TOPICAL PHARMACEUTICAL COMPOSITION FOR TREATMENT OF ANAL FISSURES AND HEMORRHOIDS

Abstract

The present invention relates to a topical pharmaceutical composition to be used in the anal region for anal fissures and hemorrhoids, including the postoperative period of hemorrhoidectomy. The pharmaceutical composition comprises an anal dilator, a mucoadhesive polymer and a non-aqueous vehicle. Also described is a method of manufacturing the pharmaceutical composition.

Claims

1. A topical pharmaceutical composition, comprising: a mucoadhesive polymer, and an anal dilator, formulated in a non-aqueous vehicle.

2. The pharmaceutical composition according to claim 1, wherein the composition is a semi-solid formulation selected from an ointment, cream, gel, organogel, and colloid.

3. (canceled)

4. The pharmaceutical composition according to claim 1, further comprising a topical local anesthetic.

5. The pharmaceutical composition according to claim 4, wherein the topical local anesthetic is one or more of mepivacaine, etidocaine, lidocaine base, lidocaine hydrochloride, prilocaine, bupivacaine, procaine, chlorprocaine, ropivacaine, tetracaine, cocaine, amethocaine and cinchocaine.

6. The pharmaceutical composition according to claim 5, wherein the local anesthetic is an amide anesthetic.

7-8. (canceled)

9. The pharmaceutical composition according to claim 5, wherein the composition includes 0.5% to 5% w/w lidocaine hydrochloride.

10. The pharmaceutical composition according to claim 1, wherein the anal dilator is a calcium channel blocker.

11. The pharmaceutical composition according to claim 10, wherein the calcium channel blocker is one or more of diltiazem, nifedipine, felodipine, amlodipine, lacidipine, verapamil, indoramine and mebefradil.

12-13. (canceled)

14. The pharmaceutical composition according to claim 11, wherein the composition includes 0.1% to 10% w/w of diltiazem.

15. The pharmaceutical composition according to claim 5, wherein the topical local anesthetic and the anal dilator are solubilized in one or more organic solvents and the mucoadhesive polymer is dispersed in the one or more organic solvents.

16. The pharmaceutical composition according to claim 1, wherein the mucoadhesive polymer is derived from cellulose.

17. The pharmaceutical composition according to claim 16, wherein the mucoadhesive polymer comprises one or more of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, hydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, polysaccharides, acacia, agar, pectin, sodium and calcium alginate, xanthan gum, tragacanth, carrageenan, polypeptides, casein, gelatin, vinyls, polyvinyl alcohol, povidone, carbomers, polyethylene glycols, poloxamers, polyacrylic acid derivatives, sodium carboxymethylcellulose, polyacrylic acid derivatives, chitosan, hyaluronic acid, gellan gum, alginates, pectin, carrageenan, gelatin, acacia, gum tragacanth, xanthan gum, poloxamers, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, hydroxyethylcellulose, ethylcellulose, polyvinyl alcohol, pyroxylin, polyethylene oxide, and povidone.

18-19. (canceled)

20. The pharmaceutical composition according to claim 1, wherein the mucoadhesive polymer is one or more of sodium alginate, hydroxypropylmethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose.

21. The pharmaceutical composition according to claim 20, wherein the composition includes 0.5% to 10% w/w of mucoadhesive polymers selected from one or more of hydroxypropylmethylcellulose and hydroxyethylcellulose.

22. (canceled)

23. The pharmaceutical composition according to claim 1, further comprising one or more of a healing adjuvant and an antioxidant.

24. The pharmaceutical composition according to claim 23, wherein the healing adjuvant is one or more selected from papain, D-panthenol, propolis, sunflower oil, calcium alginate, hyaluronic acid, camomile, grape seed oil, and Calendula officinalis; and the antioxidant is one or more selected from tocopherol in the alpha, gamma and beta form; ascorbic acid; citric acid monohydrate; ascorbyl palmitate; butylated hydroxytoluene; butylated hydroxyanisole; erythorbic acid; fumaric acid; malic acid; methionine; monothioglycerol; metabisulfite and sodium bisulfate; propionic acid; propylgalate; sodium ascorbate; sodium formaldehyde sulfoxylate; sodium sulfite; sodium thiosulphate; sulfur dioxide; thymol; and polyethylene glycol succinate of vitamin E.

25. (canceled)

26. The pharmaceutical composition according to claim 23, wherein the composition includes one or more of 0.5% to 7% of the healing adjuvant and 0.01 to 1.0% w/w of the antioxidant.

27. The pharmaceutical composition according to claim 1, wherein the non-aqueous vehicle is one or more selected from capryric capric acid triglyceride oil, diethyleneglycol monoethyl ether, medium chain mono- and di-diglycerides, castor oil, mineral oil, coconut oil, oleic acid, medium chain triglycerides, caprylocaproyl macrogol-8 glyceride, propylene glycol, glycerin and polyethylene glycol derivatives, diethyleneglycol monoethyl ether, and polyethylene glycol.

28-31. (canceled)

32. The pharmaceutical composition according to claim 27, wherein the composition includes 0.5% to 50% w/w of the non-aqueous vehicle.

33-34. (canceled)

35. The pharmaceutical composition according to claim 4, wherein the topical local anesthetic is lidocaine hydrochloride; the anal dilator is diltiazem hydrochloride; the non-aqueous vehicle comprises one or more of propylene glycol, coconut oil, oleic acid, polyethylene glycol, diethyleneglycol monoethyl ether, glycerin, medium chain triglycerides, and caprylocaproyl macrogol-8 glyceride; and the mucoadhesive polymer comprises one or more of sodium alginate, hydroxypropylmethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention includes a topical pharmaceutical composition suitable for application to the anal region, said pharmaceutical composition comprising the following elements: a mucoadhesive polymer, optionally a local anesthetic (e.g., for topical use), an anal dilator, and a vehicle. Typically, the vehicle is non-aqueous. By “anal dilator” is meant any vasodilator such as “nitrates and nitrites” (e.g., nitroglycerin/glyceryl trinitrate (GTN), isosorbide dinitrate, isosorbide mononitrate, butyl nitrite, amyl nitrite) and “calcium channel blockers” (e.g., amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil) capable of being applied via topical use, having a local effect on the anal sphincter.

[0027] A “non-aqueous vehicle” refers to a component of the formulation which serves to form, dissolve, suspend or mix homogeneously with other ingredients to facilitate its administration or makes it possible to prepare the pharmaceutical form; said component being substantially free of water (e.g., less than 1% v/v, less than 0.5% v/v or even less than 0.1% water). Exemplary compounds for the non-aqueous vehicle include, alone or in combinations: caprylic capric acid triglyceride oil, diethyleneglycol monoethyl ether, medium chain mono-diglyceride, castor oil, polyethylene glycol (PEG, e.g., PEG 400), mineral oil, coconut oil, oleic acid, medium chain triglycerides, caprylocaproyl macrogol-8 glyceride, propylene glycol, glycerin and polyethylene glycol derivatives. A preferred combination of compounds for the vehicle comprises propylene glycol, polyethylene glycol 400, diethylene glycol monoethyl ether and caprylocaproyl macrogol-8 glycerides.

[0028] Typically, non-aqueous vehicles used in the formulation of the invention are: Propylene glycol and/or Polyethylene glycol and/or diethyleneglycol monoethyl ether and/or Caprylo-caproyl macrogol-8 glyceride, which are often in the proportion of 5.0 to 90.0% w/w, such as 70% to 90% w/w or 80% to 90% w/w. In certain embodiments, the non-aqueous vehicle constitutes 70% to 90% w/w of the total composition, with 10% to 20% w/w (14% to 18% w/w) PEG 400, 25% to 35% w/w (30% to 35% w/w) propylene glycol, 20% to 30% w/w (20% to 25% w/w) diethylene glycol monoethyl ether and 10% to 20% w/w (14% to 18% w/w) caprylocaproyl macrogol-8 glycerides.

[0029] More preferably, the present invention consists of an organogel for the treatment of anal fissures and/or hemorrhoids in the anal canal, with a formulation consisting of a mucoadhesive platform, a non-aqueous vehicle, diltiazem hydrochloride as an anal dilator, and lidocaine (e.g., the hydrochloride salt) as a local anesthetic.

[0030] An “organogel” is a type of gel composed of a gelling agent dispersed in an organic solvent (e.g., a non-aqueous vehicle).

[0031] In one embodiment, diltiazem hydrochloride is the anal dilator, as this calcium channel blocker has proven effective in reducing the resting pressure of the anal sphincter. It has already shown good results in the treatment of chronic anal fissure and in the treatment of hemorrhoids, including in the postoperative period following a hemorrhoidectomy. Studies comparing the use of oral and topical diltiazem on decreasing the maximum anal pressure found that topical was more effective, with fewer side effects and cure rates similar to those found with topical nitroglycerin.

[0032] In certain embodiments, diltiazem is present at concentrations of 0.1 to 10%, such as 0.5 to 5%, particularly 1% to 3%, more particularly 1% to 2% (e.g., 1%, 2%).

[0033] In certain embodiments, lidocaine Hydrochloride or lidocaine base is the anesthetic.

[0034] Typically, the concentrations of the two active agents in the formulation of the invention are: lidocaine hydrochloride or lidocaine base, in the proportion of 0.5% to 5% w/w; and diltiazem hydrochloride in the proportion of 0.1% to 10% w/w. Formulations may also include mucoadhesive polymers: hydroxypropylmethylcellulose and/or sodium alginate and/or hydroxyethylcellulose, and/or hydroxypropylcellulose in the proportion of 0.1% to 10% w/w.

[0035] In addition to the combination of the two aforementioned active agents in a single pharmaceutical composition, the invention also provides for the placement of such active agents in the form of a gel having suitable viscosity, spreadability and adhesion, which solves problems encountered in the use of petroleum jelly.

[0036] Bioadhesion is an interfacial phenomenon in which two materials, at least one of which is of biological origin, are held together for an extended period of time by interfacial forces. The bond may be between an artificial material and a biological substrate, such as adhesion between a polymer and a biological membrane. Adhesion may be defined as a bond produced by the contact between a pressure sensitive adhesive and a surface.

[0037] Mucoadhesion is a property arising from the use of bioadhesive polymers with the ability to bind to biological substrates by binding to the mucosal layer or to the cell membrane. This feature allows the residence time of the preparation at the site of action or absorption to be prolonged, enhancing drug contact with the skin and/or mucosal epithelial barrier. Preferably, mucoadhesive polymers used in the present invention have the ability to increase residence time with both the skin and anal mucosa.

[0038] Some examples of mucoadhesive polymers are derivatives of cellulose (e.g., methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium), carbomers, polyethylene glycols, polycarbophil, polyhydroxyethylmethacrylate, poloxamers, ethylene polyoxides, polyvinylpyrrolidone (povidone), vinyls, polyvinyl alcohol, polyacrylic acid derivatives, pyroxylin, hyaluronic acid, sodium and/or calcium alginate, polysaccharides, acacia, agar, pectin, tragacanth, carrageenan, polypeptides, casein, gelatin, karaya gum, guar gum, xanthan gum, pectin and chitosan. Particularly suitable mucoadhesive polymers include hydroxyethylcellulose, hydroxypropylcellulose, sodium alginate and/or hydroxypropylmethylcellulose.

[0039] Hydroxypropylmethylcellulose (HPMC) is a nonionic, cold water soluble, hydrophilic polymer that forms a viscous colloidal solution, practically insoluble in hot water, in chloroform, ethanol (95%) and ether, but soluble in mixtures of ethanol and dichloromethane, mixtures of methanol and dichloromethane and mixtures of water and alcohol. Certain degrees of hydroxypropylmethylcellulose are soluble in aqueous solutions of acetone, mixtures of dichloromethane and propane-2-ol and other organic solvents. HPMC exerts some buffering power and can make systems independent of pH. Of the various types of HPMC, the most widely used to prepare swelling matrix systems are those having a high viscosity grade—HPMC 2208, HPMC 2906 and HPMC 2910, according to the specifications of USP XXV/NF XX.

[0040] Hydroxyethylcellulose (HEC) is a nonionic ether obtained from the processing of cellulose pulp or cellulose pulp, soluble in water at room temperature, used as a general purpose thickener. It is biodegradable, physiologically inert and forms a hydrocolloid with various applications in the industry. It is soluble in both hot and cold water, forming clear and uniform solutions. It is practically insoluble in acetone, ethanol (95%), ether, toluene and most other organic solvents. In some polar solvents, such as glycols, hydroxyethylcellulose also dissolves or is partially soluble. Aqueous solutions of HEC are relatively stable at pH 2 to 12, without effectively changing the viscosity. Hydroxyethylcellulose solutions are less stable at pH below 5.0, with hydrolysis occurring. At high pHs, oxidation may occur. Hydroxyethylcellulose is subject to enzymatic degradation, with consequent loss of the viscosity of the solution. Enzymes that catalyze this degradation are produced by many bacteria and fungi present in the environment. Therefore, for prolonged storage of such excipient, an antimicrobial preservative should be added in aqueous solutions. Such a polymer may be used with a wide variety of water-soluble antimicrobial preservatives. However, sodium pentachlorophenate produces an immediate decrease in viscosity when added to HEC solutions.

[0041] Hydroxypropylcellulose (HPC) is a non-ionic, partially substituted poly (hydroxypropyl) cellulose ether compatible with cationic surfactants. HPC is very soluble in water below 38° C., forming a clear colloidal solution. In hot water, it is insoluble and precipitates as swollen flakes at a temperature between 40 and 45° C. It is soluble in several polar solvents such as short chain alcohols (ethanol, isopropyl alcohol, etc.) and glycols, such as propylene glycol, but insoluble in glycerol. It is also insoluble in aliphatic hydrocarbons such as oils and aromatic hydrocarbons. It is incompatible with methylparaben and propylparaben.

[0042] Typically, hydroxypropylmethylcellulose and/or hydroxyethylcellulose and/or hydroxypropylcellulose are combined in proportions of 0.1 to 10% w/w to provide organogel performance.

[0043] Sodium alginate is a further suitable mucoadhesive polymer. Alginate is a linear copolymer composed of α-L-guluronic and β-D-manuronic acids with 1-4 linkages. The material varies widely in terms of its ratio between the manuronic (M) and guluronic (G) residues, as well as its sequence structure and degree of polymerization. In this way, the material can present alternating sequences of MG residues and blocks consisting of two or more residues M or G. Sodium alginate is slightly soluble in water, forming a viscous colloidal solution. It is practically insoluble in alcohol (95%), ether, chloroform, and alcohol/water mixtures in which the ethanol content is greater than 30% by weight. Also, it is practically insoluble in other organic solvents and acidified aqueous solutions in which the pH is less than 3. The characteristics of the gels depend on the ratio M/G and the number of cross-links between the polymer chains. Gels are formed in the presence of divalent cations such as Ca.sup.2+ or Mg.sup.2+ and the presence of guluronic residue sequences.

[0044] In one example, a formulation of the invention includes 0.5 to 10% w/w of hydroxypropylcellulose (HPC). In another example, sodium alginate and/or hydroxyethylcellulose is present at 0.5 to 10% w/w.

[0045] In another embodiment of the invention, a skin healing adjuvant is used in the manufacture of the pharmaceutical composition. Although this element is not essential for the healing of wounds, its use can aid in tissue repair, promoting faster healing with better results. Some examples of skin healing adjuvants are: papain, D-panthenol, propolis, sunflower oil, calcium alginate, grape seed oil, hyaluronic acid, chamomile or calendula officinalis. In a particular embodiment, the skin healing adjuvant is D-panthenol, for example used in the proportion of 0.5 to 5% w/w.

[0046] Formulations of the invention may also include one or more antioxidants. Antioxidants that can be used include: tocopherol in alpha form (0.01 to 1.0% w/w), gamma and beta form (0.01 to 1.0% w/w); ascorbic acid (0.01 to 1.0% w/w); citric acid monohydrate (0.01 to 1.0% w/w), ascorbyl palmitate (0.01 to 1.0% w/w); butylated hydroxytoluene (0.01 to 1.0% w/w); butylated hydroxyanisole (0.01 to 1.0% w/w); erythorbic acid (0.01 to 1.0% w/w); fumaric acid (0.01 to 1.0% w/w); malic acid (0.01 to1.0% w/w); methionine (0.01 to 1.0% w/w), monothioglycerol (0.01 to 1.0% w/w); metabisulfite and sodium bisulfite (0.01 to 1.0% w/w); propionic acid propylgalate (0.01 to 1.0% w/w); sodium ascorbate (0.01 to 1.0% w/w); sodium formaldehyde sulfoxylate (0.01 to1.0% w/w); sodium sulfite (0.01 to 1.0% w/w); sodium thiosulfate (0.01 to 1.0% w/w); dioxide sulfur (0.01 to 1.0% w/w); thymol and polyethyleneglycol succinate of vitamin E (0.01 to1.0% w/w).

[0047] The non-aqueous vehicle aims to promote the dissolution and increase of the solubility of a given active and, in certain embodiments, to improve the cutaneous and percutaneous administration of drugs. A mucoadhesive polymer, dispersed in the vehicle in question forms an organogel. An organogel is a specific type of gel in which the polymer swells and retains the organic solvent in a three-dimensional network. In view of this, some of the advantages of using a medicament given in the form of an organogel may be: delivery of the drug in a way directed to the place of action, longer period of action, improvement in cutaneous and percutaneous administration, ease of administration and non-invasive. Another advantage of organogels is that because of the adhesive power of the pharmaceutical form to the skin, it remains for relatively long periods before washing away and the contact typically occurs in a non-irritating way.

[0048] Although the active agents of lidocaine hydrochloride (as an anesthetic) and diltiazem (as an anal dilator) are the preferred active agents used by the present invention, other anesthetics and dilators may be used in place of these drugs.

[0049] Alternatives for lidocaine include mepivacaine, etidocaine, lidocaine base, prilocaine, bupivacaine, procaine, chlorprocaine, ropivacaine, tetracaine, cocaine, ametocaine and cinchocaine. It is preferable to use the anesthetics of the amide group to anesthetics of the ester group, since the latter are metabolized into methylparabenzoic acid, which may cause a higher incidence of irritation and allergic reactions.

[0050] The anal dilator, in place of diltiazem, may be a drug belonging to the families: dihydropyridine (e.g., nifedipine, felodipine, amlodipine, lacidipine), phenylalkylamines (verapamil), benzodiazepines, and tetralol (mebefradil). Some examples of dilators not belonging to the class of calcium channel blockers that could be applied to the present invention are: topical nitrates, muscarinic agonists, agonists and adrenergic antagonists (indoramine).

[0051] Further, it is possible to include Aloe vera in the formulation of the invention. This component acts simultaneously as a moisturizer, astringent, emollient, anti-inflammatory agent, analgesic and skin protector against the UV rays, and immunostimulant.

[0052] Manufacturing process:

[0053] The manufacturing process of the pharmaceutical composition of the present invention preferably comprises the following sequential steps:

[0054] Step 1: In a suitable vessel add the non-aqueous vehicle, heat to 20° C. to 50° C.;

[0055] Step 2: Add the active ingredients (e.g., diltiazem and lidocaine hydrochloride) and shake;

[0056] Step 3: Cool the solution to between 20° C. and 40° C., if required, and set aside;

[0057] Step 4: In another vessel, add the polymer, such as a mucoadhesive polymer, to the non-aqueous vehicle and stir until complete dispersion;

[0058] Step 5: Optionally add a healing adjuvant together with the product of step 4;

[0059] Step 6: Optionally add an antioxidant to the product of step 5, shake until complete homogenization.

[0060] Step 7: Pour the product of step 3 into the product of step 6 and stir until complete homogenization.

[0061] A particular composition includes the following components:

TABLE-US-00001 Agents Amount for 1 gram (g) % Lidocaine hydrochloride 0.02 2.0 Diltiazem hydrochloride 0.02 2.0 Hydroxypropylcellulose 0.04 4.0 Polyethylene glycol 400 0.16 16.0 Propylene glycol 0.32 32.0 D-panthenol 0.05 5.0 Diethylene glycol monoethyl ether 0.2296 22.96 (Transcutol P) Alpha-tocopherol 0.0005 0.05 Caprylocaproyl macrogol-8 0.16 16.0 glycerides (Labrasol)