WO2008070950A1 - Formulations de solutions pharmaceutiques pour une encapsulation dans des capsules de gélatine ou autres formes posologiques - Google Patents

Formulations de solutions pharmaceutiques pour une encapsulation dans des capsules de gélatine ou autres formes posologiques Download PDF

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Publication number
WO2008070950A1
WO2008070950A1 PCT/CA2006/002036 CA2006002036W WO2008070950A1 WO 2008070950 A1 WO2008070950 A1 WO 2008070950A1 CA 2006002036 W CA2006002036 W CA 2006002036W WO 2008070950 A1 WO2008070950 A1 WO 2008070950A1
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formulation
acid
salt
therapeutically active
active agent
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PCT/CA2006/002036
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English (en)
Inventor
Canh Tien Le
Catherine Dupuis
Claudia Schlegel
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Laboratoires Mauves Inc.
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Priority to PCT/CA2006/002036 priority Critical patent/WO2008070950A1/fr
Publication of WO2008070950A1 publication Critical patent/WO2008070950A1/fr

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • 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
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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 invention relates to a liquid pharmaceutical formulation of a therapeutically active agent, a pharmaceutical dosage form containing same and method for preparing a liquid pharmaceutical formulation.
  • Non-steroidal anti-inflammatory drugs may show various unpleasant effects such as a burning sensation, a bitter taste and aftertaste, and/or an adverse mouth feel when taken orally.
  • NSAIDs such as ibuprofen, naproxen and aspirin (acetyl salicylic acid) have been widely prescribed by physicians in the treatment of pains. These drugs are in general tolerated well by most patients and provide an effective means for control of pain and inflammatory processes, particularly for the rheumatoid arthritis and osteoarthritis patients.
  • ibuprofen is a white powder or crystal which is practically insoluble in water. Ibuprofen is absorbed from the gastro-intestinal tract and the peak plasma concentrations occur approximately one to two hours after ingestion of the solid powder or crystal form.
  • a standard dosage form widely in use for the delivery of ibuprofen is the solid dosage form or tablet, which displays a relatively long time to reach the peak plasma concentration because of two significant factors.
  • the first factor is that the tablet needs to dissolve before to be absorbed and the second factor is that absorption is delayed because ibuprofen is practically insoluble in water or the acidic environment of the stomach (Rouffer, US 6,221 ,391 ).
  • active ingredients with a bitter taste have been the subject of numerous studies in order to formulate stable compositions with the prevention of the bitterness and the quick-activeness.
  • ibuprofen namely 2-(4-isobutylphenyl) propionic acid which is an analgesic, antiinflammatory and anti-pyretic compound.
  • Ibuprofen is a white powder or crystal sparingly soluble in water, has a very bitter taste (Haas, US Pat. No. 4,859,704; Ramachandran et al., US patent application publication 2003/0232097).
  • This medicament is used for the treatment of painful and anti-inflammatory disorders including rhumatoid arthritis, osteoarthritis, post-operative pain, etc.
  • ibuprofen is administered at doses of up to 3200 mg per day.
  • the active ingredient is coated with a lipid substance, either directly or after incorporation into a core.
  • the lipid substances used are, for example, a partially hydrogenated vegetable oil, stearic acid and/or palmitic acid, glyceryl tripalmitate, etc. (EP 664 701 ).
  • the active ingredient is also coated with a polymer intended to mask its bitter taste. This polymer is for example a methacrylic acid copolymer (EP 524 180), a cellulose acetate phthalate (WO 95/05166) or a vinyl acetal (JP 91/83922).
  • Peck et al. U.S. 4,316,580
  • a pharmaceutical liquid composition of the aluminium salt of ibuprofen comprising of microcrystalline cellulose, sodium carboxymethyl cellulose, magnesium aluminium silicate powder and sucrose, fructose, glucose or mixture thereof.
  • ibuprofen salt in which unpleasant taste of salt is masked by the taste masking agent, comprising an alkali metal carbonate, alkali metal monohydrogen phosphate or alkali metal tribasic citrate.
  • the taste masking agent comprising an alkali metal carbonate, alkali metal monohydrogen phosphate or alkali metal tribasic citrate.
  • Suspension of ibuprofen for the encapsulation in the gelatin capsule has also been described in the literature. Since the dosage form is generally swallowed, it is unnecessary to flavor or otherwise mask any unpleasant taste of the active pharmaceutical ingredients. Furthermore, the patient compliance is improved if soft gelatin capsule is used for drug administration, because of its soft, and has an elastic character making it easier to swallow compared to conventional tablets or hard gelatin capsules. Finally, unlike tablets, soft gelatin capsules do not chip or powder (US patent application publication 2003/0232097).
  • liquids are suitable as vehicles or carriers for inclusion in gelatin capsules.
  • certain compounds such as water, propylene glycol, glycerol, alcohols, ketones and esters, etc. can't be used as a carrier in gelatin capsules since they interact with the gel, and can change the mechanical properties of gelatin capsules.
  • these compounds if present, can only represent a relatively small amount (US patent application publication 2003/0232097).
  • gelatin capsules Another limitation associated with gelatin capsules is the ability to incorporate a single dose of the pharmaceutically active ingredient in solution in an acceptable fill volume. Often, it is difficult to dissolve the pharmaceutically active ingredient in a volume of solvent small enough to produce a gelatin capsule, which delivers the desired dosage amount, is economically appropriate and comfortable to ingest by the patient. Developing solvent systems for pharmaceutically active ingredients that neither significantly interacts with the active ingredient nor the gelatin capsule casing it self, has proven a difficult art (US patent application publication 2003/0232079).
  • Radhakrishnan et al. (US patent application publication 2003/0232097) describe an oily wax matrix pharmaceutical suspension for encapsulation in gelatin capsules in embedding the active ingredient (i.e. Ibuprofen) in an oily wax (i.e. mixture of soybean oil and beeswax) which is blended with a surfactant (i.e. lecithin).
  • Hu et al. (US patent application publication 2005/0137262) describe ibuprofen liquid composition comprising potassium ibuprofen, water and alcohol for which is suitable for use as liquid-filled soft gelatin capsules.
  • Kato et al (US patent application publication 2003/0187070) describe a fill liquid composition for capsules which is produced by mixing ibuprofen, polyethylene glycol, water and terpenoid selected from menthol, limonene, borneol, etc.
  • Guillapalli (US 4,859,704) describes a formulation including polyethylene glycol, polyvinylpyrrolidone and alpha-tocopherol.
  • the surfactant agents i.e. lecithin, miglyol, polyoxyethylene sorbitan mono-oleate, etc.
  • solubilizer agent such as propylene glycol, ethylene glycol and glycerol
  • patent application publication 2003/ 0187070 of thickening (viscosity) agent including xanthan gum, hydroxypropylmethyl cellulose
  • thickening agent including xanthan gum, hydroxypropylmethyl cellulose
  • complexing agents comprising polyvinyl pyrrolidone (US 6,221 ,391 ), and certain terpenoids such as menthol, limonene, borneol, etc.
  • menthol polyvinyl pyrrolidone
  • limonene borneol, etc.
  • formulations previously described in the literature requires, in addition to an active ingredient, a solvent (e.g. alcohol) a liposoluble (e.g. soybean oil) or hydrosoluble (e.g. polyethylene glycol) suspending agents, emulsifying agents or surfactants (e.g. Tween), a thickening agent (e.g. Carbomer) and in the certain cases, terpenoids (e.g. menthol).
  • a solvent e.g. alcohol
  • a liposoluble e.g. soybean oil
  • hydrosoluble e.g. polyethylene glycol
  • suspending agents e.g. polyethylene glycol
  • emulsifying agents or surfactants e.g. Tween
  • thickening agent e.g. Carbomer
  • terpenoids e.g. menthol
  • liquid pharmaceutical formulation comprising:
  • a therapeutically active agent having at least one carboxylic acid group or its salt thereof ;
  • organic monocarboxylic acid or its salt is present in an amount suitable to produce the formulation having substantially no visible precipitated or crystallized therapeutically active agent.
  • a method for preparing a liquid pharmaceutical formulation of a therapeutically active agent comprising: i) mixing the therapeutically active agent with a suspending agent until substantial dispersion is achieved; ii) mixing a suitable amount of an organic monocarboxylic acid or its salt thereof with the mixture obtained from step i), or i') mixing a suitable amount of an organic monocarboxylic acid or its salt thereof with a suspending agent until substantial dispersion is achieved; ii') mixing the therapeutically active agent with the mixture obtained from step i'), to obtain the liquid pharmaceutical formulation having substantially no visible precipitated or crystallized therapeutically active agent.
  • a pharmaceutical dosage form comprising a liquid pharmaceutical formulation as defined herein.
  • Fig. 1 is a FTIR spectra of three mixtures of ibuprofen/ sodium acetate, as well as FTIR spectra of ibuprofen, acetic acid and sodium acetate.
  • liquid pharmaceutical formulation for a therapeutically active agent having at least one carboxylic acid group or its salt.
  • the carboxylic acid group of the therapeutically active agent can associate with the carboxylic acid group of an organic monocarboxylic acid or its salt thereof (e.g. acetic acid or sodium acetate) via dipole-dipole attraction and others polar interactions generating a complex «active agent / organic monocarboxylic acid» which has increased solubility is soluble in a suitable suspending agent without substantially precipitating crystals of the active agent.
  • an organic monocarboxylic acid or its salt thereof e.g. acetic acid or sodium acetate
  • the therapeutically active agent advantageously used in the present invention is not particularly limited; however they must possess at least one carboxylic acid group or its corresponding carboxylate salt.
  • Therapeutically active agents having more than one carboxylic acid group are also contemplated within the scope of the invention.
  • the carboxylate salts of those active agents are also contemplated as useful active agent in the present invention.
  • Example of classes of those therapeutically active agents includes NSAIDs and certain antibiotics.
  • Non limiting examples of NSAIDs for use, as the active agent having at least a free carboxylic acid group (either as a single agent or as a mixture of active agents), in the pharmaceutical formulation, dosage forms and processes of the present invention include the following categories:
  • the acetic acid derivatives Indomethacin, Sulindac, Diclofenac, Fenclofenac, Bromfenac, Ibufenac, Aceclofenac.Tolmetin, Zomepirac, Nabumetone, Oxaprofen, Acemetacin, Fentiazac, Clidanac, Etodolac, Oxpimac, Acetyl salicylic acid, or their salts.
  • Meclofenamic acid Flufenamic (Nifluminic) acid, Tolfenamic acid or their salts.
  • the biphenyl carboxylic acid derivatives Diflunisal, Flufenisal or their salts.
  • active agents suitable for use in the present invention include certain antibiotic derived from penicillanic acid:
  • Penicillin Carbenicillin, Ampicillin, Cephalosporin, Ceftriaxone, Amoxicillin, Imipenem, Clavulanate, Carbapenem, Para-aminosalicylic acid.
  • Organic monocarboxylic acid or its salt suitable for use in the present invention includes without limitation those having a non polar acyl chain (lipophile) such as acetic acid (pKa 4.76), propanoic acid (pKa 4.87), butanoic acid (pKa 4.82), etc. or a polar acyl chain such as lactic acid (pKa 3,86), glycolic acid (pKa 3,83), pyruvic acid (pKa 2,49), etc.
  • a non polar acyl chain such as acetic acid (pKa 4.76), propanoic acid (pKa 4.87), butanoic acid (pKa 4.82), etc.
  • a polar acyl chain such as lactic acid (pKa 3,86), glycolic acid (pKa 3,83), pyruvic acid (pKa 2,49), etc.
  • FDA U.S. Food and Drug Administration
  • GRAS generally recognized as safe
  • Short chain acyclic acids having 8 carbon atoms or less or a mixture of those, such as formic acid, pyruvic acid, gluconic acid, ascorbic acid, caprylic acid, caproic acid, sorbic acid and their salts and derivatives, are also suitable.
  • Organic polycarboxylic acid compounds i.e. those with more than one -COOH groups are susceptible to cause crystallization of the active agents in the formulation and may not be useful as solubility increasing agent in the formulation.
  • one of the therapeutically active agent or the organic monocarboxylic acid is provided as its salt while the other is provided as carboxylic acid.
  • the pharmaceutical formulation is provided using a therapeutically active agent as its carboxylic acid and an organic monocarboxylic acid salt.
  • the organic monocarboxylic acid salt is an alkali salt such as sodium or potassium and their mixtures thereof.
  • the organic monocarboxylic acid salt is a salt of sodium or potassium of acetic acid or propionic acid and their mixtures thereof.
  • organic monocarboxylic acid may be described by formula
  • R is an alkyl
  • X 2 is a hydrogen atom or an alkali salt.
  • R is an alkyl of 1 to 7 carbon atoms, preferably of 1 to 6 carbon atoms and more preferably 1 or 2 carbon atoms, the alkyl being optionally substituted with a hydroxyl or an oxo group.
  • X2 is a hydrogen, a sodium of potassium salt.
  • suspending agent described here is used as a means a pharmaceutically acceptable diluent miscible or dissolvable material that yields a clear suspension or solution for the complex drug/acid.
  • the suitable suspending agent could be a hydrophobic compound.
  • Suitable suspending agent include vegetal oil such as Coconut oil, Corn oil, Cottonseed oil, canola oil, Olive oil, Palm oil, Peanut oil, Safflower oil, Sesame oil, Soybean oil, or Sunflower oil, preferably canola oil; mineral oil, mint natural oil or compounds including polyalkylene glycol such as polyethylene glycol (PEG), polypropylene glycol (PPG) and glycerol.
  • a preferred polyalkylene glycol is PEG.
  • Polyethylene glycols are soluble in water and many organic solvents. These polymers correspond to the general formula: H(OCH 2 CH 2 ) n OH preferably having an average molecular weight between about 200 to 800, and most preferably having an average molecular weight between about 400-600.
  • the polyethylene glycols useful herein are those which are liquids at room temperature or have a melting point slightly thereabove.
  • mixtures of two or more polyethylene glycols of different average molecular weight range or n value can also be employed in the present invention. Liquid and low-melting polyethylene glycols are commercially available from various sources.
  • alkyl represents a linear or branched hydrocarbon moiety having 1 to 7 carbon atoms preferably 1 to 3 carbon atoms.
  • alkyl is also meant to include alkyls in which one or more hydrogen atom is replaced by a halogen, i.e. an alkylhalide.
  • alkyl may also mean cyclic alkyls including for example cyclopropyl and cyclohexyl.
  • the use of the surfactant agent, thickening agent, polysaccharides or terpenoid are not necessary to increase solubility of the active agent and its homogeneous stability in the formulation.
  • the addition of solvent such as ethanol or complexing agent such as PVP, previously used in the art to increase solubility of an active agent is not necessary to increase solubility of the active agent and its homogeneous stability in the formulation of the present invention.
  • the liquid formulation is comprising: i) about 20-90% wt combined amount of therapeutically active agent and organic monocarboxylic acid or its salt; and ii) about 10-80% wt suspending agent.
  • the amount of the organic monocarboxylic acid or its salt with regard to the amount of therapeutically active agent must be an amount suitable to produce the formulation having substantially no visible precipitated or crystallized therapeutically active agent for a suitable period of time at a storage temperature.
  • Typical storage temperature is from room temperature (about 22 0 C) to about O 0 C.
  • the suitable period of time during which substantially no visible precipitated or crystallized therapeutically active agent is produced in the formulation is not particularly limited and depends on the required or desired shelf life. It may vary generally from months to years.
  • organic monocarboxylic acid or its salt may vary depending on the nature of the therapeutically active agent, however when the active agent has one carboxylic acid group, the molar ratio is more than about 1 : 8 (organic monocarboxylic acid : therapeutically active agent), preferably about 1 : 6, alternatively about 1 : 4 and more preferably about 2 : 5. Typical ranges include from more than about 1 : 8 to about 1 : 1 , preferably about 1 : 6 to about 2 : 5.
  • the molar ratio should be adjusted accordingly.
  • an active agent possessing two carboxylic acid groups should have a molar ratio of more than about 2 : 8 (organic monocarboxylic acid : therapeutically active agent).
  • the molar ratio could be changed in the case that therapeutic agent is a polycarboxylic acids.
  • the active agent concentration in the formulation could reach up to 80 wt% of the total weight of the formulation without visible precipitation or crystallization. In certain cases (e.g. ibuprofen) up to 90 wt% can be reached if required.
  • the liquid formulation as comprises about 20%, 40%, 60% or 80% wt of the therapeutically active agent; and the molar ratio of said organic monocarboxylic acid or its salt with regard to therapeutically active agent is about 2:5.
  • the composition remained homogenously stable at various temperatures (-10 to 22 0 C) and different pH values (3-10).
  • the active agent is likely to remain soluble in acidic media, particularly in gastric acid, so that the active agent is quickly released which can favor the resorption.
  • organic monocarboxylic acids or their salts are for their antibacterial and antifungal effects.
  • sodium propionate is one of the food preservatives that used alone or in combination with other agents as a preservative to inhibit mold production in bakery, dairy products or other foods and in pharmaceuticals. It is also used as a topical antifungal in the treatment of various mycoses. Consequently, the addition of the preservatives, in the certain case, is not necessary.
  • a feature of this invention is that the therapeutically active agent possesses at least a free carboxylic group which can be protonated (acid form) or non- protonated (salt form).
  • the pH value of filling liquid used to encapsulate into gelatin capsules should not be below 2.5 or above 7.5 due to the gelatin hydrolysis causing leakage.
  • the organic monocarboxylic acid is preferably used under salt form (potassium acetate, sodium propionate, sodium gluconate, etc.) and vice versa for the active agent possessing non-protonated carboxylic group
  • the stabilizer is preferably in acidic form (acetic acid, propionic acid, gluconic acid, etc.).
  • the liquid formulation of the instant invention can also combine with one or more additional therapeutically active agents.
  • additional therapeutically active agents include antipyretics, expectorants, decongestants and antitussives. Examples include, but are not limited to dextromethorphan and its salts such as dextromethorphan hydrobromide, pseudoephedrine and its salts such as pseudoephedrine hydrochloride, phenylephrine and its salts such as phenylephrine hydrochloride, diphenhydramine and it salts such as diphenhydramine hydrochloride, chlorpheniramine and its salts such as chlorpheniramine maleate, and their mixtures thereof.
  • Those additional therapeutically active agents can be added at either of the preparation process steps.
  • the formulation of the present invention can be encapsulated within any conventional soft gelatin shell that is capable of supporting the formulation for a suitable period of time.
  • the soft gelatin shells can be prepared according to methods known in the art by combining appropriate amounts of gelatin, water, plasticizer, and any optional components. This soft gelatin shell preparation can then be used for encapsulating the formulation of the present invention employing standard encapsulation methodology to produce one-piece soft gelatin capsules.
  • the size and strengh of soft gelatine capsules comprising the formulation of the present invention may vary. This allows for sufficient flexibility to provide the dosage/ strengh required.
  • a soft capsule that can accept about a gram (of roughly 1 ml) of an approximately 40% wt ibuprofen formulation (which is about 400mg d'ibuprofen per gram of solution) contains about 400mg ibuprofen/capsule.
  • similar capsule filled up with a 80% wt ibuprofen formulation will provide a 800mg/ capsule.
  • a liquid pharmaceutical formulation comprising ibuprofen; an organic monocarboxylic acid or its salt selected from sodium acetate, potassium acetate, sodium propionate and potassium propionate; and canola oil; wherein the molar ratio of said organic monocarboxylic acid or its salt with regard to ibuprofen is more than about 1 : 8.
  • the molar ratio is at least about 1 : 6, alternatively at least about 1 : 4, preferably about 1 : 4, more preferably about 2:5.
  • Typical ranges include from more than about 1 : 8 to about 1 : 1 , preferably about 1 : 4 to about 2 : 5.
  • the formulation comprises about 20 to 90% wt combined amount of ibuprofen and about 10 to 80% wt of the organic monocarboxylic acid.
  • a method for preparing a liquid pharmaceutical formulation of therapeutically active agent comprising: i) mixing the therapeutically active agent with a suspending agent until substantial dispersion is achieved; ii) mixing a suitable amount of an organic monocarboxylic acid or its salt thereof with the mixture obtained from step i) or i') mixing a suitable amount of an organic monocarboxylic acid or its salt thereof with a suspending agent until substantial dispersion is achieved; and ii') mixing the therapeutically active agent with the mixture obtained from step i'), to obtain the liquid pharmaceutical formulation having substantially no visible precipitated or crystallized therapeutically active agent.
  • flavoring, coloring and preservative agents can be added to the formulation obtained previously at either of the preparation process steps to improve appearance, patient comfort and compliance.
  • pH of the formulation can be adjusted at either of the process steps (using pH adjusting agents such as HCI or NaOH or KOH) to improve compatibility with the dosage formulation used (e.g. soft gel capsule wall, container ect.)
  • polar suspending agents such as Propylene glycol, Glycerol, Sorbitol, etc. or their mixtures thereof, however smaller quantities are required.
  • the liquid pharmaceutical formulation of the invention may advantageously be presented in various pharmaceutical dosage form known in the art including an oral dosage form selected from i) a soft gelatin shell comprising the liquid formulation, wherein said gelatin shell is compatible with said liquid formulation and ii) syrup.
  • the pharmaceutical dosage form may also advantageously be a topical dosage form.
  • an oral pharmaceutical dosage form comprising a) a liquid pharmaceutical formulation comprising a therapeutically active agent having at least one carboxylic acid group or its salt thereof ; an organic monocarboxylic acid or its salt thereof; and a suspending agent; wherein said organic monocarboxylic acid or its salt in an amount suitable to produce the formulation having substantially no visible precipitated or crystallized therapeutically active agent; b) a soft gelatin shell comprising the liquid formulation a), said gelatin shell being compatible with said liquid formulation.
  • the soft gelatin shell is comprising a liquid pharmaceutical formulation comprising a therapeutically active agent that is ibuprofen, an organic monocarboxylic acid salt selected from sodium acetate, potassium acetate, sodium propionate, potassium propionate and a mixture thereof, and a suspending agent that is canola oil; wherein the molar ratio of said organic monocarboxylic acid salt with regard to therapeutically active agent is more than about 1 : 8;
  • ingredients/ reagents were obtained from commercial sources: lbuprofen : ALBEMARLE Corporation, Orangeburg, South Carolina (USA); Sodium Acetate: SIGMA-ALDRICH, Inc., St Louis, MO (USA); Canola oil: SOBEYS, Missisauga, Ontario (Canada); PEG 400 : FLUKA (Ph Eur, 400), Sigma-Aldrich Canada, Ltd. Oakville ON. CANADA.
  • Example 1 Oily formulation for lbuprofen: Formulation for 200 mg/g of solution
  • the formulation was prepared by heating 76.5g of canola oil to 60-70 0 C and an amount of 20.Og of ibuprofen was added under mild stirring until complete dispersion. Thereafter, an amount of 3.5g of sodium or potassium acetate was slowly added, as a solid, to the solution. The mixture was continued to be stirred at the same temperature during at least one hour.
  • the sodium acetate/propionate could be equally prepared by dissolving in a minimum quantity of water just prior to add in the ibuprofen-oil solution.
  • 3g sodium acetate was dissolved in 6-8ml water
  • 3g sodium propionate was dissolved in 4-6ml water. In this case, the mixture became slightly turbid.
  • the mixture was continued to be stirred and heated up to 90-95 0 C at least one hour or until the solution was clear (i.e. evaporation of water).
  • the evaluation of stability was performed by visually observing of the appearance of the solution immediately after production and after storage at various temperatures (-10-60 0 C) at different pH values (3 to10) during 2 weeks.
  • a solution of ibuprofen was prepared at the desired concentration with the required amount of organic monocarboxylic acid or its salt.
  • the pH was then adjusted in the range of 3 to 10 using HCI or NaOH (or KOH) while the mixture is heated.
  • the resulting mixtures were then left standing at various temperatures (-10, 0, 4, 10 and 22 0 C).
  • An assessment of the formulation was made every 4 hours during the first 24 hours and then daily for one to two weeks.
  • Example 2- Oily formulation for ibuprofen at high concentrations
  • ibuprofen solutions at high concentrations were prepared as described previously in example 1. Indeed, various quantities of 40, 60, and 8Og of ibuprofen were introduced in to 55, 32 and 10g of heated canola oil, respectively. Then, suitable sodium acetate amount (5-1Og respectively for a total to 100g) was added in corresponding solution.
  • a control was carried out for each concentration (10-80%) of ibuprofen described above, but in absence of organic monocarboxylic acid (i.e. without sodium acetate).
  • the formation of crystals in these control solutions was observed after 24 h at 4.0 0 C for concentrations of ibuprofen >20% and after 48-72h at the same temperature for concentrations between 10-20%.
  • no precipitate of crystal was observed for those in presence the organic monocarboxylic acid (i.e. with sodium acetate).
  • the formulation was prepared as described previously for oily formulation, but instead of canola oil, polyethylene glycol (PEG) 400 was used. An amount of 40.Og of ibuprofen was dispersed in 54.Og of PEG 400 which was heated to 70- 80 0 C. When the ibuprofen was completely dispersed, an amount about of 4.0- 6.Og of sodium propionate was slowly added and the mixture was continued to be stirred and heated up to 90-95 0 C during at least 2 hours. A formulation control (without sodium propionate) was equally prepared.
  • PEG 400 polyethylene glycol
  • FTIR spectra analysis permitted to highlight these interactions as shown in Fig. 1.
  • the various ratios are expressed as weight ratio (w/w) of ibuprofen and sodium acetate.
  • the FTIR spectra shows from top to bottom: a) ibuprofen/ sodium acetate (20/3), b) ibuprofen/ sodium acetate (20/2), c) ibuprofen/ sodium acetate (20/1 ), d) ibuprofen, e) acetic acid and f) sodium acetate respectively.
  • Other smaller bands in the region 1200-1000 cm “1 are contributions from the benzene ring (Socrates, G. 1994. Infrared Characteristic Groups Frequencies. Tables and Charts, 2 nd ed., Wiley, New York).
  • the intensity of carbonyl band was decreased and shifted to low wavenumber from 1710 to 1685 cm “1 .
  • a new band located at 1593 cm "1 was noticed.
  • Example 5 Combination of NSAIDs liquid with other therapeutic agents for encapsulation into gelatin capsules
  • the ibuprofen solution (20.0 %) was prepared as described previously in example 3. Practically, an amount of 20.0 g of ibuprofen was dispersed into solution at 60°C containing 67.Og of PEG 400 and 3.Og of sodium acetate. The mixture was continued to stir and heated up to 95°C during at least 2h. In parallel, an amount of 3.Og of pseudoephedrine hydrochloride was gradually dispersed in 7.Og of glycerol. When the pseudoephedrine solution was homogenized, this was slowly added in the ibuprofen solution and was cooled to room temperature.
  • the formulation was prepared as described above in example 5-1 , but 1.Og of phenylephrine hydrochloride was added into the glycerol (4.0-5.Og) instead of pseudoephedrine hydrochloride.
  • the PEG 400 was used to complete at 100g of solution.
  • the formulation was prepared as described above in example 5-1 , but 1.Og of dextromethorphan hydrobromide was added at the same time of pseudoephedrine hydrochlodride into the glycerol.
  • Example 6- Liquid ibuprofen syrup (400 mg/5 ml_ or one teaspoon)
  • the stabilized liquid ibuprofen syrup was prepared by dispersing 8.0 g of ibuprofen in 52.Og of PEG 400 heating at about of 70-80 0 C. When the solution was homogenized, an amount of 1.2g of sodium propionate (or acetate) was added and the mixture was continued to stir and heated at the same temperature during at least 1-2h. Thereafter, quantities of 3Og of glycerol, 2.Og of sucralose and others ingredients such as citrus lemon flavor (2.OmL), dye (0.05-0.1Og) and preservatives (0.05-0.1 ) were added. The distilled water could be used to complete the volume of solution at 10OmL.
  • Example 7 - Liquid ibuprofen using in other formulation topical preparation
  • the cream was prepared by dispersing of 3g of alginate and 3g of glycerol in 37g of purified water at 70 0 C. In parallel, an amount of 8.Og of PolawaxTM and 4.0g of stearic acid were heated at 70 0 C. Thereafter, the polawax and stearic acid mixture were added in the alginate solution at the same temperature with strong agitation until a uniform suspension.
  • the ibuprofen solution was prepared as described previously in example 1
  • the ibuprofen cream was obtained after addition of 45mL of ibuprofen solution into the cream suspensions with moderate agitation.
  • the addition of Tween is optional to obtain the desired texture and the obtained cream was cooled to room temperature until a uniform suspension.
  • Example 8 High concentration liquid ibuprofen formulation.
  • ibuprofen 9Og of ibuprofen was added to 10ml of ethanol and 5g of mineral oil and the mixture heated to 7O 0 C. Once homogenized, 5g of sodium acetate was added to the mixture followed by heating for 1-2 hours at 95 to 100 0 C to remove essentially all ethanol. The resulting formulation remained stable (i.e. no visible precipitation or crystallization) once cooled down to room temperature.

Abstract

La présente invention porte sur une formulation liquide d'un composé biologiquement actif ayant un ou plusieurs groupes acide carboxylique, tel que les analgésiques, et, en particulier, des anti-inflammatoires non-stéroïdiens (AINS), comme l'ibuprofène. Un acide monocarboxylique organique est utilisé pour créer des interactions qui génèrent une formulation soluble qui reste stable de façon homogène, avec pratiquement pas de cristallisation du composé biologiquement actif à une concentration élevée pendant une période de temps appropriée. La formulation peut être utilisée en tant que solution de remplissage pour des capsules de gélatine ou diverses formes posologiques pharmaceutiques, telles qu'un sirop ou une crème, et dans certains cas, des préparations pour une administration parentérale.
PCT/CA2006/002036 2006-12-13 2006-12-13 Formulations de solutions pharmaceutiques pour une encapsulation dans des capsules de gélatine ou autres formes posologiques WO2008070950A1 (fr)

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WO2012053008A1 (fr) * 2010-10-21 2012-04-26 Cadila Healthcare Limited Compositions pharmaceutiques topiques à base d'étodolac
WO2012056251A1 (fr) * 2010-10-29 2012-05-03 Biocopea Limited Maladie inflammatoire
WO2012104654A1 (fr) * 2011-02-04 2012-08-09 Biocopea Limited Compositions et méthodes de traitement de maladies cardiovasculaires
US20130005740A1 (en) * 2009-08-05 2013-01-03 7267207 Canada Limited Corporation Process for preparation of over-the-counter gelatin or pectin-based drug delivery
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JP2014131996A (ja) * 2012-12-07 2014-07-17 Fuji Capsule Kk ロキソプロフェンナトリウム含有軟カプセル用内容物、及び、それを含有する軟カプセル製剤
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