WO2020094736A1 - Lipidic solutions of nsaids - Google Patents
Lipidic solutions of nsaids Download PDFInfo
- Publication number
- WO2020094736A1 WO2020094736A1 PCT/EP2019/080435 EP2019080435W WO2020094736A1 WO 2020094736 A1 WO2020094736 A1 WO 2020094736A1 EP 2019080435 W EP2019080435 W EP 2019080435W WO 2020094736 A1 WO2020094736 A1 WO 2020094736A1
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- WIPO (PCT)
- Prior art keywords
- oil
- aspirin
- choline
- liquid
- choline salt
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
Definitions
- the present invention relates to the field of liquid pharmaceutical compositions comprising a non-steroidal anti-inflammatory agent (NS AID) dissolved in a lipidic liquid, particularly aspirin dissolved in a lipidic liquid.
- a non-steroidal anti-inflammatory agent NSARI
- aspirin dissolved in a lipidic liquid
- Soft gelatine capsules known also as liquid capsules, are suitable dosage forms for peroral administration.
- non-aqueous solvents used for soft gelatine capsules may not be directly equivalent to the aqueous solutions in terms of bioavailability, there are numerous drug products on the market that allow administration of active pharmaceutical agents per os in dissolved form, and claim the advantages of rapid onset of action, and others.
- NSAIDs are drugs pertaining to an important class, wherein the rapid onset of action is sometimes particularly desired.
- Acetylsalicylic acid known also as aspirin, for example, is one such drug, that is now extensively used as platelets’ aggregation inhibitor.
- Aspirin being chemically an ester, is sensitive to hydrolysis by water, therefore its stability is of particular importance for the formulation.
- PCT publication WO 2017/095736 discloses aspirin soft gel capsules, comprising a suspension of aspirin in an oil and a surfactant.
- US patent 9,687,551 discloses a dispersion of a phospholipid and an NSAID in a liquid gel capsule.
- US patent 8,802,656 discloses complex formation between ibuprofen and lecithin under heating in acetone, and evaporation of solvent to obtain the complex that is dispersible in an oil or water.
- Chinese patent application CN106928055 discloses syntheses of aspirin in several ionic liquids, comprising choline chloride and various acids, in which the separation of aspirin is effected by addition of water.
- NSAIDs particularly aspirin
- lipids such as oils
- choline salt e.g. chloride
- a polar aprotic solvent e.g. dimethyl sulfoxide
- aspirin may combine with choline chloride and a tertiary solid component, such as proline, malic acid, citric acid, urea, or D-xylitol, to create a liquid.
- This aspirin-containing liquid is obtained under heating.
- Binary complexes of aromatic acids and polar solvents were also discussed in Kochegina, A. A. et al, Zhurnal Obshchei Khimii (1976), 46(5), 1141-6.
- compositions comprising an NSAID, particularly aspirin, in a liquid form suitable for manufacturing of soft gel capsules.
- these compositions remain stable under prolonged storage.
- method for manufacturing such liquid compositions using conventional pharmaceutical processing equipment, e.g. without the need for prolonged and/or extreme heating, preferably at ambience.
- the present invention demonstrates a solution for such problems, by providing a composition and a process for manufacturing (preferably under ambient conditions) of a liquid mixture of aspirin comprising choline salt, e.g. chloride, an aprotic polar solvent, e.g.
- a pharmaceutical liquid mixture of an NSAID preferably of aspirin.
- the mi ture comprises the NSAID, choline salt, preferably choline chloride, an aprotic polar solvent, and optionally a polar protic cosolvent, especially polyol.
- choline salts may include tartrate, bitartrate, dihydrogen citrate, acetate and sulphate.
- the aprotic polar solvent is DMSO.
- Other aprotic polar solvents may include dimethylacetamide (DMA). Examples of polyols that can serve as cosolvents are glycerol and propylene glycol.
- the pharmaceutical liquid mixture of aspirin has the advantage of being miscible with lipids, e.g. oils, to form pharmaceutical lipid solution of aspirin; i.e. aspirin remains in dissolved form upon addition of an oil to the mixture, preferably in the proportions suitable for filling soft gelatine capsules.
- the term“miscible with oil” may usually indicate that a composition remains clear from solid particles upon addition of an oil, e.g. soybean lecithin oil or olive oil, from 0.1 %wt of oil and up to 75 %wt of oil.
- the liquid mixture e.g. aspirin / choline salt / aprotic polar solvent
- the lipid solutions e.g. aspirin / choline salt / aprotic polar solvent dissolved in a suitable oil
- aspirin can be successfully solubilized in oils, at ambient temperature and in all proportion, in the presence of a choline salt, e.g. chloride, and an aprotic polar solvent, optionally with the aid of a cosolvent.
- a choline salt e.g. chloride
- an aprotic polar solvent optionally with the aid of a cosolvent.
- a method of manufacturing of a pharmaceutical liquid mixture of NSAID preferably of aspirin.
- the method comprises combining, preferably at a temperature below 35 °C, e.g., under ambient temperature, aspirin, choline salt, an aprotic polar solvent (preferably DMSO), optionally a polar protic cosolvent, and mixing until dissolution.
- aprotic polar solvents may include dimethylacetamide.
- the ambient temperature is usually the acceptable temperature at the production floor of a pharmaceutical factory, e.g. controlled room temperature.
- suitable temperature is in the range between 20.0 and 29.0 °C, or from 25.0 °C to 29.0-3l.0°C, i.e., with slight heating.
- a stable pharmaceutical lipid solution of aspirin comprises aspirin, choline salt, e.g. chloride, an aprotic polar solvent, (preferably DMSO), optionally a polar protic cosolvent and a liquid lipid.
- aprotic polar solvents may include dimethylacetamide.
- the liquid lipid is preferably an oil, e.g. lecithin-rich oil.
- the lipid solution of aspirin may be filled into soft gelatine capsules to provide a dosage form of aspirin.
- a soft gelatine capsule comprising the lipid solution of aspirin forms an additional aspect of the invention.
- the capsule size suitable for such dosage forms may vary from size“1” to size“00”.
- the concentration of aspirin therefore in the stable pharmaceutical lipid solution may vary from about 7.5 weight by volume % (i.e. 75 mg per 1000 pL) to about 32 weight by volume % (i.e. 160 mg per 500 pL).
- Another aspect of the invention is a process of preparing a pharmaceutical lipid solution, comprising combining aspirin, choline salt, an aprotic polar solvent and optionally a polar protic solvent preferably at ambient temperature/at a temperature below 35 °C to form a liquid, and mixing the obtained liquid with an oil to form the pharmaceutical lipid solution.
- a preferred order of addition consists of dissolving the choline salt in the aprotic polar solvent (optionally in the presence of the polar protic solvent; that is, when used, glycerol, propylene glycol or polyethylene glycol is combined with the polar aprotic solvent before choline chloride addition), then adding the aspirin to form a clear liquid, following which the oil is mixed with said clear liquid to afford the pharmaceutical lipid solution.
- the polar protic solvent that is, when used, glycerol, propylene glycol or polyethylene glycol
- the pharmaceutical solution of the invention is pharmaceutically acceptable, i.e. do not produce an adverse, allergic or other untoward reaction when administered to a patient.
- aspirin in the present invention means molecular aspirin.
- An aprotic polar solvent suitable for use in the invention is a pharmaceutically acceptable aprotic polar solvent that may be selected from classes such as sulfoxides, ketones, esters, amides, either linear or cyclic, which is liquid at ambient temperature.
- suitable aprotic polar solvents for a lipid solution of the present invention are dimethyl acetamide, dimethyl sulfoxide and/or a mixture of at least two of these.
- a polyol cosolvent such as glycerol, polyethylene glycol or propylene glycol
- glycerol polyethylene glycol or propylene glycol
- the polyol cosolvent is usually needed when dimethylacetamide acts as the major solvent.
- solubilization of aspirin in oil is most preferably achieved according to the invention with the aid of ternary mixture consisting of aspirin/choline salt/DMSO, or a quaternary mixture consisting of aspirin/choline salt/DMA/polyol; experimental results reported below indicate that both the ternary and quaternary systems can be readily dissolved in various oils to afford the desired lipidic solutions of aspirin. DMSO-based systems could also benefit from the addition of the polyol, to achieve increased aspirin loading in the oil (lipidic) solution.
- a lipid liquid according to the invention may be an oil, liquid at ambient temperature.
- the oil may be poor in or devoid of lecithin, e.g. containing less than 20 %wt, e.g. or less than 10 %wt, or less than 5 %wt, or less than 1 %wt, or 0.5 %wt of lecithin.
- the oil may be a lecithin oil.
- lecithin oil refers to any natural or synthetic lipid mixtures, which are naturally rich or fortified with phosphatidylcholines.
- lecithin oil may have at least 20 % wt of lecithin, and up to 80 %wt of lecithin.
- the suitable oils may be any liquid lipid, e.g. oil, of animal and vegetable origin, or/and fractions thereof, virgin or refined, for food and pharmaceutical uses.
- the oil may be selected from the group consisting of seaweed oil, almond oil, peanut oil, argan oil, avocado oil, wheat germ oil, camelina oil, safflower oil, hemp or goatseed oil, canola oil, cotton oil, coprah or coconut oil, pumpkin seed oil, prickly pear oil, linseed oil, corn oil, mustard oil, hazelnut oil, walnut oil, macadamia nut oil, olive oil, evening primrose oil, palm oil, eyelet oil, pistachio oil, grape seed oil, castor oil, sesame oil, soya oil, sunflower oil, coconut oil, olea europaea oil, soybean lecithin oil, rapeseed lecithin oil, sunflower lecithin oil, and lysolecithin oil, sacha Inchi oil, tiger nut oil, fish oils, cod liver oil, palm oil and paraffin oil, an omega 3 oil, docosahexaenoic acid (DHA) and/or its esters
- soybean oil olive oil, almond oil, sunflower oil, paraffin oil, grape seed oil, peanut oil, myglyol, rapeseed oil, palm oil, argan oil, corn oil, omega 3 oil, castor oil, EPA and DHA (alone or mixed together at 50/50), and mixtures thereof.
- the pharmaceutical lipid solution of the present invention can further comprise at least one antioxidant agent suitable for lipid systems.
- suitable antioxidant agent is alpha (a)-tocopherol.
- suitable antioxidants include lipopholic antioxidants, such as beta-, delta- and gamma- tocopherols, ascorbyl palmitate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and a combination of two or more of the above.
- a molar ratio between aspirin and choline salt (e.g., chloride) may usually be from 1: 1 up to 13:1 aspirin to choline salt, e.g., from 1 :1 to 10:1.
- a ratio from 1 :1 to 3: 1, such as 1.75: 1 to 2.25:1 aspirin to choline salt, more preferably about 2: 1, can be used.
- broader aspirin/choline salt molar ratios are also workable, e.g., from 1 :1 to about 5: 1, for example, from 3: 1 to 5:1, e.g., 3.75: 1 to 4.25: 1, namely around 4: 1.
- the molar ratio between the aprotic polar solvent and choline salt may be from 5: 1 to 50: 1, e.g. molar ratio from 5:1 to 20:1, such as 5:1 to 10:1, e.g., 7:1 to 10:1.
- the dimethyl sulfoxide and choline salt can be combined at a molar ratio from 5:1 to 50:1, e.g., 5: 1 to 10: 1, such as 7: 1 to 9: 1, particularly at molar ratio about 8: 1.
- a molar ratio between aspirin, choline salt and DMSO may be in the range of (1.75-13) : 1 : (5- 10), e.g., (1.75-5) : 1 : (5-10), more specifically (1.75-5) : 1 : (7-9).
- Illustrative ratios are about 2: 1:8 and 4: 1:8.
- a molar ratio from 5: 1 to 50: 1 of dimethyl acetamide to choline salt can be used, e.g., molar ratio of 10: 1 to 25:1.
- a molar ratio between aspirin, choline salt and DMA may be in the range of (1.75-13) : 1 : (10-25).
- the molar ratio between the aprotic polar solvent and the polyol cosolvent, e.g., glycerol may be from 3: 1 to 15: 1.
- lipid solution comprising or consisting of:
- - Choline salt such as chloride or bitartrate
- the molar ratio choline salt to aspirin is from 1: 1 to 1 :5, more particularly at molar ratio about 1 :2 or 1 :4 choline salt : aspirin
- - Dimethyl sulfoxide wherein the molar ratio dimethyl sulfoxide to choline salt (e.g., chloride) is from 5: 1 to 10: 1 dimethyl sulfoxide : choline salt, more particularly at molar ratio 8: 1 dimethyl sulfoxide : choline salt
- lipid solution comprising or consisting of:
- choline chloride such as chloride or bitartrate
- molar ratio choline chloride to aspirin is from 1 :1 to 1:5, more particularly at molar ratio about 1:2 or 1:4 choline salt : aspirin;
- Dimethyl sulfoxide wherein the molar ratio dimethyl sulfoxide to choline chloride is from 5:1 to 10: 1 dimethyl sulfoxide : choline salt, more particularly at molar ratio 8: 1 dimethyl sulfoxide : choline salt,
- lipid solution comprising or consisting of:
- choline salt such as chloride or bitartrate
- the molar ratio choline salt to aspirin is from 1: 1 to 1 :5, more particularly at molar ratio about 1 :2 or 1 :4 choline salt : aspirin,
- dimethylacetamide e.g., chloride
- choline salt e.g., chloride
- polystyrene resin such as glycerol, polyethylene glycol or propylene glycol, wherein the molar ratio dimethylacetamide to polyol is from 3:1 to 15:1,
- lipid solution comprising or consisting of:
- choline chloride such as chloride or bitartrate
- molar ratio choline chloride to aspirin is from 1 :1 to 1:5, more particularly at molar ratio about 1:2 or 1:4 choline salt : aspirin;
- dimethylacetamide e.g., chloride
- choline salt e.g., chloride
- polystyrene resin such as glycerol, polyethylene glycol or propylene glycol, wherein the molar ratio dimethylacetamide to polyol is from 3:1 to 15:1,
- a pharmaceutical liquid mixture of aspirin, and the lipid solution of aspirin of the present invention can be advantageously prepared according to any conventional methods for solution preparation.
- the ingredients may be added consequently one after another after complete dissolution of each previously added ingredient, e.g. by mixing together choline chloride and an aprotic polar solvent (and optionally the protic polar solvent), and adding consecutively aspirin and optionally the oil.
- the dissolution of ingredients can be achieved under agitation at room temperature or slightly above, e.g., up to 35 °C.
- an oil e.g. lecithin oil
- the lipid formulations can be used in the manufacture of soft gelatine capsules as known in the art.
- Another aspect of the present invention provides a unit dose of aspirin comprising a pharmaceutical lipid solution described herein, e.g. soft gelatine capsules as described herein.
- the unit doses of aspirin, e.g. soft gelatine capsules may be prepared as known in the art, using the pharmaceutical lipid solution.
- the pharmaceutical lipid solution is formulated as oral pharmaceutical composition, especially as soft gelatine capsules, providing a unit dose of aspirin comprising a pharmaceutical lipid solution described before.
- Said soft gelatine capsules of the present invention may have a volume, e.g. in the range of 0.5 -1.0 ml.
- a unit dose of the solution comprises aspirin in a weight in the range of between 75 and 160 mg, particularly 81-100 mg, more particularly about 81 mg.
- the unit dose of the present invention has a volume of 0.5-1.0 ml, which contains aspirin by weight in the range of between 75-160 mg, particularly 80-100 mg, more particularly about 81 mg.
- the unit dose of the present invention is of a volume of 0.5 ml minimum and contains 81 mg of aspirin and lecithin oil, in sufficient quantity for 0.5 ml minimum.
- the present invention provides a pharmaceutical lipid solution, or a pharmaceutical lipid solution in a unit dose containing 75-160 mg of aspirin, for its use as a medicament in the prevention of cardiovascular disorders, such as myocardial infarction and/or stroke, and/or symptomatic treatment of mild to moderate pain and fever.
- Figures 1A is a photograph showing that the combination of an oil (soybean oil) with the ternary mixture aspirin/choline salt/DMSO affords a solution.
- Figure 1B is a photograph showing that addition of aspirin to soybean oil at ambience does not result in a formation of a solution.
- Figure 2A is a photograph showing that addition of aspirin to DMSO at ambience does not result in a formation of a solution.
- Figure 2B a photograph showing a solid mixture consisting aspirin and choline chloride.
- Figure 2C is a photograph of a clear transparent colourless liquid obtained by dissolving choline chloride in DMSO.
- Figure 2D is a photograph of clear transparent colourless liquid consisting of the ternary mixture aspirin/choline salt/DMSO.
- Figures 3A-3C are chromatograms attesting to the stability of the formulation of the invention.
- Stage 1 DMSO was poured into a volumetric 20-mL Pyrex glass vessel.
- Stage 2 an appropriate amount of choline chloride according to Table 1 was added to the DMSO while maintaining the mixing using magnetic stirrer at ambient temperature until the choline chloride was completely dissolved. A clear liquid was obtained, as shown in the Figure 2C, demonstrating the photograph of a clear transparent colourless liquid.
- Stage 3 suitable quantity of aspirin according to Table 1 was added to solution from step 2, while maintaining the mixing until complete dissolution of aspirin. A clear mixture was obtained, as shown in the Figure 2D, demonstrating the photograph of a further clear transparent colourless liquid.
- Stage 4 suitable quantity of soybean lecithin oil was added to the previous mixture while maintaining the mixing until a clear lipid solution is obtained.
- a photograph of the obtained solution is presented in the Figure 1A. The solution is clear of a yellow hue, and air bubbles can be seen at the bottom.
- the chemical stability of aspirin was evaluated by HPLC. Said procedure is suitable for the aspirin assay using an external standard.
- the assay of aspirin is achieved by comparing the response of a sample solution with the response of aspirin reference standard solution prepared at a similar nominal concentration and analysed in the same way.
- the sample and reference standard solutions, 20 pL injections, were analysed by reversed phase HPLC and UV detection using a suitable column and chromatography conditions as described herein.
- HPLC assay uses a liquid chromatograph fitted with a UV detector set to 222 nm, equipped with column of Interchim® VKR5 Cl 8 (250 x 4.6 mm, 5 pm particle size).
- Acetonitrile, acetic acid and pure water are used to prepare mobile phase A (5/95/0.07 v/v/v Acetonitrile/Water/Acetic acid) and mobile phase B (50/50/0.05 v/v/v Acetonitrile/Water/Acetic acid), eluting at 1 mL/min.
- the gradient was set as follows in the table 1.1 below:
- Figures 3A-3C demonstrate the obtained chromatograms.
- Figure 3A demonstrates excipients-only chromatogram, with very few minor peaks and no peaks eluting at either 17 minutes or 19 minutes.
- the areas under the curve inherent in the aspirin peaks are comparable at time 0 (figure 3B) and at 15 days (figure 3C), which shows that the formulation does not make aspirin unstable, even under stress conditions. No degradant peak was observed at 17 minutes (corresponding to the salicylic acid) in either chromatogram.
- Binary and ternary mixtures were prepared according to Table 4 below, along the lines outlined in Example 1. The outcome was recorded as either liquid or solid. The amounts are expressed in molar ratios. The reference in given to the Examples of the present application.
- Ternary mixtures were prepared according to Table 5 below, and tested for solubility in oil. The amounts are expressed in molar ratios.
- oils tested included in addition to the previously tested olive oil and soybean oil: almond oil, sunflower oil, paraffin oil, peanut oil, myglyol, rapeseed oil, palm oil, argan oil, corn oil, omega 3 and castor oil. All tested oils formed readily mixable solutions with the aspirin/choline chloride/DMSO ternary mixture. The oil solutions exhibit good stability against precipitate formation or phase separation during storage.
- Ternary/quaternary mixtures consisting of aspirin, choline chloride, DMSO and glycerol were prepared by the order of mixing set out in Example 1, at a temperature of 29-30 °C (when used, glycerol was combined with DMSO, before choline chloride addition).
- the formulations are presented in Table 7 below, where the molar ratio corresponds to aspirin : choline chloride : DMSO : glycerol. Transparent liquids were formed. Next, the oil component was added, the resultant formulations were stored under ambient conditions and visually inspected once a week over a period of one month.
- the aspirin/choline chloride/DMSO mixtures could be formulated across a broad range of molar ratios, optionally with the aid of glycerol (or propylene glycol, which has been found to be suitable as well), to create transparent liquids.
- these transparent liquids are soluble in oils, with the resultant solutions being stable against precipitate formation during storage.
- glycerol or propylene glycol, which has been found to be suitable as well
- Ternary/quaternary mixtures consisting of aspirin, choline bitartrate, DMSO and glycerol were prepared by the order of mixing set out in Example 1 , at a temperature of 29-31 ° C (when used, glycerol was combined with DMSO, before choline chloride addition) .
- the formulations are presented in Table 8 below, where the molar ratio that is indicated corresponds to aspirin : choline bitartrate : DMSO : glycerol. Transparent liquids were formed. Next, the oil component was added, the resultant formulations were stored under ambient conditions and visually inspected each day over a period of seven days.
- Quaternary mixtures consisting of aspirin, choline chloride, DMA and glycerol were prepared by the order of mixing set out in Example 1 (glycerol was combined with DMA before choline chloride addition) at a temperature of 29-31 °C.
- the formulations are presented in Table 9 below, where the molar ratio corresponds to aspirin : choline chloride : DMA : glycerol. The clarity of the so-formed mixtures was examined.
- Example 10 (comparative based on US 9,731,026)
- the liquids reported in US 9,731,026 consist of aspirin, choline chloride and a third component, as shown in Table 1 of US 9,731,026.
- the formulations chosen for the comparative study are l5b, l7a and l8b of Table 1 of US 9,731,026, where the third component of the aspirin-containing liquid is tartaric acid, citric acid and urea, respectively.
- the aspirin-containing ternary mixtures were prepared by vigorously mixing the individual components at 70 °C to form a liquid. Then oil was added, and the mixture was stirred at 70 °C to solubilize the aspirin-containing liquid in the oil.
- the compositions prepared and the results are shown in Table 10. The molar ratio corresponds to aspirin/choline chloride/third component. Table 10
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Abstract
A pharmaceutical liquid mixture comprising aspirin, choline salt and an aprotic polar solvent, wherein said pharmaceutical liquid mixture is miscible with an oil. An oil solution comprising said mixture and a process for preparing such oil solutions are also provided.
Description
LIPIDIC SOLUTIONS OF NSAIDS
The present invention relates to the field of liquid pharmaceutical compositions comprising a non-steroidal anti-inflammatory agent (NS AID) dissolved in a lipidic liquid, particularly aspirin dissolved in a lipidic liquid.
The availability of an administered drug to the treated subject, and hence the efficacy of the treatment, is in many ways dependent on the solubility of the drug. Drugs that are administered perorally, for example, as solid dosage forms, require that the drug be released from them before it could be available for absorption into the body, from the gastrointestinal tract. Poorly soluble drugs, in which the extent and/or sometimes the kinetics of the dissolution process is low, may miss the opportunity to absorb, and may then be excreted in faeces. Solutions are sometimes attractive dosage forms for active pharmaceutical agent, as they contain the agent in a dissolved form, and are often used as reference dosage forms to evaluate the peroral bioavailability. While the advantages of the solutions are apparent, their drawbacks as being liquid result in poor taste-masking, large volumes to administer, and sometimes impaired stability of labile active pharmaceutical agents. Soft gelatine capsules, known also as liquid capsules, are suitable dosage forms for peroral administration. Whereas non-aqueous solvents used for soft gelatine capsules may not be directly equivalent to the aqueous solutions in terms of bioavailability, there are numerous drug products on the market that allow administration of active pharmaceutical agents per os in dissolved form, and claim the advantages of rapid onset of action, and others.
NSAIDs are drugs pertaining to an important class, wherein the rapid onset of action is sometimes particularly desired. Acetylsalicylic acid, known also as aspirin, for example, is one such drug, that is now extensively used as platelets’ aggregation inhibitor. Aspirin being chemically an ester, is sensitive to hydrolysis by water, therefore its stability is of particular importance for the formulation.
PCT publication WO 2017/095736 discloses aspirin soft gel capsules, comprising a suspension of aspirin in an oil and a surfactant. Similarly, US patent 9,687,551 discloses a dispersion of a phospholipid and an NSAID in a liquid gel capsule. US patent 8,802,656 discloses complex formation between ibuprofen and lecithin under heating in acetone, and evaporation of solvent to obtain the complex that is dispersible in an oil or water. Intriguingly, Chinese patent application CN106928055 discloses syntheses of aspirin in several ionic liquids, comprising choline chloride and various acids, in which the separation of aspirin is effected by addition of water.
It has now been found that NSAIDs, particularly aspirin, can be readily dissolved in lipids, such as oils, at ambient temperature, with the aid of choline salt, e.g. chloride, and a polar aprotic solvent, e.g. dimethyl sulfoxide. It is perhaps worth mentioning that it has been reported in US 9,731,026 that aspirin may combine with choline chloride and a tertiary solid component, such as proline, malic acid, citric acid, urea, or D-xylitol, to create a liquid. This aspirin-containing liquid is obtained under heating. Binary complexes of aromatic acids and polar solvents were also discussed in Kochegina, A. A. et al, Zhurnal Obshchei Khimii (1976), 46(5), 1141-6.
There is a need in the art to provide a composition comprising an NSAID, particularly aspirin, in a liquid form suitable for manufacturing of soft gel capsules. There is a further need in the art that these compositions remain stable under prolonged storage. There is a further need to provide a method for manufacturing such liquid compositions using conventional pharmaceutical processing equipment, e.g. without the need for prolonged and/or extreme heating, preferably at ambience. The present invention demonstrates a solution for such problems, by providing a composition and a process for manufacturing (preferably under ambient conditions) of a liquid mixture of aspirin comprising choline salt, e.g. chloride, an aprotic polar solvent, e.g. dimethyl sulfoxide (DMSO), the mixture being miscible with lipids, e.g. oils, in the proportions suitable for filling soft gelatine capsules.
Thus, in a broadest aspect of the invention there is provided a pharmaceutical liquid mixture of an NSAID, preferably of aspirin. The mi ture comprises the NSAID, choline salt, preferably choline chloride, an aprotic polar solvent, and optionally a polar protic cosolvent, especially polyol. Other choline salts may include tartrate, bitartrate, dihydrogen citrate, acetate and sulphate. Preferably, the aprotic polar solvent is DMSO. Other aprotic polar solvents may include dimethylacetamide (DMA). Examples of polyols that can serve as cosolvents are glycerol and propylene glycol.
The pharmaceutical liquid mixture of aspirin has the advantage of being miscible with lipids, e.g. oils, to form pharmaceutical lipid solution of aspirin; i.e. aspirin remains in dissolved form upon addition of an oil to the mixture, preferably in the proportions suitable for filling soft gelatine capsules. For example, the term“miscible with oil” may usually indicate that a composition remains clear from solid particles upon addition of an oil, e.g. soybean lecithin oil or olive oil, from 0.1 %wt of oil and up to 75 %wt of oil. The liquid mixture (e.g. aspirin / choline salt / aprotic polar solvent) and the lipid solutions (e.g. aspirin / choline salt / aprotic polar solvent dissolved in a suitable oil) are homogeneous systems with the components being dispersed on molecular level one in another.
It has now been unexpectedly found that without resorting to high temperature and/or large volume of organic solvents, as demonstrated in the appended examples, aspirin can be successfully solubilized in oils, at ambient temperature and in all proportion, in the presence of a choline salt, e.g. chloride, and an aprotic polar solvent, optionally with the aid of a cosolvent.
Thus in a further aspect there is provided a method of manufacturing of a pharmaceutical liquid mixture of NSAID, preferably of aspirin. The method comprises combining, preferably at a temperature below 35 °C, e.g., under ambient temperature, aspirin, choline salt, an aprotic polar solvent (preferably DMSO), optionally a polar protic cosolvent, and mixing until dissolution. Other aprotic polar solvents may include dimethylacetamide. The ambient temperature is usually the acceptable temperature at the production floor of
a pharmaceutical factory, e.g. controlled room temperature. For example, suitable temperature is in the range between 20.0 and 29.0 °C, or from 25.0 °C to 29.0-3l.0°C, i.e., with slight heating.
It has been observed that aspirin and small amounts of an aprotic polar solvent such as dimethyl sulfoxide, or dimethylacetamide, and a choline salt, e.g. chloride, particularly when present in a certain molar ratio range, become liquid at ambient temperature. Without being bound by a theory it is believed that due to reciprocal interactions involving the formation of hydrogen bonds a complex, e.g. between aspirin / choline chloride / dimethyl sulfoxide, is formed which makes it possible to substantially increase aspirin solubility in oils. In addition, it is observed that the resultant aspirin-containing oil solution, was stable against precipitation and degradation, at 40°C for at least 15 days, i.e. for the duration of the test as demonstrated herein below. It is also believed that hydrogen bonds formed between aspirin, dimethyl sulfoxide and choline may prevent the ester function of aspirin from being exposed to hydrolysis.
In a further aspect there is provided a stable pharmaceutical lipid solution of aspirin. The lipid solution comprises aspirin, choline salt, e.g. chloride, an aprotic polar solvent, (preferably DMSO), optionally a polar protic cosolvent and a liquid lipid. Other aprotic polar solvents may include dimethylacetamide. The liquid lipid is preferably an oil, e.g. lecithin-rich oil. The lipid solution of aspirin may be filled into soft gelatine capsules to provide a dosage form of aspirin. A soft gelatine capsule comprising the lipid solution of aspirin forms an additional aspect of the invention. The capsule size suitable for such dosage forms may vary from size“1” to size“00”.
The concentration of aspirin therefore in the stable pharmaceutical lipid solution may vary from about 7.5 weight by volume % (i.e. 75 mg per 1000 pL) to about 32 weight by volume % (i.e. 160 mg per 500 pL).
Another aspect of the invention is a process of preparing a pharmaceutical lipid solution, comprising combining aspirin, choline salt, an aprotic polar solvent and optionally a polar
protic solvent preferably at ambient temperature/at a temperature below 35 °C to form a liquid, and mixing the obtained liquid with an oil to form the pharmaceutical lipid solution.
A preferred order of addition consists of dissolving the choline salt in the aprotic polar solvent (optionally in the presence of the polar protic solvent; that is, when used, glycerol, propylene glycol or polyethylene glycol is combined with the polar aprotic solvent before choline chloride addition), then adding the aspirin to form a clear liquid, following which the oil is mixed with said clear liquid to afford the pharmaceutical lipid solution.
The pharmaceutical solution of the invention is pharmaceutically acceptable, i.e. do not produce an adverse, allergic or other untoward reaction when administered to a patient.
As used herein, the term“aspirin” in the present invention means molecular aspirin.
An aprotic polar solvent suitable for use in the invention is a pharmaceutically acceptable aprotic polar solvent that may be selected from classes such as sulfoxides, ketones, esters, amides, either linear or cyclic, which is liquid at ambient temperature. Examples of specific suitable aprotic polar solvents for a lipid solution of the present invention are dimethyl acetamide, dimethyl sulfoxide and/or a mixture of at least two of these.
As pointed out above, a polyol cosolvent, such as glycerol, polyethylene glycol or propylene glycol, may be used to facilitate the creation of homogeneous pharmaceutical lipid solutions of aspirin, that are stable against precipitate formation or phase separation. The polyol cosolvent is usually needed when dimethylacetamide acts as the major solvent. Stated otherwise, solubilization of aspirin in oil is most preferably achieved according to the invention with the aid of ternary mixture consisting of aspirin/choline salt/DMSO, or a quaternary mixture consisting of aspirin/choline salt/DMA/polyol; experimental results reported below indicate that both the ternary and quaternary systems can be readily dissolved in various oils to afford the desired lipidic solutions of aspirin.
DMSO-based systems could also benefit from the addition of the polyol, to achieve increased aspirin loading in the oil (lipidic) solution.
A lipid liquid according to the invention may be an oil, liquid at ambient temperature. The oil may be poor in or devoid of lecithin, e.g. containing less than 20 %wt, e.g. or less than 10 %wt, or less than 5 %wt, or less than 1 %wt, or 0.5 %wt of lecithin. Alternatively, and more preferably, the oil may be a lecithin oil. The term“lecithin oil” as used herein refers to any natural or synthetic lipid mixtures, which are naturally rich or fortified with phosphatidylcholines. Particularly, lecithin oil may have at least 20 % wt of lecithin, and up to 80 %wt of lecithin. The suitable oils may be any liquid lipid, e.g. oil, of animal and vegetable origin, or/and fractions thereof, virgin or refined, for food and pharmaceutical uses. For instance, the oil may be selected from the group consisting of seaweed oil, almond oil, peanut oil, argan oil, avocado oil, wheat germ oil, camelina oil, safflower oil, hemp or goatseed oil, canola oil, cotton oil, coprah or coconut oil, pumpkin seed oil, prickly pear oil, linseed oil, corn oil, mustard oil, hazelnut oil, walnut oil, macadamia nut oil, olive oil, evening primrose oil, palm oil, eyelet oil, pistachio oil, grape seed oil, castor oil, sesame oil, soya oil, sunflower oil, coconut oil, olea europaea oil, soybean lecithin oil, rapeseed lecithin oil, sunflower lecithin oil, and lysolecithin oil, sacha Inchi oil, tiger nut oil, fish oils, cod liver oil, palm oil and paraffin oil, an omega 3 oil, docosahexaenoic acid (DHA) and/or its esters, eicosapentaenoic acid (EPA) and/or its esters, docosapentaenoic acid (DPA) and/or its esters.
Especially preferred are soybean oil, olive oil, almond oil, sunflower oil, paraffin oil, grape seed oil, peanut oil, myglyol, rapeseed oil, palm oil, argan oil, corn oil, omega 3 oil, castor oil, EPA and DHA (alone or mixed together at 50/50), and mixtures thereof.
According to an embodiment of the present invention, the pharmaceutical lipid solution of the present invention can further comprise at least one antioxidant agent suitable for lipid systems. An example of suitable antioxidant agent is alpha (a)-tocopherol. Other suitable antioxidants include lipopholic antioxidants, such as beta-, delta- and gamma- tocopherols, ascorbyl palmitate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and a combination of two or more of the above.
A molar ratio between aspirin and choline salt (e.g., chloride) may usually be from 1: 1 up to 13:1 aspirin to choline salt, e.g., from 1 :1 to 10:1. For example, a ratio from 1 :1 to 3: 1, such as 1.75: 1 to 2.25:1 aspirin to choline salt, more preferably about 2: 1, can be used. But broader aspirin/choline salt molar ratios are also workable, e.g., from 1 :1 to about 5: 1, for example, from 3: 1 to 5:1, e.g., 3.75: 1 to 4.25: 1, namely around 4: 1.
The molar ratio between the aprotic polar solvent and choline salt (e.g., chloride) may be from 5: 1 to 50: 1, e.g. molar ratio from 5:1 to 20:1, such as 5:1 to 10:1, e.g., 7:1 to 10:1.
For example, in the variant of the invention involving the use of dimethyl sulfoxide, the dimethyl sulfoxide and choline salt can be combined at a molar ratio from 5:1 to 50:1, e.g., 5: 1 to 10: 1, such as 7: 1 to 9: 1, particularly at molar ratio about 8: 1. Thus, a molar ratio between aspirin, choline salt and DMSO may be in the range of (1.75-13) : 1 : (5- 10), e.g., (1.75-5) : 1 : (5-10), more specifically (1.75-5) : 1 : (7-9). Illustrative ratios are about 2: 1:8 and 4: 1:8.
For example, in the variant of the invention involving the use of dimethylacetamide/polyol system, a molar ratio from 5: 1 to 50: 1 of dimethyl acetamide to choline salt can be used, e.g., molar ratio of 10: 1 to 25:1. Thus, a molar ratio between aspirin, choline salt and DMA may be in the range of (1.75-13) : 1 : (10-25). In such cases, the molar ratio between the aprotic polar solvent and the polyol cosolvent, e.g., glycerol, may be from 3: 1 to 15: 1.
In specific embodiments, there is provided a pharmaceutical lipid solution comprising or consisting of:
- 75-100 mg of aspirin per 0.5 ml minimum, particularly 75-81 mg per 0.50 ml minimum, more particularly 81 mg per 0.50 ml minimum,
- Choline salt, such as chloride or bitartrate, wherein the molar ratio choline salt to aspirin is from 1: 1 to 1 :5, more particularly at molar ratio about 1 :2 or 1 :4 choline salt : aspirin,
- Dimethyl sulfoxide, wherein the molar ratio dimethyl sulfoxide to choline salt (e.g., chloride) is from 5: 1 to 10: 1 dimethyl sulfoxide : choline salt, more particularly at molar ratio 8: 1 dimethyl sulfoxide : choline salt,
- oil, in particular the preferred oils mentioned above, in sufficient quantity for 0.5 ml minimum.
In another specific embodiment, there is provided a pharmaceutical lipid solution comprising or consisting of:
- 75-160 mg of aspirin per 1.0 ml maximum, particularly 75-81 mg per 1.0 ml maximum, more particularly 81 mg per 1.0 ml maximum or 160 mg per 1.0 ml maximum;
- Choline salt, such as chloride or bitartrate, wherein the molar ratio choline chloride to aspirin is from 1 :1 to 1:5, more particularly at molar ratio about 1:2 or 1:4 choline salt : aspirin;
- Dimethyl sulfoxide, wherein the molar ratio dimethyl sulfoxide to choline chloride is from 5:1 to 10: 1 dimethyl sulfoxide : choline salt, more particularly at molar ratio 8: 1 dimethyl sulfoxide : choline salt,
- oil, in particular the preferred oils mentioned above, in sufficient quantity for 1.0 ml maximum.
In another specific embodiment, there is provided a pharmaceutical lipid solution comprising or consisting of:
- 75-100 mg of aspirin per 0.5 ml minimum, particularly 75-81 mg per 0.50 ml minimum, more particularly 81 mg per 0.50 ml minimum,
- Choline salt, such as chloride or bitartrate, wherein the molar ratio choline salt to aspirin is from 1: 1 to 1 :5, more particularly at molar ratio about 1 :2 or 1 :4 choline salt : aspirin,
- Dimethylacetamide, wherein the molar ratio dimethylacetamide to choline salt (e.g., chloride) is from 10: 1 to 25:1 dimethylacetamide : choline salt,
- polyol, such as glycerol, polyethylene glycol or propylene glycol, wherein the molar ratio dimethylacetamide to polyol is from 3:1 to 15:1,
- oil, in particular the preferred oils mentioned above, in sufficient quantity for 0.5 ml minimum.
In another specific embodiments, there is provided a pharmaceutical lipid solution comprising or consisting of:
- 75-160 mg of aspirin per 1.0 ml maximum, particularly 75-81 mg per 1.0 ml maximum, more particularly 81 mg per 1.0 ml maximum or 160 mg per 1.0 ml maximum;
- Choline salt, such as chloride or bitartrate, wherein the molar ratio choline chloride to aspirin is from 1 :1 to 1:5, more particularly at molar ratio about 1:2 or 1:4 choline salt : aspirin;
- Dimethylacetamide, wherein the molar ratio dimethylacetamide to choline salt (e.g., chloride) is from 10: 1 to 25:1 dimethylacetamide : choline salt,
- polyol, such as glycerol, polyethylene glycol or propylene glycol, wherein the molar ratio dimethylacetamide to polyol is from 3:1 to 15:1,
- oil, in particular the preferred oils mentioned above, in sufficient quantity for 1.0 ml maximum.
A pharmaceutical liquid mixture of aspirin, and the lipid solution of aspirin of the present invention can be advantageously prepared according to any conventional methods for solution preparation. The ingredients may be added consequently one after another after complete dissolution of each previously added ingredient, e.g. by mixing together choline chloride and an aprotic polar solvent (and optionally the protic polar solvent), and adding consecutively aspirin and optionally the oil. The dissolution of ingredients can be achieved under agitation at room temperature or slightly above, e.g., up to 35 °C. After complete dissolution of all ingredients in an oil, e.g. lecithin oil, the lipid formulations can be used in the manufacture of soft gelatine capsules as known in the art.
Another aspect of the present invention provides a unit dose of aspirin comprising a pharmaceutical lipid solution described herein, e.g. soft gelatine capsules as described herein. The unit doses of aspirin, e.g. soft gelatine capsules, may be prepared as known in the art, using the pharmaceutical lipid solution.
In one embodiment of the present invention, the pharmaceutical lipid solution is formulated as oral pharmaceutical composition, especially as soft gelatine capsules, providing a unit dose of aspirin comprising a pharmaceutical lipid solution described before. Said soft gelatine capsules of the present invention may have a volume, e.g. in the range of 0.5 -1.0 ml. According to an embodiment of the invention, a unit dose of the solution comprises aspirin in a weight in the range of between 75 and 160 mg, particularly 81-100 mg, more particularly about 81 mg. In a preferred embodiment, the unit dose of the present invention has a volume of 0.5-1.0 ml, which contains aspirin by weight in the range of between 75-160 mg, particularly 80-100 mg, more particularly about 81 mg. In a more preferred embodiment, the unit dose of the present invention is of a volume of 0.5 ml minimum and contains 81 mg of aspirin and lecithin oil, in sufficient quantity for 0.5 ml minimum.
The present invention provides a pharmaceutical lipid solution, or a pharmaceutical lipid solution in a unit dose containing 75-160 mg of aspirin, for its use as a medicament in the prevention of cardiovascular disorders, such as myocardial infarction and/or stroke, and/or symptomatic treatment of mild to moderate pain and fever.
In the drawings:
Figures 1A is a photograph showing that the combination of an oil (soybean oil) with the ternary mixture aspirin/choline salt/DMSO affords a solution.
Figure 1B is a photograph showing that addition of aspirin to soybean oil at ambience does not result in a formation of a solution.
Figure 2A is a photograph showing that addition of aspirin to DMSO at ambience does not result in a formation of a solution.
Figure 2B a photograph showing a solid mixture consisting aspirin and choline chloride. Figure 2C is a photograph of a clear transparent colourless liquid obtained by dissolving choline chloride in DMSO.
Figure 2D is a photograph of clear transparent colourless liquid consisting of the ternary mixture aspirin/choline salt/DMSO.
Figures 3A-3C are chromatograms attesting to the stability of the formulation of the invention.
EXAMPLES
Example 1
Aspirin 81 mg formulation with choline chloride, DMSO and soybean lecithin oil
The formulation is presented in Table 1 below.
Table 1
Preparation method:
Stage 1: DMSO was poured into a volumetric 20-mL Pyrex glass vessel.
Stage 2: an appropriate amount of choline chloride according to Table 1 was added to the DMSO while maintaining the mixing using magnetic stirrer at ambient temperature until the choline chloride was completely dissolved. A clear liquid was obtained, as shown in the Figure 2C, demonstrating the photograph of a clear transparent colourless liquid.
Stage 3: suitable quantity of aspirin according to Table 1 was added to solution from step 2, while maintaining the mixing until complete dissolution of aspirin. A clear mixture was obtained, as shown in the Figure 2D, demonstrating the photograph of a further clear transparent colourless liquid.
Stage 4: suitable quantity of soybean lecithin oil was added to the previous mixture while maintaining the mixing until a clear lipid solution is obtained. A photograph of the
obtained solution is presented in the Figure 1A. The solution is clear of a yellow hue, and air bubbles can be seen at the bottom.
The following experiments below were also conducted.
When 81 mg of aspirin are added to soybean lecithin oil at ambience, a dispersion is formed, a photograph whereof can be seen in the Figure 1B. Similarly, when 81 mg of aspirin were mixed with either 150 mg of DMSO or with 35 mg of choline chloride, at ambience, no solution was obtained, as demonstrated in the Figures 2A (DMSO) and 2B (choline chloride) - a white solid is readily observed in both photographs. Moreover, when the clear liquid obtained at stage 2 was directly mixed with lecithin oil, without aspirin, a dispersion was obtained.
The chemical stability of aspirin was evaluated by HPLC. Said procedure is suitable for the aspirin assay using an external standard. The assay of aspirin is achieved by comparing the response of a sample solution with the response of aspirin reference standard solution prepared at a similar nominal concentration and analysed in the same way. The sample and reference standard solutions, 20 pL injections, were analysed by reversed phase HPLC and UV detection using a suitable column and chromatography conditions as described herein. HPLC assay uses a liquid chromatograph fitted with a UV detector set to 222 nm, equipped with column of Interchim® VKR5 Cl 8 (250 x 4.6 mm, 5 pm particle size). Acetonitrile, acetic acid and pure water are used to prepare mobile phase A (5/95/0.07 v/v/v Acetonitrile/Water/Acetic acid) and mobile phase B (50/50/0.05 v/v/v Acetonitrile/Water/Acetic acid), eluting at 1 mL/min. The gradient was set as follows in the table 1.1 below:
The approximate equilibration time required was 45 minutes. Aspirin was eluted under these conditions at about 19 minutes, and salicylic acid at about 17 minutes.
The following samples were prepared and analysed by said HPLC method:
- Aspirin reference standard (STD): about 30 mg of accurately weighed aspirin were transferred quantitatively into a lOO-ml volumetric flask and filled to volume with mobile phase B to obtain a concentration of about 0.30 mg/ml.
- Excipients sample free of aspirin (EXC): about 12 mg of choline chloride, 52 mg of DMSO and 167 mg of lecithin were transferred into a 100-ml volumetric flask and filled to volume with mobile phase B .
- Aspirin product (formula with excipients, ASP): About 10 mL of the formulation of Table 1, were exposed to 40°C for 15 days, in a heating oven. At the end of this exposure, an aliquot of about 265 mg from this sample was accurately weighed into a 300-ml volumetric flask, and filled to volume with mobile phase B.
The chromatographic profile of the product resulting from the heat treatment of the tested formulation was identical to that of the starting solution.
Figures 3A-3C demonstrate the obtained chromatograms. Figure 3A demonstrates excipients-only chromatogram, with very few minor peaks and no peaks eluting at either 17 minutes or 19 minutes. As can be readily seen in the Figures 3B-3C, for both solutions, the areas under the curve inherent in the aspirin peaks are comparable at time 0 (figure 3B) and at 15 days (figure 3C), which shows that the formulation does not make aspirin unstable, even under stress conditions. No degradant peak was observed at 17 minutes (corresponding to the salicylic acid) in either chromatogram.
Example 2
Aspirin 81 mg formulation with choline chloride, DMSO and olive oil
The formulation is presented in Table 2 below.
Preparation method: as in Example 1, with olive oil used instead of soybean lecithin oil. A clear solution was obtained.
Table 2
Example 3
Aspirin 81 mg formulation with choline chloride, DMA and soybean lecithin oil
The formulation is presented in Table 3 below.
Table 3:
Preparation method: as in Example 1, with DMA used instead of DMSO. A clear solution was obtained.
Example 4
Binary and ternary mixtures were prepared according to Table 4 below, along the lines outlined in Example 1. The outcome was recorded as either liquid or solid. The amounts
are expressed in molar ratios. The reference in given to the Examples of the present application.
Table 4
Example 5
Ternary mixtures were prepared according to Table 5 below, and tested for solubility in oil. The amounts are expressed in molar ratios.
Table 5
* Soybean lecithin
Examples 6A-6B
Aspirin formulations with choline chloride, DMSO and various oils
A series of tests was performed to evaluate the compatibility of the aspirin/choline chloride/DMSO ternary mixture with various oils. The ternary mixture was prepared by the order of steps described in Example 1 at temperature of about 30 °C to give a transparent liquid, following which the oil was added. The samples obtained were stored under ambient conditions and visually inspected once a week over a period of at least one month. Compositions (e.g., molar ratio of the aspirin/choline chloride/DMSO and amounts) and results are set out in Table 6.
Table 6
The oils tested included (in addition to the previously tested olive oil and soybean oil): almond oil, sunflower oil, paraffin oil, peanut oil, myglyol, rapeseed oil, palm oil, argan oil, corn oil, omega 3 and castor oil. All tested oils formed readily mixable solutions with the aspirin/choline chloride/DMSO ternary mixture. The oil solutions exhibit good stability against precipitate formation or phase separation during storage.
Examples 7A-7E (of the invention) and 7F (comparative)
Aspirin formulations with choline chloride, DMSO, glycerol (optionally)
and olive oil
Ternary/quaternary mixtures consisting of aspirin, choline chloride, DMSO and glycerol were prepared by the order of mixing set out in Example 1, at a temperature of 29-30 °C (when used, glycerol was combined with DMSO, before choline chloride addition). The formulations are presented in Table 7 below, where the molar ratio corresponds to aspirin
: choline chloride : DMSO : glycerol. Transparent liquids were formed. Next, the oil component was added, the resultant formulations were stored under ambient conditions and visually inspected once a week over a period of one month.
Table 7
It is seen that the aspirin/choline chloride/DMSO mixtures could be formulated across a broad range of molar ratios, optionally with the aid of glycerol (or propylene glycol, which has been found to be suitable as well), to create transparent liquids. In turn, these transparent liquids are soluble in oils, with the resultant solutions being stable against precipitate formation during storage. By contrast, in the absence of the choline salt, full dissolution of the drug was not achieved and formation of crystals was observed almost instantaneously upon addition of the oil (comparative Example 7F).
Examples 8A and 8B
Aspirin formulation with choline bitartrate, DMSO, glycerol (optionally)
and olive oil
Ternary/quaternary mixtures consisting of aspirin, choline bitartrate, DMSO and glycerol were prepared by the order of mixing set out in Example 1 , at a temperature of 29-31 ° C (when used, glycerol was combined with DMSO, before choline chloride addition) . The
formulations are presented in Table 8 below, where the molar ratio that is indicated corresponds to aspirin : choline bitartrate : DMSO : glycerol. Transparent liquids were formed. Next, the oil component was added, the resultant formulations were stored under ambient conditions and visually inspected each day over a period of seven days.
Table 8
The results tabulated in Table 8 indicate the stability of the tested aspirin formulations against precipitate formation. The same results were obtained on replacing glycerol with propylene glycol.
Examples 9A-9C
Aspirin formulation with choline chloride, dimethylacetamide, glycerol
and olive oil
Quaternary mixtures consisting of aspirin, choline chloride, DMA and glycerol were prepared by the order of mixing set out in Example 1 (glycerol was combined with DMA before choline chloride addition) at a temperature of 29-31 °C. The formulations are presented in Table 9 below, where the molar ratio corresponds to aspirin : choline chloride : DMA : glycerol. The clarity of the so-formed mixtures was examined.
Next, the oil component was added, the resultant formulations were stored under ambient conditions and visually inspected once a week over a period of one month.
Table 9
It is seen that quaternary mixtures consisting of aspirin, choline chloride, DMA and glycerol enable dissolution of the drug in oil. Although increased aspirin loading may result in hazy appearance of the aspirin/choline chloride/DMA/ glycerol system (see example 9C), an effective solubilization is achieved in the final oily solution, which retained it stability against precipitate formation over the test period.
Example 10 (comparative based on US 9,731,026)
Three illustrative aspirin-containing liquids reported in US 9,731,026 were reproduced, to test their solubility in oil. The liquids reported in US 9,731,026 consist of aspirin, choline chloride and a third component, as shown in Table 1 of US 9,731,026. The formulations chosen for the comparative study are l5b, l7a and l8b of Table 1 of US 9,731,026, where the third component of the aspirin-containing liquid is tartaric acid, citric acid and urea, respectively.
The aspirin-containing ternary mixtures were prepared by vigorously mixing the individual components at 70 °C to form a liquid. Then oil was added, and the mixture was stirred at 70 °C to solubilize the aspirin-containing liquid in the oil. The compositions prepared and the results are shown in Table 10. The molar ratio corresponds to aspirin/choline chloride/third component.
Table 10
It is seen that the ternary mixtures create viscous liquids (at 70 °C and after cooling to room temperature, in line with the observations made in US 9,731,026). However, these viscous liquids did not mix with the oil at 70° C under stirring for six hours. Full phase separation was observed upon cooling the oil-containing mixture to room temperature and allowing it to stand for twenty-four hours. Thus, the aspirin-containing liquids of US 9,731,026 do not enable solubilization of aspirin in oil.
Claims
1. A pharmaceutical liquid mixture comprising aspirin, choline salt and an aprotic polar solvent, wherein said pharmaceutical liquid mixture is miscible with an oil.
2. The liquid mixture according to claim 1, wherein said choline salt is selected from the group consisting of choline chloride, choline tartrate, choline bitartrate, choline dihydrogen citrate, choline acetate or choline sulphate.
3. The liquid mixture according to claim 2, wherein the choline salt is choline chloride or choline bitartrate.
4. The liquid mixture according to any one of claims 1 to 3, wherein the aprotic polar solvent is dimethyl sulfoxide or dimethylacetamide.
5. The liquid mixture according to claim 4, wherein the aprotic polar solvent is dimethyl sulfoxide.
6. The liquid mixture according to claim 5, comprising aspirin, choline salt and dimethyl sulfoxide, wherein the molar ratios of the aspirin, choline salt and dimethyl sulfoxide solvent are in the ranges of (1.75-13) : (1) : (5-10).
7. The liquid mixture according to any one of the preceding claims, wherein the mixture further comprises a polar protic cosolvent.
8. The liquid mixture according to claim 7, wherein the polar protic cosolvent is a polyol.
9. The liquid mixture according to claim 8, wherein the polyol is glycerol, propylene glycol or a mixture thereof.
10. The liquid mixture according to claim 7 or 8, comprising aspirin, choline salt, dimethylacetamide and a polyol.
11. The mixture according to claim 10, wherein the molar ratios of the aspirin, choline salt and dimethylacetamide are in the ranges of (1.75:13) : (1) : (10-25).
12. The mixture according to claim 11, wherein the molar ratio of the dimethylacetamide and polyol is in the range of 3: 1 to 15:1.
13. A pharmaceutical lipid solution comprising an oil and the pharmaceutical liquid mixture as defined in any one of claims 1 to 12.
14. The pharmaceutical lipid solution according to claim 13, wherein the oil is selected from the group consisting of soybean oil, olive oil, almond oil, sunflower oil,
paraffin oil, peanut oil, myglyol, rapeseed oil, palm oil, argan oil, corn oil, omega 3 oil, castor oil and a combination thereof.
15. A unit dose of aspirin comprising a pharmaceutical lipid solution as defined in any one of claims 13 or 14, comprising aspirin, choline salt, an aprotic polar solvent, optionally a protic polar cosolvent and an oil.
16. The unit dose according to claim 15, comprising between 75 mg and 160 mg of aspirin.
17. The unit dose according to any one of claims 15 or 16, being a liquid capsule of a size between“1” and“00”.
18. A process of preparing a pharmaceutical lipid solution, comprising combining aspirin, choline salt, an aprotic polar solvent and optionally a polar protic solvent at a temperature below 35 °C to form a liquid, and mixing the obtained liquid with an oil to form the pharmaceutical lipid solution.
19. A process according to claim 18, wherein the choline salt is dissolved in the aprotic polar solvent, optionally in the presence of the polar protic solvent and then aspirin is added to form a clear liquid, following which said clear liquid is mixed with the oil.
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