Patent ID: 12201600

DETAILED DESCRIPTION OF THE INVENTION

Tetracaine is a white, or light yellow, waxy solid melting in the range of 41° C. to 46° C. It is very slightly soluble in water, and soluble in alcohol, ether, benzene and chloroform.

In certain embodiments of any of the methods descried herein, the tetracaine is provided in base form, i.e., not as a pharmaceutically acceptable salt, such as the hydrochloride salt.

In certain embodiments of any of the methods descried herein, the concentration of the tetracaine is from about 2 or 3 wt. % to about 10 wt. % of the total composition, such as from about 2 wt. % to about 6 wt. % of the total composition, e.g., to deliver an effective dosage. In another embodiment of any of the methods descried herein, the concentration of the tetracaine is about 2 wt. % of the total composition. In yet another other embodiment of any of the methods descried herein, the concentration of the tetracaine is about 6 wt. %.

In certain embodiments of any of the methods descried herein, one or more mucoadhesives is included in the composition. As used herein the term mucoadhesive means a natural or synthetic substance, e.g., gels, pastes, macromolecules, polymers, and oligomers, or mixtures thereof, that can adhere to a subject's mucous membrane for a period of time sufficient to locally deliver a therapeutically effective amount of tetracaine. The composition itself need not be mucoadhesive, as long as it can form a mucoadhesive upon on the contact with the mucosa.

Examples of mucoadhesives for use in any of the compositions described herein include, but are not limited to, pectin, alginic acid, chitosan, hyaluronic acid, polysorbates, such as polysorbate-20, -21, -40, -60, -61, -65, -80, -81, -85; polyethylene glycol, such as PEG-7, -14, -16, -18, -55, -90, -100, -135, -180, -4, -240, -6, -8, -9, -10, -12, -20, or -32; oligosaccharides and polysaccharides, such as gellan, carrageenan, xanthan gum, gum arabic, and dextran; cellulose esters and cellulose ethers; modified cellulose polymers, such as carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl ethylcellulose; polyether polymers and oligomers, such as polyoxyethylene; condensation products of polyethylene oxide with various reactive hydrogen containing compounds having long hydrophobic chains, such as condensation products of poly(ethylene oxide) with fatty acids, fatty alcohols, fatty amides, or polyhydric alcohols; polyether compounds, such as poly(methyl vinyl ether), or polyoxypropylene of less than 10 repeating units; polyether compounds, such as block copolymers of ethylene oxide and propylene oxide; ORABASE7 (a mixture of gelatine, pectin and sodium carboxymethyl cellulose in a plasticized hydrocarbon gel, commercially available from Hoyt laboratories, Needham, Mass.), or any combination of any of the foregoing.

In certain embodiments of any of the compositions described herein, the mucoadhesive is water soluble and a combination of mucoadhesives is used. For example, homopolymers of ethylene oxide in combination with a second mucoadhesive such as sodium carboxymethylcellulose. Commercially available homopolymers of ethylene oxide are sold under the trademark POLYOX by Dow Chemical Company, Midland, Mich. POLYOX poly(ethylene oxide) polymers have a number of properties for mucoadhesion—namely, water solubility, hydrophilicity, high molecular weight, hydrogen bonding functionality, and good biocompatibility. The polymers have a long linear chain structure which allows them to form a strong interpenetrating network with mucus. In one preferred embodiment, the mucoadhesive includes poly(ethylene oxide) polymers with a molecular weight of 4,000,000 Daltons and higher. The amount of mucoadhesive in the formulation depends upon the mucoadhesives selected and the consistency desired in the composition.

In one embodiment of any of the compositions described herein, the composition comprises sodium carboxymethyl cellulose. In certain embodiments of any of the compositions described herein, the composition comprises between about 1 wt. % and about 10 wt. % sodium carboxymethyl cellulose or between about 3 wt. % and about 5 wt. % sodium carboxymethyl cellulose. In certain embodiments of any of the compositions described herein, the composition comprises between about 4 wt. % sodium carboxymethyl cellulose.

In one embodiment of any of the compositions described herein, the composition comprises POLYOX WSR 301 (a water-soluble, nonionic poly(ethylene oxide) polymer with a molecular weight of 4,000,000 Daltons (g/mol) (available from DuPont) in combination with sodium carboxymethylcellulose (medium viscosity). In one embodiment, the sodium carboxymethylcellulose having medium viscosity has a viscosity in a 2% solution in water at 25° C. of 400-800 cps. In this embodiment, the combined mucoadhesive comprises up to about 10 wt. %, such as about 9 wt. %, of the composition, with POLYOX WSR 301 comprising about 3 wt. % to about 8 wt. %, such as about 5 wt. % of the composition and sodium carboxymethylcellulose comprising about 2 wt. % to about 5 wt. %, such as about 4 wt. % of the composition. In the absence of a mucoadhesive like POLYOX WSR 301, the topical adhesive tends to migrate from the site of application, spreading the therapeutic action of the tetracaine to unintended areas.

In one embodiment of any of the compositions described herein, the composition comprises propylene glycol, for example, as a penetration enhancer to increase the absorption of the tetracaine into the mucosa. Other suitable penetration enhancers may be included. The penetration enhancers should be physicochemically stable and not have pharmacologic effects and preferably should not have disagreeable smell, color or taste. Without limitation, in addition to propylene glycol, other glycols, monohydric alcohols, and fatty acid glycerides may also serve as penetration enhancers. In one embodiment, any of the compositions described herein does not include glycerin.

In one embodiment of any of the compositions described herein, the propylene glycol is present in an amount from about 5 wt. % to 15 wt. %.

In one embodiment of any of the compositions described herein, when the poly (ethylene oxide) homopolymer (such as POLYOX WSR 301) is present in an amount of about 5 wt. % and the sodium carboxymethylcellulose is present in an amount of about 4 wt. %, the propylene glycol may be present in an amount of about 10 wt. % as larger amounts of propylene glycol may render the paste too fluid to stay in place at the site of application.

In one embodiment, a plasticized hydrocarbon gel completes the carrier vehicle for tetracaine in any of the compositions described herein. The plasticized hydrocarbon gel may be mixture of polyethylene in mineral oil, such as light mineral oil (e.g., Jelene, available from Fagron, Inc.). The plasticized hydrocarbon gel keeps the paste from dissolving away quickly, giving tetracaine time to penetrate. In one embodiment of any of the compositions described herein, the plasticized hydrocarbon gel makes up about 70 wt. % to about 80 wt. %, such as about 75 wt. % or about 79 wt. %, of the composition.

In one embodiment, any of the compositions described herein may include one or preservatives. Preferably, if present, the preservative comprises no more than about 1 wt. % but may vary depending on the other components.

In one embodiment, any of the compositions described herein may include one or more odor masking agents. Suitable odor masking agents include, but are not limited to, peppermint oil,

In one embodiment of any of the compositions described herein, the odor masking agent (such as peppermint oil) makes up about 0.1 wt. % to about 1 wt. %, such as about 0.6 wt. % to about 0.7 wt. %, of the composition.

In one embodiment, any of the compositions described herein has a pH of between about 8 and about 10, such as between 8.5 and about 9.5, such as about 9.

In one embodiment, the composition contains (a) from about 2 wt % to about 10 wt % of tetracaine base, (b) from about 2 to about 8 wt % sodium carboxymethyl cellulose, (c) from about 2 to about 10 wt % of polyethylene oxide (preferably having a molecular weight ranging from about 2,000,000 to about 6,000,000 Daltons), (d) from about 5 to about 15 wt % propylene glycol, (e) from about 65 to about 85 wt % plasticized base (such as a base comprising from about 92 to about 98 wt % mineral oil and about 2 to about 8 wt % polyethylene), and optionally (f) about 0.4 to about 1.0 wt % peppermint oil. Preferably, the sodium carboxymethyl cellulose has a viscosity in a 2% solution in water at 25° C. of 400-800 cps. In one preferred embodiment, the composition contains (a) from about 6 wt % of tetracaine base, (b) about 4 wt % sodium carboxymethyl cellulose, (c) about 5 wt % of polyethylene oxide (preferably having a molecular weight ranging from about 2,000,000 to about 6,000,000 Daltons), (d) about 10 wt % propylene glycol, (e) about 74 wt % plasticized base (such as a base comprising about 95 wt % mineral oil and about 5 wt % low molecular weight polyethylene), and optionally (f) about 0.7 wt % peppermint oil.

The topical anesthetic compositions of the present invention may be prepared using ordinary production methods. In one embodiment, the composition is prepared as described in Example 1.

The compositions may include the excipients and be prepared by the methods described in U.S. Pat. Nos. 8,263,047, 8,623,334, and 8,968,710, which are hereby incorporated by reference.

EXAMPLES

Example 1

A topical composition containing 6 wt. % tetracaine base having the formulation shown in the table below was prepared by mixing the appropriate components in the specified amounts.

INGREDIENTWEIGHT (% w/w)Tetracaine USP Base6.0Sodium Carboxymethylcellulose USP,4.0medium viscosityPolyOx WSR 3015.0Propylene Glycol USP10.0Plasticized Base (Jelene)74.33(95% mineral oil and 5% low molecularweight polyethylene)Peppermint Oil, NF0.67%

The topical composition can be prepared as follows. Sodium carboxymethyl cellulose, PolyOx WSR 301, and tetracaine are ground in separate glass mortars to a fine powder and set aside. Ten percent extra tetracaine is weighed out because some of the tetracaine may adhere to the mortar. By starting with 10% extra, the ground tetracaine available for transfer results in a 6 wt. % composition.

Plasticized base (Jelene) is placed in a 200 ml beaker and the beaker placed directly onto a hotplate. The temperature of the hot plate is set on its lowest position. The plasticized base is gently heated until it became soft and semi-fluid. At which point, the plasticized base is workable for compounding purposes. plasticized base melts at about 82° F. Heating is stopped before the plasticized base totally melts as separation may occur and plasticized base may not resume its original consistency when cooled.

The ground sodium carboxymethylcellulose is added in small portions to the heated plasticized base with stirring after each addition to ensure a uniform mix. The beaker is removed from the heat and the mixture allowed to cool.

On an ointment slab, a portion of the finely ground tetracaine is worked with propylene glycol (25% of the total propylene glycol). The tetracaine and propylene glycol mixture is combined with a portion of plasticized base via geometric dilution. The cooled plasticized base and sodium carboxymethylcellulose mixture is then worked into the tetracaine, propylene glycol (25% of the total propylene glycol) and plasticized base mixture via geometric dilution.

In a glass mortar, the ground PolyOx WSR 301 is wetted with propylene glycol (75% of the total propylene glycol).

The Polyox WSR 301 and propylene glycol mixture is then incorporated via geometric dilution with the other ingredients previously mixed together on the ointment slab to form the topical paste.

Example 2

A topical composition containing 2 wt. % tetracaine base having the formulation shown in the table below was prepared by mixing the appropriate components in the specified amounts. This composition can be prepared as described in Example 1.

INGREDIENTWEIGHT (% w/w)Tetracaine USP Base2.0Sodium Carboxymethylcellulose USP,4.0medium viscosityPolyOx WSR 3015.0Propylene Glycol USP10.0Plasticized Base (Jelene)78.33Peppermint Oil, NF0.67

Example 3

A 31 year old female patient presented with shingles in the active eruptive phase on her face, in her mouth, and on her cornea. The patient was currently taking 3 eye medications and valacyclovir (Valtrex). The patient was topically administered the topical composition of Example 1 three times a day. After seven days, the shingles was almost resolved and the patient had no pain.FIG.1shows the face of the patient prior to treatment (Day 0) and on Days 1-5 and 7 of treatment with the topical composition of Example 1.

Example 4

A 10 year old male patient presented with shingles on his arms. The patient was topically administered the topical composition of Example 1 three times a day. After five days, the shingles was almost completely resolved.

FIG.2Ashows the arms of the patient at Day 0 (prior to treatment).FIG.2Bshows the arms of the patient after administration of the topical composition of Example 1 three times a day for five days.

Example 5

A 57 year old female patient presents with severe blisters on the left torso. The patient was topically administered the topical composition of Example 1 three times a day. Upon applying the topical composition of Example 1, the patient immediately felt no pain. After four days, the shingles was completely resolved.

Example 6

An 83 year old female patient presents with severe blisters on the left torso and in great pain. The patient was taking an antiviral and pain medication (acyclovir and oxycodone). The patient was then topically administered the topical composition of Example 1 three times a day. Upon applying the topical composition of Example 1, the patient immediately felt no pain. After seven days, the shingles was completely resolved.

All references (including patents, patent applications, and literature) cited herein are hereby incorporated by reference in their entireties.