JP2012521410A - Medicinal antibacterial cream and method for producing the same - Google Patents

Abstract

  The present invention relates to a composition for treating bacterial skin infections and rejuvenating the skin. More particularly, the present invention relates to a pharmaceutical cream comprising a biopolymer and an antibacterial active ingredient. The present invention comprises a) a biopolymer in the form of chitosan, b) active ingredients (APIs) used to treat bacterial skin infections, c) primary and secondary emulsifiers, waxy substances, cosolvents, acids, Disclosed are compositions for treating bacterial skin infections and rejuvenating skin, comprising a cream base containing preservatives, buffers, antioxidants, chelating agents, and wetting agents, d) water. The active ingredients, chitosan and antibacterial agent, are incorporated into a cream base for use in the treatment of bacterial skin infections.

Description

  The present invention relates to a composition for treating bacterial skin infections and rejuvenating the skin. More particularly, the present invention relates to a pharmaceutical cream comprising a biopolymer and an antibacterial active ingredient.

  Skin disorders can be broadly classified as arising from bacterial types or fungi. Antifungal or antibacterial compositions are traditionally applied as lotions, creams or ointments. Furthermore, in many cases, it is difficult to ascertain whether the skin condition is caused by bacterial pathogens or fungi.

  One approach to treating skin disorders is by trial and error exclusion. Antibacterial or antifungal compositions are applied sequentially and responses are monitored to correct treatment. The main disadvantage of this approach is that the treatment needs to be applied multiple times a day during the treatment period. This is very inconvenient and is not cost effective in the majority of human populations, especially in developing countries.

  Several treatments are available for treating skin disorders caused by bacteria or fungi. Typically, such compositions use steroids, antibacterial or antifungal agents (or combinations of these fixed doses) and focus on these pharmaceutically active ingredients. The composition of such a formulation is such that it enhances its physical / chemical / biorelease profile.

  Many skin disorders are caused by inflammation, and bacterial attacks result in pruritus and subsequent scratches, which can, among other causes, lead to serious and complex secondary infections. is there. Conventionally available treatments do not focus on skin healing or rejuvenation and usually these two aspects are left to natural healing.

  Words related to easily infectious skin conditions (cuts, wounds, infections, inflammation, abrasions, etc.), healing refers to the prevention, control, elimination of sources of causes such as bacteria or fungi, as well as the infection of the skin It also relates to restoring the previous state.

  Current approaches to skin treatment include two stages: a. Healing and b. It can be broadly categorized as skin repair to pre-disease state. The healing part includes the elimination of the root cause of the disorder to the best possible extent. This can be the elimination of bacteria or fungi causing the infection by appropriate treatment of antibacterial or antifungal agents, or reduction of inflammation by steroid treatment. During the course of this treatment, the ongoing skin susceptibility status continues to be susceptible to secondary infections, which may be of very severe nature. In the case of scratched or wounded skin, it is important that clotting occurs quickly, since this reduces the possibility of secondary infections. The focus of such treatments administered via creams, lotions, ointments is on the action of the drug substance. A cream or ointment base is simply a carrier to carry the API to the site of injury.

  However, the aspect of restoring the skin to its pre-disorder state and repairing is left almost completely naturally. Thus, one major drawback of existing skin treatment procedures is that there is a risk of secondary infection due to the slow clotting and wound healing processes.

In addition, some of the scarce aspects of existing prescription skin products used for topical treatment of skin disorders from prior art studies. This is manifested in that any potential therapeutic benefit of the cream base matrix or ointment base was overlooked. Specifically, no available prior art suggests:
-A topical skin formulation can provide skin healing or regeneration beyond the activity of the main API, such that the therapeutic outcome of the main API is enhanced.
-The addition of bioactive polymers (so-called biopolymers) is well-considered by the precise biopolymer or naturally interacting formulation excipients or process parameters at the drug design stage itself so that the therapeutic results are enhanced and complemented. If not optimized, it is a complex process that compromises the stability of the formulation.
-Incorporation of functionally bioactive excipient polymer into the cream matrix while retaining the functional stability of the API in a single dose mode dermatological cream is Includes solutions to stability-specific problems.

  A look at some of the existing patents illustrates the above points.

  Patent applications EP 2092935 and PCT / IN2008 / 000577 provide insight into typical methods of using steroids such as mometasone furoate for topical prescription skin products.

  EP 2092935 relates to an aerosolized formulation for the treatment of asthma containing mometasone furoate and formoterol fumarate, and a method for its preparation. EP 2092935 is an aerosol suspension formulation that is non-toxic, substantially free of CFCs, has improved stability, is easily manufacturable, and is substantially free of carriers and excipients. Insist on novelty with respect to not including. In addition, Applicants prepare a formulation that mixes dry powder of active agent and surfactant together, fills a metered dose inhaler, then crimps a metering valve to the can and fills it with a non-chlorofluorocarbon propellant. A method is also disclosed.

  PCT / IN2008 / 000577 provides for the treatment of inflammatory skin diseases associated with secondary bacterial infections using a combination therapy of topical antibiotics and topical steroids. PCT / IN2008 / 000577 claims novelty over existing prior art with respect to the claim that the applicant has found a very effective combination for the treatment of inflammatory skin diseases associated with secondary bacterial infections. Yes. Applicants have disclosed two formulations, the first of which a) 1% w / w to 5% w / w fusidic acid, b) 0.05% w / w 2% w / w mometasone furoate and c) a pharmaceutically acceptable carrier.

  PCT / GB2007 / 004373, US6,899,897, US6,080,744, US6,537,970 are examples of typical use of antifungal agents such as clotrimazole in prescription skin products. It is.

  PCT / GB2007 / 004373 provides pharmaceuticals and methods for treating infections caused by or contributing to multi-drug resistant Staphylococcus species using effective amounts of clotrimazole and its derivatives. This claims novelty with respect to the claim that the pharmaceutical composition according to the invention possesses the ability to inhibit methicillin resistant Staphylococcus species. The compositions described in this invention by the applicant can be used for oral administration and can be used locally or intravenously at the site of infection. The composition can also be used as a sterilizing or cleaning solution for decontaminating furniture, floors, and equipment including specialized hospital equipment and / or surgical equipment.

  US 6,899,897 discloses a biological dressing comprising an adhesive film of benzoin, a gum resin, and clotrimazole, a pharmacologically active agent, after the volatile solvent ethanol has evaporated. Remains on the skin or mucous membrane. The composition can further include a penetration enhancer. This is in the claim that the bandage disclosed herein is a clean and inexpensive vehicle / carrier for locally applied pharmaceuticals, increasing the convenience and effectiveness of the treatment and reducing the time required for the treatment. Insist on sex. This appears to be associated with less waste, less expensive costs, and improved treatment. The formed film is resistant to scuffing by water and clothing, and thus appears to have increased retention on the skin.

  US 6,537,970 relates to a composition comprising clindamycin and clotrimazole for use in the treatment of vaginal infections. This asserts novelty over conventional treatments because of the unique combination of various fungal toxins present in the composition and their synergism. It also claims that the composition can be used for the treatment of bacterial, fungal and mixed infections. Also, treatment can be performed either orally or topically.

  US Pat. No. 6,080,744 discloses clotrimazole, ketoconazole, miconazole, nystatin, tolnaphthalate, propionic acid, sodium propionate so that the composition can overcome a wide range of fungi and eliminate local fungal infections Relates to topical compositions for use in medicine, veterinary medicine or dentistry, containing active antifungal ingredients such as undecylenic acid and zinc undecylenate in natural bases. Ingredients used in the composition are mixed in a natural cream base and also claimed advantages over existing prior art based on being effective over a wide range of fungal diseases and helping quick recovery. ing.

  These examples will be sufficient to give a reasonable picture of how clotrimazole has been used in the industry.

None of the above-mentioned patent applications teach or suggest the following simultaneously.
-Use the cream base matrix as a functional element of the cream, not just the main API carrier.
-Using known biopolymers as functional excipients with antibacterial agents.
-Provides much better healing effects, as microfilm formation, clotting, epidermal growth support, and microbial electrostatic immobilization occur simultaneously rather than one after the other as in conventional single drug therapy To be done.
-The overall medicinal properties of the cream are improved and complemented with the API used in the cream matrix.

  Thus, a single dose of API topical provided in a cream base that provides therapeutic value that complements that provided by the main API and serves more than just a carrier or delivery mechanism. There is a need for treatment.

  Thus, there is a need to provide a single dose API topical treatment formulation that provides effective treatment against bacterial infections and helps active healing of skin rejuvenation.

A further object of the present invention is to provide a topical skin treatment formulation as follows.
-It can lead to skin healing or regeneration beyond the activity of the main API, so that the treatment outcome of the main API is enhanced.
-Contains bioactive polymers (so-called biopolymers) without compromising the stability of the formulation which may be compromised if the correct biopolymer is not selected.
-Functional bioactive excipient polymer is incorporated into the cream matrix while maintaining functional stability of the API in a single dose mode.

FIG. 6 shows the non-homogeneous nature of a cream containing chitosan using incompatible excipients such as carbomers. It is a figure which shows the film formation (film formation) using chitosan.

The present invention
a) Biopolymer in the form of chitosan b) Drug substance (API) used to treat bacterial skin infections
c) Cream base containing primary and secondary emulsifiers, waxy substances, co-solvents, acids, preservatives, buffers, antioxidants, chelating agents, and humectants d) Bacterial skin containing water It is directed to compositions that treat infections and rejuvenate the skin.

  For use in the treatment of allergies and pruritus involving active ingredients, ie chitosan and antibacterial agents, in contact with human skin with the composition identified above, and bacterial skin infections with wounds on human skin Is incorporated into the cream base.

  It is understood that all numerical values representing amounts of ingredients are modified in all cases by the term “about”, except where noted in the examples or otherwise specified.

  The present invention provides a single dose API formulation for topical skin treatment in the field of prescription pharmaceuticals. The use of prescription drugs is clearly different compared to so-called medicated cosmetics. Medicinal cosmetics are directed to beautifying or improving nearly intact skin or skin that does not suffer from serious disorders. On the other hand, prescription skin formulations are directed at providing treatment for serious skin disorders resulting from infections and wounds.

From the prior art studies, some of the scarce aspects of existing topical treatment formulations in the field of prescription medicine are evident. The prior art does not teach or suggest the following.
-A topical skin formulation can provide skin healing or regeneration beyond the activity of the main API, such that the therapeutic outcome of the main API is enhanced.
Addition of bioactive polymers (so-called biopolymers) is a complex process where the stability of the formulation is compromised if the correct biopolymer is not selected.
-Incorporation of functionally bioactive excipient polymer into the cream matrix while retaining the functional stability of the API in a single dose mode dermatological cream is Includes solutions to stability-specific problems.

  Active compounds that can be used in the present invention include either acid or basic active substances or salts thereof well known in the field of treatment of bacterial infections and contacting human skin with the compositions identified above. A biopolymer for treating wounds and rejuvenation of human skin.

  Examples of suitable biopolymers that can be used include, but are not limited to, chitosan and the like.

  Examples of suitable topical antibacterial agents that may be used include, but are not limited to, sodium fusidate, calcium mupirocin, gentamicin, neomycin, silver sulfadiazine, ciprofloxacin, flamicetin sulfate, quinidochlor, povidone iodine, Sisomycin, nitrofural, etc. are included.

  Since the compounds cannot be placed directly on human skin by themselves because of their strong irritation, this acid or basic active compound or salt thereof is the basic composition used in the pharmaceutical composition in which the compound is used. Requires ingredients.

  Base constituents usually contain primary and secondary emulsifiers, waxy substances, cosolvents, acids, preservatives, buffers, antioxidants, chelating agents, wetting agents and the like.

Chitosan Chitosan is a linear chain consisting of randomly distributed β- (1-4) -linked D-glucosamine (deacetylated units) and N-acetyl-D-glucosamine (acetylated units). It is a polysaccharide. It is known to have several commercial uses in agriculture and horticulture, water treatment, chemical industry, pharmaceuticals and biomedicine.

  Its known properties include clotting acceleration. However, it is not known to those skilled in the art that the behavior of chitosan with pharmaceutically active ingredients such as antibacterial or antifungal agents requires careful handling.

  It is known to have film-forming, mucoadhesive and thickening properties and is used as a binder and disintegrant in tablet formulations.

  Chitosan generally absorbs moisture from the atmosphere / environment, and the amount absorbed depends on the initial moisture content of the environment, temperature and relative humidity.

  This is regarded as a non-toxic and non-irritating substance. It has been shown to be biodegradable because it is biocompatible with both healthy and infected skin and is derived from shrimp, squid and crabs.

  Chitosan accelerates wound healing and wound repair due to its unique physical properties. It is positively charged and is soluble in acidic to neutral solutions. Chitosan is bioadhesive and easily binds to negatively charged surfaces such as mucous membranes. Chitosan enhances the transport of polar drugs across the epithelial surface. The characteristics of chitosan allow blood to clot quickly and have recently been approved in the United States for use in bandages and other hemostatic agents.

  Chitosan is non-allergenic and has natural antibacterial properties, further supporting its use. As a micro-film forming biomaterial, chitosan helps reduce the width of the wound, controls oxygen permeability at the site, absorbs wound secretions, and is broken down by tissue enzymes, which are It is highly needed for faster healing. This also reduces pruritus by providing a sedative effect. This also acts as a humectant. It is also useful for the treatment of everyday small cuts and wounds, burns, keloids, diabetic ulcers and venous ulcers. The chitosan used in the present invention has various molecular weights ranging from 1 kdal to 5000 kdal.

  Chitosan is discussed at the USP Forum regarding its functional excipient classification. Since chitosan is basically a polymer, it is available in various grades depending on the molecular weight. Various grades of chitosan include chitosan long chain, chitosan medium chain and chitosan short chain. Long, medium and short chain grades correspond directly to the molecular weight of chitosan.

  In general, long chain grades have a molecular weight in the range of 500,000 to 5,000,000 Da, medium chain grades have a molecular weight in the range of 1,000,000 to 2,000,000 Da, and short chain grades have It has a molecular weight in the range of 50,000 to 1,000,000 Da.

  The molecular weight of chitosan plays an important role in the formulation. Higher molecular weight chitosan gives higher viscosity to the system, and lower molecular weight chitosan gives lower viscosity to the system. However, medium chain grade chitosan provided optimum levels of formulation viscosity. Since the dosage form is a cream, an appropriate level of viscosity is required to achieve good application on the skin.

  The inventors finally decided on a chitosan medium chain grade for the present invention because the necessary rheological properties were imparted to the cream without compromising the therapeutic activity of either the active substance or chitosan. Chitosan medium chain grade concentrations were carefully concluded based on several in-house trials and preclinical animal studies on efficacy.

Topical antibacterial agents:
Topical antibacterial agents are intended to target the skin for bacterial infections caused by Staphylococcus aureus, Staphylococcus epidermidis, methicillin-resistant Staphylococcus aureus (MRSA), and the like.

  Antibacterial agents act by combining with bacterial ribosomes and inhibiting cell wall synthesis by interfering with the combination of mRNA ribosomes.

  Another hypothesis is that antibacterial agents induce ribosomes to produce peptide chains with erroneous amino acids, which are ultimately thought to destroy bacterial cells.

  Topical antibacterial agents include, but are not limited to, sodium fusidate, calcium mupirocin, gentamicin, neomycin, silver sulfadiazine, ciprofloxacin, flamicetin sulfate, quinidochlor, povidone iodine, sisomycin, nitrofural, etc. It is.

Most topical products are formulated as either creams or ointments. A cream is a topical preparation used for application to the skin. A cream is a semi-solid emulsion that is a mixture of oil and water into which an API (API) is incorporated. These are of two types: oil-in-water (O / W) creams consisting of small droplets of oil dispersed in a continuous aqueous phase, and small droplets of water dispersed in a continuous oily phase Water-in-oil (W / O) cream consisting of Oil-in-water creams are cosmetically acceptable because they are easy to use and are therefore less greasy and easier to wash with water. An ointment is a viscous semi-solid preparation containing API and is used topically on various body surfaces. An ointment vehicle is known as an ointment base. The choice of base depends on the clinical indication of the ointment, and the various types of ointment bases commonly used are as follows:
Hydrocarbon bases such as solid paraffin and soft paraffin Absorbent bases such as wool fat and beeswax

  Both of the above bases are oily and greasy in nature, which results in undesirable effects such as difficulty in application and removal from the skin. In addition, this also leads to clothes stains. Most of the topical products are available as cream formulations because of their cosmetic appeal.

  The acidic scale of pH is 1-7 and the base scale of pH is 7-14. The pH value of human skin is around 4.5-6. The pH of the neonatal skin is close to neutral (pH 7) but quickly changes to acidic. Since acidity kills bacteria, perhaps nature designed it to protect the skin of young children. As a person grows older, the skin becomes increasingly neutral and does not kill more bacteria than before. This is why the skin becomes weak and problems begin to occur. When a person actually has a skin problem or skin disease, the pH value exceeds 6. This indicates that a topical agent with a pH value close to that of young adult skin needs to be selected.

  A slight shift towards alkaline pH provides a better environment for microorganisms to thrive. Most topical products are available as creams. While the active compounds in the cream formulation are available in an ionized state, in the case of an ointment, they are present in an unionized state. In general, cream formulations are cosmetically sophisticated, and because active compounds are available in an ionized state, cream formulations are the first choice for formulators in the design and development of topical dosage forms. Yes, the drug can penetrate the skin layer quickly, which makes the formulation completely user-friendly.

  The cream of the present invention containing functional biopolymers such as chitosan, steroids, antifungal agents, etc. has a pH of about 3-6. On the other hand, commercial ointments are greasy and not cosmetically refined. Furthermore, since the active compound in the ointment is in a non-ionized form, the skin penetration is slow.

  It is essential that the active drug penetrates the skin for optimal biodermatological effectiveness. Here, the particle size of the active drug plays an important role. In order for the product to be in a highly effective form, it is necessary that the active drug be available in a colloidal or molecular dispersion. This should also be achieved at a safe pH (4.0-6.0) compatible with the skin environment. In order to achieve all of these, it is essential to select an appropriate vehicle or co-solvent to dissolve or disperse the drug. The products of the present invention are highly effective due to the remarkable antibacterial and wound healing activity of the active ingredients, which are available in an ultra-fine sized colloidal form, which enhances skin penetration To do.

Rationale for the use of a combination of antibacterial and chitosan:
A number of topical treatments are currently used to treat bacterial infections. However, there is no effective single dose therapy to protect the skin and control surface bleeding, wounds and burns. A unique combination of chitosan, a biopolymer with skin rejuvenation properties, and an antibacterial agent to meet this need and provide an affordable and safe treatment for distributed population divisions across all countries / regions The treatment with is proposed as a new cream.

  Topical antibacterial agents have significant efficacy in primary and secondary bacterial skin infections of various etiologies due to their antibacterial properties. The disadvantage of monotherapy with any topical antibacterial agent was the relatively slow onset of effect.

  By using an antibacterial agent and chitosan in the formulation, the properties of both the antibacterial agent and chitosan are optimized. Since chitosan is a film-forming, biocompatible, non-allergenic substance, it helps protect the skin by acting as a barrier. In addition, it controls surface bleeding caused by scratches and also inhibits pathogen mobility due to its cationic charge.

  The characteristics of the anti-bacterial and chitosan skin regeneration aspects are fully exploited in the present invention to provide the patient with the greatest therapeutic benefit and thus assist in faster healing. This ensures that the patient will benefit from the treatment of skin wounds, burns with bacterial infections.

  Inclusion of chitosan in the formulation provides many properties that are considered very essential for the treatment of skin diseases. The combination of chitosan and antibacterial is unique and novel because it is not sold anywhere in the world.

  The concept of combination is proved by considering the physical, chemical and therapeutic properties of chitosan used in combination with antibacterial agents.

Invention aspect of the present invention:
Another inventive aspect of the present invention is that adding a functional excipient in a cream base is not a simple process of simply adding. The inventor has found that the compatibility of functional excipients such as chitosan with other drugs in the cream is of critical importance. This is because incompatibility impairs the stability of the final product. By way of example, the inventors have found that well-known excipients such as xanthan gum and carbopol, which are variously used as stabilizers, cannot be used in combination with functional biopolymers such as chitosan.

  Topical excipients include polymers, surfactants, waxes, emulsifiers and the like. The polymers are used as gelling agents, suspending agents, viscosity increasing agents, release modifiers, diluents and the like. Surfactants are used as wetting agents, emulsifiers, solubilizers, release enhancers and the like.

  In general, the polymer and surfactant may or may not possess an ionic charge. These can be anionic or cationic or nonionic properties. When anionic excipients are included in the formulation, they interact with the cationic formulation excipients to produce a non-homogeneous, aesthetically unattractive product, which is desirable due to incompatibility. By-products, sometimes allergens, impurities, toxic substances, etc.

  Since the medication is for treating patients with a pathological condition, these incompatibilities in the product are not tolerated and these add additional complications to the patient.

  We have carefully screened excipients including polymers and surfactants to develop formulations. A thorough study was conducted after screening a short list of excipients. Detailed experiments were conducted with a great focus on possible interactions between excipients.

  To name a few experiments on anion-cation interactions in cream dosage forms, we have xanthan gum and chitosan, acrylic acid polymers and chitosan, sodium lauryl sulfate and chitosan, doxate sodium and chitosan and Some formulations (see Tables 1-5) containing gum arabic and chitosan were made. The results clearly showed the occurrence of interaction, which was very clearly seen and seen as a lump throughout the system. Also, the final product was not aesthetically attractive and was not homogeneous. The attached FIG. 1 clearly illustrates the interaction between chitosan and inappropriate anionic excipients. Based on excipient observations and detailed knowledge, we have arrived at a robust formulation with no possible interactions.

Table 1: Formulation of antibacterial cream using chitosan and xanthan gum

Table 2: Formulation of antibacterial cream using chitosan and acrylic acid polymer

Table 3: Formulation of antibacterial cream using chitosan and sodium lauryl sulfate

Table 4: Formulation of antibacterial cream using chitosan and doxate sodium

Table 5: Antibacterial cream formulation using chitosan and gum arabic

  The above products (Tables 1-5) are examples of products that do not form a homogenous cream and yield a heterogeneous cream of the type illustrated in FIG. Nonetheless, the proportions described in these examples are some of what a person skilled in the art can use based on the knowledge currently available. Only after exhaustive and extensive trial and error will it be possible to reach the correct type and proportion of excipients.

  As we have previously described, in treatment, antibacterial agents provide relief against bacterial infections. However, aspects such as skin protection, site bleeding, and pathogen mobility from one site to another have not been addressed to date in single dose therapy.

  The present invention incorporates chitosan in its single-dose application to provide skin protection (due to film-forming properties), hemostasis (due to clotting properties) and immobilization of pathogenic microorganisms (due to its cationic electrostatic properties). Compensate for defects by leveraging the required benefits.

Addition of therapeutic value by incorporating functional excipients that are biopolymers in the cream matrix in the form of chitosan. Value addition is an integrated subset of the following functional attributes of a biopolymer:
-Formation of microfilm on skin surface-Accelerated clotting than cream without membrane-forming biopolymer-Electrostatic immobilization of surface microorganisms due to biopolymer cationic charge-Significant epithelialization or regeneration of skin Enhancement

Attempts of the present invention involved in the development of platform technology covered by incorporating functional biopolymers into prescription dermatological medicinal products include:
-Identification of complementary therapeutic value resulting from such uptake-Identification of problems associated with the physiochemical stability of the product resulting from biopolymer uptake-Single in case bacterial infections have been identified Provide a dosage form.

  The importance of single dose treatment, especially in developing countries, cannot be emphasized. In some areas of South Asia or Africa, single-dose formulations can regenerate the skin while eliminating the root cause of skin disorders when dermatologists are not available, not to mention dermatologists Sex is also dramatically increased.

  During dermatological conditions, currently available treatments do not address issues such as skin protection and bleeding control. The unique innovative formulation of the present invention solves skin conditions by controlling surface bleeding at the site and treating the skin condition. It is well understood that leaving the surface bleeding untreated results in a secondary microbial infection. The present invention advantageously provides a solution to this unmet need.

In addition, due to the ever-increasing pressure on medical support systems and the accompanying shortages / high prices,
・ Patients waiting too long for treatment ・ Staying unnecessarily when arriving at the hospital ・ Immediately tackling problems in cases such as having to come back more often than necessary There is a need. In most cases, reducing residence time is the main underlying problem to be addressed. The present invention significantly shortens the overall treatment time for severe skin disorders in its single dose therapy.

Preferred first embodiment:
A biopolymer provided in an antibacterial agent and a cream base, the cream base comprising preservatives, primary and secondary emulsifiers, waxy substances, cosolvents, acids, and water, preferably purified water, respectively A novel dermatological cream for topical treatment of bacterial skin infections and associated wound healing comprising at least one of the following.

First Embodiment For the novel skin disclosed in the preferred first embodiment, further comprising any of the group comprising buffers, antioxidants, chelating agents, wetting agents, or any combination thereof Medicinal cream.

Second Embodiment-The antibacterial agent is added in an amount of about 0.5% w / w to about 15% w / w, more preferably 0.5 to 5.0% w / w,
The biopolymer is in the form of chitosan and is about 0.01% to about 1% by weight, preferably about 0.01% w / w to about 0.5% w / w, most preferably about 0.25%; added in an amount of w / w, the chitosan follows the United States Pharmacopeia with respect to its functional excipient classification and is selected from any grade, such as long chain, medium chain and short chain, ranging from 50 kDa to 5000 kDa Having a molecular weight of
The primary and secondary emulsifiers are selected from the group comprising cetostearyl alcohol, cetomacrogol-1000, cetyl alcohol, stearyl alcohol, polysorbate-80, Span-80, etc., from about 1% (w / w) to 20 Added in an amount of% (w / w), wherein the waxy material is selected from the group comprising white soft paraffin, liquid paraffin, solid paraffin, etc., or any combination thereof, about 5% (w / w) ˜50% (w / w) and the co-solvent is selected from the group comprising propylene glycol, hexylene glycol, polyethylene glycol-400, etc., or any combination thereof, about 5% (w / w) It added in an amount of ~50% (w / w), the _{acid, HCl, H 2 SO 4,} HNO 3, lactate, etc., or any of those unions And is added in an amount of about 0.005% (w / w) to 0.5% (w / w), and the preservative comprises methylparaben, propylparaben, chlorocresol, potassium sorbate, Selected from the group comprising benzoic acid, 2phenoxyethanol, benzyl alcohol, etc., or any combination thereof, added in an amount of about 0.05% (w / w) to 2.5% (w / w), Water is 20% (w / w) to 75% (w / w), preferably 35% (w / w) to 50% (w / w), more preferably 40% (w / w) to 43% Added in an amount in the range of (w / w), preferably purified water,
A novel skin medicinal cream disclosed in the preferred first embodiment.

Third embodiment:
A group comprising disodium hydrogen orthophosphate, sodium hydrogen orthophosphate, calcium lactate, etc., or any combination thereof, added in an amount of about 0.05% (w / w) to 1.00% (w / w) The novel cream disclosed in preferred first and second embodiments, further comprising a buffer selected from:

  Fourth embodiment: from the group comprising butylated hydroxyanisole, butylated hydroxytoluene, etc., or any combination thereof, added in an amount of about 0.05% (w / w) to 5% (w / w) The novel cream disclosed in preferred first and second and third embodiments, further comprising a selected antioxidant.

  Fifth embodiment: a chelating agent selected from the group comprising disodium EDTA, etc., or any combination thereof, added in an amount of about 0.05% (w / w) to 1% (w / w) A novel cream disclosed in preferred first and second to fourth embodiments.

  Sixth embodiment: further comprising a wetting agent selected from the group comprising glycerin, sorbitol, etc., or any combination thereof, added in an amount of about 5% (w / w) to 50% (w / w) The novel cream disclosed in the preferred first embodiment and the second to fourth embodiments.

  Seventh Embodiment: Further comprising a stabilizer selected from the group comprising guar gum or the like, or any combination thereof, added in an amount of about 0.1% (w / w) to 5% (w / w) A novel cream disclosed in preferred first and second to fourth embodiments.

  Eighth embodiment: an antibacterial agent in a cream base comprising preservatives, primary and secondary emulsifiers, waxy substances, co-solvents, acids and at least one of each of water, preferably purified water And a biopolymer, and a method for making a cream comprising the steps of mixing all ingredients together to form a homogeneous cream.

  Ninth embodiment: disclosed in the seventh embodiment, wherein the ingredients further comprise any of the group comprising buffers, antioxidants, chelating agents, wetting agents, stabilizers or any combination thereof. Cream making method.

  Tenth Embodiment: A novel cream as disclosed in any of the previous embodiments, wherein the chitosan has a molecular weight range of 1 kdal to 5000 kdal.

  The invention will be further elucidated with reference to the accompanying examples containing composition and stability study data, which are not intended to limit the invention in any manner.

Example I: Table 6: Cream of sodium fusidate + chitosan

Example II: Table 7: Mupirocin calcium + chitosan cream

Example III: Table 8: Flamicetine sulfate + chitosan cream

Example IV: Table 9: Silver sulfadiazine + chitosan cream

  Comparison of Tables 6-9 with Tables 1-5 illustrates product differences based on conventional drug design and the innovative approach employed in the present invention.

  API stability experiments were performed with the products of the present invention (see Tables 10-21). Tests were performed to observe (or measure as needed) the physical appearance of the product, pH value and API assay over time.

  Each gram of the product of the present invention used in the test contained the appropriate amount of antibacterial agent.

  The product used for stability study testing contained approximately 10% excess API (excess). This was packed in an extruded tube made of aluminum. Detailed test results of four products were presented. The percentage of antibacterial agent used in all examples was measured in w / w for the final product.

Product: Sodium fusidate cream packaging: Aluminum extruded tube Composition: Each gram contains: Sodium fusidate, BP equivalent to 2.0% fusidic acid BP

Table 10: Explanatory test, batch number SCC-41
Measured parameter: Physical appearance Best value of measured parameter: homogeneous white to off-white viscous cream, measuring method: naked eye observation

Table 11: pH test, batch number SCC-41
Measured parameter: pH, limit of measured parameter: 3-6
Measuring method: Digital pH meter

Table 12: Assay (%) test, batch number SCC-41
Measured parameter: assay (%), limit of measured parameter: 90-110
Measuring method: HPLC method

Product: Cream cream of mupirocin calcium: Aluminum extruded tube Composition: Each gram contains: i) Mupirocin calcium, USP equivalent to mupirocin, USP 2.0% w / w

Table 13: Explanatory test, batch number MUC-16
Measured parameter: Physical appearance Best value of measured parameter: homogeneous white to off-white viscous cream, measuring method: naked eye observation

Table 14: pH test, batch number MUC-16
Measured parameter: pH
Measured parameter limits: 3-6
Measuring method: Digital pH meter

Table 15: Assay (%) test, batch number MUC-16
Measured parameters: Assay (%)
Measured parameter limit: 90-110
Measuring method: HPLC method

Product: Creamed Flamicetine Sulfate Packing: Aluminum Extruded Tube Composition: Each gram contains: i) Flamicetine sulfate IP, 1.0% w / w

Table 16: Explanatory test, batch number FSC-13
Measured parameter: Physical appearance Best value of measured parameter: homogeneous white to off-white viscous cream, measuring method: naked eye observation

Table 17: pH test, batch number FSC-13
Measured parameter: pH, limit of measured parameter: 3-6
Measuring method: Digital pH meter

Table 18: Assay (%) test, batch number FSC-13
Measured parameter: assay (%), limit of measured parameter: 90-110
Measuring method: HPLC method

Product: Cream packaging of sulfadiazine silver: Aluminum extruded tube Composition: Each gram contains: i) Sulfadiazine silver, USP 1.0% w / w

Table 19: Explanatory test, batch number SSC-10
Measured parameter: Physical appearance Best value of measured parameter: homogeneous white to off-white viscous cream, measuring method: naked eye observation

Table 20: pH test, batch number SSC-10
Measured parameter: pH, limit of measured parameter: 3-6
Measuring method: Digital pH meter

Table 21: Assay (%) test, batch number SSC-10
Measured parameter: assay (%), limit of measured parameter: 90-110
Measuring method: HPLC method

How to apply cream:
The cream is applied after the affected area has been thoroughly washed and dried. Sufficient cream should be applied to cover the affected skin and surrounding area. The cream should be applied 2-4 times a day depending on the skin condition throughout the treatment period, even if symptoms may have improved.

Experiment:
Experiments with cream were performed in the laboratory and with the appropriate animal model that provided the excised wound. Four aspects were examined: wound reduction, epithelialization, blood clotting time, and membrane formation. Together, these aspects suggest that microorganisms are immobilized and thus provide effective wound healing.

A. Wound reduction:
The healing activity of the excised wound of the cream of the present invention was determined by animal testing. An excision wound with a diameter of 2.5 cm was given by cutting out the entire layer of skin. The amount of wound shrinkage observed over a period of time has shown that the creams of the present invention provide significantly improved wound shrinkage over that achieved by conventional cream application.

B. Period of epithelialization:
Wound epithelialization occurred in fewer days using the cream of the present invention than the days it took to epithelize using conventional creams. Thus, one advantage of the cream of the present invention is that it promotes faster skin epithelialization than using conventional creams.

C. Clotting:
Blood clotting time was observed in both animal groups, an untreated control group and a test group of animals treated with the product of the invention. A statistically significant reduction in blood clotting time was observed in the treated animals compared to the control animals. Using the product of the present invention, an average percent reduction of 20-70% in blood clotting time was observed.

Film formation characteristics:
From FIG. 1 it is clear that chitosan does not lose its film-forming properties in the presence of excipients used in cream preparations in the present invention.

Results and Discussion:
It is clear that the properties of chitosan are not impaired in any manner when used in formulations containing excipients used in the present invention. This was achieved by careful selection of excipients. For example, our experiments show that widely used excipients such as xanthan gum or carbopol precipitate when combined with chitosan due to cationic and anionic interactions. .

  The following table shows the therapeutic effects observed from animal studies of adding chitosan to antibacterial agents by considering various aspects of therapeutic healing of susceptible skin conditions.

Table 18

  It is clear that the ability of the chitosan film incorporated into the cream to make the antibacterial agent more accessible to the infected area leads to better functioning of these APIs.

  The therapeutic efficacy of the topically applied creams of the present invention includes the remarkable antibacterial activity of the active substance against the organism causing the skin infection, the unique ability of the active substance to penetrate intact skin, and Due to the wound healing and sedative properties of chitosan.

From the foregoing description, it is apparent that the present invention provides the following advantages and unique aspects over currently available dermatological compositions for bacterial infections.
1. The cream of the present invention incorporates a skin-friendly biopolymer in the form of chitosan and provides enhanced therapeutic results. This is evident from shortened blood clotting times, increased epithelial effects, and faster relief from infection.
2. The cream of the present invention incorporates the biopolymer without compromising the stability of the cream matrix and without adversely affecting the function of the known drug substance. This was achieved by careful selection of functional excipients to avoid undesirable physiochemical compatibility / stability and biorelease aspects.
3. The cream of the present invention provides an integrated single dose or single dose therapy that was not previously available in prescription dermatological formulations.
4). The novel creams of the present invention are sufficiently stable / effective at ambient conditions and do not require special temperature control during transport / storage, and therefore play a major role in achieving these social goals.

  According to another embodiment of the present invention, there is also provided a method of treating bacterial skin infections and a method of wound healing comprising contacting human skin with the disclosed composition.

  While the above description contains a number of specificities, these are not limitations on the scope of the invention, but rather should be construed as examples of preferred embodiments thereof. It should be understood that modifications and variations can be made based on the above disclosure without departing from the spirit and scope of the invention. Accordingly, the scope of the invention should be determined not by the embodiments illustrated, but by the appended claims and their legal equivalents.

Claims (10)

  Novel skin medicated cream for topical treatment of bacterial skin infections and associated wound healing, said cream comprising an antibacterial agent and a biopolymer provided in a cream base, said cream base The agent comprises at least one of each of preservatives, primary and secondary emulsifiers, waxy materials, co-solvents, acids, and water, preferably purified water, and the biopolymer is preferably chitosan New skin medicinal cream.   The novel dermatological cream of claim 1, further comprising any of the group comprising a buffer, an antioxidant, a chelating agent, a wetting agent, a stabilizing agent, or any combination thereof. The novel skin medicated cream according to claim 1,
The antibacterial agent is added in an amount of about 0.5% w / w to about 15% w / w, more preferably 0.5 to 5.0% w / w;
The biopolymer is in the form of chitosan and is about 0.01% to about 1% by weight, preferably about 0.01% w / w to about 0.5% w / w, most preferably about 0. Added in an amount of 25% w / w,
The primary and secondary emulsifier is selected from the group comprising cetostearyl alcohol, cetomacrogol-1000, cetyl alcohol, stearyl alcohol, polysorbate-80, Span-80, etc. and about 1% (w / w) Added in an amount of ˜20% (w / w), wherein the waxy material is selected from the group comprising white soft paraffin, liquid paraffin, solid paraffin, etc., or any combination thereof, and about 5% Added in an amount of (w / w) to 50% (w / w), and the co-solvent is selected from the group comprising propylene glycol, hexylene glycol, polyethylene glycol-400, etc., or any combination thereof. and added in an amount of about 5% (w / w) ~50 % (w / w), the _{acid, HCl, H 2 SO 4,} HNO 3, lactate Or any combination thereof and is added in an amount of about 0.005% (w / w) to 0.5% (w / w), wherein the preservative is methylparaben , Propylparaben, chlorocresol, potassium sorbate, benzoic acid, 2phenoxyethanol, benzyl alcohol, etc., or any combination thereof, and from about 0.05% (w / w) to 2. Added in an amount of 5% (w / w) and the water is 20% (w / w) to 75% (w / w), preferably 35% (w / w) to 50% (w / w) More preferably added in an amount ranging from 40% (w / w) to 43% (w / w), and preferably purified water.
New medicinal cream for skin.   Selected from the group comprising disodium hydrogen orthophosphate, sodium hydrogen orthophosphate, calcium lactate, etc., or any combination thereof and from about 0.05% (w / w) to 1.00% (w / w The novel cream of claim 1 and 3 further comprising a buffer added in an amount of   Selected from the group comprising butylated hydroxyanisole, butylated hydroxytoluene, etc., or any combination thereof and added in an amount of about 0.05% (w / w) to 5% (w / w) The novel cream according to claim 1, 3 and 4, further comprising an antioxidant.   Further comprising a chelating agent selected from the group comprising EDTA disodium etc. or any combination thereof and added in an amount of about 0.05% (w / w) to 1% (w / w) The novel cream according to claims 1 and 3-5.   A humectant selected from the group comprising glycerin, sorbitol, etc., or any combination thereof, and further comprising a wetting agent added in an amount of about 5% (w / w) to 50% (w / w). Novel creams according to 1 and 3-6.   Further comprising a stabilizer selected from the group comprising guar gum or the like or any combination thereof and added in an amount of about 0.1% (w / w) to 5% (w / w). Item 8. A novel cream according to items 1 and 3-7. A method for making a cream, the method comprising:
Antibacterial agents and biopolymers in a cream base comprising preservatives, primary and secondary emulsifiers, waxy substances, co-solvents, acids, and at least one of each of water, preferably purified water. A method of making a cream comprising the steps of providing and mixing all ingredients together to form a homogeneous cream.   9. The method of making a cream of claim 8, wherein the ingredient further comprises any of the group comprising a buffer, an antioxidant, a chelating agent, a wetting agent, a stabilizing agent, or any combination thereof. .

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