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WO2008079818A2 - Administration intraveineuse de formulations analgésiques hydrosolubles - Google Patents

Administration intraveineuse de formulations analgésiques hydrosolubles Download PDF

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Publication number
WO2008079818A2
WO2008079818A2 PCT/US2007/087943 US2007087943W WO2008079818A2 WO 2008079818 A2 WO2008079818 A2 WO 2008079818A2 US 2007087943 W US2007087943 W US 2007087943W WO 2008079818 A2 WO2008079818 A2 WO 2008079818A2
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Prior art keywords
analgesic
aspirin
intravenous administration
hours
solution
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PCT/US2007/087943
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WO2008079818A3 (fr
Inventor
Robert E. Martin
Arthur M. Felix
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SOLUPRIN PHARMACEUTICALS Inc
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SOLUPRIN PHARMACEUTICALS Inc
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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/606—Salicylic acid; Derivatives thereof having amino groups
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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]

Definitions

  • the present invention relates generally to aspirin and other analgesic compositions and, more specifically, to water soluble aspirin and other analgesic compositions which have enhanced stability and bioactivity as compared to previously known water soluble aspirin and other analgesic compositions.
  • the present invention provides intravenous formulations of such aspirin and other analgesic compositions as well as methods of intravenous administration of aspirin and other analgesic compositions.
  • Acetylsalicylic acid (aspirin), an important member of a family of therapeutics known as non-steroidal anti-inflammatory drugs (NSAIDs), is known to have analgesic, antipyretic and anti-inflammatory properties. These multiple properties make it an ideal therapeutic for pain relief (including, but not limited to, the treatment of headaches), fever reduction and treatment of arthritis and other related indications.
  • Aspirin's mechanism of action involves the inhibition of the synthesis of prostaglandins from arachidonic acid. Aspirin acetylates a serine residue in the active site of PGhfe synthase, the enzyme that catalyzes the conversion of arachidonic acid to PGH 2 .
  • Aspirin has also been shown to have remarkable antithrombotic benefits. Aspirin's antithrombotic effect is mediated by inhibition of blood platelets. The drug blocks a platelet enzyme, cyclo-oxygenase, by acetylating the enzyme's active site. Inhibition of the enzyme blocks production of an important prothrombotic agent known as thromboxane A2. Thromboxane A2 causes activation and aggregation of platelets, which is an early step in thrombosis.
  • Aspirin Today, several platelet inhibitors are available, but aspirin remains the most commonly used drug in this category and is still a very cost-effective antithrombotic drug. Aspirin (either 81 mg or 325 mg daily) is indicated in the following conditions: unstable angina (acute coronary syndrome), acute myocardial infarction, secondary prevention of myocardial infarction, secondary prevention of stroke ⁇ carotid or primary cerebrovascular disease), prevention of peripheral arterial thrombosis, and prevention of venous thrombosis (deep venous thrombosis, pulmonary embolism). There has also been investigation recently of using aspirin (either alone or in combination with other medications) for the treatment of various types of cancer.
  • the degree of absorption is related to solubility, dosage form, excipients and particle size.
  • lipid-soluble, undissociated forms of a drug readily pass through membranes. Ionization of aspirin is suppressed in the stomach (low pH); therefore aspirin is absorbed into the bloodstream in significant quantities in its unionized (uncharged) form through the stomach membrane.
  • the main metabolic pathway for aspirin is via esterase-catalyzed hydrolysis to salicylic acid which is unable to inhibit the synthesis of prostaglandins.
  • aspirin has been reported to be useful in a variety of pathophysiological settings, ranging from low doses for heart-attack and stroke prevention to high doses for rheumatoid arthritis, its application has been limited due to its poor solubility in water. Side-effects stemming from undissolved particles that can adhere to gastrointestinal mucosa may cause gastric or intestinal ulceration and bleeding that may lead to anemia from resultant blood loss.
  • the common dosages of aspirin are generally considered adequate for "aspirin therapy” to reduce the likelihood of heart-attack and/or stroke.
  • these dosages only provide relief of the symptom of arthritis (i.e., pain), and do not treat the underlying inflammation.
  • daily dosages of 4,000 to 5,000 mg or greater are generally needed to maintain plasma salicylate concentrations in the range of 120 to 350 ⁇ g/ml.
  • the rate of successful treatment is over 70%.
  • the success rate fads off dramatically at lower daily dosages, and with 2500 mg, for example, it is less than 10%.
  • the cause of failure, or the lack of success, with aspirin therapy in the context of treating arthritis inflammation may be due, at least in part, to the use of inadequate dosages.
  • aspirin exhibits a number of undesirable side effects.
  • the most commonly experienced side effects are nausea, gastric upset (heartburn) and pain.
  • these side effects will generally occur in about 2-10% of adult users of aspirin.
  • this number increases dramatically with extended aspirin consumption.
  • antiinflammatory dosages With higher antiinflammatory dosages, the incidence of these undesirable side effects generally rises to about 25%. Again, this number increases significantly with extended treatment regimes.
  • aspirin The gastrointestinal side effects of aspirin are typically localized, and when aspirin is used in its current conventional form, as a suspension its undissolved particles tend to adhere to the stomach mucosa, causing irritation, inflammation and injury.
  • the localized nature of these detrimental side effects has been established by gastroscopy and autopsies. Erosion, for example, around undissolved particles of aspirin in the stomach has been well documented and photographed. Because aspirin is a direct irritant to the gastrointestinal mucosa, its effects are both cumulative and persistent.
  • U.S. Patent Nos. 5,665,388 and 5,723,453 to Phykitt disclose an essentially sodium free soluble alkaline aspirin compound.
  • the formulations disclosed in these references suffer from a number of disadvantages.
  • One of such disadvantages is that the use of bicarbonates, as disclosed therein, causes gas to be formed when ingested by patients.
  • Another disadvantage is that the relatively high pH of the compositions disclosed therein (i.e., greater than 8.0) leads to rapid hydrolysis and instability and, therefore, a shortened shelf-life.
  • U.S. Patent Nos. 5,157,030 and 5,776,431 to Galat also disclose aspirin compounds, which aspirin compounds have disadvantages similar to those disclosed in the above-referenced prior art patents.
  • the compositions disclosed in these references have resulting pH values, when mixed with water, of over pH 6.0. This causes the compositions to be relatively unstable, have a shortened shelf-life, and be less readily absorbed by the body, since the aspirin component is in a less undissociated form. This also causes a relatively slow dissolution of the compositions in water, it having been found that compositions formulated in accordance with the Galat patents take up to two to three minutes to substantially completely dissolve in water.
  • the present invention provides formulations of analgesics suitable for intravenous administration, methods of formulating analgesics for intravenous administration, as well as methods of using the formulations of analgesics suitable for intravenous administration to treat or prevent various diseases or medical conditions.
  • the analgesic is aspirin.
  • an object of the present invention to provide aqueous analgesic formulations suitable for intravenous administration, preferably to humans.
  • the analgesic formulations of the present invention have excellent stability and bioactivity.
  • Another object of the present invention is to provide a water soluble analgesic composition having the above characteristics which is sodium free and which can be used to provide a sodium free aqueous analgesic solution suitable for intravenous administration.
  • a further object of the present invention is to provide a water soluble analgesic composition having the above characteristics and which is rapidly water soluble.
  • Such compositions can be rapidly mixed with aqueous solutions to provide formulations suitable for intravenous administration of the analgesic.
  • Still another object of the present invention is to provide aqueous analgesic formulations suitable for intravenous administration having the above characteristics and which allow for rapid delivery of the analgesic to the bloodstream.
  • Yet a further object of the present invention is to provide aqueous analgesic formulations suitable for intravenous administration having the above characteristics and which may be used to administer the relatively large dosages that are required for certain medical conditions, and/or that may be used for extended periods of time, without causing gastrointestinal upset and/or damage.
  • Use of the intravenous route of administration avoids any potential problems caused by particulate analgesic accumulating in the gastrointestinal tract and thus allows such large doses and extended periods of treatment to be used without causing gastrointestinal upset and/or damage.
  • a water soluble analgesic composition including a plurality of granules where the water soluble analgesic composition can be used to produce an analgesic formulation suitable for intravenous administration.
  • Each of the granules Includes a substrate core and a coating disposed on the substrate core forming an agglomerated product, the coating including a salt of an analgesic, but substantially no particles of a non-salt form of the analgesic.
  • the substrate core is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, dipeptides and combinations of these.
  • the substrate core comprises sucrose, cellulose, xylitol, or D-glucose.
  • the granules have a median diameter falling within a range from about 10O ⁇ to about 400 ⁇ . In certain of these embodiments, the granules have a median diameter of about 200 ⁇ .
  • the analgesic is selected from the group consisting of aspirin, 5-aminosalicylic acid, ibuprofen, naproxen, acetaminophen and combinations of these. In certain of these embodiments, the analgesic comprises aspirin.
  • the salt of the analgesic comprises a potassium salt of the analgesic.
  • the analgesic is selected from the group consisting of aspirin, 5-aminosalicylic acid, ibuprofen, naproxen, acetaminophen and combinations of these. In certain of these embodiments, the analgesic comprises aspirin. In some embodiments, the base comprises tripotassium citrate monohydrate. In some embodiments, the first solution further comprises a surfactant. In certain of these embodiments, the surfactant comprises sodium lauryl sulfate. In some embodiments, the substrate is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, dipeptides and combinations of these.
  • the substrate comprises sucrose, cellulose, xylitol, or D-glucose.
  • the step of spray drying the filtered second solution onto a substrate employs a fluid- bed spray drying process.
  • the granules have a median diameter falling within a range from about 100 ⁇ to about 400 ⁇ . In certain of these embodiments, the granules have a median size of about 200 ⁇ .
  • a water soluble analgesic composition suitable for producing intravenous formulations includes aspirin and tripotassium citrate monohydrate, with the aspirin comprising at least about 26% by weight of a combined weight of the aspirin and the tripotassium citrate monohydrate.
  • the aspirin comprises from about 26% to about 40% by weight of a combined weight of the aspirin and the tripotassium citrate monohydrate.
  • a pH of the composition, when dissolved in water, is below about 6.0.
  • the water soluble analgesic composition suitable for producing intravenous formulations further includes a substrate.
  • the substrate is selected from the group consisting of monosaccharides, dtsaccharides, polysaccharides, dipeptides and combinations of these.
  • the substrate comprises sucrose or D-gtucose.
  • the substrate comprises a substrate core onto which the aspirin and the tripotassium citrate monohydrate are coated.
  • the water soluble analgesic composition suitable for producing intravenous formulations further includes a surfactant.
  • the surfactant comprises sodium lauryl sulfate.
  • the water soluble analgesic composition further includes a supplemental active ingredient selected from the group consisting of ascorbic acid, caffeine and combinations of these.
  • a water soluble analgesic composition suitable for producing intravenous formulations includes aspirin and tripotassium citrate monohydrate, with a pH of the composition, when dissolved in water, being below about 6.0.
  • the pH of the composition when dissolved in water, falls within a range from about 5.2 to about 6.0.
  • the pH of the composition when dissolved in water, falls within a range from about 5.6 to about 6.0.
  • the aspirin comprises at least about 26% by weight of a combined weight of the aspirin and the tripotassium citrate monohydrate.
  • a method of creating a water soluble analgesic composition suitable for producing intravenous formulations includes the steps of: ⁇ i) providing aspirin, tripotassium citrate monohydrate, a surfactant, and a substrate, (ii) creating a first solution including the tripotassium citrate monohydrate, (iii) adding the aspirin to the first solution to create a second solution, (iv) adding the surfactant to the second solution, (v) filtering the second solution to remove residual amounts of undissolved aspirin to create a filtered second solution, and (vi) spray drying the filtered second solution onto the substrate so as to form an agglomerated product comprising a plurality of granules.
  • the aspirin comprises at least about 26% by weight of a combined weight of the aspirin and the tripotassium citrate monohydrate provided in step (i).
  • a pH of the composition, when dissolved in water, is below about 6.0.
  • the surfactant comprises sodium lauryl sulfate.
  • the substrate is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, dipeptides and combinations of these.
  • the substrate comprises sucrose, cellulose, xylitol, or D-glucose.
  • the step of spray drying the filtered second solution onto a substrate employs a fluid-bed spray drying process.
  • the granules have a median diameter falling within a range from about 100 ⁇ to about 400 ⁇ . In certain of these embodiments, the granules have a median diameter of about 200 ⁇ .
  • a rapidly dissolving composition comprising an aspirin salt
  • a portion of the composition containing 650 mg of aspirin is completely soluble in 100 ml of water in less than 60 seconds.
  • the rapidly dissolving composition comprising an aspirin salt can be used to produce aqueous formulations of aspirin suitable for intravenous administration.
  • the portion of the composition containing 650 mg of aspirin is completely soluble in 100 ml of water in less than 30 seconds. In certain of these embodiments, the portion of the composition containing 650 mg of aspirin is completely soluble in 100 ml of water in less than 15 seconds.
  • a pH of the composition, when dissolved in water is below about 6.0. In certain of these embodiments, the pH of the composition, when dissolved in water, falls within a range from about 5.2 to about 6.0. In certain embodiments, the pH of the composition, when dissolved in water, falls within a range from about 5.6 to about 6.0.
  • the water is at room temperature (about 21 "C) and/or is deionized.
  • Figure 1 graphically illustrates, based upon data collected after oral administration to human patients, salicylate levels versus time for a water soluble aspirin composition and for a well-known commercially available aspirin formulation.
  • Figure 2 graphically illustrates the % product by weight as a function of median diameter of granules for a water soluble aspirin composition suitable for producing intravenous formulations in accordance with the present invention.
  • Figures 3-6 show scanning electron micrographs of a water soluble aspirin composition suitable for producing intravenous formulations in accordance with the present invention at different magnifications: Figure 3 (magnification ruler: 290 ⁇ ); Figure 4 (magnification ruler: 140 ⁇ ); Figure 5 (magnification ruler: 20 ⁇ ); and Figure 6 (magnification ruler: 7.4 ⁇ ).
  • Figure 7 graphically illustrates the relationship between pH and % aspirin by weight of a combined weight of aspirin and tripotassium citrate monohydrate for a water soluble aspirin composition suitable for producing intravenous formulations in accordance with the present invention.
  • Effective amount means the amount of an analgesic that, when administered to a patient in need thereof for treating a disease or other medical condition, is sufficient to have a beneficial effect with respect to that disease or condition.
  • the “effective amount” or “amount effective” will vary depending on the analgesic, the disease or condition and its severity, and the species, age, weight, gender, etc., of the patient to be treated. Determining the "effective amount” or “amount effective” of a given analgesic is within the ordinary skill of the art and requires no more than routine experimentation.
  • Aqueous solution means a water-based liquid without undissolved solids above 0.5 microns in size.
  • the aqueous solutions of analgesic described herein include greater than 60%, 70%, 80%, 90%, 95%, 97%, 98%, or even 99% water (w/w) and the analgesic is essentially completely dissolved.
  • Examples of aqueous solutions include pure water, physiological saline (including 0.9%, 0.45%, and 0.33% physiological saline), xylitol solutions, and 5% dextrose.
  • Suitable for intravenous administration refers to an aqueous solution containing a dissolved analgesic that can be administered intravenously, preferably to a human, without causing unacceptable side effects, considering the purpose for which the aqueous solution containing the analgesic is being administered.
  • AUC means "area under the curve” and refers to the area under the serum concentration profile (concentration versus time curve).
  • Sodium free refers to a solution of an analgesic or to a solid analgesic compound where the amount of sodium by weight is less than about 50%, about 20%, about 10%, about 5%, about 2%, about 1%, or about 0.5% of analgesic by weight.
  • the weight of an analgesic refers to the analgesic, either in unionized form or in the form in which the analgesic appears in a salt, but does not include the weight of the counterion in the salt.
  • “1 g of aspirin” when the aspirin is present as a tripotassium citrate salt, refers to the weight of the acetylsalicylate portion in the tripotassium citrate salt of the aspirin, and does not include the weight of the potassium in the salt.
  • the present invention satisfies the needs left unattained by the prior art, and is based, in part, upon the discovery that certain mixtures of aspirin with sodium lauryl sulfate (which serves as a surfactant), citrate salts, and disaccharides (such as sucrose), monosaccharides (such as D-glucose) or other non-nutritive flavoring agents (which also serve as preservatives, antioxidants and demulcents) give aqueous solutions that are stable and have lower pH (specifically those that have pH in the range of 5.2 - 6.0) as compared to previously known formulations.
  • sodium lauryl sulfate which serves as a surfactant
  • citrate salts and disaccharides (such as sucrose), monosaccharides (such as D-glucose) or other non-nutritive flavoring agents (which also serve as preservatives, antioxidants and demulcents) give aqueous solutions that are stable and have lower pH (specifically those that have pH
  • FIG. 1 shows a graphic illustration, in which data collected from measurements of plasma salicylate levels in human patients after orai administration is plotted for an aqueous solution of a water soluble aspirin composition and for a known commercial product, specifically, Bayer® aspirin tablets. Both products were orally administered at the same 100mg aspirin dose.
  • Therapeutic levels of plasma salicylate were achieved within 5-10 minutes with the water soluble aspirin composition, compared to 30-40 minutes for aspirin in tablet or capsule form.
  • a method in accordance with which the ingredients are formulated is provided.
  • an aqueous solution such as water and does not contain any particles of aspirin
  • the aspirin is first added to a solution of potassium citrate and sodium lauryl sulfate.
  • trace amounts of aspirin particles that have not been converted to its potassium salt are removed by filtration and the clear solution is then spray dried onto a core, such as crystalline sucrose, so as to form an agglomerated product.
  • a fluid-bed spray-drying process (a process using a combination of spray drying and agglomeration using air suspension technology) provides a coating of aspirin onto the sucrose core.
  • the resultant free-flowing solid composition is freely soluble in aqueous solutions such as water, giving a clear aspirin solution (see Example 1 below).
  • This granulation process provides product that contains granules of varying diameters ranging from about 100 to 400 ⁇ with a median of about 200 ⁇ , as illustrated in Figure 2.
  • Figures 3-6 illustrate the agglomerated product obtained from this process at varying magnification ( Figure 3 with the magnification ruler at 290 ⁇ , Figure 4 with the magnification ruler at 140 ⁇ , Figure 5 with the magnification ruler at 20.0 ⁇ , and Figure 6 with the magnification ruler at 7.4 ⁇ ).
  • the resultant free-flowing solid composition contains a large number of granules, the granules comprising a substrate (such as sucrose or D-glucose) and a coating agglomerated onto the substrate core.
  • the coating includes a salt of aspirin, but substantially no particles of a non-salt form of the aspirin. That is not to say that the coating includes no non-salt form of the aspirin itself whatsoever, but rather that there are substantially no particles of the non-salt form of the aspirin contained in the coating, since substantially all of such particles are filtered during the process described above.
  • the coating may include amounts of non-salt form of the aspirin that had been previously dissolved in the solution before spray coating, since such dissolved amounts would not have been filtered as would particles thereof.
  • compositions using sucrose or other non-nutritive sweeteners that are prepared directly and without incorporation of the fluid-bed spray-drying procedure also provide free-flowing products that are substantially soluble in water, but that may require a slightly longer time to dissolve completely (see Examples 2, 3 and 4 below).
  • supplemental active ingredients have been reported to enhance the beneficial effects of acetylsalicylic acid.
  • the combination of acetylsalicylic acid with ascorbic acid (Vitamin C) is rapidly transferred from the small intestines into the blood stream.
  • This combination of aspirin and Vitamin C has been reported to be well suited for the treatment of headaches, pain and fever connected with colds.
  • acetylsalicylic acid in combination with ascorbic acid has been reported to significantly reduce gastric lesion.
  • the combination of Vitamin C with the novel formulation results in a product that is fully soluble in water (see Example 5 below).
  • the intravenous formulations of the present invention are also completely compatible with the addition of caffeine, which has been reported to enhance the pain-relieving (analgesic) effects of acetylsalicylic acid, and has been proposed for use with other agents for the treatment of migraines.
  • disaccharides such as sucrose
  • substrates including monosaccharides such as D-glucose, polysaccharides, dipeptides, etc.
  • monosaccharides such as D-glucose
  • polysaccharides such as D-glucose
  • dipeptides such as D-glucose
  • acetylsalicylic acid may be used in combination with acetylsalicylic acid in the compositions described herein.
  • the monosaccharide, xylitol has been reported to be useful in multilayered tablets containing aspirin, and may be used in the novel formulations (see Example 8 below).
  • Cellulose a polysaccharide that is insoluble in water, has been used in sustained-release tablet formulations of aspirin and may also be used in the novel formulations (see Example 9 below).
  • the present invention features an aqueous solution of an analgesic suitable for intravenous administration to a patient, preferably a human, wherein the solution has an analgesic concentration of between about 100 ⁇ g/ml and about 15 mg/ml, preferably between about 500 ⁇ g/ml and about 10 mg/ml, and even more preferably between about 1 mg/ml and about 7 mg/ml,
  • the aqueous solution of an analgesic suitable for intravenous administration has a pH less than 6.0.
  • the pH is between about 5.2 and about 6.0, preferably between about 5.6 and about 6.0.
  • the analgesic is selected from the group consisting of: aspirin, 5-aminosalicylic acid, ibuprofen, naproxen, acetaminophen and combinations of these. In certain embodiments, the analgesic is aspirin.
  • aqueous solutions of analgesics suitable for intravenous administration are stable.
  • aqueous solutions of aspirin suitable for intravenous administration are provided by the present invention which contain no detectable levels of salicylic acid using the ferric chloride procedure.
  • Such aspirin solutions may contain no detectable levels of salicylic acid using the ferric chloride procedure after incubation for 2 hours, 24 hours, or even 44 hours at room temperature (about 2TC).
  • Such aspirin solutions may exhibit less than 0.25%, less than 0.25%, less than 1%, less than 5%, or less than 25%, hydrolysis of aspirin to salicylic acid and acetic acid, even after incubation for 2 hours, 24 hours, or even 44 hours at room temperature (about 21 "C).
  • the aqueous solutions of analgesics suitable for intravenous administration provided by the present invention will be stable as described above when present in the bags for holding intravenous solutions that are commonly used in the art.
  • the present invention also provides methods of treatment or prevention using aqueous solutions of an analgesic suitable for intravenous administration.
  • the aqueous analgesic formulations may be used to treat or prevent any disease or condition for which treatment or prevention with the analgesic has been carried out by conventional means.
  • the present invention provides methods of treating a patient in need of analgesic therapy comprising intravenous administration of an aqueous analgesic formulation to a patient in need thereof, preferably a human, where an effective amount of analgesic is administered,
  • the aqueous analgesic formulation is administered intravenously in an amount effective to treat or prevent the disease or condition for which the patient is in need of treatment or prevention thereof.
  • the intravenous formulation is administered in a daily dose of analgesic of between about 50 mg to about 20 g, preferably between about 500 mg to about 10 g, and more preferably between about 1 g to about 5 g.
  • the analgesic is aspirin and intravenous administration of an aqueous aspirin formulation provides a plasma salicylate concentration of between about 10 ⁇ g/ml to about 500 ⁇ g/rnl, about 15 ⁇ g/ml to about 400 ⁇ g/ml, about 20 ⁇ g/ml to about 250 ⁇ g/ml, about 20 ⁇ g/ml to about 150 ⁇ g/ml, or about 30 ⁇ g/ml to about 100 ⁇ g/ml.
  • the plasma salicylate concentration can be even less than 10 ⁇ g/ml.
  • the intravenous administration provides an amount of analgesic and a duration of administration sufficient to achieve the desired therapeutic effect. This typically takes from a few minutes to a few hours, but may take longer, e.g., up to one, two, three, or more days,
  • the intravenous administration may be by intravenous infusion, wherein between about 50 mg to about 40 g of the analgesic is administered at a more or less steady rate over a period of about 1 hour to about 7 days, or even longer.
  • between about 800 mg to about 20 g, more preferably between about 1 g to about 15 g, and even more preferably between about 4 g to about 10 g of analgesic is administered over a period of about 2 hours to about 72 hours, preferably about 6 hours to about 48 hours, and even more preferably about 12 hours to about 24 hours.
  • the intravenous administration may provide a rate of delivery of the analgesic of about 2 mg/hrto about 1 g/hr, about 10 mg/hr to about 750 mg/hr, about 20 mg/hr to about 400 mg/hr, or about 50 mg/hr to about 200 mg/hr, and includes rates of about 10 mg/hr, about 20 mg/hr, about 25 mg/hr, about 30 mg/hr, about 40 mg/hr, about 50 mg/hr, about 75 mg/hr, about 100 mg/hr, about 125 mg/hr, about 150 mg/hr, about 200 mg/hr, about 250 mg/hr, about 300 mg/hr, about 350 mg/hr, about 400 mg/hr, about 500 mg/hr, and about 750 mg/hr.
  • aspirin is administered by intravenous infusion, wherein about 400 mg to about 40 g of aspirin is administered at a more or less steady rate over a period of about 1 hour to about 120 hours.
  • about 800 mg to about 20 g is administered at a more or less steady rate over a period of about 1 hour to about 120 hours.
  • between about 800 mg to about 20 g is administered over a period of about 2 hours to about 72 hours, preferably about 6 hours to about 48 hours, and even more preferably about 12 hours to about 24 hours.
  • the intravenous administration may also be by intravenous bolus of between about 50 mg to about 5 g of analgesic over about 1 minute to about 5 minutes.
  • intravenous bolus of between about 50 mg to about 5 g of analgesic over about 1 minute to about 5 minutes.
  • this may be followed by a slow infusion of about 100 mg to about 1 g per hour for up to about 1 hour to about 120 hours.
  • aspirin is administered by intravenous bolus of between about 100 mg to about 1 g of aspirin over about 1 minute to about 5 minutes.
  • this may be followed by a slow infusion of about 100 mg to about 1 g per hour for up to about 1 hour to about 120 hours.
  • the intravenous administration of analgesic may be repeated as needed.
  • the administration may be repeated daily, or every other day, for a period of two to fourteen days, or can be repeated every third day for a period of three to fifteen days, or once weekly for a period of three to sixteen weeks, or for any other suitable time periods.
  • the present invention provides for the intravenous administration of an analgesic at a rate that maintains a plasma concentration of analgesic or a metabolite of the analgesic of between about 10 ⁇ g/ml to about 500 ⁇ g/ml, about 15 ⁇ g/ml to about 400 ⁇ g/ml, about 20 ⁇ g/ml to about 250 ⁇ g/ml, about 20 ⁇ g/ml to about 150 ⁇ g/mt, or about 30 ⁇ g/ml to about 100 ⁇ g/ml, for a period between about 1 hour to about 7 days or longer, preferably between about 10 hours to about 76 hours, and more preferably between about 24 hours to about 48 hours.
  • the present invention provides for the intravenous administration of aspirin at a rate that maintains a plasma concentration of salicylate of between about 10 ⁇ g/ml to about 500 ⁇ g/ml, about 15 ⁇ g/ml to about 400 ⁇ g/mi, about 20 ⁇ g/ml to about 250 ⁇ g/ml, about 20 ⁇ g/ml to about 150 ⁇ g/ml, or about 30 ⁇ g/ml to about 100 ⁇ g/ml, for a period between about 1 hour to about 7 days or longer, preferably between about 10 hours to about 76 hours, and more preferably between about 24 hours to about 48 hours.
  • a plasma concentration of salicylate of between about 10 ⁇ g/ml to about 500 ⁇ g/ml, about 15 ⁇ g/ml to about 400 ⁇ g/mi, about 20 ⁇ g/ml to about 250 ⁇ g/ml, about 20 ⁇ g/ml to about 150 ⁇ g/ml, or about 30 ⁇ g/m
  • the intravenous formulations of the present invention allow for the maintenance of desired, substantially constant concentrations of analgesics in the blood.
  • a substantially constant low level of analgesic is provided.
  • a substantially constant moderate level of analgesic is provided.
  • a substantially constant high level of analgesic is provided.
  • the present invention provides for the intravenous administration of an analgesic so as to maintain a plasma concentration of the analgesic or a metabolite of the analgesic of 5 ⁇ g/ml ⁇ 10%, 10 ⁇ g/ml ⁇ 10%, 15 ⁇ g/ml ⁇ 10%, 20 ⁇ g/ml ⁇ 10%, 25 ⁇ g/ml ⁇ 10%, 30 ⁇ g/ml ⁇ 10%, 40 ⁇ g/ml ⁇ 10%, 60 ⁇ g/ml ⁇ 10%, or 75 ⁇ g/ml ⁇ 10% for about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 96 hours, about 144 hours, or longer.
  • the present invention provides for the intravenous administration of aspirin so as to maintain a plasma concentration of salicylate of 5 ⁇ g/ml ⁇ 10%, 10 ⁇ g/ml ⁇ 10%, 15 ⁇ g/ml ⁇ 10%, 20 ⁇ g/ml ⁇ 10%, 25 ⁇ g/ml ⁇ 10%, 30 ⁇ g/ml ⁇ 10%, 40 ⁇ g/ml ⁇ 10%, 60 ⁇ g/ml ⁇ 10%, or 75 ⁇ g/ml ⁇ 10% for about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 96 hours, about 144 hours, or longer.
  • the present invention also provides for the intravenous administration of an analgesic so as to maintain a plasma concentration of the analgesic or a metabolite of the analgesic of 100 ⁇ g/ml ⁇ 10%, 110 ⁇ g/ml ⁇ 10%, 120 ⁇ g/ml ⁇ 10%, 130 ⁇ g/m!
  • the present invention provides for the intravenous administration of aspirin so as to maintain a plasma concentration of salicylate of 100 ⁇ g/ml ⁇ 10%, 110 ⁇ g/ml ⁇ 10%, 120 ⁇ g/ml ⁇ 10%, 130 ⁇ g/ml ⁇ 10%, 140 ⁇ g/ml ⁇ 10%, 150 ⁇ g/ml ⁇ 10%, 175 ⁇ g/ml +10%, 200 ⁇ g/ml ⁇ 10%, or 250 ⁇ g/ml ⁇ 10% for about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 96 hours, about 144 hours, or longer.
  • the present invention also provides for the intravenous administration of an analgesic so as to maintain a plasma concentration of the analgesic or a metabolite of the analgesic of 250 ⁇ g/ml ⁇ 10%, 300 ⁇ g/ml ⁇ 10%, 400 ⁇ g/ml ⁇ 10%, or 500 ⁇ g/ml ⁇ 10% for about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 96 hours, or about 144 hours.
  • the present invention provides for the intravenous administration of aspirin so as to maintain a plasma concentration of salicylate of 250 ⁇ g/ml ⁇ 10%, 300 ⁇ g/ml ⁇ 10%, 400 ⁇ g/ml ⁇ 10%, or 500 ⁇ g/ml ⁇ 10% for about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 96 hours, or about 144 hours.
  • the present invention provides for the intravenous administration of aspirin such that a plasma salicylate concentration of between about 120 ⁇ g/ml to about 350 ⁇ g/ml is obtained within about 1 minute, preferably within about 5 minutes, and even more preferably within about 20 minutes.
  • a plasma salicylate concentration of between about 120 ⁇ g/ml to about 350 ⁇ g/ml is reached, the plasma salicylate concentration of between about 120 ⁇ g/ml to about 350 ⁇ g/ml may be maintained for about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 96 hours, or about 144 hours.
  • the present invention provides for the intravenous administration of an analgesic to provide a 6 hour AUC for the analgesic or a metabolite of the analgesic of between about 0.3 mM * hr to about 15 mM * hr, preferably between about 2 mM*hrto about 10 mM * hr, and even more preferably between about 3 mM*hr to about 8 mM * hr.
  • the present invention provides for the intravenous administration of an analgesic to provide a 12 hour AUC for the analgesic or a metabolite of the analgesic of between about 0.6 mM*hrto about 30 mM * hr, preferably between about 4 mM*hr to about 20 mlvThr, and even more preferably between about 6 mM*hr to about 16 mM*hr.
  • the present invention provides for the intravenous administration of an analgesic to provide a 24 hour AUC for the analgesic or a metabolite of the analgesic of between about 1.2 mM*hr to about 60 mM * hr, preferably between about 8 mM*hr to about 40 mM*hr, and even more preferably between about 12 mM*hr to about 32 mM*hr.
  • the present invention provides for the intravenous administration of aspirin to provide a 6 hour AUC for salicylate of between 0.3 mM*hr to about 15 mM*hr, preferably between about 2 mM * hr to about 10 mM*hr, and even more preferably between about 3 mM * hr to about 8 mM*hr.
  • the present invention provides for the intravenous administration of aspirin to provide a 12 hour AUC for salicylate of between about 0.6 mM*hr to about 30 mM * hr, preferably between about 4 mM * hr to about 20 mM * hr, and even more preferably between about 6 mM*hr to about 16 mM*hr .
  • the present invention provides for the intravenous administration of aspirin to provide a 24 hour AUC for salicylate of between about 1.2 mM * hr to about 60 mM*hr, preferably between about 8 mM*hr to about 40 mM*hr, and even more preferably between about 12 mM*hr to about 32 mlvThr .
  • the present invention provides methods of making intravenous formulations of analgesics.
  • methods of making intravenous formulations are well known in the art and can be found, for example, in "Remington: The Science and Practice of Pharmacy” (20th ed., ed. A. R. Gennaro AR., 2000, Lippincott Williams & Wilkins).
  • the water soluble analgesic compositions described herein can be formulated using known methods of preparing intravenous formulations.
  • Formulations for intravenous administration according to the present invention may be made, for example, using any one or combination of such aqueous solutions as sterile water, isotonic saline, isotonic dextrose, or other aqueous solutions commonly used to make intravenous formulations.
  • the pH of the formulation for intravenous administration may be adjusted to about the normal pH of human blood (i.e., pH 7.4). Preferably, this is done more or less immediately before administering the formulation for intravenous administration.
  • the present invention provides a method of making a formulation of an analgesic suitable for intravenous administration comprising:
  • an analgesic composition comprising granules, the granules comprising:
  • the salt of the analgesic is a potassium salt of the analgesic.
  • the step of providing the analgesic composition comprises: providing a first solution comprising a base; adding the analgesic to the first solution to create a second solution comprising a salt of the analgesic; filtering the second solution to remove residual particles of the analgesic to create a filtered second solution; and spray drying the filtered second solution onto a substrate so as to form an agglomerated product comprising a plurality of granules.
  • the base comprises tripotassium citrate monohydrate.
  • the first solution further comprises a surfactant, preferably sodium lauryl sulfate.
  • the substrate is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, dipeptides and combinations of these.
  • the substrate is sucrose, cellulose, xylitol, or D-glucose.
  • the step of spray drying the filtered second solution onto a substrate employs a fluid-bed spray drying process.
  • the present invention also includes methods of making intravenous formulations of analgesics comprising:
  • the analgesic is selected from the group consisting of: aspirin, 5-aminosalicylic acid, ibuprofen, naproxen, acetaminophen and combinations of these. In certain embodiments, the analgesic is aspirin.
  • the dissolving occurs in less than about 15 seconds, less than about 30 seconds, less than about 60 seconds, less than about 120 seconds, or less than about 240 seconds. In certain embodiments, the dissolving occurs in about 15 seconds to about 240 seconds, preferably in about 30 seconds to about 120 seconds.
  • a mixture of 30.0 g of aspirin, 70.0 g of tripotassium citrate monohydrate, 100.0 g of sucrose and 60 mg of sodium lauryl sulfate was thoroughly shaken on a rocker assembly to ensure homogeneity.
  • the resultant free-flowing product was stable for at least 3 weeks at 50 0 C and at least 2 weeks at 75 0 C and completely stable to ultraviolet light (254 nm) for at least 1 week.
  • Addition of 3.33 g of the mixture (containing 500 mg of aspirin) to 150 ml of purified water with stirring and mixing was palatable and substantially soluble within 15 seconds, completely soluble in 180 seconds, and gave a pH of 5.67.
  • a mixture of 30.0 g of aspirin, 70.0 g of tripotassium citrate monohydrate, 20.0 g of aspartame and 36 mg of sodium lauryl sulfate was thoroughly shaken on a rocker assembly to ensure homogeneity.
  • the resultant free-flowing product was stable for at least 3 weeks at 50 0 C and at least 2 weeks at 75 0 C.
  • a mixture of 30.0 g of aspirin, 70.0 g of tripotassium citrate monohydrate, 20.0 g of sucralose and 36 mg of sodium iauryl sulfate was thoroughly shaken on a rocker assembly to ensure homogeneity.
  • the resultant free-flowing product was stable for at least 3 weeks at 50 0 C.
  • Addition of 2.00 g of the mixture (containing 500 mg of aspirin) to 150 ml of purified water with stirring and mixing was palatable and substantially soluble within 30 seconds, completely soluble in 210 seconds, and gave a pH of 5.74.
  • a 4.75 g portion of the product from Example 1 (containing 561 mg of aspirin) was thoroughly mixed with 200 mg of Vitamin C.
  • the resulting free- flowing product was dissolved in 100 ml of water with stirring and mixing. It was fully soluble within 30 seconds, gave a pH of 5.63, and was palatable.
  • Example 7 A 4.75 g portion of the product from Example 1 (containing 561 mg of aspirin) was thoroughly mixed with 50 mg of caffeine. The resulting free- flowing product was dissolved in 100 ml of water with stirring and mixing. It was fully soluble within 30 seconds, gave a pH of 5.86, and was palatable. [00105] Example 7
  • a mixture of 4.8 g of aspirin, 13.4 g of tripotassium citrate monohydrate, 20.0 g of crystalline xylitol and 12 mg of sodium lauryl sulfate was thoroughly shaken on a rocker assembly to ensure homogeneity, resulting in a free- flowing white product.
  • Addition of 2.60 g of the mixture (containing 325 mg of aspirin) to 100 ml of purified water with stirring and mixing was palatable and substantially soluble within 15 seconds, completely soluble in 60 seconds, and gave a pH of 5.99.
  • the pH of each of the intravenous formulations is below 6.0, which, as described above, provides a number of distinct advantages. It can be ensured to keep the pH in the desired range (i.e., ⁇ 6.0) by varying the amount of aspirin in the composition used to prepare the intravenous formulations as compared to the amount of tripotassium citrate monohydrate. More specifically, with an aspirin content of greater than about 26% by weight of a combined weight of aspirin and tripotassium citrate monohydrate (i.e., between 26% and 40% aspirin) the pH of the resulting solution is less than 6.0.
  • Example 1 above has approximately 26.3% aspirin content and has a pH of 5.87
  • Example 2 above has approximately 30.0% aspirin content and has a pH of 5.67
  • the pH of the resulting solution is greater than 6.0.
  • Example 5 in U.S. Patent No. 5,776,431 to Gaiat has about 20.0% aspirin content and has a pH of 6.12.
  • the relationship between percent aspirin content and the resulting pH of the solution is graphically shown in Figure 7.
  • the present invention encompasses formulations where water insoluble derivatives of salicylic acid are used as the active therapeutic.
  • 5-Aminosalicylic acid (mesalamine)
  • mesalamine is used to treat inflammatory bowel diseases, such as ulcerative colitis.
  • Mesalamine is insoluble in water and is, therefore, usually used in extended release capsules or, alternatively, as a suppository.
  • large daily doses of mesalamine (4 g/day) are required for treatment of inflammatory bowel diseases. It has been reported that the solubility-pH profile of mesalamine is increased at pH ⁇ 2.0 and pH > 5.5.
  • Formulations of mesalamine in accordance with the teachings of the present application result in a pH of 6.86, which results in a homogeneous aqueous solution that is fast acting.
  • the formulation may include a variety of substrates, including sucrose.
  • a mixture of 125 mg of ibuprofen, 2.50 g of tripotassium citrate monohydrate, 3.73 g of sucrose and 2 mg of sodium lauryl sulfate was thoroughly shaken on a rocker assembly to ensure homogeneity, resulting in a free-flowing white product.
  • Addition of the mixture (containing 125 mg of ibuprofen) to 75 ml of purified water with stirring was substantially soluble within 15 seconds and completely soluble in 240 seconds. This solution had a pH of 7.23 and was palatable.
  • a mixture of 125 mg of naproxen, 2.50 g of tripotassium citrate monohydrate, 3.73 g of sucrose and 2 mg of sodium lauryl sulfate was thoroughly shaken on a rocker assembly to ensure homogeneity, resulting in a free-flowing white product.
  • Addition of the mixture (containing 125 mg of ibuprofen) to 75 ml of purified water with stirring was substantially soluble within 15 seconds and completely soluble in 60 seconds. This solution had a pH of 7.40 and was palatable.
  • Aspirin (375.0 g) was added portionwise to a solution of 1050.0 g of tripotassium citrate monohydrate in 6.0 L of water containing sodium lauryl sulfate ⁇ 0.9 g). Mechanical stirring continued for a period of 15 minutes until the solution was nearly homogenous. A trace amount of undissolved aspirin was removed by vacuum filtration through a 2.0 L medium sintered glass funnel into a 4.0 L. The resultant clear solution was charged into a stainless steel reservoir and slowly applied onto 3148.2 g of sucrose using a 22 L granulator Fluid-Bed spray Processor.
  • the above aspirin solution (14772 g) was sprayed into the Fluid Bed Spray Processor (GPCG 5) over 567 minutes.
  • the initial spray rate was 21 g/min for the first 323 minutes of spray.
  • a final spray rate of 35 g/min was obtained.
  • the inlet air temperature was between 45-47 0 C throughout the process, which yielded a product temperature between 38-39 0 C during spraying and a final product temperature of 42°C after drying.
  • the total processing time in the GPCG 5 was 574 minutes.
  • the resulting agglomeration contained granulated product with a median particle size of about 200 ⁇ and contained 11.8% aspirin by hplc analysis. There was no detectable level of salicylic acid using the ferric chloride procedure, which can detect as little as 0.25% hydrolysis. A 5.2 g portion (containing 614 mg of aspirin) of the resultant free-flowing product in 100 ml of water with stirring and mixing was palatable and fully soluble within 30 seconds and gave a pH of 5.87. [00129] Since the intravenous formulations of analgesics in accordance with the present invention employ known analgesics, the formulations are anticipated to be useful to prevent and treat substantially all known conditions, diseases, types of patients, etc. currently treated using the known formulations of these analgesics. However, given the many benefits of the intravenous formulations of analgesics in accordance with the present invention discussed above, it is anticipated that such formulations will have even a wider range of applications.
  • the present invention therefore, provides intravenous formulations of analgesics which have enhanced stability and bioactivity as compared to previously known analgesic formulations, which are sodium free and allow for rapid delivery of analgesic to the bloodstream, and which may be used in the relatively large dosages that are required for certain medical conditions, and/or that may be used for extended periods of time, without causing gastrointestinal upset and/or damage.

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Abstract

L'invention concerne des compositions de produits analgésiques appropriées pour une administration par voie intraveineuse, de préférence à un être humain. Elle concerne également des procédés de composition d'analgésiques pour une administration par voie intraveineuse ainsi que des procédés d'utilisation des formulations d'analgésiques appropriées pour une administration par voie intraveineuse pour le traitement de diverses pathologies ou affections médicales. Dans des modes de réalisation préférés, l'analgésique est l'aspirine. Les formulations permettent l'administration d'aspirine à des patients nécessitant un traitement à l'aspirine à des doses importantes et sur des périodes prolongées sans les effets secondaires gastro-intestinaux qui accompagnent souvent un traitement à l'aspirine classique.
PCT/US2007/087943 2006-12-21 2007-12-18 Administration intraveineuse de formulations analgésiques hydrosolubles Ceased WO2008079818A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012060719A1 (fr) * 2010-11-04 2012-05-10 Aft Pharmaceuticals Limited Composition combinée
US11197830B2 (en) 2019-02-27 2021-12-14 Aft Pharmaceuticals Limited Pharmaceutical composition containing acetaminophen and ibuprofen

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US4123523A (en) * 1976-06-21 1978-10-31 Imperial Chemical Industries Limited Analgesic and sedative polypeptides
US5149320A (en) * 1988-04-11 1992-09-22 Dhaliwal Avtar S Composite anesthetic article and method of use
US5739118A (en) * 1994-04-01 1998-04-14 Apollon, Inc. Compositions and methods for delivery of genetic material
US7374779B2 (en) * 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
DE10355251A1 (de) * 2003-11-26 2005-06-23 Merck Patent Gmbh Pharmazeutische Zubereitung enthaltend einen Antikörper gegen den EGF-Rezeptor
TW200616604A (en) * 2004-08-26 2006-06-01 Nicholas Piramal India Ltd Nitric oxide releasing prodrugs containing bio-cleavable linker

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012060719A1 (fr) * 2010-11-04 2012-05-10 Aft Pharmaceuticals Limited Composition combinée
CN103298464A (zh) * 2010-11-04 2013-09-11 阿福特药物有限公司 复方组合物
RU2707089C2 (ru) * 2010-11-04 2019-11-22 АФТ Фармасьютикалз Лимитед Комбинированная композиция
US11446266B2 (en) 2010-11-04 2022-09-20 Aft Pharmaceuticals Limited Combination composition
US11896567B2 (en) 2010-11-04 2024-02-13 Aft Pharmaceuticals Limited Combination composition
US12220392B2 (en) 2010-11-04 2025-02-11 Aft Pharmaceuticals Limited Combination composition
US11197830B2 (en) 2019-02-27 2021-12-14 Aft Pharmaceuticals Limited Pharmaceutical composition containing acetaminophen and ibuprofen
US11534407B2 (en) 2019-02-27 2022-12-27 Aft Pharmaceuticals Limited Pharmaceutical compostion containing acetominophen and ibuprofen
US11872317B2 (en) 2019-02-27 2024-01-16 Aft Pharmaceuticals Limited Pharmaceutical composition containing acetominophen and ibuprofen
US12194151B2 (en) 2019-02-27 2025-01-14 Aft Pharmaceuticals Limited Pharmaceutical compostion containing acetominophen and ibuprofen

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