WO2009078872A1 - Formulations analgésiques hydrosolubles se délitant dans la bouche et leurs procédés de production - Google Patents

Formulations analgésiques hydrosolubles se délitant dans la bouche et leurs procédés de production Download PDF

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Publication number
WO2009078872A1
WO2009078872A1 PCT/US2007/087946 US2007087946W WO2009078872A1 WO 2009078872 A1 WO2009078872 A1 WO 2009078872A1 US 2007087946 W US2007087946 W US 2007087946W WO 2009078872 A1 WO2009078872 A1 WO 2009078872A1
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Prior art keywords
wafer
pellet
lozenge
orally disintegrating
aspirin
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PCT/US2007/087946
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English (en)
Inventor
Robert E. Martin
Arthur M. Felix
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Soluprin Pharmaceuticals, Inc.
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Priority to PCT/US2007/087946 priority Critical patent/WO2009078872A1/fr
Publication of WO2009078872A1 publication Critical patent/WO2009078872A1/fr

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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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/14—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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/1611—Inorganic 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
    • A61K9/14—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
    • 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

Definitions

  • the present invention relates generally to aspirin and other analgesic compositions and, more specifically, to orally disintegrating formulations of water soluble aspirin and other analgesic compositions which have enhanced stability and bioactivity as compared to previously known water soluble formulations 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 PGH 2 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 falls 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.
  • a water soluble analgesic composition which has enhanced stability and bioactivity as compared to previously known water soluble analgesic compositions, and which does not suffer from the disadvantages described above.
  • the present invention provides such an analgesic composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge suitable for the rapid sublingual, buccal, or gingival administration of the analgesic.
  • a water soluble analgesic composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge which has enhanced stability and bioactivity, as compared to previously known water soluble analgesic compositions.
  • Another object of the present invention is to provide a water soluble analgesic composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge having the above characteristics and which is sodium free.
  • a further object of the present invention is to provide a water soluble analgesic composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge having the above characteristics and which is rapidly water soluble.
  • Still another object of the present invention is to provide a water soluble analgesic composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge having the above characteristics and which is fast acting and enters the bloodstream rapidly.
  • Yet a further object of the present invention is to provide a water soluble analgesic composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge having the above characteristics and which may be used in the relatively large dosages that are required for treatment of certain medical conditions, and/or that may be used for extended periods of time, without causing gastrointestinal upset and/or damage.
  • a water soluble analgesic composition including a plurality of granules.
  • 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.
  • Such a water soluble analgesic composition can be formulated into an orally disintegrating tablet, wafer, pellet, or lozenge.
  • the substrate core is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, dipeptides and combinations of these.
  • the substrate core comprises cellulose, xylitol, or sucrose.
  • 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 ⁇ .
  • 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 cellulose, xylitol, or sucrose.
  • 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 in the form of an orally disintegrating tablet, wafer, pellet, or lozenge 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 in the form of an orally disintegrating tablet, wafer, pellet, or lozenge further includes a substrate.
  • the substrate is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, dipeptides and combinations of these.
  • the substrate comprises cellulose, xylitol, or sucrose.
  • the substrate comprises a substrate core onto which the aspirin and the tripotassium citrate monohydrate are coated.
  • the water soluble analgesic composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge further includes a surfactant.
  • the surfactant comprises sodium lauryl sulfate.
  • the water soluble analgesic composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge further includes a supplemental active ingredient selected from the group consisting of ascorbic acid, caffeine and combinations of these.
  • a water soluble analgesic composition in the form of an oraily disintegrating tablet, wafer, pellet, or lozenge includes aspirin and tripotassium citrate monohydrate, with a pH of the composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge, when dissolved in water, being below about 6.0.
  • the pH of the composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge, when dissolved in water falls within a range from about 5.2 to about 6.0. In certain of these embodiments, the pH of the composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge, 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 in the form of an orally disintegrating tablet, wafer, pellet, or lozenge 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 the aspirin to create a filtered second solution, (vi) spray drying the filtered second solution onto the substrate so as to form an agglomerated product comprising a plurality of granules, and ⁇ vii) compressing, molding, or otherwise forming the agglomerated product, optionally with other excipients, into an orally disintegrating tablet, wafer, pellet, or lozenge.
  • 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 in the form of an orally disintegrating tablet, wafer, pellet, or lozenge, 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 cellulose, xylitol, or sucrose.
  • 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 10O ⁇ to about 400 ⁇ . In certain of these embodiments, the granules have a median diameter of about 200 ⁇ .
  • a rapidly dissolving composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge comprising an aspirin salt is provided, wherein a portion of the composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge containing 650 mg of aspirin is completely soluble in 100 ml of water in less than 60 seconds.
  • the portion of the composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge 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 in the form of an orally disintegrating tablet, wafer, pellet, or lozenge containing 650 mg of aspirin is completely soluble in 100 ml of water in less than 15 seconds. In some embodiments, a pH of the composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge, when dissolved in water, is below about 6.0.
  • the pH of the composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge, when dissolved in water falls within a range from about 5.2 to about 6.0. In certain embodiments, the pH of the composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge, when dissolved in water, falls within a range from about 5.6 to about 6.0. In the embodiments relating to solution times and pHs described herein, preferably the water is at room temperature (about 21 0 C). [0039]
  • Figure 1 graphically illustrates, based upon data collected from 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 described herein.
  • Figures 3-6 show scanning electron micrographs of a water soluble aspirin composition described herein 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 described herein.
  • Orally disintegrating tablet, wafer, pellet, or lozenge means a tablet, wafer, pellet, or lozenge that is adapted for delivering an analgesic via absorption through the mucosal lining of the mouth, either sublingual ⁇ (i.e., from the area beneath the tongue) or bucally (i.e., from the area between the cheek and gum).
  • Orally disintegrating tablet, wafer, pellet, or lozenge may also mean a tablet, wafer, pellet, or lozenge that is adapted for delivering an analgesic via absorption through the tongue, after being placed on top of the tongue.
  • 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.
  • 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.
  • 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 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 cellulose, disaccharides (such as sucrose), monosaccharides 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. This compares favorably to formulations prepared by the prior art which, when dissolved in water, are generally not palatable and give solutions with pH greater than 6.0.
  • novel formulations of the present invention at lower pH, containing citrate, sodium lauryl sulfate, cellulose or sucrose and aspirin are designed to be more readily absorbed since they are in a more undissociated form.
  • the major decomposition pathway of acetylsalicylic acid to salicylic acid and acetic acid is via hydrolysis. In the absence of water, decomposition of acetylsalicylic acid does not occur. It has been reported that hydrolysis of aspirin is reduced in the presence of citric acid. In addition, sodium lauryl sulfate has been reported to act both as a lubricant and a stabilizing agent.
  • sucrose hinders this decomposition pathway of acetylsalicylic acid, presumably by providing a protective layer that has low moisture content, which may protect the acetylsalicylic acid from hydrolysis. It is likely that the hydroxyl groups in sucrose are able to hydrogen bond with water and, thereby, provide a level of protection from hydrolysis to acetylsalicylic acid.
  • FIG. 1 shows a graphic illustration, in which data collected from measurements of plasma salicylate levels in human patients who were administered a water soluble aspirin composition is plotted for an aqueous solution of the composition and for a known commercial product, specifically, Bayer® aspirin tablets. Both products were administered at the same 100mg aspirin dose.
  • Therapeutic levels of plasma salicylate were achieved within 5-10 minutes for the water soluble aspirin composition, compared to 30-40 minutes for aspirin in tablet or capsule form.
  • plasma salicylate levels were approximately twice as high for the water soluble aspirin composition as compared to the commercial product.
  • water soluble aspirin compositions can achieve comparable salicylate levels, and thereby minimize potential side effects of aspirin.
  • the improved water solubility and palatability of the water soluble aspirin composition enables administration of larger doses of aspirin, as may be required for treating certain medical conditions, while minimizing the potential gastric side-effects that are observed with commercially available aspirin in tablet or capsule form.
  • Water soluble aspirin compositions can also be formulated into an orally disintegrating tablet, wafer, pellet, or lozenge that possesses similar advantageous characteristics.
  • a method in accordance with which the ingredients are formulated for the water soluble aspirin composition described herein that can be formulated into an orally disintegrating tablet, wafer, pellet, or lozenge.
  • the aspirin is first added to a solution of potassium citrate and sodium lauryl sulfate. Then, 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 cellulose, xylitol, or 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 cellulose, xylitol, or sucrose core.
  • the resultant free-flowing solid agglomerated product contains a large number of granules, the granules consisting of a substrate (such as cellulose, xylitol, or sucrose) 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.
  • Formulations 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).
  • acetylsalicylic acid has been reported to enhance the beneficial effects of acetylsalicylic acid.
  • acetylsalicylic acid with ascorbic acid 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 reduces 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 formulation is 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.
  • caffeine 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.
  • the combination of caffeine with the novel formulation results in a product that is fully soluble in water (see Example 6 below).
  • 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 formulation and pressed into tablets, wafers, pellets, or lozenges (see Example 9 below).
  • the orally disintegrating tablet, wafer, pellet, or lozenge of the present invention is a sublingual tablet, wafer, pellet, or lozenge, i.e., a tablet, wafer, pellet, or lozenge adapted to deliver an analgesic via absorption from the area beneath the tongue.
  • a sublingual tablet, wafer, pellet, or lozenge is designed to be placed beneath the tongue and held there until sufficient absorption of the analgesic contained in the sublingual tablet, wafer, pellet, or lozenge has occurred.
  • a sublingual tablet, wafer, pellet, or lozenge should dissolve or disintegrate quickly, allowing the analgesic to be rapidly absorbed.
  • the compressed or molded tablets, wafers, pellets, or lozenges may contain rapidly soluble excipients such as lactose, dextrose, sucrose (additional to that in the granules), mannitol, or others known in the art.
  • rapidly soluble excipients such as lactose, dextrose, sucrose (additional to that in the granules), mannitol, or others known in the art.
  • Other excipients that may be used include rapidly disintegrating excipients such as Ac-Di-SoI, Kollidon CL, or sodium starch glycolate.
  • the granules and additional excipients may be subject to a process, e.g., screening or micronizing, to reduce particle size.
  • a suitable particle size e.g., an average particle size of about 100-400 ⁇ , preferably 100-200 ⁇
  • the granules and additional excipients may be blended together and then moistened with a suitable liquid.
  • the liquid is added to make a workable mass without overwetting the ingredients or destroying the structure of the granules.
  • the blended, moistened ingredients are then subjected to a compression or molding process to form the orally disintegrating tablets, wafers, pellets, or lozenges. In particular, compression on a tableting machine at low to medium compression force may be used.
  • the water soluble analgesic compounds described herein may be dissolved in a suitable aqueous solution and the solution containing dissolved analgesic may then be freeze-dried to produce the orally disintegrating tablets, wafers, pellets, or lozenges of the present invention.
  • 6,596,311 describes a method of producing a fast disintegrating tablet comprising a drug in multiparticulate form, e.g., granular or microencapsulated, by formulating the drug with one or more water insoluble inorganic excipients, one or more disintegrants, and optionally, one or more substantially water soluble excipients, the amounts of said ingredients being such as to provide a disintegration time in the mouth in the order of 75 seconds or less, e.g., 40 seconds or less, preferably less than 30 seconds, most preferably less than 20 seconds.
  • 7,125,562 describes a rapidly disintegrating tablet made by blending two phases, the first phase comprising methylcellulose and a diluent while the second phase comprises at least two ingredients selected from among a disintegrating agent, a wetting agent, a lubricant, and a second diluent.
  • U.S. Patent 5,501,861 discloses methods for producing fast dissolving tablets by compression molding in a semi-dry state.
  • 5,837,285 discloses a drug-containing a fast soluble tablet which has a pharmaceutical additive rapidly soluble in water as a tablet base component and is produced using a kneaded mixture of a drug and a pharmaceutical additive rapidly soluble in water that is subjected to compressive shaping while in a wet state.
  • the disclosures of these patents are incorporated by reference herein.
  • the orally disintegrating tablets, wafers, pellets, or lozenges of the present invention are designed to dissolve in saliva.
  • the pH of the saliva in the region of the tablet, wafer, pellet, or lozenge be slightly acidic, e.g. less than about 6, preferably about 4 to about 6, in order to improve the stability of the aspirin after it has been released from the tablet or wafer.
  • This can be accomplished by including as an excipient in the tablet, wafer, pellet, or lozenge an effective buffering amount of one or more buffering agents such as, e.g., mono- and di-sodium phosphates and borates, basic magnesium carbonate and combinations of magnesium and aluminum hydroxide.
  • the orally disintegrating tablets, wafers, pellets, or lozenges of the present invention may be of a suitable size, shape, weight, consistency or hardness.
  • One possibility is a coin-shaped disc or wafer of about 4 to about 15 mm in diameter and about 5 to 2 mm in thickness, the thickness usually varying inversely to the diameter.
  • the orally disintegrating tablets, wafers, pellets, or lozenges of the present invention release their analgesic content over a period of about 5 seconds to about 120 seconds, about 5 seconds to about 90 seconds, about 5 seconds to about 60 seconds, about 5 seconds to about 30 seconds, or about 10 seconds to about 60 seconds, when placed under the tongue of a human.
  • the orally disintegrating tablets, wafers, pellets, or lozenges of the present invention dissolve completely over a period of about 10 seconds to about 120 seconds, about 10 seconds to about 90 seconds, about 10 seconds to about 60 seconds, about 10 seconds to about 30 seconds, or about 20 seconds to about 60 seconds, when placed into human saliva or a solution that mimics human saliva.
  • the present invention provides an orally disintegrating tablet, wafer, pellet, or lozenge comprising granules, the granules comprising:
  • the salt of the analgesic is 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 embodiments, the analgesic is aspirin.
  • the substrate is selected from the group consisting of cellulose, monosaccharides, d [saccharides, polysaccharides, dipeptides and combinations of these.
  • the substrate is cellulose, xylitol, or sucrose.
  • the granules comprise: (i) the analgesic;
  • the analgesic is aspirin and the aspirin comprises at least about 26% by weight of a combined weight of the aspirin and the tripotassium citrate monohydrate. In other embodiments, the aspirin comprises about 26% to about 40% by weight of a combined weight of the aspirin and the tripotassium citrate monohydrate.
  • the orally disintegrating tablet, wafer, pellet, or lozenge has a pH of less than about 6.0, preferably a pH of between about 5.2 and about 6.0, and even more preferably a pH of between about 5.6 and about 6.0 when a portion of the tablet, wafer, pellet, or lozenge containing about 650 mg of analgesic is dissolved in about 100 ml of water.
  • the orally disintegrating tablet, wafer, pellet, or lozenge comprises from about 50 mg to about 5 g of the analgesic, preferably about 150 mg to about 3 g, and even more preferably about 500 mg to 1 g. In certain embodiments, the orally disintegrating tablet, wafer, pellet, or lozenge comprises from about 75 mg to about 325 mg of the analgesic. In certain embodiments, the orally disintegrating tablet, wafer, pellet, or lozenge comprises about 81 mg, 325 mg, or 500 mg of the analgesic.
  • the present invention provides a method of making a water soluble analgesic composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge comprising: providing a first solution comprising a base; adding an 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; spray drying the filtered second solution onto a substrate so as to form an agglomerated product comprising a plurality of granules; and compressing, molding, or otherwise forming the agglomerated product, optionally with other excipients, into an orally disintegrating tablet, wafer, pellet, or lozenge.
  • the analgesic is selected from the group consisting of aspirin, 5-aminosalicylic acid, ibuprofen, naproxen, acetaminophen and combinations of these; preferably the analgesic is aspirin;
  • 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; preferably the substrate is cellulose;
  • the step of spray drying the filtered second solution onto a substrate employs a fluid-bed spray drying process; and/or • the granules have a median diameter falling within a range from about 100 ⁇ to about 400 ⁇ ; preferably the granules have a median diameter of about 200 ⁇ .
  • the analgesic is aspirin
  • the base is tripotassium citrate monohydrate
  • the aspirin comprises at least about 26% by weight of a combined weight of the aspirin and the tripotassium citrate monohydrate, preferably from about 26% to about 40% by weight of a combined weight of the aspirin and the tripotassium citrate monohydrate.
  • the orally disintegrating tablet, wafers, pellets, or lozenges can be evaluated with respect to disintegration properties in a USP disintegration apparatus, without disks, using water at various temperatures, e.g., room temperature or 37 ⁇ 2°C.
  • the present invention provides a method of administering an analgesic comprising administering to a patient in need thereof an orally disintegrating tablet, wafer, pellet, or lozenge comprising an analgesic so as to deliver an effective amount of the analgesic to the patient.
  • the patient is a human.
  • the present invention also provides methods of treatment or prevention using an orally disintegrating tablet, wafer, pellet, or lozenge comprising an analgesic.
  • the orally disintegrating tablet, wafer, pellet, or lozenge comprising an analgesic of the present invention may be used to treat or prevent any disease or condition for which treatment with the analgesic has been carried out by conventional means.
  • the orally disintegrating tablet, wafer, pellet, or lozenge is administered in an amount effective to treat the disease or condition for which the patient is in need of treatment.
  • the orally disintegrating tablet, wafer, pellet, or lozenge is administered so as to provide 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 administration of the orally disintegrating tablet, wafer, pellet, or lozenge provides a plasma salicylate concentration 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/ml, or about 30 ⁇ g/ml to about 100 ⁇ g/ml.
  • the plasma salicylate concentration can be even less than 10 ⁇ g/ml.
  • the administration of the orally disintegrating tablet, wafer, pellet, or lozenge provides an amount of analgesic and a duration of administration of the analgesic 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 present invention provides for the administration of an orally disintegrating tablet, wafer, pellet, or lozenge comprising an analgesic so as to maintain 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/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.
  • the present invention provides for the administration of an orally disintegrating tablet, wafer, pellet, or lozenge comprising 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/ml t 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/ml t about 20 ⁇ g/ml to about 250 ⁇ g/ml, about 20 ⁇ g/ml to
  • the orally disintegrating tablets, wafers, pellets, or lozenges 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 orally disintegrating tablets, wafers, pellets, or lozenges for the 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 orally disintegrating tablets, wafers, pellets, or lozenges for the 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 orally disintegrating tablets, wafers, pellets, or lozenges for the 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/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 provides orally disintegrating tablets, wafers, pellets, or lozenges for the 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 orally disintegrating tablets, wafers, pellets, or lozenges for the 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 orally disintegrating tablets, wafers, pellets, or lozenges for the 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 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 administration of an orally disintegrating tablet, wafer, pellet, or lozenge comprising 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 administration of an orally disintegrating tablet, wafer, pellet, or lozenge comprising 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 * 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 administration of an orally disintegrating tablet, wafer, pellet, or lozenge comprising an analgesic to provide a 12 hour AUC for the analgesic or a metabolite of the analgesic of between about 0.6 mM*hr to about 30 mM*hr, preferably between about 4 mM*hr to about 20 rnWThr, and even more preferably between about 6 mlvThr to about 16 mM * hr.
  • the present invention provides for the administration of an orally disintegrating tablet, wafer, pellet, or lozenge comprising 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 mlvThr, and even more preferably between about 12 mM*hrto about 32 mM*hr.
  • the present invention provides for the administration of an orally disintegrating tablet, wafer, pellet, or lozenge comprising aspirin to provide a 6 hour AUC for salicylate of between about 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 mlvThr.
  • the present invention provides for the administration of an orally disintegrating tablet, wafer, pellet, or lozenge comprising aspirin to provide a 12 hour AUC for salicylate of between about 0.6 mM*hr to about 30 mlvThr, 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 administration of an orally disintegrating tablet, wafer, pellet, or lozenge comprising 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 mM * hr.
  • Example 1 Following are several exemplary formulations of water soluble aspirin compositions which can be used to produce the orally disintegrating tablet, wafers, pellets, or lozenges in accordance with the present invention. It should be understood that the solubility tests described below were performed using deionized water and rapid magnetic stirring, that the tests were conducted at an ambient temperature of 20 0 C ⁇ 2°C, and that the portions of the inventive composition were added to the water ail at once. It should also be understood that what is meant by the term "completely soluble” as used herein is that no particulates were visible to the naked eye in the solution resulting from the mixing of the inventive composition with water after the specified time period. [0093] Example 1
  • Aspirin (625.0 g) was added portionwise to a solution of 1750.0 g of tripotassium citrate monohydrate in 10.0 L of water containing sodium lauryl sulfate (1.5 g). A trace amount of undissolved aspirin was removed by filtration. The resultant clear solution was slowly applied onto 2623.5 g of sucrose using a fluid-bed spray processor (inlet temperature: 45 - 47 0 C; outlet temperature: 38 - 39 0 C). The resulting agglomeration contained granulated product with a median particle size of about 200 ⁇ . 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 650 mg of aspirin) of the resultant free-flowing product in 100 ml of water with stirring and mixing was palatable and completely soluble within 15 seconds and gave a pH of 5.87.
  • 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.
  • 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 15 seconds, completely soluble in 240 seconds, and gave a pH of 5.93.
  • 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 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.
  • 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.
  • 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 solutions produced by the water soluble compositions 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 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 Galat 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 and enters the blood stream rapidly (see Example 10 below).
  • the formulation is palatable and may include a variety of substrates, including cellulose, xylitol, or sucrose.
  • Other water insoluble analgesics including acetaminophen (see Example 11 below), ibuprofen (see Example 12 below) and naproxen (see Example 13 below), were prepared using the novel formulation procedure.
  • 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.
  • water soluble analgesic compositions in the form of an orally disintegrating tablet, wafer, pellet, or lozenge in accordance with the present invention employ known analgesics
  • the compositions 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.
  • water soluble analgesic compositions in the form of an orally disintegrating tablet, wafer, pellet, or lozenge in accordance with the present invention discussed above, it is anticipated that such compositions will have even a wider range of applications.
  • the present invention therefore, provides a water soluble analgesic composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge which has enhanced stability and bioactivity as compared to previously known water soluble analgesic compositions, which is sodium free, which is rapidly water soluble, which is fast acting and enters the bloodstream rapidly, 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.

Abstract

L'invention concerne une composition analgésique hydrosoluble sous la forme d'un comprimé, d'une gaufrette, d'une pastille ou d'une tablette à sucer se délitant dans la bouche qui comprend une pluralité de granulés, chaque granulé comprenant un cœur formant substrat et un revêtement disposé sur le cœur formant substrat pour donner un produit aggloméré. Le revêtement contient un sel d'un analgésique, mais pratiquement aucune particule de type non-sel ne forme l'analgésique. La composition peut être obtenue par un procédé comprenant les étapes suivantes : (i) préparation d'une première solution comprenant une base, (ii) ajout d'un analgésique à la première solution pour obtenir une seconde solution comprenant un sel de l'analgésique, (iii) filtration de la seconde solution pour éliminer les particules résiduelles de l'analgésique et obtenir une seconde solution filtrée, (iv) lyophilisation de la seconde solution filtrée sur un substrat pour obtenir un produit aggloméré comprenant une pluralité de granulés, et (v) compression, moulage ou autre mise en forme quelconque du produit aggloméré, éventuellement, avec d'autres excipients, pour obtenir un comprimé, un cachet, une pastille ou une tablette à sucer se délitant dans la bouche.
PCT/US2007/087946 2007-12-18 2007-12-18 Formulations analgésiques hydrosolubles se délitant dans la bouche et leurs procédés de production WO2009078872A1 (fr)

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CN102552164A (zh) * 2012-01-05 2012-07-11 金陵药业股份有限公司 一种枸橼酸钾缓释微丸及其制备方法
US8580302B2 (en) 2000-11-20 2013-11-12 Warner Chilcott Company, Llc Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures

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US20060292225A1 (en) * 2005-06-24 2006-12-28 Felix Arthur M Water soluble analgesic formulations and methods for production

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US20060292225A1 (en) * 2005-06-24 2006-12-28 Felix Arthur M Water soluble analgesic formulations and methods for production

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8580302B2 (en) 2000-11-20 2013-11-12 Warner Chilcott Company, Llc Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures
US9089492B2 (en) 2000-11-20 2015-07-28 Warner Chilcott Company, Llc Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures
CN102552164A (zh) * 2012-01-05 2012-07-11 金陵药业股份有限公司 一种枸橼酸钾缓释微丸及其制备方法
CN102552164B (zh) * 2012-01-05 2014-07-16 金陵药业股份有限公司 一种枸橼酸钾缓释微丸及其制备方法

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