A method for producing adapalene gels

The invention is in the domain of manufacturing processes and relates to the manufacture of adapalene aqueous gel at industrial level.

Adapalene is a retinoid derived from naphthoic acid. It is 6-[3-(1 -adamantyl)- 4-methoxyphenyl]-2-naphthanoic acid and has been described in EP 0 199 636. A method for synthesizing this component has been described in EP 0 358 574.

Adapalene is marketed in the form of an alcoholic solution, an aqueous gel and a cream, at a weight concentration of 0.1 %. These compositions are intended for the treatment of acne.

WO 03/075908 describes the use of adapalene at a weight concentration of 0.3 % in an aqueous gel, for the treatment of dermatological disorders.

Classical formulation processes are known to need that mixture is cooled to obtain an adequate mixing of all ingredients which induced additional industrial equipment.

Thus, there remains a need for improved process for the production of aqueous gel of adapalene at the industry level.

The inventors now report a new and advantageous method for producing such adapalene aqueous gels, at industrial level.

A subject of the present invention is thus a method for producing an adapalene aqueous gel, which method comprises the steps of: i) preparing a gelling medium A by mixing water and propylene glycol and adding a gelling agent ii) preparing an adapalene medium B by dispersing adapalene in water, in the presence of a surfactant ; wherein steps i) and ii) are performed in parallel or any of step i) or ii) is performed after the other ; iii) adding the adapalene medium B to the gelling medium A ; iv) adjusting the pH whereby a gel is formed.

In a specific embodiment, the gelling agent in step i) is added after propylene glycol. In another specific embodiment the pH is adjusted to about 4.7-5.3

For the purpose of the said method each step is advantageously carried out at room temperature. Therefore, drawbacks of classical formulation processes are overcame with the present invention.

In addition, the medium A may further contain a preservative agent which is dissolved in propylene glycol at room temperature. The preservative agent is preferably methylparaben.

Further more, the medium A may further contain a chelating agent and preferably

EDTA disodium which is dissolved in water before addition of propylene glycol and the gelling agent. The gelling agent is preferably Carbopol 980. In a preferred embodiment of the invention, the surfactant is a non-ionic surfactant and preferentially a block copolymer surfactant and more preferred a poloxamer as example poloxamer 182, poloxamer 124 and is preferentially Poloxamer 124 (

Polyethylene-Polypropylene Glycol also known as Pluronic® L44).

The adapalene quantity range is from 0.01% to 1 %, preferably from 0.1 % to 0.3% and the weight ratio of adapalene/water in the adapalene medium B is between 6% and

23% and preferably between 6 % and 20%. .

In a specific embodiment of the invention, the said method comprises the steps of: i) preparing a gelling medium A by mixing and dissolving/solubilising EDTA disodium in water, adding propylene glycol and methylparaben, mixing and adding Carbopol® 980, wherein the proportion of propylene glycol/water is between 4% and 5% and preferably around 4.5%; separately ii) dispersing adapalene in water in the presence of Poloxamer 124, whereby an adapalene medium B is obtained wherein the proportion of adapalene/active phase the weight ratio of adapalene/water in the adapalene medium B is between 6% and 23% and preferably between 6 % and 20% ; iii) adding the adapalene medium B to the gelling medium A ; iv) adding sodium hydroxide to adjust the pH. In the said method, the sodium hydroxide is added after step (iii). In a specific embodiment the pH is adjusted to about 4.7-5.3.

The scope of the present invention encompasses also an adapalene gel obtainable by the said method and the gel produced following the method as described earlier.

In the context of the present description, "an adapalene aqueous gel" means a gelified aqueous composition, that is preferably monophasic, and that contains

adapalene, preferably as a sole active ingredient that shows a cosmetic or therapeutic effect, and preferably in a dispersed state.

Adapalene is present in the gel in a therapeutically efficient quantity. It ranges from 0.001% to 5% and preferably ranges from 0.01 % to 1 % in weight, typically between 0.1% and 0.3% in weight, with regard to the total weight of the aqueous gel. In a preferred embodiment 0.3% is preferred.

The addition of propylene glycol at a very early stage in the process is a particular feature of the invention. By very early stage it should be understood the first step and particularly in step i) of the process. Therefore, in a specific embodiment, the gelling agent in step i) is added after propylene glycol.

The current invention is based in a specific embodiment on the solubilisation of the preservative in the propylene glycol at 1 to 10%, preferably about 4-5%. This preservative agent is advantageously present in a quantity sufficient for inhibiting microbial growth in the gel during storage and particularly at 0.01 % to 3% with regard to the total weight of the aqueous gel.

The preservative agent is selected from the following agents: benzalkonium chloride, bronopol, chlorhexidin, chlorocresol and derived products thereof, ethylic alcohol, phenethylic alcohol, phenoxyethanol, potassium sorbate, benzylic alcohol, diazolidinylurea, parabens,or mixture thereof .

This preservative agent is preferably selected from the paraben family. For example, it can be methylparaben.

This solubilisation is obtained advantageously at room temperature, with common stirring equipment at low or moderate speed. This represent an advantage for manufacturing process as it avoids to heat the gelling medium A, so at industrial level, this invention advantageously reduce manufacturing duration and energy used.

In a particular embodiment, medium A may further comprise a chelating agent. The chelating agent selected from the following: ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA), ethylene diamine-di (O- hydroxyphenyl acetic acid (EDDHA), hydroxy-2-ethylene diamine triacetic acid (HEDTA), ethyldiamine-di (O-hydroxy-p-methyl phenyl) acetic acid (EDDHMA) and ethylene diamine-di (5-carboxy-2-hydroxyphenyl) acetic acid (EDDCHA). In a preferred embodiment, the chelating agent is ethylene diamine tetraacetic acid (EDTA) or one of its salts, such as EDTA disodium, as an additional ingredient. EDTA or its salts is useful to chelate metal cations that may be present as impurities in the composition, which makes it possible to avoid side effects in certain patients. EDTA

further inhibits browning of the composition during storage of the gel. The gels prepared according to the method of the invention advantageously contain EDTA, or its salts, preferably EDTA disodium, in an amount of 0.05 to 0.5 %, typically about 0.1 %. In a preferred embodiment, EDTA, or EDTA disodium, is dissolved in water before addition of propylene glycol and the gelling agent.

The gelling agent is adapted to make a gel out of an aqueous medium. It is preferably a hydrodispersible polymer that exhibits a high affinity with water. This polymer preferably contains free carboxylic groups that are all or partly neutralised in a form of carboxylate through the use of a base. Preferred gelling agents are vinyl polymers with hydrodispersible carboxylate groups, such as a polyacrylic acid gel, that is neutralised by a base, e.g. sodium hydroxide. Also preferred are polymers with a molecular weight of about 1 250 000 to 4 000 000. Cross-linked polyacrylic acids with such as polyacrylic acid reticulated with polyalkenyl polyethers are also encompassed. For example suitable gelling agent are selecting from the following list: electrolytes non sensible carbomers, sold with the tradename Ultrez 20®, Carbopol 1382 or Carbopol ETD2020® by BF Goodrich company, polysaccharides and as non limitating example xanthane gum such as XanturaM δO® sold by Kelco company, guar gum, chitosans, carraghenanes, cellulose and the derivatives therefrom such as hydroxypropylmethylcellulose particularly the product sold with the tradename Methocel E4 premium by Dow Chemical company or hydroxyethylcellulose, particularly the product sold with the tradename Natrosol HHX 250® by Aqualon company, family of aluminium or magnesium silicates such as Veegum K sold by Vanderbilt company, family of acrylic polymers coupled with hydrophobic chains such PEG-150/decyl/SMDI copolymer sold with the tradename Aculyn 44 (polycondensat comprising at least as element one polyethyleneglycol with 150 or 180 moles of ethylene oxide, decylic acid and methylene bis(4-cyclohexylisocyanate) (SMDI), 35% by weight in a mixture of propylene glycol (39%) and water (26%)), family of modified starch such as potatoes starch sold with the tradename Structure Solanace or mixture thereof, family of polyacrylamides such as the mixture Sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 sold with the tradename Simulgel 600 by Seppic company, mixture polyacrylamide / isoparaffine C13-14 / laureth-7 such the product sold with the tradename Sepigel 305 Seppic company.

Suitable preferred gelling agents are family of polymers and preferably those called carbomer polymers which are a crosslinked polyacrylate polymer such as carbomer 940, i.e. carbopol® 980 (2-Propenoic acid, polymer with 2,2-

bis(hydroxymethyl)propane-1 ,3-diol 2-propenyl ether) by the Goodrich company or family of polyacrylamides and preferably those called Simulgel 600 or Sepigel 305.

The gels prepared according to the invention preferably contain from about 0.5 % to about 2 % of the gelling agent, preferably about 1 %, e.g. 1 .1 %. The weight ratio of the gelling agent/water in medium A may range 1% to 1 ,5 %.

Adapalene medium B, that is advantageously prepared in parallel, is typically a medium wherein adapalene is dispersed.

Advantageously, the weight ratio of adapalene/water in the adapalene medium B is between 6% and 23% and preferably between 6 % and 20%. Medium B preferably comprises a surfactant. The surfactant may preferably be selected from ethylene oxide and propylene oxide block copolymers, and their mixtures, and, preferably, the gel is devoid of any surfactant other than ethylene oxide and propylene oxide block copolymers. The ethylene oxide and propylene oxide block copolymers which can be used as surfactant in the nanoemulsion of the invention can be selected, in particular, from the block copolymers of formula (I) HO(C ₂ H ₄ θ) _x (C ₃ H ₆ θ) _y (C ₂ H ₄ O) _z H, wherein x, y, and z are integers such that x+z ranges from 2 to 100 and y ranges from 14 to 60, and their mixtures, and more particularly from the above block copolymers having an HLB (Hydrophilic Lipophilic Balance) ranging from 2 to 16.

These block copolymers can be selected, in particular, from poloxamers and in particular from Poloxamer 231 , such as the product sold by ICI under the name Pluronic® L81 , of formula (I) where x=z=6 and y=39 (HLB 2); Poloxamer 282, such as the product sold by ICI under the name Pluronic® L92, of formula (I) where x=z=10 and y=47 (HLB 6) ; and most preferably Poloxamer 124, such as the product sold by ICI under the name Pluronic® L44, of formula (I) where x=z=1 1 and y=21 (HLB 16). In a preferred embodiment, the suitable surfactants have an HBL from 7 to 9, or many non-ionic of polyoxyethylene and/or polyoxypropylene copolymers type. They must be liquid so as to be incorporated easily in the composition without it being necessary to heat it.

The surfactant can be classified, according to their structure, under the generic terms "ionic" (anion, cation, amphoteric) or "non-ionic". The non-ionic surfactants are those which does not dissociate in ions in water and are thus insensitive with the variations of pH. Among the surfactants, one uses preferentially, without this list being restrictive, those of the family of Poloxamers and more particularly Poloxamer 124 and/or Poloxamer

182 or such as the propylene glycol, the dipropylene glycol, the propylene glycol dipelargonate, the lauroglycol, the ethoxydiglycol, the sodium docussate.

The gels prepared according to the invention may comprise such surfactant in an amount of about 0.1 % to about 0.5%, preferably about 0.2 %.

The amount of surfactant in medium B can range, for example, from 0.01% to 0.4% by weigh with respect to the total weight of medium B.

The neutralisation of the carboxylic groups in the gelling polymers may be achieved by adding a neutralising agent selected from a base, such as ammoniac, sodium hydroxide, organic amines such as alkylamine, or dialkylamine, trialkyamine, alkanolamine, or dialkanolamine. Said alkylamine can be selected from methylamine, ethylamine. The pH of the final mixture, i.e. after mixing the adapalene medium B in the gelling medium A, is adjusted to about 4.7-5.3.

In a preferred embodiment, the invention provides a method which comprises the steps of: i) preparing a gelling medium A by mixing and optionally dissolving/ solubilising the chelating agent such as EDTA disodium in water, adding propylene glycol and optionally the preservative agent such as methylparaben, mixing, and adding the gelling agent such as Carbopol® 980 (or Carbomer 940), wherein the proportion of propylene glycol/water is between 4% and 5% and preferably around 4,5%; separately ii) dispersing adapalene in water in the presence of a surfactant such as Poloxamer 124, whereby an adapalene medium B is obtained wherein the proportion of adapalene/active phase ration is between water is between 6% and 20%; iii) adding the adapalene medium B to the gelling medium A ; iv) adjusting the pH to about 4.7-5.3 by adding a neutralising agents such as sodium hydroxide

Another subject of the invention is an adapalene gel obtainable by the method of manufacture described herein. Particularly, the subject of the invention is that the gel is produced following this method. Preferably, the gel comprises 0.3% of adapalene. This gel is of particular interest for the treatment of dermatological ailments with an inflammatory or proliferative component, chosen from :

- common acne (acne vulgaris), comedones, polymorphous acne, nodulocystic acne, acne conglobata, secondary acne such as solar, drug-related or occupational acne,

- widespread and/or severe forms of psoriasis, ichtyoses and ichtyosiform states ;

- Darier's disease ;

- actinic keratoses ;

- palmo plantar keratoderma and keratosis pilaris ;

- leucoplasias and leucoplasiform states, lichen planus ; - any benign or malignant, severe and extensive dermatological preparations.

The gel is particularly suitable for the treatment of acne, such as common acne, and in particular for the treatment of common acne of moderate to moderately severe intensity.

The below example is given for illustrative purpose.

BRIEF DESCRIPTION OF THE DRAWING :

Figure 1 is a flow diagram that illustrates the manufacturing process of adapalene gel.

EXAMPLES

EXAMPLE 1 : manufacturing process of adapalene gel 0.3 % (2000kg)

The manufacturing process for commercial production of Adapalene Gel, 0.3% is described as follows. See Figure 1 also. I. CARBOMER MEDIUM a) In a suitably sized, stainless steel primary compounding vessel, purified water is added (88.92%) b) It is placed under a dissolver and mixed. c) The pre-weighed quantity of Edetate Disodium (0.10%) is added and mixed. d) In a stainless steel container, using a dissolver, the pre-weighed quantities of propylene glycol (4%) and methylparaben (0.2%) are added and mixed until completely dissolved. e) The propylene glycol/methylparaben solution is added to the primary compounding vessel and mixed.

f) While mixing, the pre-weighed quantity of Carbomer 940 (Carbopol 980) is added (1.10%). g) The mixing is maintained until the medium is smooth..

II. ADAPALENE MEDIUM a) In another stainless steel vessel, the specified quantity of purified water (1%) is added and mixed. b) The pre-weighed quantities of Poloxamer 124 (0.2%) and Adapalene (0.3%) are added. c) Mixing is maintained until the adapalene is dispersed, d) The adapalene medium is mixed with a dissolver.

III. PRIMARY COMPOUNDING PHASE a) The adapalene medium is transferred to the carbomer medium. b) The medium newly obtained is mixed.

IV. FINAL COMPOUNDING PHASE a) The batch is moved to a counter motion mixer and mixed. b) A solution of pre-weighed sodium hydroxide (0.18%) is prepared with purified water (1%) in a separate container and added to the primary compounding phase. c) The batch is mixed. d) pH is checked and recorded (Range: 4.7 - 5.3). e) If pH is within range, the remaining volume of purified water is added qsp 100%. If pH is below or above the specified range, the batch is adjusted with a solution of hydrochloric acid or sodium hydroxide to pH 5.0 ± 0.3.

V. PRODUCT TESTING, FILLING, AND PACKAGING a) Using a transfer pump, the product is filtered through an 80 mesh filter screen to the filler. b) The bulk product is filled into the specified tubes. The lot code and expiration date are applied to the tube-end seal during the tube sealing operation. c) Representative samples of the packaged product are submitted for testing.

d) Secondary packaging is performed, so that the finished product is obtained.

EXAMPLE 2: manufacturing process of adapalene gel 0.1 % (2000kg) The manufacturing process for commercial production of Adapalene Gel, 0.1% is described as follows. See Figure 1 also.

I. CARBOMER MEDIUM a) In a suitably sized, stainless steel primary compounding vessel, purified water is added (88.92%) b) It is placed under a dissolver and mixed. c) The pre-weighed quantity of Edetate Disodium (0.10%) is added and mixed. d) In a stainless steel container, using a dissolver, the pre-weighed quantities of propylene glycol (4%); phenoxyethanol and methylparaben (0.1%) are added and mixed until completely dissolved. e) The propylene glycol/methylparaben solution is added to the primary compounding vessel and mixed. f) While mixing, the pre-weighed quantity of Carbomer 940 (Carbopol 980) is added (1.10%). g) The mixing is maintained until the medium is smooth..

II. ADAPALENE MEDIUM a) In another stainless steel vessel, the specified quantity of purified water (1%) is added and mixed. b) The pre-weighed quantities of Poloxamer 182 (0.2%) and Adapalene

(0.1%) are added. c) Mixing is maintained until the adapalene is dispersed. d) The adapalene medium is mixed with a dissolver.

III. PRIMARY COMPOUNDING PHASE a) The adapalene medium is transferred to the carbomer medium. b) The medium newly obtained is mixed.

IV. FINAL COMPOUNDING PHASE a) The batch is moved to a counter motion mixer and mixed.

b) A solution of pre-weighed sodium hydroxide (0.18%) is prepared with purified water (1%) in a separate container and added to the primary compounding phase. c) The batch is mixed. d) pH is checked and recorded (Range: 4.7 - 5.3). e) If pH is within range, the remaining volume of purified water is added qsp 100%. If pH is below or above the specified range, the batch is adjusted with a solution of hydrochloric acid or sodium hydroxide to pH 5.0 ± 0.3.

V. PRODUCT TESTING, FILLING, AND PACKAGING a) Using a transfer pump, the product is filtered through an 80 mesh filter screen to the filler. b) The bulk product is filled into the specified tubes. The lot code and expiration date are applied to the tube-end seal during the tube sealing operation. c) Representative samples of the packaged product are submitted for testing. d) Secondary packaging is performed, so that the finished product is obtained.