composition.
  • the present invention provides a uni-dose single-API Miconazole Nitrate formulation for topical skin treatment in the field of prescription medicaments.
  • the prescription medication is distinct in its use as compared with the so-called cosmeceuticals.
  • the cosmeceuticals are aimed towards beautification or betterment of a more-or-less intact skin or of a skin not suffering from a serious disorder.
  • prescription skin formulations are aimed to provide treatment for serious skin disorders resulting from infections and wounds.
  • Topical skin formulations can deliver skin healing or regeneration beyond the activity of the main API such that the therapeutic outcomes of the main APIs are enhanced.
  • biopolymers biologically active polymers
  • Miconazole Nitrate which may be employed in the present invention are well known in the art of treatment of diaper rashes and a bio polymer for treating wounds and rejuvenating human skin involving contacting human skin with the above identified composition.
  • biopolymer examples include, but are not limited to chitosan and the like.
  • suitable topical diaper rash agents include, but are not limited to Miconazole Nitrate, Benzalkonium chloride, Cetrimide, Zinc oxide, Allantoin, Hydrocortisone and the like.
  • the active compound Miconazole Nitrate require a base component to be used in the pharmaceutical composition that uses the compounds, since the compounds cannot, by themselves, be deposited directly on to human skin due to their harshness.
  • the base component usually contains primary and secondary emulsifiers, waxy materials, co-solvents, acids, preservatives, chelating agents, humectants and the like.
  • Chitosan Chitosan is a linear polysaccharide composed of randomly distributed -(l-4)-linked D- glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). It is known to have a number of commercial uses in agriculture and horticulture, water treatment, chemical industry, pharmaceuticals and biomedics. It's known properties include accelerated blood clotting. However, it is not known to a person skilled in the art that chitosan' s behaviour with a pharmaceutical active ingredient such as an antibacterial or antifungal agent needs to be treated with caution.
  • Chitosan generally absorbs moisture from the atmosphere / environment and the amount absorbed depends upon the initial moisture content, temperature and relative humidity of the environment. It is regarded as a non-toxic and non-irritant material. It is biocompatible with both healthy and infected skin and has been shown to be biodegradable as it is derived from shrimps, squids and crabs.
  • Chitosan due to its unique physical property accelerates wound healing and wound repair. It is positively charged and soluble in acidic to neutral solution. Chitosan is bioadhesive and readily binds to negatively charged surfaces such as mucosal membranes. Chitosan enhances the transport of polar drugs across epithelial surfaces. Chitosan's properties allow it to rapidly clot blood, and it has recently gained approval in the USA for use in bandages and other hemostatic agents.
  • Chitosan is nonallergenic, and has natural anti-bacterial properties, further supporting its use. As a micro-film forming biomaterial, chitosan helps in reducing the width of the wound, controls the oxygen permeability at the site, absorbs wound discharge and gets degraded by tissue enzymes which are very much required for healing at a faster rate. It also reduces the itching by providing a soothing effect. It also acts like a moisturizer. It is also useful in treatment of routine minor cuts and wounds, burns, keloids, diabetic ulcers and venous ulcers. Chitosan used in the present invention comes in various molecular weights ranging from lkdal to 5000kdal.
  • Chitosan is discussed in the US Pharmacopoeia forum with regard to its functional excipient category. Since chitosan is basically a polymer, it is available in various grades depending upon the molecular weight.
  • the various grades of chitosan include chitosan long chain, chitosan medium chain & chitosan short chain.
  • the grades long, medium & short chain directly correspond to the molecular weight of the chitosan.
  • the long chain grade has a molecular weight in the range of 500,000- 5,000,000 Da
  • the medium chain grade has a molecular weight in the range of 1,00,000- 2,000,000 Da
  • the short chain grade has a molecular weight in the range of 50,000- 1,000,000 Da.
  • the molecular weight of the chitosan plays an important role in the formulation, higher molecular weight chitosan imparts a higher viscosity to the system and lower molecular weight chitosan imparts a lower viscosity to the system.
  • medium chain grade chitosan delivered an optimum level of viscosity to the formulation. Since the dosage form is a cream, appropriate levels of viscosity is required to achieve a good spreadability over the skin.
  • chitosan medium chain grade for the present invention since it imparted the required rheologic properties to the cream without compromising the therapeutic activity of the actives Miconazole Nitrate and chitosan.
  • concentration of chitosan medium chain grade was carefully arrived based on several in house trials and Preclinical animal studies for efficacy.
  • Topical Diaper Rash agents are intended to target skin for Diaper Rash.
  • Topical Diaper Rash agents include, but are not limited to, Miconazole Nitrate and the like.
  • Miconazole Nitrate is intended to target skin for Diaper Rash in low concentration & in high concentration acts as an antifungal agent with similar antimicrobial activity to ketoconazole.
  • Chemically, Miconazole Nitrate is l-[2-(2,4-Dichlorophenyl)-2-[(2,4- dichlorophenyl)methoxy]ethyl]-lH- imidazole with the empirical formula CI S HMC NZC.HNO S , and a molecular weight of 479.15.
  • Miconazole Nitrate is a White or almost white, crystalline or micro-crystalline powder, freely soluble in methanol; slightly soluble in ethanol (95%) and in chloroform; very slightly soluble in water and in ether. It is administered by intravenous infusion in the treatment of severe systemic fungal infections including candidiasis, coccidioidomycosis, cryptococcosis paracoccidioidomycosis, and infections due to Pseudeliescheria boydii. Miconazole may be given by mouth for the treatment of oral and intestinal candidiasis. It has been given prophylactically to patients at high risk of opportunistic fungal infections.
  • mice In fungal meningitis, intravenous treatment may be supplemented with intrathecal injections of Miconazole. Miconazole nitrate is used locally for treating various fungal skin infections.
  • Miconazole nitrate is a synthetic antifungal agent which inhibits the growth of the common dermatophytes, Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum, the yeast-like fungus, Candida albicans, and the organism responsible for tinea versicolor (Malassezia furfur).
  • mice nitrate inhibits biosynthesis of ergosterol, damaging the fungal cell wall membrane, which increases permeability causing leaking of nutrients
  • Pharmacokinetics :
  • Miconazole nitrate Absorption of Miconazole nitrate is negligible by topical route. Miconazole nitrate is widely distributed to body tissues; penetrates well into inflamed joints, vitreous humor of eye, and peritoneal cavity, but poorly into saliva and sputum; crosses blood-brain barrier but only to a small extent. Protein binding of Miconazole nitrate is about 91 % to 93%. Miconazole nitrate is metabolized in liver and excreted in feces (-50%) and urine ( ⁇ 1 % as unchanged drug).
  • tinea pedis athlete's foot
  • tinea cruris and tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum
  • cutaneous candidiasis moniliasis
  • tinea versicolor and in the treatment of diaper rashes at low concentration.
  • Creams are topical preparation used for application on the skin.
  • Creams are semi-solid emulsions, which are mixtures of oil and water in which APIs (Active Pharmaceutical Ingredients) are incorporated. They are divided into two types: oil-in-water (O/W) creams which compose of small droplets of oil dispersed in a continuous water phase, and water-in-oil
  • ointment is a viscous semisolid preparation containing APIs, which are used topically on a variety of body surfaces.
  • the vehicle of an ointment is known as ointment base.
  • the choice of a base depends upon the clinical indication of the ointment, and the different types of ointment bases normally used are: ⁇ Hydrocarbon bases, e.g. hard paraffin, soft paraffin
  • Absorption bases e.g. wool fat, bees wax
  • the acidic scale of pH is from 1 to 7, and the base scale of pH is from 7 to 14.
  • Human skins pH value is some where between 4.5 and 6. Newborn baby's skin pH is closer to neutral (pH 7), but it quickly turns acidic. Nature has designed this probably to protect young children's skin, since acidity kills bacteria. As people become older, the skin becomes more and more neutral, and won't kill as many bacteria as before. This is why the skin gets weak and starts having problems.
  • the pH value goes beyond 6 when a person actually has a skin problem or skin disease. This shows that it is necessary to choose topicals that have a pH value close to that of skin of a young adult. A slight shift towards the alkaline pH would provide a better environment for microorganisms to thrive.
  • cream formulations are available as creams. Active compounds in cream formulations are available in ionized state, whereas in case of ointments these are present in non-ionized state.
  • the cream formulations are the first choice of the formulators in design and development of topical dosage forms, as the cream formulations are cosmetically elegant, and also as the active compound is available in ionized state, and the drug can penetrate the skin layer fast which makes the formulation totally patient friendly.
  • the pH of the cream of the present invention with a functional biopolymer such as chitosan with Miconazole Nitrate is from about 3 to 6.
  • a functional biopolymer such as chitosan with Miconazole Nitrate
  • ointments that are commercially available are greasy and cosmetically non elegant.
  • the active compound in an ointment is in non-ionized form, the penetration of skin is slow.
  • the particle size of the active drug plays an important role here. It is necessary that the active drug is available in colloidal or molecular dispersed state for the product being highly efficacious form. Also this is to be achieved in the safe pH compatible environment of skin (4.0 to 6.0). To achieve all these, it is essential to choose proper vehicles or co-solvents for the dissolution or dispersion of the drug.
  • the product of the present invention is highly efficacious due to the pronounced antidiaper rash activity & wound healing activity of the active ingredient Miconazole Nitrate, which are available in ultra micro-size, colloidal form, which enhances skin penetration.
  • Topical Miconazole Nitrate have profound efficacy in diaper rashes of varied etiology due to their antidiaper rash properties.
  • a drawback of the monotherapy with topical antidiaper rash agents like Miconazole Nitrate has been the relatively slow onset of the effect.
  • Miconazole Nitrate and chitosan By employing Miconazole Nitrate and chitosan in a formulation, the properties of Miconazole Nitrate and chitosan are optimized.
  • chitosan is film forming, biocompatible, non- allergenic material it helps in protecting the skin by acting as a barrier. It further controls the superficial bleeding caused by scratching and also arrests the mobility of pathogens due to its cationic charge.
  • Miconazole Nitrate and chitosan' s skin regenerative aspects are well exploited in the present invention and the maximum therapeutic benefit is passed on to the patient thereby aiding in faster healing. This ensures that the patient would benefit for the treatment of skin diaper rashes and wounds.
  • chitosan in the formulation takes care of many attributes, which are considered to be very much essential in treating skin ailments.
  • the combination of chitosan with Miconazole Nitrate is unique and novel since this is not available commercially across the globe.
  • Another inventive aspect of the present invention is that the addition of a functional excipient in the cream base is not a straight forward process of mere addition.
  • the inventor has found that the compatibility of the functional excipient such as chitosan with other agents in the cream is of critical importance. This is because incompatibility would compromise the stability of the final product.
  • the inventors have found that well known excipients such as Xanthan Gum and carbomer which have been variously used as stabilising agents, cannot be used in combination with functional biopolymers such as chitosan.
  • Excipients for topical dosage forms include Polymers, Surfactants, Waxy Materials, and Emulsifiers etc. Polymers are used as gelling agents, suspending agents, viscosity builders, release modifiers, diluents, etc. Surfactants are used as wetting agents, emulsifiers, solubilising agents, release enhancers, etc. Generally Polymers & Surfactants may or may not possess ionic charge. They may be anionic or cationic or non-ionic in nature. If anionic excipients are included in the formulation they interact with cationic formulation excipients and produce products which are not homogenous, aesthetically not appealing and give rise to unwanted by products, possible allergens, impurities, toxic substances etc due to incompatibility.
  • tablettes 1 to 5 are examples of products that do not form homogeneous creams, and produce non-homogeneous creams of the type illustrated in figure 1. Yet the proportions stated in these examples are some things that a person skilled in the art may use based on currently available knowledge. Only after a thorough and extensive trials and errors would it be possible to arrive at right types and proportions of excipients.
  • Miconazole Nitrate provide relief against diaper rashes.
  • the aspects such as like skin protection, bleeding at the site, mobility of pathogens from one site to another, etc are not addressed so far in a single dose therapy.
  • This present invention with its single-dose application fills this gap by incorporating chitosan and tapping the required benefits of skin protection (by way of film forming property), stopping the bleeding (by way of blood clotting property) and immobilization of pathogenic microbes (due to its cationic electrostatic property).
  • Therapeutic value addition by incorporation of a functional excipient in the form of a chitosan which is a biopolymer in the cream matrix.
  • the value addition is an integrated sub-set of the following functional attributes of the biopolymer:
  • the unique innovative formulation of the present invention takes care of the skin conditions by treating them along with controlling the superficial bleeding at the site. It is well understood that if the superficial bleeding is left untreated, it will lead to secondary microbial infections.
  • the present invention advantageously provides a solution to this unmet need.
  • the present invention with its single-dose therapy reduces the overall treatment time of a serious skin disorder significantly.
  • a novel dermaceutical cream for topical treatment of diaper rashes, and for related wound healing wherein said cream comprises antidiaper rash agents Miconazole Nitrate and a biopolymer provided in a cream base, said cream base comprising at least one of each of a preservative, a primary and a secondary emulsifier, a waxy material, a co- solvent, an acid, and water, preferably purified water.
  • Miconazole Nitrate is added in an amount between about 0.001 % w/w and about 5% w/w, preferably between 0.01 and 1.0% w/w; more preferably about 0.25% w/w and
  • said biopolymer is in the form of chitosan, added in an amount between about 0.01 % and about 1 % by weight, preferably added in an amount from about 0.01 % w/w to about 0.5% w/w and most preferably about 0.1% w/w, said chitosan being US Pharmacopoeial Forum conformant with regard to its functional excipient category and selected from any grades such as Long Chain, Medium Chain & Short Chain, and has a molecular weight in the range between 50kDa to 5000 kDa,
  • said primary and secondary emulsifiers are selected from a group comprising Cetostearyl alcohol, Cetomacro go 1-1000, Polysorbate-80, Span-80, and the like and added in an amount from about 1 % (w/w) to 20% (w/w); said waxy materials is selected from a group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 30% (w/w); said co-solvent is selected from a group comprising Propylene Glycol, Hexylene Glycol, PolyEthylene Glycol-400, Isopropyl Myristate and the like, or any combination thereof, and added in an amount from about 5% (w/w) to
  • said acid is selected from a group comprising HC1, H 2 SO 4 , HNO 3 , Lactic acid and the like, or any combination thereof, and added in an amount from about 0.005% (w/w) to 0.5% (w/w);
  • said preservative is selected from a group comprising Methyl paraben, Propyl paraben, Chlorocresol, Potassium sorbate, Benzoic acid and the like, or any combination thereof, and added in an amount from about 0.01 % (w/w) to 0.5% (w/w); said water is added in the amount in the range of 20% (w/w) to 75% (w/w), preferably 45% (w/w) to 75% (w/w), more preferably 60 % (w/w) to 70% (w/w), preferably purified water.
  • Embodiment no. 3 is
  • a chelating agent which is selected from a group comprising Disodium EDTA and the like, or any combination thereof, and added in an amount from about 0.05% (w/w) to 1% (w/w).
  • Embodiment no. 4 is a diagrammatic representation of Embodiment no. 4:
  • a humectant which is selected from a group comprising Glycerin, Sorbitol, Propylene Glycol and the like, or any combination thereof, and added in an amount from about 5% (w/w) to 50% (w/w).
  • Embodiment no. 5 is a diagrammatic representation of Embodiment no. 5:
  • a process of making a cream comprising the steps of providing ant diaper rash agent, Miconazole Nitrate and a biopolymer in a cream base comprising at least one of each of a preservative, a primary and a secondary emulsifier, waxy material, a co-solvent, an acid, and water, preferably purified water, and mixing all the ingredients together to form a homogeneous cream.
  • Embodiment no. 6 is a diagrammatic representation of Embodiment no. 6:
  • Embodiment no. 7 is a diagrammatic representation of Embodiment no. 7:
  • table 6 A comparison of table 6, and tables 1 to 5 will illustrate the difference in the products that would be based on the conventional drug design and the innovative approach adopted in the present invention.
  • API-stability experiments were carried out (see tables 7- 9) using the product of the present invention. Tests were carried out to observe (or measure as appropriate) the physical appearance of the product, the pH value and assay of the API over a period of time. Each gram of product of the present invention used for the tests contained appropriate amount of antidiaper rash agent Miconazole Nitrate.
  • the product used for the Stability Studies tests contained approximately 10% extra APIs (overages). It was packaged in an aluminium collapsible tube.
  • Each gm contains: Miconazole Nitrate IP 0.25% w/w
  • Measured parameter pH; Limits of measured parameter: 3-6
  • the cream is applied after thorough cleansing and drying the affected area. Sufficient cream should be applied to cover the affected skin and surrounding area. The cream should be applied two - four times a day depending upon the skin conditions for the full treatment period, even though symptoms may have improved.
  • Excision wound healing activity of the cream of the present invention was determined through animal testing. An excision wound 2.5 cm in diameter was inflicted by cutting away full thickness of the skin. The amount of contraction of the wound observed over a period indicated that the cream of present invention provides significantly improved wound contraction than that achieved through application of a conventional cream.
  • Epithelisation of the wound occurred within shorter number of days using the cream of the present invention as compared to the days taken for epithelisation using the conventional cream. Therefore one benefit of the cream of the present invention is that it facilitates faster epithelisation of the skin than through the use of conventional creams.
  • Blood clotting time was observed in both groups of animals, untreated control group and the test group of animals treated with the product of the present invention. Statistically significant decrease in the blood clotting time in treated group animals was observed when compared with that of the control group animals. The mean percent reduction of 15 - 25 % was observed for the blood clotting time using the product of the present invention.
  • the anticandidal activity of the product is confirmed by the In- Vitro Zone Of Inhibition studies for the product against Candida albicans.
  • the results of the studies were analyzed by using Mann - Whitney U test, and found to be statistically significant.
  • the film forming ability of the chitosan incorporated in the cream allows better access of the anti diaper rash agent, Miconazole Nitrate to the infected / inflamed area and results in better functioning of these API.
  • the therapeutic efficacy of topically applied cream of the present invention is due to the pronounced anti diaper rash activity of Miconazole Nitrate against the organisms responsible for skin infections, the unique ability of actives to penetrate intact skin and wound healing & soothing properties of chitosan.
  • the cream of the present invention incorporates a skin- friendly biopolymer in the form of chitosan provides enhanced therapeutic outcomes. This is evident from the reduced blood clotting time, increased epithelial effect, and faster relief from infection and inflammation.
  • the cream of the present invention incorporates a biopolymer without compromising the stability of the cream matrix and without adversely affecting the functioning of known active pharmaceutical ingredients. This has been achieved through a careful selection of functional excipients to bypass undesirable aspects of physio-chemical compatibility/stability and bio-release. 3.
  • the cream of the present invention provides an integrated uni-dose or a single-dose therapy hitherto unavailable in prescription dermaceutical formulations.
  • the novel cream of the present invention is adequately stable/efficacious at ambient conditions and does not need special temperature control during transportation/storage - hence will go a long way in achieving these social objectives.

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Abstract

La présente invention concerne une composition destinée au traitement des érythèmes fessiers des nourrissons, accompagnée d'une réjuvénation cutanée contenant a) un biopolymère sous la forme de chitosane, b) des principes actifs pharmaceutiques (PAP), à savoir du nitrate de miconazole, utilisés dans le traitement de l'érythème fessier du nourrisson, c) une base de crème contenant des émulsifiants primaires et secondaires, des substances cireuses, des cosolvants, des acides, des conservateurs, des agents tampons, des antioxydants, des agents chélateurs et des humectants et d) de l'eau. Les principes actifs, à savoir le chitosane, un agent actif contre l'érythème fessier du nourrisson sous la forme de nitrate de miconazole, sont incorporés dans une base de crème pour une utilisation dans le traitement des érythèmes fessiers des nourrissons dus à une allergie, des démangeaisons et des plaies sur la peau humaine impliquant le contact de la peau humaine avec la composition identifiée ci-dessus.
PCT/IB2010/053598 2009-09-03 2010-08-10 Crème contenant du nitrate de miconazole et biopolymère destiné au traitement de l'érythème fessier du nourrisson Ceased WO2011027246A1 (fr)

Applications Claiming Priority (2)

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IN1808MU2009 2009-09-03
IN1808/MUM/2009 2009-09-03

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WO2011027246A1 true WO2011027246A1 (fr) 2011-03-10

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PCT/IB2010/053598 Ceased WO2011027246A1 (fr) 2009-09-03 2010-08-10 Crème contenant du nitrate de miconazole et biopolymère destiné au traitement de l'érythème fessier du nourrisson

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2540764A (en) * 2015-07-24 2017-02-01 Fontus Health Ltd Topical composition
CN115227641A (zh) * 2022-07-19 2022-10-25 华润三九（南昌）药业有限公司 一种硝酸咪康唑乳膏及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005074883A1 (fr) * 2004-01-29 2005-08-18 Sinclair Pharmaceuticals Limited Compositions aqueuses contenant des melanges de polymeres synthetiques et de biopolymeres, utilisees pour traiter la secheresse de la peau et des muqueuses, et aptes a etre utilisees comme vehicules d'ingredients actifs
US20060159645A1 (en) * 2004-10-04 2006-07-20 Jonathan Miller Method of providing lubricious surfaces
US20080050434A1 (en) * 2004-03-18 2008-02-28 Rajesh Jain Novel Composition for Topical Delivery
WO2010109422A1 (fr) * 2009-03-25 2010-09-30 Sulur Subramaniam Vanangamudi Crème médicinale pour érythème fessier et son procédé de production

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005074883A1 (fr) * 2004-01-29 2005-08-18 Sinclair Pharmaceuticals Limited Compositions aqueuses contenant des melanges de polymeres synthetiques et de biopolymeres, utilisees pour traiter la secheresse de la peau et des muqueuses, et aptes a etre utilisees comme vehicules d'ingredients actifs
US20080050434A1 (en) * 2004-03-18 2008-02-28 Rajesh Jain Novel Composition for Topical Delivery
US20060159645A1 (en) * 2004-10-04 2006-07-20 Jonathan Miller Method of providing lubricious surfaces
WO2010109422A1 (fr) * 2009-03-25 2010-09-30 Sulur Subramaniam Vanangamudi Crème médicinale pour érythème fessier et son procédé de production

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CONCANNON P ET AL: "Diaper dermatitis: a therapeutic dilemma. Results of a double-blind placebo controlled trial of miconazole nitrate 0.25%", PEDIATRIC DERMATOLOGY, BLACKWELL SCIENTIFIC PUBLICATIONS, BOSTON, MA, US, vol. 18, no. 2, 1 March 2001 (2001-03-01), pages 149 - 155, XP009105010, ISSN: 0736-8046, DOI: DOI:10.1046/J.1525-1470.2001.018002149.X *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2540764A (en) * 2015-07-24 2017-02-01 Fontus Health Ltd Topical composition
CN115227641A (zh) * 2022-07-19 2022-10-25 华润三九（南昌）药业有限公司 一种硝酸咪康唑乳膏及其制备方法

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