Topical pharmaceutical compositions for treatment of pilonidal sinus wounds

Abstract

A topical composition comprising about 5 wt % to about 12.5 wt % of metronidazole or a pharmacologically acceptable salt thereof in a non-aqueous vehicle. The composition may be used in the treatment of skin damage due to inflammatory skin conditions; thermal, chemical or electrical burns; infections or radiation treatment. One advantage of the composition is that topical administration of metronidazole results in a primarily local effect, and thus, side effects observed from systemic administration are avoided.

Claims

1. A method of relieving pain and/or promoting wound healing in a patient due to a pilonidal sinus wound, hidradenitis or pressure sore wounds, the method comprising: applying to the damaged skin area a topical composition, wherein the topical composition consists essentially of (a) metronidazole in a therapeutically effective concentration of 10 wt % to treat the pilonidal sinus wound, hidradenitis or pressure sore wounds and (b) a pharmacologically acceptable non-aqueous vehicle.

2. The method of claim 1, wherein said vehicle is an organic vehicle.

3. The method of claim 1, wherein the vehicle comprises at least one hydrocarbon compound.

4. The method of claim 1, wherein the vehicle comprises a mixture of at least two semi-solid saturated hydrocarbon compounds.

5. The method of claim 1, wherein the vehicle comprises white petrolatum (USP).

6. The method of claim 1, wherein said topical composition is in the form of an ointment, lotion, gel, foam or cream.

7. The method of claim 1, wherein metronidazole is applied at a dosage for each application from about 125 mg to about 1250 mg.

8. The method of claim 7, wherein the dosage of metronidazole for each application is from about 125 mg to about 375 mg.

9. The method of claim 8, wherein the dosage of metronidazole for each application is about 250 mg.

10. The method of claim 1, wherein said topical composition is applied between from 2 to 4 times daily.

11. The method of claim 1, wherein said topical composition has a fluffy texture.

12. The method of claim 11, wherein said topical composition is obtained by passing metronidazole and white petrolatum through an ointment mill.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) Throughout the instant specification and claims, the following definitions and general statements are applicable.

(2) As used herein, whether in a transitional phrase or in the body of a claim, the terms comprise(s) and comprising are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases having at least or including at least. When used in the context of a process, the term comprising means that the process includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term comprising means that the composition includes at least the recited features or components, but may also include additional features or components.

(3) The terms consists essentially of or consisting essentially of have a partially closed meaning, that is, they do not permit inclusion of steps or features or components which would substantially change the essential characteristics of a process or composition; for example, steps or features or components which would significantly interfere with the desired properties of the compositions described herein, i.e., the process or composition is limited to the specified steps or materials and those which do not materially affect the basic and novel characteristics of the invention.

(4) The terms consists of and consists are closed terminology and allow only for the inclusion of the recited steps or features or components.

(5) As used herein, the singular forms a, an and the specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise.

(6) The term about is used herein to mean approximately, in the region of, roughly, or around. When the term about is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term about or approximately is used herein to modify a numerical value above and below the stated value by a variance of 10%.

(7) As used herein, treating means reducing, hindering or inhibiting the development of, controlling, alleviating and/or reversing the symptoms in the individual to which a combination or composition of the invention has been administered, as compared to the symptoms of an individual not being treated according to the invention. A practitioner will appreciate that the combinations, compositions, dosage forms and methods described herein are to be used in concomitance with continuous clinical evaluations by a skilled practitioner to determine subsequent therapy.

(8) Without wishing to be bound by any particular theory, it is believed that the use of metronidazole by direct application to the diseased or otherwise affected is primarily a local effect. Minimal systemic absorption is observed and therefore systemic side effects are effectively reduced or eliminated. As such, the dose of metronidazole can be altered for specific tissue and applied directly to the diseased or otherwise effected area thereby increasing the efficacy of the medication.

(9) The topical compositions of the present invention are generally cream or viscous suspensions having at least one active ingredient and at least one additional component including preservatives, chelating agents, surfactants, thickeners, thickeners-solubilizers, buffers, co-solvents, or lubricants.

(10) According to one embodiment of the present invention, the pharmaceutical composition takes the form of a cream, ointment or foam suspension that is applied topically to a damaged skin surface. The formulations comprise metronidazole dissolved or dispersed in a suitable flowable carrier vehicle. The formulation can be thickened with one or more thickeners, can contain a buffer, and can also comprise an effective amount of a lubricant such as a natural or synthetic fat or oil, e.g. a tris-fatty acid glycerate or lecithin. Non-toxic non-ionic surfactants can also be included as wetting agents and dispersants. Preferably, the composition does not include an alcohol because of the painful effect caused by alcohol on damaged skin. Further, the pH of the composition is preferably 5.5 to 8.5, and more preferably a pH of about 7.

(11) The composition according to the present invention may also comprise additional pharmaceutically acceptable compounds and/or compositions. It is thus to be understood that all the additional compounds and/or compositions mentioned below have to be physiologically acceptable.

(12) The composition according to the present invention may be topically applied as such within a suitable carrier, solvent, dissolvent, extract, solutions e.g. oily, suspension; microemulsion, vesicles, etc. Where employed, the carrier is inert in the sense of not bringing about a deactivation or oxidation of the metronidazole, and in the sense of not bringing about any adverse effect on the skin areas to which it is applied.

(13) In one aspect of the invention, the metronidazole is applied in admixture with a dermatologically acceptable carrier or vehicle (e.g., as a lotion, cream, ointment, soap or the like) so as to facilitate topical application and, in some cases, provide additional therapeutic effects as might be brought about, e.g., by moisturizing of the affected and/or damaged skin. The metronidazole carrier for dermatological compositions preferably comprises a carrier which will form a film or layer on the skin to which it is applied so as to localize the application and provide some resistance to washing off by immersion in water or by perspiration.

(14) Many preparations are known in the art, and include lotions containing oils and emollients such as hydrocarbon oils and waxes, silicone oils, vegetable, animal or marine fats or oils, glyceride derivatives, fatty acids or fatty acid esters, lanolin and derivatives, wax esters, sterols, phospholipids and the like, and generally also emulsifiers (nonionic, cationic or anionic), although some of the emollients inherently possess emulsifying properties. These same general ingredients can be formulated into a cream rather than a lotion, or into gels, by utilization of different proportions of the ingredients and/or by inclusion of thickening agents such as gums or other forms of hydrophilic colloids.

(15) Various types of other ingredients may be present in the metronidazole compositions of the present invention. For example, sunscreens may be included such as those materials commonly employed to block ultraviolet light. Illustrative compounds are the derivatives of PABA, cinnamate and salicylate. The exact amount of sunscreen employed in the compositions can vary depending upon the degree of protection desired from the sun's UV radiation.

(16) The compositions for use in the methods of the present invention may include components suitable as carriers, such as starches, emollients, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, surfactants including amphoteric, binders, disintegrating agents, and the like, with the topical preparations being preferred.

(17) Emollients are often incorporated into the therapeutic compositions of the present invention. Levels of such emollients may range from about 0.5% to about 60%, preferably between about 5% and 30% by weight of the total composition. Emollients may be classified under such general chemical categories as esters, fatty acids and hydrocarbons. Esters may be mono- or di-esters. Acceptable examples of fatty di-esters include dibutyl adipate, diethyl sebacate, diisopropyl dimerate, and dioctyl succinate. Acceptable branched chain fatty esters include 2-ethyl-hexyl myristate, isopropyl stearate and isostearyl palmitate. Acceptable tribasic acid esters include triisopropyl trilinoleate and trilauryl citrate. Acceptable straight chain fatty esters include lauryl palmitate, myristyl lactate, oleyl eurcate and stearyl oleate.

(18) Suitable fatty acids include those compounds having from 10 to 20 carbon atoms. Especially preferred are compounds such as cetyl, arachidyl, behenyl, cetearyl, myristyl, palmitic and stearyl acids.

(19) Exemplary hydrocarbons which may serve as emollients are those having hydrocarbon chains anywhere from 12 to 30 carbon atoms. Specific examples include mineral oil, petroleum jelly, paraffin oil, squalene and isoparaffins.

(20) Another category of functional ingredients within the therapeutic compositions of the present invention are thickeners. A thickener will usually be present in amounts anywhere from 0.1% to 20% by weight, preferably from about 0.5% to 10% by weight of the composition. Exemplary thickeners are cross-linked polyacrylate materials. Gums may be employed such as xanthan, carrageenan, gelatin, karaya, pectin and locust beans gum. Under certain circumstances the thickening function may be accomplished by a material also serving as a silicone or emollient. For instance, silicone gums having a viscosity in excess of 10 mPas and esters such as glycerol stearate have dual functionality.

(21) Still further, the therapeutic compositions of the present invention may include preservatives, moisturizers, surfactants, antimicrobials, etc. Preservatives may include tetrasodium ethylene-diamine tetraacetic acid (EDTA), methylparaben, benzophenone-4, methylchloroisothiazolinone, sodium benzoatemethylisothiazolinone, and the like, and mixtures thereof. Preservatives, when used, are typically present in an amount from about 0.01% to 10% weight, preferably about 0.05% to 4% weight, and more preferably, from about 0.1% to 2% weight.

(22) Preferred moisturizers may include wheat protein (e.g., laurdimonium hydroxypropyl hydrolyzed wheat protein), hair keratin amino acids, sodium peroxylinecarbolic acid, panthenol, tocopherol (Vitamin E), dimethicone, arachidylglucoside and the like, and mixtures thereof. Moisturizers, when used, are typically present in an amount from about 0.01% to 10% weight, preferably about 0.05% to 1.5% weight, more preferably, from about 0.1% to 1% weight of the composition.

(23) Preferred surfactants, including both the foaming and non-foaming type, include sodium laureth sulfate, sodium laureth-13 carboxylate, disodium laureth sulfosuccinate, disodium cocoamphodiacetate, glycol stearate, PEG-150 distearate and the like, and mixtures thereof. More preferably, at least one amphoteric surfactant is included in the composition, selected from the group consisting of lauroamphocarboxypropionate, lauroamphopropionate, lauroamphoglycinate, lauroamphocarboxyglycinate, lauroamphopropyl sulfonate, lauroamphocarboxypropionic acid, myristoamphocarboxy-propionate, myristoamphopropionate, myristoamphoglycinate, myristoamphocarboxyglycinate, myristoamphopropylsulfonate, myristoamphocarboxypropionic acid, cocoamphocarboxypropionate, cocoamphopropionate, cocoamphoglycinate, cocoamphocarboxyglycinate, cocoamphopropylsulfonate, cocoamphocarboxypropionic acid and mixtures thereof. The surfactant component may be present in an amount from about 0.1% to about 20% weight of the composition.

(24) The compounds of the present invention include pharmaceutically acceptable salts that can be prepared by those of skill in the art. As used herein, by pharmaceutically acceptable salt it is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art, such as hydrochloride, hydrobromide, mesylate, acetate, trifluoroacetate, propionate, fumarate, tartrate, citrate, phosphate, succinate, bisulfate, etc. For example, S. M Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.

(25) The topical skin treatment composition of the invention can be formulated as a lotion having a viscosity of from 4,000 to 10,000 mPas, a fluid cream having a viscosity of from 10,000 to 20,000 mPas or a cream or a gel having a viscosity of from 20,000 to 100,000 mPas or above.

(26) The metronidazole composition can be packaged in a suitable container to suit its viscosity and intended use by the consumer. For example, a lotion or fluid cream can be packaged in a bottle, a propellant-driven aerosol device or a container fitted with a pump suitable for finger operation. When the composition is a cream, it can simply be stored in a non-deformable bottle or squeeze container, such as a tube or a lidded jar.

(27) Generally, in the practice of methods of the invention, the composition is topically applied to the damaged skin area in a predetermined or as-needed regimen either at intervals by application of a lotion or the like, it generally being the case that gradual improvement is noted with each successive application.

(28) Because of its ease of administration, a cream, lotion, gel or ointment represents the most advantageous topical dosage unit form, and such forms may be prepared as rinse-off or leave-on products, as well as two stage treatment products for use with other skin cleansing or managing compositions. Each of these forms is well understood by those of ordinary skill in the art, such that dosages may be easily prepared to incorporate the pharmaceutical composition of the invention.

(29) In general, the compositions of the present invention are intended to be applied topically and directly to the burns or wound as described above. When the wound is deep, or the burn severe, it is preferred that the composition is in the form of an ointment, salve or cream which is spread directly onto the wound and then covered with a standard sterile dressing pad or other appropriate dressing material. Alternatively, the ointment, cream or salve of the present composition is applied directly onto the dressing pad or other appropriate dressing material. The pad or dressing material is then placed over the wound or burn with the medicine-side down. This latter approach works better when applying dressing to severe burns and shallow wounds.

(30) Thus, the pharmaceutical composition of the present invention is applied to a wound so as to cover the injured surface completely. Dressing-change schedules are of course dictated by the condition of the wound. Dressings are advantageously changed three to four times a day. Repeated daily dressing changes are continued until the wound or burn is healed. Healing time varies, depending upon the type and depth of the wound or the severity of the burn.

(31) The present pharmaceutical composition is effective in the treatment of a large variety of wounds and burns to a mammal, subject or patient in need thereof where bacterial and fungal contamination would ordinarily occur in the absence of treatment.

(32) The present medicinal composition can of course also be used to treat burns and wounds in other mammals, such as veterinary animals including, without limitation, dogs, cats, other household pets, horses, farm animals, and the like. The magnitude of a prophylactic or therapeutic dose of the pharmaceutical composition of the invention in the acute or chronic management of pathology and pain associated with above-mentioned indications will vary with the severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual.

(33) Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. It is within the skill of the art to start doses of the pharmaceutical compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

Example 1

(34) Method of Production of the Composition

(35) 100 g of metronidazole powder (USP) was mixed with 900 g of white petrolatum (USP) and the mixture passed through a mixer known as an ointment mill to produce a 10 wt % metronidazole composition having a fluffy texture.

Example 2

(36) Treatment for Radiation Damage

(37) Because of metronidazole's unique spectrum, it has additional anti-inflammatory properties, possibly as a result of free radical scavenging, and is effective in non infective inflammatory processes, such as thermal burns and radiation burns. Metronidazole is therefore effective in the treatment of radiation burns, radiation dermatitis or radiation ulcers.

(38) Topical 10% metronidazole is effective in treating radiation burns, radiation dermatitis or radiation ulcers after external beam radiation for cancer.

(39) A 54 year old male underwent neoadjuvant chemoradiation with flouro uracil and 4500 rads of external beam radiation for a T3 N1 adenocarcinoma of the rectum. The patient experienced severe perianal erythema, induration and pain due to the radiation. Topical 10% metronidazole was applied to the area, and after 72 hours he experienced significant pain relief and resolution of the erythema and induration.

(40) A 54 year old female received external beam radiation for a T3 N1 adenocarcinoma of the breast with axillary lymph node involvement. She experienced severe radiation dermatitis in the axillary and chest area. Topical 10% metronidazole was applied to the skin area exposed to the radiation and after 5 days she experienced significant resolution of the erythema and induration.

(41) Thermal or radiation burns from solar radiation (sunburn) and thermal burns (first, second, third, or fourth degree) may be treated with the metronidazole composition of the present invention.

(42) A 14 year old boy developed severe sunburn over his upper arms after spending a weekend swimming in a local lake without adequate sun block. Topical 10% metronidazole was applied to the sunburned area, and after 24 hours he experienced significant pain relief and resolution of the erythema.

Example 3

(43) Hidradenitis

(44) A 34 year old male presents with Hidradenitis in both groins. Topical 10% metronidazole was applied to the area of damage. After 4 weeks, the induration and discharge were decreased significantly.

(45) Fistula in Ano/Perianal Abscess

(46) A 24 year old female underwent incision and drainage of a perianal abscess. The abscess cavity is typically slow to heal. Topical 10% metronidazole was applied and after 2 weeks the cavity had closed and epithelialized.

(47) Thrombosed External Hemorrhoid

(48) A 34 year old presents with a thrombosed external hemorrhoid after planting trees in his yard. The thrombus measured 2 cm diameter, and the patient declined excision. Topical 10% metronidazole was applied to the area and after 1 week, the thrombus had almost entirely resolved.

(49) Pyoderma Gangenosum

(50) A 34 year old with Crohn's disease presents with Pyoderma gangenosum over the pretibial area. Topical 10% metronidazole was applied to the area and after 4 weeks, the ulcer had contracted to 50% of its original size.

(51) Perineal Sinus (Post-Proctectomy for Cancer or Crohn's Disease)

(52) A 54 year old presents with a perineal sinus after proctectomy for Crohn's proctitis. The patient experienced pain and discharge. Topical 10% metronidazole was applied to the area and after 4 weeks, the discharge had ceased and the sinus had closed.

Example 4

(53) Treatment after Post-Operative Anorectal Surgery

(54) Because of its gram-negative anaerobic spectrum, topical metronidazole is also ideal for applying to perianal incisions after surgery. Its effectiveness has been demonstrated after surgical hemorrhoidectomy, but it is also effective for any perianal/perineal operation, such as a fissurectomy/sphincterotomy.

(55) A 34 year old female experienced pain and bleeding from a fissure in ano. Fiber supplements failed to heal the fissure. Topical 10% metronidazole was applied to the area and after 3 weeks, the patient's pain had resolved and bleeding had ceased.

(56) Non Healing Surgical Incisions

(57) A 54 year old underwent a low anterior resection for a rectal cancer. The patient is obese and is a heavy smoker. He developed a chronic wound infection in his midline incision. The wound was debrided and topical 10% metronidazole was applied to the area and after 4 weeks, the wound had closed and epithelialized.

(58) Excision Pilonidal Sinus

(59) A 34 year old male had persistent pain and discharge after excision of a pilonidal sinus. A chronic ulcer remained. The wound was debrided and topical 10% metronidazole was applied to the area. After 4 weeks, the ulcer had closed and pain and discharge were resolved completely.

Example 5

(60) Effective Treatment of Skin Ulcers

(61) Gram-negative anaerobic bacteria are also the major pathogens in ischemic/decubitus (pressure sores) or diabetic skin ulcers.

(62) Decubitus Ulcers (Pressure Sores or Bed Sores)

(63) A 79 year old nursing home patient developed a decubitus ulcer in the pre-sacral area. The ulcer was surgically debrided and topical 10% metronidazole was applied to the area. After 4 weeks, the ulcer had contracted to 50% of its original size and eschar was significantly reduced.

(64) Varicose Ulcers (Due to Varicose Veins)

(65) A 60 year old female presents with chronic varicose ulcers over the medal malleolus. Compression therapy failed to heal the ulcers. Topical 10% metronidazole was applied to the area. After 6 weeks, the ulcer had contracted to 75% of its original size and induration was significantly reduced.

(66) Ischemic Ulcers (Peripheral Vascular Disease)

(67) A 58 year old male presents with chronic peripheral vascular disease and ischemic ulcers over the medial aspect of the hallux. The drug Trental failed to improve healing and he had already undergone emoral-tibial bypass. Topical 10% metronidazole was applied to the area. After 4 weeks, the ulcer had contracted to roughly 50% of its original size and necrotic tissue was significantly reduced.

(68) Diabetic Ulcers

(69) A 68 year old male presents with chronic type 2 diabetes and a non healing ulcer over the lateral aspect of the fore foot. Topical 10% metronidazole was applied to the area. After 6 weeks, the ulcer had contracted to roughly 50% of its original size and necrotic tissue was significantly decreased.