IE20110556A1 - A process for the manufacture of an antifungal nail lacquer - Google Patents

Abstract

The present invention is directed to a process for the large-scale manufacture of an antifungal nail lacquer, for the use in the treatment of fungal nail infections. According to the process, the antifungal nail lacquer is produced by homogenisation of the active ingredient amorolfine hydrochloride, solvent(s), plasticizer and a bioadhesive/release polymer, using two distinct dissolution stages which are carried out at below approximately 20 degrees C. In a first dissolution stage, the active ingredient and excipients (excluding the bioadhesive/release polymer) are homogenised at high shear to form a clear homogenous solution and then in a second dissolution stage, the bioadhesive/release polymer is added and blended with the clear homogenous solution using a paddle mixer to form a clear lacquer solution. By using two distinct dissolution stages, complete mixture of all the ingredients is achieved.

Description

OPEN TO PUBLIC IN SPECTIOft QINBER SECTION 28 ANO RULE 23 JNL Rio, of TRUE COPY_ AS A lodged )CESS FOR THE MANUFACTURE kN ANTIFUNGAL NAIL LACQUER The present invention provides a process for the large-scale manufacture of an antifungal nail lacquer comprising the active ingredient amorolfine. Ideally, the process comprises two consecutive dissolution stages followed by filtration, filling into the final containers and packing.

BACKGROUND Amorolfine is an antifungal drug used in the treatment or prevention of fungal infections, such as onychomycosis. Amorolfine exhibits a broad spectrum of action against many species of fungus, which are responsible for fungal infections. Amorolfine is presently available in the form of a topical nail lacquer.

The present invention is directed to providing an improved industrial-scale manufacturing process for nail lacquer comprising amorolfine.

SUMMARY OF THE INVENTION According to the invention there is provided a process for the large scale manufacture of a nail lacquer which includes amorolfine hydrochioride, anhydrous ethanol, ethyl acetate, n-butyl acetate, triacetin and ammonio methacrylate copolymer Type A, wherein the process takes place in a closed mixing vessel with a filling port at a temperature in the range of 17°C ± 5°C and includes the following steps: carrying out a first dissolution step using a homogeniser for homogenising the amorolfine hydrochioride, ethanol, ethyl acetate, n-butyl acetate and triacetin in the mixing vessel at high shear until the amorolfine hydrochloride is fully dissolved and a clear homogenous solution is formed; carrying out a second dissolution step including adding the ammonio methacrylate copolymer Type A to the clear homogenous solution and using a paddle mixer to mix the clear homogenous solution and ammonio IEl 1 0 5 56 -2methacrylate copolymer Type A until a clear nail lacquer solution is obtained; and agitating the mixing vessel during the second dissolution step.

In one embodiment of the invention the nail lacquer comprises from 1 to 10% amorolfine hydrochloride by weight.

In another embodiment the nail lacquer comprises from 70 to 88% anhydrous 10 ethanol, ethyl acetate and n-butyl acetate by weight. in another embodiment the naii lacquer comprises from 0.1 to 5% triacetin by weight.

In another embodiment the nail lacquer comprises from 10 to 20% ammonio 15 methacrylate copolymer Type A by weight.

In a further embodiment the process includes adding the ammonio methacrylate copolymer Type A to the clear homogenous solution in a continuous stream.

In another embodiment the process includes filtering the nail lacquer solution.

In another embodiment the process includes weighing each ingredient and dispensing said ingredients into separate seaied containers.

In another embodiment the process includes adding each weighed ingredient sequentially into the closed mixing vessel through the filling port.

In another embodiment the process includes delivering the filtered nail lacquer to a filling station where it is filled into containers at a set weight and capped.

In another embodiment the process includes packaging the filled containers.

In another embodiment the process includes maintaining the temperature of the solution beiow 20°C during the entire process.

In another embodiment the nail lacquer comprises: IE 1 1 0 5 5 6 -3from 5 to 8% amorolfine hydrochloride by weight; from 75 to 80% anhydrous ethanol, ethyl acetate and n-butyl acetate by weight; from 13 to 17% ammonio methacrylate copolymer Type A by weight; and from 0.5 to 2% triacetin by weight. !n another embodiment there is provided a process for the manufacture a nail lacquer consisting of from 1 to 10% amorolfine hydrochloride by weight; from 70-88% anhydrous ethanol, ethyl acetate and n-butyl acetate by weight; from 10 to 20% ammonio methacrylate copolymer Type A by weight; and from 0.1 to 5% triacetin by weight wherein the process takes place in a ciosed mixing vessel with filling port at a temperature below approximately 20°C and includes the following steps: weighing each ingredient and placing each weighed ingredient into separate sealed containers; attaching a homogeniser to the closed mixing vessel; adding the weighed ethanol, amorolfine hydrochloride, ethyl acetate, n-butyl acetate and triacetin sequentially into the closed mixing vessel through the filling port; carrying out a first dissolution step involving homogenising, at 1 bar pressure, the ingredients in the mixing vessel using high shear in the range of approximately 200 to 3400 rpm until the amorolfine hydrochloride is fully dissolved and a clear homogeneous solution is formed; removing the homogeniser from the mixing vessel; attaching a paddie mixer to the mixing vessel; carrying out a second dissolution step involving setting the paddle mixer at a speed from approximately 400 to 800rpm, adding the ammonio methacrylate copolymer Type A in a continuous stream to the homogenous solution, mixing for approximately 3 hours until a clear nail Eacquer solution is obtained, and IE 1 1 0 5 5 6 -4agitating the mixing vessel during this second dissolution step to prevent the adherence of the ammonio methacrylate copolymer Type A to the base of the mixing vessel; filtering the nail lacquer solution through a 250 micron mesh; passing the filtered nail lacquer to the filling station where it is filled into a container at a set weight and capped; and packaging the filled containers.

Quality control checks are carried out throughout the process.

It will be understood that all percentages are by weight based on the weight of the total solution.

We found that the nature of the ingredients themselves provides manufacturing problems particularly when taking place on a large scale.

Several different ways of adding the various Ingredients were tested and several problems were encountered. The present invention has been designed to overcome these problems.

Firstly, is essential that the nail lacquer solution is a homogenous mixture of the active ingredient. We found that achieving a homogenous mixture of the active ingredient can be difficult as the ingredients may be added in many different ways which potentially result in non-homogenous mixtures.

As the process of the present invention is designed to take place on a large scale, it is imperative that the process results in an end product which meets the quality control standards and that the process is reproducible each time.

Specifically, we found that it is essential to ensure the active ingredient, amorolfine hydrochloride, is dissolved completely before the addition of the bioahesive/release polymer, and the process of the invention is designed to ensure this by comprising two separate dissolution steps. If the amorolfine hydrochloride is not fully dissolved IE 1 1 0 5 5 6 -5before adding the bioadhesive/release polymer, it will clot with the polymer and form globules which are detrimental to production. The present invention is designed to avoid this.

In the first dissolution step, all of the excipients, including the active ingredient and excluding the bioadhesive/release polymer, are added to the mixing vessel and mixed using high shear, preferably using an air powered homogeniser. High shear is herein defined as the rate of shear required to ensure complete mixture of the active ingredient, solvent(s) and plasticizer. Typically, the homogeniser is set at a speed in the range of 200 to 3400 rpm to achieve the required high shear rate. Mixing is continued untii all of the active agent has dissolved and a homogeneous solution is formed. it is important when adding the polymer that the polymer latex remains intact to ensure the desired end properties of the nail lacquer in terms of gloss surface, smooth appearance, adhesion to the surface of the nail and water resistance. It is imperative that the bioadhesive/retease polymer is not subjected to high shear or homogenised to prevent coagulation of the polymer. Thus, the use of a homogeniser with high shear is undesirable when adding the bioadhesive/release polymer. Hence, due to the nature of the bioadhesive/release polymer, this second dissolution step takes place using a paddle mixer.

In this manner, the homogeniser from the first dissolution step is detached from the mixing vessel and replaced with a paddle mixer. This ensures that when the bioahesive/release polymer is added, that the polymer latex formed is not broken. The bioadhesive/release polymer is then added to the homogenous solution.

This two step dissolution process ensures both a homogenous solution of the active ingredient is made and that the bioadhesive/release polymer is also homogeneously distributed throughout the solution and does not adhere to the vessel base.

Furthermore, we have found that the bioadhesive/release polymer presents processing problems as following contact with the solvent mixture, polymer granules were found to adhere to the base of the mixing vessel. Thus, mixing with agitation was required. Hence, the process of the present invention has been designed to prevent the adherence of the bioadhesive/release polymer to the mixing vessel base.

IE 1 1 0 5 5 6 -6Additionally, testing showed that ethanol was the best solvent for the active ingredient. However, when we tested the use of ethanol as the only solvent, we found this solvent alone was not adequate for the complete dissolution of the active ingredient. Thus, after testing various different solvents and co-solvent mixtures, we found that the use of three co-solvents (ethanol, ethyl acetate and n-butyl acetate) was necessary for the complete dissolution of the active ingredient.

Additionally, the solvents themselves must be prevented from evaporating during the process. In order to prevent the evaporation and loss of co-solvents during manufacture, the process takes place in a closed system.

Finally, we found that the use of a semi-automatic filling line and manual capping of the products controlled any potential evaporation from the bottles.

DETAILED DESCRIPTION OF THE INVENTION The invention will now be described with reference to the following non-limiting figures and examples.

Figure 1 is a flowchart of the major stages of the process for the manufacture of the nail lacquer according to the invention.

Equipment used An appropriately sized sealed stainless steel mixing vessel that can be fitted with a homogeniser and paddle stirrer and a filling line are the main pieces of required equipment. • electronic balance • bulk sample storage containers in various sizes • sealed stainless steel 25 litre mixing vessel with filling port • stainless steel powder funnel • air powered homogeniser • paddle mixer • digital thermometer IEl 1 0 5 5 6 -7• 5ml disposable pipette • filter assembly with 250 micron screen • peristaltic pump • platinum cured silicon tubing, disposable, 8mm • semi-automatic filling machine Ingredients The active ingredient is amorolfine hydrochloride. Ideally, the active ingredient is 10 present from 1 to 10% by weight based on the weight of the total solution. 6.4% of the hydrochloride is used to get a label claim of 5%. This is due to the potency calculation of the salt portion of the molecule. The density of the solution is approximately 0.875 g/ml, wherein approximately 0.875 g/ml is defined as 0.87 g/ml ± 5%.

The co-solvents are anhydrous ethanol, n-butyl acetate and ethyl acetate, ideally, the co-solvents are present from 70-90% by weight based on the weight of the total solution.

The bioadhesive and release polymer is ammonio methacrylate copolymer Type A. Ideally, the ammonio methacrylate copolymer Type A is present from 10 to 20% by weight based on the weight of the total solution.

The plasticizer is triacetin. Ideally, the plasticizer is present from 0.1 to 5% by weight based on the weight of the total solution.

Batch Formulae The finished product may be manufactured in batch sizes of up to 200 kg (approx. 230 litres) with a minimum size of 20 kg (approx. 23 litres). Preferred batch formulae, for example 20, 50,100 and 200 kg batches, are given in Table 1 below. »ΕΠ 0 5 5 6 -8Table 1 Ingredient % w/w 20 kg 50 kg 100 kg 200 kg (kg) (kg) (kg) (kg) Active ingredient, Amorolfine Amorolfine hydrochloride 6.40 1.28 3.20 6.40 12.80 Bioadhesive/ release polymer Eudragit RL 100 14.65 2.93 7.325 14.65 29.30 plasticer T riacetin 1.20 0.24 0.60 1.20 2.40 solvent n-Butyl acetate 5.75 1.15 2.875 5.75 11.50 solvent Ethyl acetate 16.60 3.32 8.30 16.60 33.20 solvent Ethanol, (anhydrous) 55.40 11.08 27.70 55.40 110.80 Total 100 20.00 50.00 100.00 200.00 In order to prevent the evaporation and loss of co-solvents during manufacture, the process takes place in a closed system, a sealed mixing vessel. This is an important feature of the invention. Furthermore, as the end product nail lacquer will thicken on contact with air, it is critical that a closed system is used without the influx of any air.

Ideally, the whole system is designed as a closed system made of stainless steel 316.

The addition and mixing of the ingredients takes place in a single closed vessel which is provided with two independent mixers, a homogeniser and a paddle, at different stages during the process.

The homogeniser is located/fixed at the bottom of the vessel and uses high shear forces to break up the ingredients and mix the active ingredient into the solvent so it dissolves completely.

The paddle mixer is located/fixed at the top of the vessel and is designed for gentler mixing over a longer time period than the homogenisation step (approximately 30 to minutes), forming a continuous vortex. The system is designed in this manner as «110556 -9we found that the bioadhesive/release polymer presents significant processing problems. Specifically, following contact with the solvent mixture, polymer granules were found to adhere to the base of the mixing vessel.

The process comprises the following general steps: STAGE 1 - Preparation of Ingredients Stage 1 involves the initial weighing of the active ingredient, amorolfine hydrochloride, and all other excipients except the bioadhesive/release polymer according to the amounts listed in Table 1.

All components required are weighed on electronic balances and dispensed into suitable sealed containers.

STAGE 2 - Mixinq of Ingredients (excluding the bioadhesive/release polymer) The active ingredient and excipients (excluding the bioadhesive/release polymer) are then transferred one by one from the sealed containers through a stainless steel powder funnel into a sealed mixing vessel provided with a filling port.

After the addition of each component, the mixing vessel is closed/sealed. The sealing of the container at all stages is important to improve evaporation resistance of the co-solvents.

In this step, ethanol is added to the mixing vessel initially, followed by the active ingredient amorolfine hydrochloride, followed by the addition of ethyl acetate, n-butyl acetate and triacetin.

The temperature of the solution is measured using a digital thermometer via the filling port to ensure the temperature is maintained at below approximately 20°C throughout the process. Approximately 20°C is defined herein as 17°C ± 5°C. This is critical, as if the temperature rises above approximately 20°C, the solvent evaporates and the mixture becomes extremely viscous and unworkable. Additionally, this can cause significant processing probiems, where the viscous liquid can get stuck in the vessel.

•El 1 05 5 6 -10The air powered homogeniser is then put in place over the mixing vessel, the vessel is closed and sealed, ideally at nominal 1 bar pressure.

The ingredients are mixed in the sealed stainless steel vessel for approximately 20 to 5 30 minutes until the amorolfine hydrochloride is completely dissolved and a clear solution is achieved. The ingredients are mixed at a conventional medium speed 200 - 3400 rpm, until the active ingredients are dissolved completely, and the solution becomes visually clear.

The order of the addition of the ingredients is important. The amorolfine must be completely dissolved in the solvent using the homogeniser prior to adding the bioadhesive/release polymer.

It is also very important to wash the sides of the vessel and ensure that all amorolfine is incorporated that no particles are left undissolved.

At this stage a 5mi sample is removed using a disposable pipette from the middle of the solution into a sealed vial. This is used for quality control analysis.

STAGE 3 - Addition and Mixing of bioadhesive/release polymer Once the active ingredient is fully dissolved in the solvent, the air powered homogeniser is removed from the mixing vessel and the paddle mixer is fitted to the vessel.

The temperature is measured again to ensure that it has not risen above approximately 20°C.

The paddle mixer assembly is switched on at a speed of approximately 400 to 800 rpm and the bioadhesive/release polymer (Eudragit RL100®) is added slowly in a continuous stream into a vortex formed by the paddle mixer via the stainless steel powder funnel until all the bioadhesive/release polymer has been added. This addition step generally takes about 5 to 10 minutes total.

•El 1 0 5 56 -11 The vessel is then closed and sealed and mixed for approximately 3 hours at a typical speed setting between 400-800 rpm until a clear solution is achieved which is confirmed by visual observation of the solution for clarity and the absence of solids.

During this mixing step the vessel is agitated to prevent settling of the bioadhesive/release polymer on the vessel base and to help disperse adhered polymer from the vessel base.

After mixing the stirrer is removed from the vessel and vessel is closed and sealed.

STAGE 4 Filtration The presence of small quantities of particulates (fibrous) matter in the bulk solution from Stage 3 is undesirable. Thus, a filtration step is carried out as a clarifying step prior to filling.

In-line filtration of the bulk solution from Stage 3 then takes place through a 250 micron stainless steel mesh. The solution is stirred during this filtration step.

The filtered bulk solution from Stage 4 is then passed to the automatic filling station using a peristaltic pump.

STAGE 5 Filling In this step glass bottle containers are filled to the required filling volume. Filling is generally performed at fill volumes of 2.5ml, 3ml and 5ml.

The bottles are capped immediately after filling.

Ideally, the process involves an automatic bottle feeder and automatic capping system. The automatic bottle feeder fills trays comprising empty bottles via piston or vacuum filling. The trays with filled bottles are then passed on a conveyor through the automatic capping system which adds brush or droppers with screw caps to the bottle.

IEl 1 05 5 g -12STAGE 6 - Packing The filled glass bottles with caps from Stage 5 are transferred on a conveyor to the packing station, in this step, the botties are labelled and packed into outer cardboard boxes together with an applicator to apply the product to the nail.

Again, these steps may be fully or partially automated.

General Quality Control In order to confirm that the process was sufficiently controlled to ensure a quality end product, samples of the pre and post filtered solution and filled products (start, middle and end of the fill) were tested for appearance, amorolfine content, the presence of impurities and bulk density.

In process quality controls include visual observation to confirm complete dissolution of all solid components during Stages 2 and 3. Additionally, a weight check on the final bottle containers confirms correct fill quantity in Stage 5.

The Amorolfine Nail Lacquer must achieve the following specification: Description Specification Appearance and colour Clear, colourless to pale yellow solution Filling Volume 2.5 ml: NLT 2.5 ml 25 3 ml: NLT 3 ml 5 ml: NLT 5 ml The nail lacquer should be tested both pre-filiing and post-filling.

The invention is not limited to the embodiments hereinbefore described which may be varied in construction and detail within the scope of the appended claims.

Claims (14)

1. A process for the large scale manufacture of a nail lacquer which includes 5 amorolfine hydrochloride, anhydrous ethanol, ethyl acetate, n-butyl acetate, triacetin and ammonio methacrylate copolymer Type A, wherein the process takes place in a closed mixing vessel with a filling port at a temperature in the range of 17°C ± 5°C and includes the following steps: 10 carrying out a first dissolution step using a homogeniser for homogenising the amorolfine hydrochloride, ethanol, ethyl acetate, n-butyl acetate and triacetin in the mixing vessel at high shear until the amorolfine hydrochloride is fully dissolved and a clear homogenous solution is formed; carrying out a second dissolution step including adding the ammonio methacrylate copolymer Type A to the clear homogenous solution and using a paddle mixer to mix the clear homogenous solution and ammonio methacrylate copolymer Type A until a clear nail lacquer solution is 20 obtained; and agitating the mixing vessel during the second dissolution step.

2. The process according to claim 1 wherein the nail lacquer comprises from 1 to 25 10% amorolfine hydrochloride by weight.

3. The process according to claim 1 or claim 2 wherein the nail lacquer comprises from 70 to 88% anhydrous ethanol, ethyl acetate and n-butyl acetate by weight. 30

4. The process according to any preceding claim wherein the nail lacquer comprises from 0.1 to 5% triacetin by weight.

5. The process according to any preceding claim wherein the nail lacquer comprises from 10 to 20% ammonio methacrylate copolymer Type A by weight. •Ε 1 1 Ο 5 5

6 - 146. The process according to any preceding claim wherein the process includes adding the ammonio methacrylate copolymer Type A to the clear homogenous solution in a continuous stream. 5

7. The process as claimed in any preceding claim wherein the process includes filtering the nail lacquer solution.

8. The process as claimed in any preceding claim wherein the process includes weighing each ingredient and dispensing said ingredients into separate sealed 10 containers.

9. The process according to claim 8 wherein the process includes adding each weighed ingredient sequentially into the closed mixing vessel through the filling port.

10. The process according to any preceding claim wherein the process includes delivering the filtered nail lacquer to a filling station where it is filled into containers at a set weight and capped. 20

11. The process according to claim 10 wherein the process includes packaging the filled containers.

12. The process according to any preceding claim wherein the process includes maintaining the temperature of the solution below 20°C during the entire 25 process.

13. The process according to any preceding claim wherein the nail lacquer comprises: 30 from 5 to 8% amorolfine hydrochloride by weight; from 75 to 80% anhydrous ethanol, ethyl acetate and n-butyl acetate by weight; from 13 to 17% ammonio methacrylate copolymer Type A by weight; and from 0.5 to 2% triacetin by weight. •Ε ί ί ο 5 5 6 - 15

14. A process for manufacturing an anti-fungal nail lacquer substantially as described herein with reference to the figures and examples.