Patent Application
20230233494
This invention pertains to a ready to use, liquid, orally administered sugar-based formulations of diclofenac potassium with unexpected bioavailability, chemical stability, and palatability.
Diclofenac potassium ([2-(2,6-dichlorophenyl)amino]benzeneacetate, potassium salt) is a potent NSAID (non-steroidal anti-inflammatory drug) used therapeutically for inflammatory conditions and pain management. The solubility of diclofenac potassium (pKa=3.9) is pH dependent. It is sparingly soluble at acidic pH, and the amount of the active substance dissolved in buffered solutions increases with the increasing pH of the dissolution aqueous medium. The stability of Diclofenac and its salts is well known in the solid state: Diclofenac acid and its salts are in fact characterized by a chemical stability when they are taken in their solid state. When dissolved in water, in contrast, the molecule could be expected to undergo a fast and irreversible oxidative degradation according to the auto-oxidation pathway in
Diclofenac is sold in various dosage forms, including tablets (Cataflam®), powders for oral solution (Cambia®), gel-caps (Zipsor®), patches (Flector®), and gels (Voltaren®). Other dosage forms are described, inter alia, in WO 2006/133954 (Reiner et al.), WO 1997/044023 (Reiner et al.), and WO 2003/043600 (Reiner et al.). Given its wide spectrum of action and therapeutic benefit, additional dosage forms are needed for convenience of the patient and additional therapeutic uses. These dosage forms should be bioavailable, chemically stable, and palatable to the user.
Therefore, in one embodiment the invention provides a ready to use liquid formulation of diclofenac or a pharmaceutically acceptable salt thereof comprising: (a) 200 weight parts xylitol; (b) from 150 to 1000 weight parts water; and (c) from 0.5 to 10 weight parts diclofenac or a pharmaceutically acceptable salt thereof.
In another embodiment the invention provides a ready to use liquid formulation of diclofenac or a pharmaceutically acceptable salt thereof comprising: (a) 200 weight parts xylitol; (b) from 50 to 500 weight parts water; (c) from 50 to 900 weight parts polyol (preferably sorbitol); and (d) from 0.5 to 10 weight parts diclofenac or a pharmaceutically acceptable salt thereof.
In still another embodiment the invention provides a method of treating a condition selected from pain and migraine in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the formulation of the present invention.
Additional advantages of the invention are set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
The accompanying drawing, which is incorporated in and constitutes a part of this specification, illustrates several embodiments of the invention and together with the description serves to explain the principles of the invention.
As used in this specification and in the claims which follow, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.
As used in this specification and in the claims which follow, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. When an element is described as comprising a plurality components, steps or conditions, it will be understood that the element can also be described as comprising any combination of such plurality, or “consisting of” or “consisting essentially of” the plurality or combination of components, steps or conditions.
“Therapeutically effective amount” means that amount which, when administered to a human for supporting or affecting a metabolic process, or for treating or preventing a disease, is sufficient to cause such treatment or prevention of the disease, or supporting or affecting the metabolic process.
When ranges are given by specifying the lower end of a range separately from the upper end of the range, or specifying particular numerical values, it will be understood that a range can be defined by selectively combining any of the lower end variables, upper end variables, and particular numerical values that is mathematically possible. In like manner, when a range is defined as spanning from one endpoint to another, the range will be understood also to encompass a span between and excluding the two endpoints.
When used herein the term “about” will compensate for variability allowed for in the pharmaceutical industry and inherent in products in this industry, such as differences in product strength due to manufacturing variation and time-induced product degradation. The term allows for any variation which in the practice of good manufacturing practices would allow the product being evaluated to be considered therapeutically equivalent or bioequivalent in humans to the recited strength of a claimed product.
In the context of the present invention insofar as it relates to any of the disease conditions recited herein, the term “treatment” means to reduce the occurrence of a symptom or condition, or to relieve or alleviate at least one symptom associated with such condition, or to slow or reverse the progression of such condition, or to manage or affect the metabolic processes underlying such condition. Within the meaning of the present invention, the terms also denote to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
The phrase “acceptable” as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a subject (e.g., a mammal such as a human).
In one embodiment the invention provides a ready to use liquid formulation of diclofenac or a pharmaceutically acceptable salt thereof comprising: (a) 200 weight parts xylitol; (b) from 150 to 1000 weight parts water; and (c) from 0.5 to 10 weight parts diclofenac or a pharmaceutically acceptable salt thereof. For ease of reading, the formulations covered by this embodiments will be referred to herein as “the Xylitol Formulations.” As discussed subsequently herein, this terminology does not mean that the formulations are limited to xylitol as the sole polyol, although it will be understood that any of the Xylitol Formulations can contain xylitol as the sole polyol, and that in preferred embodiments the Xylitol Formulations will have xylitol present as the sole polyol.
In another embodiment the invention provides a ready to use liquid formulation of diclofenac or a pharmaceutically acceptable salt thereof comprising: (a) 200 weight parts xylitol; (b) from 50 to 500 weight parts water; (c) from 50 to 900 weight parts polyol (preferably sorbitol); and (d) from 0.5 to 10 weight parts diclofenac or a pharmaceutically acceptable salt thereof. A particularly preferred polyol is sorbitol and an even more preferred sorbitol is non-crystallizing sorbitol, as described in the United States Pharmacopoeia in effect on Dec. 1, 2019. For ease of discussion, formulations covered by this embodiments will be referred to herein as the “the Mixed Polyols Formulations.”
In still another embodiment the invention provides a method of treating a condition selected from pain and migraine in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the formulation of the present invention.
In various subembodiments, the xylitol, water, and diclofenac in the Xylitol Formulations are present in different ratios of weight parts, including:
(a) 200 weight parts xylitol; (b) from 175 to 900 weight parts water; and (c) from 0.75 to 7.5 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 100 to 300 weight parts water; and (c) from 0.2 to 2 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 150 to 250 weight parts water; and (c) from 0.5 to 1.5 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 190 to 210 weight parts water; and (c) from 0.9 to 1.1 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 100 to 300 weight parts water; and (c) from 1 to 2.5 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 150 to 250 weight parts water; and (c) from 1.2 to 2 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 190 to 210 weight parts water; and (c) from 1.6 to 1.8 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 450 to 750 weight parts water; and (c) from 2 to 5.5 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 525 to 675 weight parts water; and (c) from 2.8 to 4.5 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 580 to 620 weight parts water; and (c) from 3.4 to 3.8 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 225 to 475 weight parts water; and (c) from 4 to 6.5 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 300 to 400 weight parts water; and (c) from 4.5 to 5.7 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 335 to 375 weight parts water; and (c) from 4.8 to 5.2 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 650 to 1100 weight parts water; and (c) from 4 to 6.5 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 750 to 1000 weight parts water; and (c) from 4.5 to 5.7 weight parts diclofenac or a pharmaceutically acceptable salt thereof.
(a) 200 weight parts xylitol; (b) from 820 to 900 weight parts water; and (c) from 4.8 to 5.2 weight parts diclofenac or a pharmaceutically acceptable salt thereof.
In like manner, in various other subembodiments, the xylitol, water, polyol and diclofenac in the Mixed Polyol Formulations are present in different ratios of weight parts, including:
(a) 200 weight parts xylitol; (b) from 260 to 360 weight parts water; (c) from 240 to 320 weight parts polyol (preferably sorbitol); and (d) from 1 to 3 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 290 to 330 weight parts water; (c) from 270 to 300 weight parts polyol (preferably sorbitol); and (d) from 1.5 to 2.5 weight parts diclofenac or a pharmaceutically acceptable salt thereof;
(a) 200 weight parts xylitol; (b) from 50 to 150 weight parts water; (c) from 600 to 900 weight parts polyol (preferably sorbitol); and (d) from 1.5 to 3.5 weight parts diclofenac or a pharmaceutically acceptable salt thereof; or
(a) 200 weight parts xylitol; (b) from 60 to 100 weight parts water; (c) from 650 to 800 weight parts polyol (preferably sorbitol); and (d) from 2 to 3 weight parts diclofenac or a pharmaceutically acceptable salt thereof.
The Xylitol Formulations and Mixed Polyol Formulations are preferably present in a unit dosage form comprising a therapeutically effective amount of diclofenac or a pharmaceutically acceptable salt thereof. In various embodiments the therapeutically effective amount comprises about 50 mg of diclofenac or a pharmaceutically acceptable salt thereof. In other embodiments therapeutically effective amount comprises about 50 mg of diclofenac or a pharmaceutically acceptable salt thereof in from about 5 or 8 to about 25 or 50 g (or ml) of said formulation. In other embodiments the therapeutically effective amount comprises about 50 mg of diclofenac or a pharmaceutically acceptable salt thereof in from about 5 or 8 to about 15 g or from about 15 to about 50 g or from about 15 to about 22 g of said formulation. In still other embodiments the therapeutically effective amount comprises about 50 mg of diclofenac or a pharmaceutically acceptable salt thereof in about 20 g of said formulation. The preferred salt of diclofenac in all embodiments is diclofenac potassium.
The unit dosage forms are preferably provided as liquid stick packs that are either consumed as-is, reconstituted in water prior to administration, or consumed as-is followed by the consumption of a liquid chaser. The stick packs are preferably made from one or two sheets of laminate configured to define an interior void sealed around its periphery. The materials used to construct the laminate sheet can be any that are customary in the art, such as polyester, polypropylene, polyethylene and polyethylene terephthalate (PET), provided that the stick pack is sufficiently tear resistant until correctly manipulated. In preferred embodiments the laminate comprises a layer of aluminum foil. Examples of suitable designs for stick packs are described, for example in US 2015/0144518A1 and US20030168375A1. Suitable stick packs can also be purchased from companies such as Unette Corporation (Randolph N.J.), Amcor 360 Packaging Solutions (Melbourne Australia).
In another embodiment the formulation is present in a stick pack marketed as Lamiflex™ 4 by G. Bianchini comprising a trilaminate of polyester, aluminum and polyethylene. In one embodiment the formulation is present in a stick pack comprising a trilaminate of polyester, aluminum and polyethylene, wherein said trilaminate: (a) has a layer thickness of 12/8.5/65 μm, respectively; (a) has a weight of 16.8/22.9/59.9 g/mq, respectively; (c) has micropores in the aluminum layer less than 300/mq.
In another embodiment the formulation is present in a stick pack marketed as PerfecPharm™ P311 by Amcor 360 Packaging Solutions characterized by one or a combination of the following physical properties:
The Xylitol Formulations of the present invention can also comprise a polyol in addition to xylitol, preferably selected from ethylene and or propylene glycol; glycerol; erythritol; threitol; arabitol; ribitol; mannitol; sorbitol; galactitol; fucitol; iditol; inositol; volemitol; isomalt; maltitol; lactitol; maltotriitol; maltotetraitol; and polyglycitol. A particularly preferred sorbitol is non-crystallizing sorbitol solution, as described in the United States Pharmacopoeia in effect on Dec. 1, 2019.
Polyols useful in the Mixed Polyol Formulations include, for example, ethylene and or propylene glycol; glycerol; sorbitol erythritol; threitol; arabitol; ribitol; mannitol; galactitol; fucitol; iditol; inositol; volemitol; isomalt; maltitol; lactitol; maltotriitol; maltotetraitol; and polyglycitol. The Mixed Polyol Formulations of the present invention can also comprise a second polyol in addition to xylitol and the first polyol. Preferred second polyols in the Mixed Polyol Formulations are preferably selected from ethylene and or propylene glycol; sorbitol; glycerol; erythritol; threitol; arabitol; ribitol; mannitol; galactitol; fucitol; iditol; inositol; volemitol; isomalt; maltitol; lactitol; maltotriitol; maltotetraitol; and polyglycitol.
Preferred embodiments of the Xylitol Formulation and the Mixed Polyol Formulations do not contain glycerol. Preferred embodiments of the Xylitol Formulation and the Mixed Polyol Formulations also do not contain ethanol.
The Xylitol Formulation and the Mixed Polyol Formulations also preferably comprise an alkalizing agent. Although bicarbonates are preferred alkalizing agents, it will be understood that the formulations can contain any alkalizing agent capable of producing the desired pH (preferably about 7.0 to about 9.5, about 7.5 to about 9.0, or about 8.0 to about 9.0). Such compounds include, by way of example and without limitation, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, triethanolamine, and trolamine and others known to those of ordinary skill in the art. The diclofenac is preferably present in the formulations of the present invention as diclofenac potassium and the alkalizing agent present as potassium bicarbonate, preferably at a weight ratio of about 50:22 (potassium bicarbonte:potassium bicarbonate).
The Xylitol Formulation and the Mixed Polyol Formulations can also comprise additional ingredients selected from the group consisting of thickeners and sweeteners and taste modifying agents. In another embodiment the formulation comprises additional ingredients selected from the group consisting of sucralose, polyvinylpyrrolidone and hydroxyethylcellulose. Suitable taste-masking agents include cellulose hydroxypropyl ethers (HPC); low-substituted hydroxypropyl ethers (L-HPC); cellulose hydroxypropyl methyl ethers (HPMC); methylcellulose polymers; ethylcelluloses (EC) and mixtures thereof; Polyvinyl alcohol (PVA); hydroxyethylcelluloses; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC); polyvinyl alcohol and polyethylene glycol co-polymers; monoglycerides, triglycerides, polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers; cellulose acetate phthalate; sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures thereof.
Suitable flavoring agents include acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate, maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, neotame, acesulfame potassium, mannitol, talin, xylitol, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, and mixtures thereof.
The Xylitol Formulation and the Mixed Polyol Formulations can also comprise various buffering agents, stabilizing agents, or antioxidants, including, in particular, EDTA as an antioxidant or chelating agent.
The Xylitol Formulation and the Mixed Polyol Formulations can also be characterized by a density from about 1.02 to about 1.5 g/ml, from about 1.05 to about 1.35 g/ml, or from about 1.1 to about 1.25 g/ml. The Xylitol Formulation and the Mixed Polyol Formulations can also be characterized by a pH of from about 7.0 to about 9.5, or a pH of from about 8.0 to about 9.0. The Xylitol Formulation and the Mixed Polyol Formulations can also be characterized by less than about 1% total impurities, or less than about 1% total impurities after storage at 40° C.±2° C. and 75% RH±5% RH for three or six months. The known impurities are reported in
In the following examples, efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods claimed herein are made and evaluated and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.
For all the prototypes the Xylisorb™ 300 manufactured by Roquette (Lestrem, France) was used. For all the stability results the reporting threshold for impurities was 0.1%, according to ICH Q3B R2.
The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac Potassium in 20 g of formula; formulations differ based on the use of nitrogen during the manufacturing.
Manufacturing Method: PFS DK 46-bkT038/122
In a glass container transfer the total quantity of water and under stirring add the Xylitol; treat the solution with nitrogen flow for about 30 minutes and wait for the complete dissolution. Add Potassium Bicarbonate and wait for the complete dissolution (about 5 minutes); maintain the system under stirring and under nitrogen flow. Add Diclofenac Potassium and wait at least 2 hours maintaining the system under stirring and under nitrogen flow for all the time. Filter and store the solution in the selected container. Treat the headspace of the container with nitrogen flow before closing the container (amber glass vial).
Manufacturing Method: PFS DK 43-bkT038/118
In a glass container transfer the total quantity of water and, under stirring, add the Xylitol and wait for complete dissolution. Add Potassium Bicarbonate and wait for complete dissolution (about 5 minutes); maintain the system under stirring. Add Diclofenac Potassium and wait at least 2 hours maintaining the system under stirring. Filter and store the solution in the selected container (amber glass vial).
The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac Potassium in 20 g of formula; sorbitol and xylitol are mixed for both the prototypes that have the same quali/quantitative formula, but differ based on the use of nitrogen during the manufacturing.
Manufacturing Method—PFS DK 49-bkT038/126
In a glass container transfer the total quantity of Non crystallizing Sorbitol Solution USP 70% and, under stirring, add the Xylitol and water; treat the solution with nitrogen flow for about 30 minutes. Add Potassium Bicarbonate and wait for the complete dissolution (about 5 minutes); maintain the system under stirring and under nitrogen flow. Add Diclofenac Potassium and wait at least 2 hours maintaining the system under stirring and under nitrogen flow for all the time. Filter and store the solution in the selected container. Treat the headspace of the container with nitrogen flow before close the container (amber glass vial).
Manufacturing Method—PFS DK 44-bkT038/119
In a glass container transfer the total quantity of Non crystallizing Sorbitol Solution 70%, and, under stirring, add the Xylitol and water. Add Potassium Bicarbonate and wait for the complete dissolution (about 5 minutes); maintain the system under stirring. Add Diclofenac Potassium and wait at least 2 hours maintaining the system under stirring. Filter and store the solution in the selected container (amber glass vial).
The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac Potassium in 20 g of formula; sorbitol and xylitol are mixed for both the prototypes that have the same quali/quantitative formula, but differ based on the use of nitrogen during the manufacturing.
For the Manufacturing Methods of-PFS DK 48-bkT038/125 and PFS DK 45-bkT038/120 (in Amber Glass Vials) Refer to Example 2
The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac Potassium in 11.8 g of formula; formulations differ for the presence of Mint flavor in the PFS DK 161-7.
For the Manufacturing Method—PFS DK 161-bkT038/294 Refer to Example 1 (Stick Pack Laminex 42
Manufacturing Method—PFS DK 161-7-bkT038/295
In a glass container transfer the total quantity of water and, under stirring, add the Xylitol and wait for the complete dissolution. Add Potassium Bicarbonate and wait for the complete dissolution (about 5 minutes); maintain the system under stirring. Add Diclofenac Potassium and wait at least 2 hours maintaining the system under stirring. Add the mint flavor and maintain the system under stirring for 30 minutes. Store the solution in the selected container (Stick Pack Laminex 4).
The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac Potassium in 20 g of formula; formulations differ for the presence of Mint flavor in the PFS DK 171-7.
Manufacturing Method—PFS DK 171-bkT038/310
Transfer water and xylitol in the equipment and heat up without exceed 40° C. of the solution; mix under vacuum for about 20 minutes combining propeller/contra-propeller (26 rpm/84 rpm); check visually for a complete dissolution and cool the solution to 25-30° C. Add Potassium Hydrogen Bicarbonate and mix under vacuum for about 5-10 minutes combining propeller/contra-propeller (26 rpm/34 rpm). Check visually for a complete dissolution. Add Diclofenac Potassium and mix under vacuum for about 30-60 minutes combining propeller/contra-propeller (26 rpm/34 rpm). Check visually for a complete dissolution. Transfer to the selected container (Stick Pack Lamiflex 4).
Manufacturing Method—PFS DK 171-7-bkT038/311
Transfer water and xylitol in the equipment and heat up without exceed 40° C. of the solution; mix under vacuum for about 20 minutes combining propeller/contra-propeller (26 rpm/84 rpm); check visually for a complete dissolution and cool the solution to 25-30° C. Add Potassium Hydrogen Bicarbonate and mix under vacuum for about 5-10 minutes combining propeller/contra-propeller (26 rpm/34 rpm). Check visually for a complete dissolution. Add Diclofenac Potassium and mix under vacuum for about 30-60 minutes combining propeller/contra-propeller (26 rpm/34 rpm). Check visually for a complete dissolution. Add the mint flavor and stir for 30 minutes. Transfer to the selected container (Stick Pack Lamiflex 4).
The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac Potassium in 11.8 of formula; formulations differ for the presence of Mint flavor in the PFS DK 172-7. The present formulations represent the big laboratory batches of the PFS DK 161 and PFS DK 161-7.
For the Manufacturing Method—PFS DK 172-bkT038/314 and PFS DK 172-7-bkT038/315 Refers to Example 5 (Stick Pack Lamiflex 4)
The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac Potassium in 11.8 g of formula; formulations differ for the presence of Mint flavor in the PFS DK 174-7.
Manufacturing Method—PFS DK 174-bkT038/329
Transfer water and xylitol in the equipment and heat up without exceed 40° C. of the solution; mix under vacuum for about 20 minutes combining propeller/contra-propeller (26 rpm/84 rpm); check visually for a complete dissolution and cool the solution to 25-30° C. Add Potassium Hydrogen Bicarbonate, Sucralose and mix under vacuum for about 5-10 minutes combining propeller/contra-propeller (26 rpm/34 rpm). Check visually for a complete dissolution. Add Diclofenac Potassium and mix under vacuum for about 30-60 minutes combining propeller/contra-propeller (26 rpm/34 rpm). Check visually for a complete dissolution. Transfer to the selected container (Stick Pack Lamiflex 4).
Manufacturing Method—PFS DK 174-7-bkT038/330
Transfer water and xylitol in the equipment and heat up without exceed 40° C. of the solution; mix under vacuum for about 20 minutes combining propeller/contra-propeller (26 rpm/84 rpm); check visually for a complete dissolution and cool the solution to 25-30° C. Add Potassium Hydrogen Bicarbonate, Sucralose and mix under vacuum for about 5-10 minutes combining propeller/contra-propeller (26 rpm/34 rpm). Check visually for a complete dissolution. Add Diclofenac Potassium and mix under vacuum for about 30-60 minutes combining propeller/contra-propeller (26 rpm/34 rpm). Check visually for a complete dissolution. Add the mint flavor and stir for 30 minutes (Stick Pack Lamiflex 4).
The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac Potassium in 11.1 g of formula; formulations differ for the presence of Mint flavor in the PFS DK 165-7.
For the Manufacturing Method—PFS DK 165-bkT038/307 and Manufacturing Method—PFS DK 165-7-bkT038/317 Refers to Example 5 (Stick Pack Lamiflex 4)
The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac Potassium in 5.6 g of formula; formulations differ for the presence of Mint flavor in the PFS DK 166-7.
For the Manufacturing Method—PFS DK 166-bkT038/308 and Manufacturing Method—PFS DK 166-7-bkT038/318 Refers to Example 5 (Stick Pack Lamiflex 4)
The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac Potassium in 10.7 g of formula; formulations differ for the presence of Mint flavor in the PFS DK 167-7.
For the Manufacturing Method—PFS DK 167-bkT038/309 and Manufacturing Method—PFS DK 167-7-bkT038/319 Refers to Example 5 (Stick Pack Lamiflex 4)
The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac Potassium in 10.7 g of formula; formulations differ for the presence of Mint flavor in the PFS DK 175-7.
Manufacturing Method—PFS DK 175-bkT038/331
In a glass container transfer the total quantity of water and, under stirring, add the Xylitol and wait for the complete dissolution. Add Potassium Bicarbonate, Sucralose and wait for the complete dissolution (about 5 minutes); maintain the system under stirring. Add Diclofenac Potassium and wait at least 2 hours maintaining the system under stirring; Store the solution in the selected container
Manufacturing Method—PFS DK 175-7-bkT038/332
In a glass container transfer the total quantity of water and, under stirring, add the Xylitol and wait for the complete dissolution. Add Potassium Bicarbonate, Sucralose and wait for the complete dissolution (about 5 minutes); maintain the system under stirring. Add Diclofenac Potassium and wait at least 2 hours maintaining the system under stirring. Add the mint flavor and stir for 30 minutes. Transfer to the selected container
For both the prototypes, the stability was evaluated in two different primary packaging materials in order to investigate their performances
At this purpose two plurilaminate materials have been investigated:_
PerfecPharm™ a plurilaminate manufactured by Perfecseal
Lamiflex 4 a plurilaminate manufactured by Bianchini
The stability data on the flavored prototype (as representative of both the prototypes) are reported.
The stability data collected highlighted the different performances of the two packaging materials; the formulation stored in the PerfecPharm stick packs is characterized by a little bit higher content of impurities at all the storage conditions.
The Lamiflex 4 material seems the most suitable for the packaging of the Diclofenac liquid formulations.
The following formulations have been prepared to obtain a ready to use liquid solution containing 50 mg of Diclofenac Potassium in 11.8 g of formula; formulations differ for the presence of Mint flavor in the PFS DK 176-7.
Manufacturing Method—PFS DK 176-bkT038/333
In a glass container transfer the total quantity of water and, under stirring, add the Xylitol and wait for the complete dissolution. Add Potassium Bicarbonate and wait for the complete dissolution (about 5 minutes); maintain the system under stirring. Add Diclofenac Potassium and wait at least 2 hours maintaining the system under stirring; Store the solution in the selected container.
Manufacturing Method—PFS DK 176-7-bkT038/334
In a glass container transfer the total quantity of water and, under stirring, add the Xylitol and wait for the complete dissolution. Add Potassium Bicarbonate and wait for the complete dissolution (about 5 minutes); maintain the system under stirring. Add Diclofenac Potassium and wait at least 2 hours maintaining the system under stirring. Add the mint flavor and stir for 30 minutes. Transfer to the selected container.
Also for these prototypes the stability has been evaluated in the two different primary packaging materials as per the formulations described in Example 11.
The stability data on the flavored prototype (as representative of both the prototypes) are reported.
The stability data collected confirmed the conclusions on the primary packaging material reported in Example 11.
The Lamiflex 4 material seems the most suitable for the packaging of the Diclofenac liquid formulations.
The following formulations have been prepared to confirm the stability of the final prototypes already described in the previous Examples 6-7-8-11-10 in the Lamiflex 4 stick packs
All the tested formulations seem stable after 3 and 6 months at 40° C. 75% HR.
The aspect of the solution changed a little bit becoming slightly yellow clear solution
The pH remains quite stable
The Assay of Diclofenac remain in the tentative specifications (95-105%)
All the known impurities remain in the tentative specifications (lower than 0.2%). There is the presence of some unknown impurities (UNK 4 and UNK 10):UNK 4 impurity for the prototypes PFS DK 180 and 180-7 showed a content higher than 0.3%.
The total impurities are lower than 1%
In consideration of the regulatory limits in terms of Xylitol content, the formulations PFS DK 179 and PFS DK 179-7 can be considered the best options because in addition to the stability profile, they are compliant with the FDA guidelines.
Xylitol based liquid diclofenac prototypes were evaluated in the presence of Simulated Gastric Fluid (SGF) prepared according to USP 42. SGF was prepared by dissolving 2.0 g of sodium chloride and 3.2 g of purified pepsin, derived from porcine stomach mucosa, with an activity of 800 to 2500 units per mg of protein, in 7.0 ml of hydrochloric acid and sufficient water to make 1000 mL. This test solution has a pH of about 1.2. Three different tests were performed:
Test 1—to Mimic the Intake of the Formulations Taken without Water
Dilute a single dose of diclofenac formulation with 45 ml of SGF (37° C.). At the acidic pH value of SGF, diclofenac precipitates. Filter the precipitate, wash it with HCl 0.1N and dry.
Dilute a single dose of each diclofenac formulation with 240 ml of drinking water. Add 45 ml of SGF (37° C.). At the acidic pH value of the test solution composed of drinking water and SGF, diclofenac precipitates. Filter the precipitate 5 minutes after the addition of SGF, wash with HCl 0.1N and dry. Centrifuge the filtered solution in order to recover the precipitate eventually passed through the filter, wash with HCl 0.1 N and dry.
Dilute a single dose of each diclofenac formulation with 45 ml of SGF (37° C.). After 1 minute, add 240 ml of drinking water. At the acidic pH value of the test solution composed of drinking water and SGF, diclofenac precipitates. Filter the precipitate 5 minutes after the addition of SGF, wash with HCl 0.1N and dry. Centrifuge the filtered solution in order to recover the precipitate eventually passed through the filter, wash with HCl 0.1 N and dry.
Product formulations tested were:
For all reported results, n.a. means there was no (or insufficient) precipitate in the centrifuge test tube to measure, and n.p. means not performed. Total diclofenac recovered means the total diclofenac recovered from the filtered precipitate and the centrifuged precipitate (after drying), and is based either on a 100 mg or 200 mg theoretical recovery.
The xylitol based formulations exhibited similar behavior to the reference marketed products in the Test 1 conditions.
The xylitol based formulations exhibited similar behavior to the reference marketed products in the Test 2 conditions.
The xylitol based formulations exhibited the same behavior of the reference marketed products in the Test 3 conditions.
According to the collected data, the xylitol based diclofenac liquid prototypes showed similar behavior to the two reference marketed products in three different methods that simulated three possible ways to take the drug products. The presence of 19-50% xylitol in the formulation (based on the dose weight) in the xylitol prototypes doesn't affect the behavior of diclofenac potassium, which showed the similar precipitation percentage and kinetics observed for the marketed products in the in vitro conditions tested. The similar behavior of the xylitol based formulations and the reference marketed products could be predictive of in vivo behavior similar to the marketed products.
Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2021/055041 | 6/8/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63037483 | Jun 2020 | US |
