LOZENGE

Abstract

The invention relates to a lozenge comprising micronized benzocaine, at least one dissolution enhancer and one or more excipients as well as the use of the lozenge for the treatment of sore throat.

Claims

1. A lozenge comprising: a. micronized Benzocaine; b. at least one dissolution enhancer, wherein the dissolution enhancer is PEG, and wherein the dissolution enhancer is present in an amount from 1 to 30 mg; and c. one or more excipients.

2-22. (canceled)

23. The lozenge according to claim 1, wherein the micronized Benzocaine has a mass median particle size of about 5 to about 30 μm.

24. The lozenge according to claim 1, wherein the PEG is polyethylene glycol (PEG) 4000 to 6000.

25. The lozenge according to claim 24, wherein the PEG is PEG 6000.

26. The lozenge according to claim 1, wherein the micronized Benzocaine has a mass median particle size of about 7 to about 18 μm.

27. The lozenge according to claim 1, wherein the micronized Benzocaine is present in an amount from about 2 to about 15 mg.

28. The lozenge according to claim 1, wherein the micronized Benzocaine is present in an amount of about 8 mg.

29. The lozenge according to claim 1, wherein the PEG is present in an amount of about 5 to about 25 mg.

30. The lozenge according to claim 1, wherein the one or more excipients is at least one sweetening agent.

31. The lozenge according to claim 30, wherein the at least one sweetening agent is selected from the group consisting of synthetic or natural sugars; artificial sweeteners including saccharin, sodium saccharin, aspartame, acesulfame, thaumatin, glycyrrhizin, sucralose, cyclamate, dihydrochalcone, alitame, miraculin and monellin; sugar alcohols including sorbitol, mannitol, glycerol, lactitol, maltitol, and xylitol; sucrose, dextrose, fructose and lactose; isomalt, stevia, and mixtures thereof.

32. The lozenge according to claim 1, wherein the one or more excipients is at least one flavoring agent.

33. The lozenge according to claim 32, wherein the at least one flavoring agent is selected from the group consisting of lime, orange, lemon, black current, blood orange, cranberry, cloudberry, goji berry, raspberry, strawberry, wild strawberry, sea buckthorn, cherry, melon, kiwi, papaya, pineapple, passion fruit, coconut, and other flavors such as honey, herbs, tea, anise, water grass, lemon grass, cooling agent ginger, coffee, eucalyptus, mangosten, peppermint, spearmint, wintergreen, cinnamon, cacao/cocoa, vanilla, liquorice, salt, pepper, chili, menthol, aniseeds, mint, natural of synthetic versions and mixtures thereof.

34. The lozenge according to claim 1, further comprising a filler, a binding/gelling agent and a lubricant.

35. The lozenge according to claim 34, wherein the filler is mannitol, the binding/gelling agent is xanthan gum, and the lubricant is magnesium stearate.

36. The lozenge according to claim 1, wherein the lozenge is coated with a film forming agent.

37. The lozenge according to claim 36, wherein the film forming agent is a cellulose ether film forming agent.

38. The lozenge according to claim 37, wherein the cellulose ether film forming agent is selected from the group consisting of hydroxy propyl methyl cellulose (HPMC), methyl hydroxy ethyl cellulose (MHEC), hydroxy propyl cellulose (HPC), hydroxyethyl cellulose (HEC), or ethyl hydroxyl ethyl cellulose (EHEC).

39. The lozenge according to claim 1, wherein the lozenge is direct compressed or granulated and compressed.

40. A method of treating a sore throat, the method comprising administering a lozenge according to claim 1.

Description

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Definitions

[0014] The term “dissolution enhancer” is intended to mean an agent that increases the dissolution of the active ingredient, i.e., benzocaine.

[0015] The term “lozenge” means preparations that are solid containing one or more active substances intended for administration to the oral cavity and/or the throat to obtain a local or systemic effect.

Lozenge

[0016] In a first aspect, the invention relates to a lozenge, which might be direct compressed or granulated and compressed, comprising micronized Benzocaine, at least one dissolution enhancer and one or more excipients.

[0017] The dissolution enhancer may be selected from the group consisting of polyethylene glycol (PEG), sodium dodecylsulphate (SDS) and poloxamer or a mixture thereof. In one example PEG may be used or mixtures of different PEGs. Examples of different PEGs are PEG 4000 to PEG 6000, PEG 6000 or mixtures thereof. The particle size range of PEG may influence the dissolution rate. Different grades of PEG may be used as well.

[0018] The micronized Benzocaine present in the lozenge may have a mass median particle size of about 5 to about 30 μm, such as about 7 to about 25 μm, about 7 to about 18 μm, about 10 to about 22 μm, about 12 to about 20 μm, about 14 to about 18 μm.

[0019] Benzocaine may be present in an amount of from about 2 to about 15 mg, about 8 to about 15, about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2 mg per unit dose.

[0020] The dissolution enhancers may be present in an amount of from about 1 to about 30 mg, about 4 to about 17 mg per unit dose. When the dissolution enhancer is PEG 6000 it is present in an amount of about 5 to about 25, such as about 10 mg per unit dose.

[0021] Examples of excipients include fillers, glidants, lubricants, sweeteners, flavors, coloring agents, binding/gelling agents and mixtures thereof.

[0022] Suitable lubricants include long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof.

[0023] Suitable glidant is colloidal silicon dioxide.

[0024] Examples of sweeteners include, synthetic or natural sugars; artificial sweeteners such as saccharin, sodium saccharin, aspartame, acesulfame, thaumatin, glycyrrhizin, sucralose, cyclamate, dihydrochalcone, alitame, miraculin and monellin; sugar alcohols such as sorbitol, mannitol, glycerol, lactitol, maltitol, and xylitol; sugars extracted from sugar cane and sugar beet (sucrose), dextrose (also called glucose), fructose (also called laevulose), and lactose (also called milk sugar); isomalt, stevia, and mixtures thereof.

[0025] Examples of flavoring agents/flavors include, fruit and berry flavors such as lime, orange, lemon, black current, blood orange, cranberry, cloudberry, goji berry, raspberry, strawberry, wild strawberry, sea buckthorn, cherry, melon, kiwi, papaya, pineapple, passion fruit, coconut, and other flavors such as honey, herbs, the, anise, water grass, lemon grass, cooling agent ginger, coffee, eucalyptus, mangostan, peppermint, spearmint, wintergreen, cinnamon, cacao/cocoa, vanilla, liquorice, salt, pepper, chili, menthol, aniseeds, mint or mixtures thereof. The flavoring agents/flavors may be natural extracts as well as synthetic versions.

[0026] Examples of coloring agents include lakes and dyes being approved as a food additive. Examples of fillers that may be used include maltitol, xylitol, sorbitol, mannitol, lactose, dextrose, saccharose or fructose, or any mixture thereof. One example is mannitol.

[0027] Examples of biding/gelling agents include but are not limited to xanthan gum, alginate, locust bean gum and guar gum as well as mixtures thereof. One example is xanthan gum.

[0028] In one example the filler is mannitol, the binding/gelling agent is xanthan gum and the lubricant is magnesium stearate.

[0029] The lozenge may be coated with a film coating agent, such as one or more fil-forming polymers. The thickness of the film coating has an influence on the degree of reduction of the organoleptically disturbing sensations. The film coating may have an average thickness from 10 to 500 microns, more preferably from 20 to 250 microns, such as from 30 to 150 microns. The film thickness may be measured using different methods known in the art such as SEM (Scanning Electron Microscopy), digital micrometer, X-ray microtomography, terahertz pulsed imaging etc. See further e g Quantitative Analysis of Film Coating in a Pan Coater Based on In-Line Sensor Measurements, Jose D. Perez-Ramos et al, AAPS PharmSciTech 2005; 6 (1) Article 20, Nondestructive analysis of tablet coating thicknesses using terahertz pulsed imaging. J Pharm Sci. 2005; 94:177Y183. Fitzgerald A J, Cole B E, Taday P F., Hancock B, Mullarney M P. X-ray microtomography of solid dosage forms. Pharm Technol. 2005; 29:92Y100.

[0030] The film-forming polymers may be chosen among cellulose ethers e g hydroxy propyl methyl cellulose (HPMC), methyl hydroxy ethyl cellulose (MHEC), hydroxy propyl cellulose (HPC), hydroxyethyl cellulose (HEC), ethyl hydroxyl ethyl cellulose (EHEC), and other film forming polymers such as methacrylic acid copolymer-type C sodium carboxy methyl cellulose, polydextrose, polyethylene glycols, acrylate polymers (e g poly vinyl acrylate (PVA)), polyvinyl alcohol-polyethylene glycol graft copolymers, complex of polyvinylpyrrolidone (PVP), such as povidone, polyvinyl alcohol, microcrystalline cellulose, carrageenan, pregelatinized starch, polyethylene glycol, and combinations thereof. Typically, the molecular weight (weight average and/or number average) of the polymer is from 1,000 to 10,000,000, preferably from 10,000 to 1,000,000, as measured by e.g. gel permeation chromatography. In one embodiment the film-forming polymers are selected among cellulose ethers e g hydroxy propyl methyl cellulose (HPMC), methyl hydroxy ethyl cellulose (MHEC), hydroxy propyl cellulose (HPC), hydroxyethyl cellulose (HEC), ethyl hydroxyl ethyl cellulose (EHEC).

[0031] In addition the film coating may contain one or more plasticizer may be added to the film-forming polymer to facilitate the spreading and film forming capability. Examples on useful plasticizers are glycerol, propylene glycol, polyethylene glycol (PEG 200-6000), organic esters e g triacetin (glyceryl triacetate), triethyl citrate, diethyl phtalate, dibutyl phtalate, dibutyl sebacete, acetyltriethyl citrate, acethyltributyl citrate, tributyl citrate, and oils/glycerides such as fractionated coconut oil, castor oil and distilled acetylated monoglycerides. Additionally, or alternatively, surfactants may be included to facilitate the incorporation of flavors and to improve penetration and spreading properties of the coating liquid. Non-limiting examples of surfactant are polysorbates derived from PEG-ylated sorbitan esterified with fatty acids such as Polysorbate 20 (Polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 (Polyoxyethylene (20) sorbitan monopalmitate), Polysorbate 60 (Polyoxyethylene (20) sorbitan monostearate), Polysorbate 80 (Polyoxyethylene (20) sorbitan monooleate) (e g Tween 80, Tween 40, Tween 20), sodium lauryl sulphate (SLS), poloxamer surfactants i.e. surfactants based on ethylene oxide-propylene oxide block copolymers and other surfactants with high HLB-value.

[0032] Other components may be included in the composition of the film such as coloring agents, opacifiers, glossing agents, pore forming agents, excipient stabilizers.

[0033] The dosage forms of the invention may be prepared by way of a variety of routine techniques, and using standard equipment, known to the skilled person (see, for example, Lachman et al, “The Theory and Practice of Industrial Pharmacy”, Lea & Febiger, 3.sup.rd edition (1986) and “Remington: The Science and Practice of Pharmacy”, Gennaro (ed.), Philadelphia College of Pharmacy & Sciences, 19.sup.th edition (1995)). In one embodiment, a core comprising Benzocaine is first produced using known tableting techniques, which is then coated with a solution containing a film-forming polymer.

[0034] Standard mixing equipment may be used for mixing together components of compositions of the invention. The mixing time period is likely to vary according to the equipment used, and the skilled person will have no difficulty in determining by routine experimentation a suitable mixing time for a given combination of ingredient(s). One way of producing the lozenges is found in the examples. The manufacturing process may as well comprise additional steps of granulation, drying and milling and/or sieving to obtain a lozenge.

Use of the Lozenge

[0035] In a final aspect the invention relates to the use of the lozenge for the treatment of sore throat.

EXAMPLES

Example 1

Production of the Core

[0036] All ingredients were purchased in pharmaceutical quality except for the flavoring agents that were of food grade.

[0037] The ingredients shown in table 1 were sieved through a 1mm mesh and blended.

[0038] The blending times were optimized to obtain a homogenous powder mixture obvious for a person skilled in the art.

[0039] The lozenges were produced by direct compression of the powder mix.

[0040] The lozenge shape was oblong with targeted lozenge weight of 600 mg.

[0041] The manufacturing was performed in manufacturing area with controlled temperature and humidity.

[0042] Table 1 and 2 shows the amounts of the different ingredients present in the core of the lozenges.

TABLE-US-00001 TABLE 1 Ingredients Amount mg/lozenge Benzocaine 15.0 Mannitol 533.5 Xanthan gum 12.0 PEG 6000 10.0 Poloxamer 4.0 SDS 2.0 Magnesiumstearate 12.0 Mint flavour 10.00 Sucralose 1.00 Acesulfame K 0.50

TABLE-US-00002 TABLE 2 Ingredients Amount mg/lozenge Benzocaine 15.0 Mannitol 537.5 Xanthan gum 12.0 PEG 4000 12.0 Magnesiumstearate 12.0 Mint flavour 10.00 Sucralose 1.00 Acesulfame K 0.50

Example 2

Coating of the Lozenge

[0043] All ingredients were purchased in pharmaceutical quality except for the flavoring agents that were of food grade.

[0044] The lozenges produced in Example 1 were film coated according to the method disclosed below.

[0045] The coating polymer was dispersed in warm water and then cooled down. The other raw materials were added into the coating solution.

[0046] The coating solution was homogenized.

[0047] The cores were then spray coated and the spray coating was controlled on the outlet air temperature of 45° C.

[0048] Table 3 shows the ingredients and the amount of a film coating that could be used for specific embodiments of the invention.

TABLE-US-00003 TABLE 3 Ingredients Amount/lozenge (mg) HPMC 16.8 Titanium dioxide 2.5 Mint flavour 2.5 PEG 400 1.5 Sucralose 0.8 Acesulfame K 0.4 Polysorbate 0.1 Aqua purificata q.s

Example 3

[0049] The dissolution rate was analyzed using the method USP paddle 2 using Liquid Chromatography (LC).

Example: Dissolution Profiles

[0050] % Benzocaine dissolved for lozenges with different mass median particle size range of PEG 6000 at given dissolution times

TABLE-US-00004 Dissolution time Standard PEG Fine Powder PEG (min) No PEG 10 mg 10 mg 3 4.7 3.9 16.4 5 20.7 24.2 30.9

[0051] % Benzocaine dissolved for lozenges with different amounts of PEG 6000 at given dissolution times

TABLE-US-00005 Dissolution time (min) 0 mg PEG 5 mg PEG 10 mg PEG 60 mg PEG 3 4.7 14.3 17.5 11.4 5 20.7 37.2 41.1 30.9 10 54.3 72.3 74.4 62.8

[0052] % Benzocaine dissolved for lozenges with different mass median particle size of Benzocaine at given dissolution times

TABLE-US-00006 Dissolution time (min) *≤207 μm *≤7 *≤3 10 25.7 44.8 38.5 15 43.1 80.0 63.4 20 53.3 85.6 79.0 *Mass median particle size

Example 4: Products for Comparison

[0053] % Benozocaine dissolved for lozenges at given dissolution times

TABLE-US-00007 Dissolution time Anaesthesin Neo Angin Lozenge produced (min) 8 mg 8 mg according to Example 1* 5 15.4 34.5 41.1 10 31.4 64.5 74.4 15 45.0 85.3 90.6 *The lozenge produced according to Example 1 having 8 mg of Benzocaine.