WO2001034114A1 - Liquid heparin formulation - Google Patents
Liquid heparin formulation Download PDFInfo
- Publication number
- WO2001034114A1 WO2001034114A1 PCT/US2000/030890 US0030890W WO0134114A1 WO 2001034114 A1 WO2001034114 A1 WO 2001034114A1 US 0030890 W US0030890 W US 0030890W WO 0134114 A1 WO0134114 A1 WO 0134114A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- dosage unit
- unit form
- heparin
- sodium
- Prior art date
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Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
Definitions
- the present invention relates to liquid compositions of heparin.
- U.S. Patent No. 5,650,386 discloses compositions for the oral delivery of active agents, such as heparin, with modified amino acids, such as sodium N-(8-[2- hydroxybenzoyl]amino)caprylate (SNAC).
- active agents such as heparin
- modified amino acids such as sodium N-(8-[2- hydroxybenzoyl]amino)caprylate (SNAC).
- SNAC sodium N-(8-[2- hydroxybenzoyl]amino)caprylate
- Current commercial formulations of heparin are delivered by routes other than the oral route. Formulations delivered orally are typically easier to administer than by other routes and improve patient compliance.
- Oral liquid dosage forms containing SNAC and heparin were found to be unpalatable. Accordingly, sweeteners, such as polysaccharides, and other flavorants were added to the formulation to improve the flavor ofthe dosage form.
- Aqueous compositions containing polysaccharides. SNAC, and heparin were found to be in the liquid phase at 22° C and above. However, at temperatures below 22° C, these compositions sometimes haze and become gels after a few days. Therefore, there is a need for aqueous compositions containing a polysaccharide, SNAC, and heparin which remain in the liquid phase between 15 and 30° C.
- the present invention provides an aqueous composition
- an aqueous composition comprising (a) from about 0.075 to about 0.160 g/mL of sodiumN-(8-[2-hydroxybenzoyl]amino)caprylate (S ⁇ AC) or other salt thereof, (b) from about 0.01 to about 0.05 g/mL of heparin, and (c) from about
- the aqueous composition is a liquid at temperatures of from about 5 to about 30° C.
- Another embodiment ofthe invention is an aqueous composition comprising
- IU International Units (IU)) of heparin per gram of SNAC, and (c) from about 0.01 to about 0.15 g/mL of a polysaccharide, such as sucrose.
- Yet another embodiment is a method of administering heparin to an animal in need thereof by orally administering the composition ofthe present invention.
- Yet another embodiment is a method of treating thrombosis in an animal in need thereof by orally administering an anti-thrombosis effective amount ofthe composition of the present invention.
- Figure 1 is a graphic illustration ofthe time for an aqueous composition ofthe present invention to become a gel at 5° C.
- Figure 2 is a graphic illustration of the time for an aqueous composition to become a gel.
- Figure 3 is a graphic illustration of clotting time in cynomolgus monkeys after oral administration of aqueous compositions containing heparin.
- Figure 4 is a graphic illustration of heparin activity in cynomolgus monkeys after oral administration of aqueous compositions containing heparin.
- Figure 5 is a graphic illustration of heparin activity in healthy human subjects after oral administration of aqueous compositions containing heparin.
- the aqueous composition of the present invention comprises (a) from about
- S ⁇ AC sodium N-(8-[2-hydroxybenzoyl]amino)caprylate
- heparin as used herein includes all forms of heparin including, but not limited to, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, and any combination of any of the foregoing.
- the heparin incorporated in the composition preferably is heparin sodium, such as heparin sodium USP available from Scientific Protein Labs of Waunakee, WI.
- the concentration of heparin in the composition ranges from about 1,000 to about 12,000 U/mL, preferably from about 4,000 to about 8,000 U/mL, and more preferably from about 5,000 to about 6,000 U/mL.
- the potency (by weight) ofthe heparin is greater than about 140 U/mg and preferably ranges from about 150 to about 210 U/mg.
- the concentration of SNAC in the composition preferably ranges from about 0.120 to about 0.150 g/mL and more preferably from about 0.130 to about 0.140 g/mL.
- the concentration of heparin preferably ranges from about 0.02 to about 0.04 g/mL and more preferably from about 0.025 to about 0.035 g/mL.
- the concentration of sucrose preferably ranges from about 0.05 to about 0.15 g/mL and more preferably from about 0.075 to about 0.125 g/mL.
- the composition contains about 0.135 g/mL of SNAC, about 0.028 g/mL of heparin, and about 0.1 g/mL of sucrose.
- the concentration of SNAC and polysaccharide is less than the saturation solubility of the composition.
- Liquid polysaccharides may be included in the composition to increase the palatability of the composition and to increase the solubility of the composition.
- the composition comprises a liquid polysaccharide and has a total polysaccharide concentration (which may include solids) of from about 0.01 to about 0.65 g/mL.
- the concentration of sucrose in the composition may be greater than 0.15 g/mL.
- the composition contains from about 33,000 to about 41,000 U of heparin per gram of SNAC.
- the composition preferably contains from about 35,000 to about 39,000 U of heparin per gram of SNAC.
- the composition contains about 37,000 U of heparin per gram of SNAC.
- the amount of heparin in the composition is an amount effective to accomplish the purpose for which it is being used.
- the amount of heparin is typically a pharmacologically or biologically effective amount.
- the amount can be less than a pharmaceutically or biologically effective amount when the composition is used in a dosage unit form, such as a capsule or a liquid, because the dosage unit form may contain a multiplicity of SNAC/heparin compositions or may contain a divided pharmacologically or biologically effective amount.
- the total effective amount can then be determined in cumulative units containing, in total, a pharmacologically or biologically effective amount of heparin.
- the total amount of heparin may be determined by those skilled in the art.
- the dosage unit form is an oral dosage unit form, i.e., a dosage unit form to be delivered by the oral route.
- the composition may contain a pH adjuster, such as sodium hydroxide or hydrochloric acid, to adjust the pH.
- the pH ofthe composition is typically greater than about 7.2.
- the pH ofthe composition is from about 7.6 to about 8.6. According to one preferred embodiment, the pH is about 8.2.
- the composition ofthe present invention typically is a liquid and substantially clear at temperatures ranging from about 5 to about 40° C.
- the composition remains a liquid and does not substantially gel, i. e. , non-gelling, at temperatures ranging from about 15 to about 30° C.
- the composition preferably contains less than about 1 g/mL of solids.
- the composition may contain other adjuvants as known in the art, such as preservatives; flavorants, including sweeteners; fragrances; humectants; tonicifiers; colorants; surfactants; plasticizers; lubricants; dosing vehicles; solubilizers; excipients; and any combination of any ofthe foregoing.
- Suitable preservatives include, but are not limited to, parabens, such as methylparaben, butylparaben, propylparaben, and any combination of any of the foregoing.
- the composition preferably contains from about 0.0001 g/mL to about 0.001 g/mL of preservative and more preferably contains from about 0.0002 g/mL to about 0.0008 g/mL of preservative.
- the composition comprises about 0.0005 g/mL of butylparaben and about 0.0002 g/mL of propylparaben.
- Suitable flavorants include, but are not limited to, sodium saccharin, ammonium glycyrrhizinate, sodium chloride, maltol, menthol, anise oil, chocolate flavor, chocolate mint flavor, and any combination of any ofthe foregoing.
- the composition comprises about 0.004 g/mL of sodium saccharin, about 0.05 g/mL of ammonium glycyrrhizinate, about 0.001 g/mL of maltol, about 0.001 g/mL of peppermint oil, about 0.0007 g/mL of menthol, and about 0.0002 g/mL of anise oil.
- Suitable fragrances include, but are not limited to, menthol.
- Sui table solubilizers include, but are not limited to, propylene glycol.
- the composition includes about 0.02 g/mL of propylene glycol.
- Suitable tonicifiers include, but are not limited to, sodium chloride. According to one preferred embodiment, the composition includes about 0.005 g/mL of sodium chloride.
- the aqueous composition ofthe present invention may be prepared as follows. Water is heated to and maintained at from about 45 to about 55° C. Sucrose and other flavorants are added to the water and mixed. SNAC is added to the solution and mixed for from about 30 minutes to about 2 hours. SNAC may be prepared as described in U.S. Patent No. 5,650,386. While the solution is stirred, heparin is added to the solution, preferably to the vortex ofthe solution. The solution is mixed for from about 30 to about 60 minutes and then allowed to cool to between about 25 and about 35° C to form a first solution.
- additional flavorants, preservatives, and other adjuvants are mixed while the container is maintained at a temperature of between about 25 and 35 ° C.
- the solution in the container is mixed to form a uniform second solution.
- the second solution is added to the first solution.
- the combined solution is mixed and maintained at between about 25 and about 35 ° C.
- the pH ofthe solution may be adjusted as appropriate with sodium hydroxide and hydrochloric acid. Water may be added to dilute the solution and obtain the desired concentrations for the ingredients.
- the solution is then mixed for from about 10 to about 30 minutes and filtered to form the aqueous composition.
- the solution is preferably filtered through a filter having a pore size of from about 0.5 to about 10 microns, and more preferably a pore size of about 4.5 microns to remove any foreign materials.
- compositions of the present invention may be orally administered to deliver heparin to any animal in need thereof, including but not limited to birds, such as chickens; mammals, such as rodents, cows, pigs, dogs, cats, primates, and particularly humans; and insects.
- an anti-thrombosis effective amount of the composition may be administered to an animal in need thereof to treat thrombosis.
- the total amount of heparin and SNAC needed to treat thrombosis in an animal may be determined by any method known in the art. Generally, for humans, from about 90,000 to about 350,000 USP heparin units and from about 1.5 to about 9.0 g of SNAC and preferably from about 180,000 to about 270,000 USP heparin units and from about 4.5 to about 6.75 g of SNAC are administered daily.
- from about 30,000 to about 120,000 USP heparin units and from about 0.5 to about 3.0 g of SNAC and preferably from about 60,000 to about 90,000 USP heparin units and from about 1.5 to about 2.25 g of SNAC are administered per dose.
- from about 5 to about 20 mL and preferably from about 12 to about 18 mL of the composition are administered per dose.
- about 2 to 4 doses of the composition are administered daily.
- 3 doses ofthe composition are administered daily. Dosages for non-human primates may be adjusted according to weight.
- a 250 mL batch ofthe aqueous composition having the formulation in Table 1 below was prepared as follows. 150 g of water was heated in a stainless steel container affixed with an overhead mixer to and maintained at about 50 ° C. Sucrose, sodium saccharin, ammonium glycyrrhizinate, sodium chloride, and maltol were added to the water and mixed to form a clear solution. 17.5 mL of IN sodium hydroxide was added. SNAC was added to the solution and mixed for about 1 hour to form a clear solution. While the solution was stirred, heparin was added to the vortex ofthe solution. Then the solution was mixed for 30- 60 minutes to form a clear solution.
- the solution was allowed to cool to between about 25 and about 35 ° C to form a first solution.
- propylene glycol, methylparaben, and propylparaben were mixed by gentle swirling in a water bath at or below about 35 ° C until a clear solution was formed.
- Pepperment oil, menthol, anise oil, liquid NorVan flavor, chocolate mint flavor, chocolate flavor, and chocolate mousse color were added to the solution and mixed in a water bath at or below about 35° C until a uniform second solution was obtained.
- the second solution was added to the first solution.
- the combined solution was mixed and maintained at between about 25 and about 35 ° C.
- the pH ofthe solution was adjusted to about 8.2 with sodium hydroxide.
- the appropriate amount of water was added to bring the total weight ofthe solution up to about 275 g.
- the solution was mixed for about 15 minutes and filtered through a 4.5 micron filter to form the aqueous composition.
- Magnasweet 110TM is ammonium glycyrrhizinate in glycerin and is available from MAFCO Worldwide of Camden, NJ.
- Maltol is available as Maltol Veltol, FCC from Cultor Food Science, Inc., of New York, NY.
- Natural Peppermint Oil and Anise Oil are available from Mane, USA of Wayne, NJ.
- a 500 mL batch ofthe aqueous composition having the formulation in Table 2 below was prepared as follows. 225 g of water was heated in a stainless steel container affixed with an overhead mixer to and maintained at about 50° C. Sucrose, aspartame, sodium chloride, and maltol were added to the water and mixed to form a clear solution. 22.5 mL of IN sodium hydroxide was added. Ammonium glycyrrhizinate was added to the solution and mixed to form a clear solution. SNAC was added to the solution and mixed for about 1 hour to form a clear solution. While the solution was stirred, heparin was added to the vortex of the solution. Then the solution was mixed for 30-60 minutes to form a clear solution. The solution was allowed to cool to between about 25 and about 35° C to form a first solution.
- propylene glycol and menthol were mixed by gentle swirling in a water bath at or below about 35 ° C until a clear solution was formed.
- Peppermint oil and anise oil were added to the solution and mixed gently in a water bath at or below about 35° C until a uniform second solution was obtained.
- the second solution was added to the first solution.
- the combined solution was mixed and maintained at between about 25 and about 35 ° C.
- the pH ofthe solution was adjusted to about 7.8 with sodium hydroxide.
- the appropriate amount of water was added to bring the total weight ofthe solution up to about 605 g.
- the solution was mixed for about 15 minutes and filtered through a 4.5 micron filter to form the aqueous composition.
- Table 2 Table 2
- Example 2 A 10% sucrose aqueous composition prepared as in Example 1 was tested as follows. 1 mg/mL of SNAC was added to about 10 mL aqueous composition and mixed to form a seeded composition. The aqueous composition was stored at 5° C. The number of days until the composition became a gel was observed.
- Comparative Example 2A A 40% sucrose aqueous composition prepared as in Comparative Example 1 A was tested as follows. 1 mg/mL of SNAC was added to about 10 mL aqueous composition and mixed to form a seeded composition. The aqueous composition was stored at 5, 10, and 25° C. The number of days until the composition became a gel was observed. This procedure was repeated without the addition of 1 mg/mL of SNAC (unseeded). The results are shown in Figure 2.
- Example 3 Cynomolgus monkeys received oral doses of 1.2 mL/kg of an aqueous composition prepared as in Example 1. Heparin activity was determined by utilizing the activated partial thromboplastic time (APTT) according to the method of Henry, J.B., Clinical Diagnosis and Management by Laboratory Methods; Philadelphia, PA; W.B. Saunders (1979). The results are shown in Figure 3. The mean peak APTT was about 200 seconds. Also, the heparin activity level was measured with an antiFactor Xa assay kit available from Chromogenix A.B., Sweden. The results are shown in Figure 4. The mean peak antiFactor Xa activity level was 1.63 ⁇ 0.44 IU/mL.
- APTT activated partial thromboplastic time
- Comparative Example 3 A Cynomolgus monkeys received oral doses of 1 mL/kg of an aqueous composition prepared as in Comparative Example 1A. Heparin activity was determined as described in Example 3. The results are shown in Figures 3 and 4. The mean peak APTT was about 185 seconds and the mean peak antiFactor Xa activity level was 1.43 ⁇ 0.39 IU/mL.
- a 10% sucrose aqueous composition was prepared having the formula described in Table 1 above, except 0.00050 g/mL of butylparaben was substituted for the 0.0020 g/mL of methylparaben.
- a single oral dose of 18 mL of the 10% sucrose aqueous composition was administered to healthy human subjects.
- Heparin activity was determined with an antiFactor Xa assay kit available from Chromogenix A.B., Sweden. The results are shown in Figure 5.
- the mean peak antiFactor Xa activity level was 0.26 ⁇ 0.06 IU/mL.
- Comparative Example 4A A 40% sucrose aqueous composition was prepared having the formula described in Table 2 above. A single oral dose of 15 mL of the 40% sucrose aqueous composition was administered to healthy human subjects. Heparin activity was determined as described in Example 4. The results are shown in Figure 5. The mean peak antiFactor Xa activity level was 0.25 ⁇ 0.05 IU/mL.
- aqueous composition About 10 mL ofthe aqueous composition was seeded with 10 mg of SNAC. A sample of the seeded aqueous composition was stored at room temperature for 28 days.
- Another sample ofthe seeded aqueous composition was stored at 2-8° C for 28 days.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MXPA02004741A MXPA02004741A (es) | 1999-11-12 | 2000-11-10 | Formulacion liquida de heparina. |
AU15948/01A AU1594801A (en) | 1999-11-12 | 2000-11-10 | Liquid heparin formulation |
DE20022960U DE20022960U1 (de) | 1999-11-12 | 2000-11-10 | Flüssige Heparinformulierung |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16520999P | 1999-11-12 | 1999-11-12 | |
US60/165,209 | 1999-11-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001034114A1 true WO2001034114A1 (en) | 2001-05-17 |
Family
ID=22597926
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/030890 WO2001034114A1 (en) | 1999-11-12 | 2000-11-10 | Liquid heparin formulation |
Country Status (4)
Country | Link |
---|---|
AU (1) | AU1594801A (de) |
DE (1) | DE20022960U1 (de) |
MX (1) | MXPA02004741A (de) |
WO (1) | WO2001034114A1 (de) |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6461643B2 (en) | 1993-04-22 | 2002-10-08 | Emisphere Technologies, Inc. | Oral drug delivery compositions and methods |
WO2005112937A1 (en) | 2004-05-19 | 2005-12-01 | Emisphere Technologies, Inc. | Acyclovir formulations |
WO2006072070A2 (en) | 2004-12-29 | 2006-07-06 | Emisphere Technologies, Inc. | Pharmaceutical formulations of gallium salts |
EP1792621A1 (de) | 2005-11-30 | 2007-06-06 | Debiopharm S.A. | Oral verabreichbare Heparinderivate |
EP1992338A2 (de) | 2001-12-11 | 2008-11-19 | Cosmo Technologies Ltd | Pharmazeutische Zubereitungen zur oralen Verwendung von Heparin und seinen Derivaten |
EP2248531A1 (de) | 2004-08-03 | 2010-11-10 | Emisphere Technologies, Inc. | Antidiabetische orale Insulinbiguanidkombination |
EP2279732A2 (de) | 2004-05-14 | 2011-02-02 | Emisphere Technologies, Inc. | Verbindungen und Zusammensetzungen zur Wirkstofffreisetzung |
WO2011017346A2 (en) | 2009-08-03 | 2011-02-10 | Emisphere Technologies, Inc. | Fast-acting naproxen composition with reduced gastrointestinal effects |
US8039018B2 (en) | 2004-05-06 | 2011-10-18 | Emisphere Technologies, Inc. | Solid dosage form of wetted heparin |
US8110547B2 (en) | 2005-01-12 | 2012-02-07 | Emisphere Technologies, Inc. | Compositions for buccal delivery of parathyroid hormone |
WO2012119007A1 (en) | 2011-03-01 | 2012-09-07 | N21 Acquisition Holding, Llc | Compositions of insulin and chromium for the treatment and prevention of diabetes, hypoglycemia and related disorders |
US8771712B2 (en) | 2006-05-09 | 2014-07-08 | Emisphere Technologies, Inc. | Topical administration of acyclovir |
US8927015B2 (en) | 2006-04-12 | 2015-01-06 | Emisphere Technologies, Inc. | Formulations for delivering insulin |
US8975227B2 (en) | 2005-07-15 | 2015-03-10 | Emisphere Technologies, Inc. | Intraoral dosage forms of glucagon |
US9005637B2 (en) | 2007-06-26 | 2015-04-14 | Jds Therapeutics, Llc | Multiple unit dosage form having a therapeutic agent in combination with a nutritional supplement |
US9119835B2 (en) | 2007-03-13 | 2015-09-01 | JDS Therapeautics, LLC | Methods and compositions for the sustained release of chromium |
US9364502B2 (en) | 2006-06-28 | 2016-06-14 | Emisphere Technologies, Inc. | Gallium nitrate formulations |
US9498487B2 (en) | 2004-05-19 | 2016-11-22 | Emisphere Technologies, Inc. | Topical cromolyn formulations |
AU2017209950B2 (en) * | 2016-01-19 | 2022-11-17 | Achromaz Pte. Ltd. | A cosmetic composition and the use thereof for regulating skin quality |
US11857553B2 (en) | 2016-02-11 | 2024-01-02 | Nutrition21, LLC | Chromium containing compositions for improving health and fitness |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5389618A (en) * | 1990-06-26 | 1995-02-14 | Rhone-Poulenc Rorer S.A. | Mixtures of particular LMW heparinic polysaccharides for the prophylaxis/treatment of acute thrombotic events |
US5650386A (en) * | 1995-03-31 | 1997-07-22 | Emisphere Technologies, Inc. | Compositions for oral delivery of active agents |
US5872110A (en) * | 1996-05-08 | 1999-02-16 | Akzo Nobel N.V. And Sanofi | Heparin-like derivatives |
-
2000
- 2000-11-10 AU AU15948/01A patent/AU1594801A/en not_active Abandoned
- 2000-11-10 MX MXPA02004741A patent/MXPA02004741A/es unknown
- 2000-11-10 DE DE20022960U patent/DE20022960U1/de not_active Expired - Lifetime
- 2000-11-10 WO PCT/US2000/030890 patent/WO2001034114A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5389618A (en) * | 1990-06-26 | 1995-02-14 | Rhone-Poulenc Rorer S.A. | Mixtures of particular LMW heparinic polysaccharides for the prophylaxis/treatment of acute thrombotic events |
US5650386A (en) * | 1995-03-31 | 1997-07-22 | Emisphere Technologies, Inc. | Compositions for oral delivery of active agents |
US5872110A (en) * | 1996-05-08 | 1999-02-16 | Akzo Nobel N.V. And Sanofi | Heparin-like derivatives |
Cited By (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6610329B2 (en) | 1993-04-22 | 2003-08-26 | Emisphere Technologies Inc. | Compositions for the delivery of antigens |
US6461643B2 (en) | 1993-04-22 | 2002-10-08 | Emisphere Technologies, Inc. | Oral drug delivery compositions and methods |
EP1992338A2 (de) | 2001-12-11 | 2008-11-19 | Cosmo Technologies Ltd | Pharmazeutische Zubereitungen zur oralen Verwendung von Heparin und seinen Derivaten |
US8039018B2 (en) | 2004-05-06 | 2011-10-18 | Emisphere Technologies, Inc. | Solid dosage form of wetted heparin |
EP2279732A2 (de) | 2004-05-14 | 2011-02-02 | Emisphere Technologies, Inc. | Verbindungen und Zusammensetzungen zur Wirkstofffreisetzung |
WO2005112937A1 (en) | 2004-05-19 | 2005-12-01 | Emisphere Technologies, Inc. | Acyclovir formulations |
US9498487B2 (en) | 2004-05-19 | 2016-11-22 | Emisphere Technologies, Inc. | Topical cromolyn formulations |
EP2248531A1 (de) | 2004-08-03 | 2010-11-10 | Emisphere Technologies, Inc. | Antidiabetische orale Insulinbiguanidkombination |
WO2006072070A2 (en) | 2004-12-29 | 2006-07-06 | Emisphere Technologies, Inc. | Pharmaceutical formulations of gallium salts |
US8110547B2 (en) | 2005-01-12 | 2012-02-07 | Emisphere Technologies, Inc. | Compositions for buccal delivery of parathyroid hormone |
US8975227B2 (en) | 2005-07-15 | 2015-03-10 | Emisphere Technologies, Inc. | Intraoral dosage forms of glucagon |
EP1792621A1 (de) | 2005-11-30 | 2007-06-06 | Debiopharm S.A. | Oral verabreichbare Heparinderivate |
US8927015B2 (en) | 2006-04-12 | 2015-01-06 | Emisphere Technologies, Inc. | Formulations for delivering insulin |
US8771712B2 (en) | 2006-05-09 | 2014-07-08 | Emisphere Technologies, Inc. | Topical administration of acyclovir |
US9364502B2 (en) | 2006-06-28 | 2016-06-14 | Emisphere Technologies, Inc. | Gallium nitrate formulations |
US9675702B2 (en) | 2007-03-13 | 2017-06-13 | Jds Therapeutics, Llc | Methods and compositions for the sustained release of chromium |
US10245325B2 (en) | 2007-03-13 | 2019-04-02 | Jds Therapeutics, Llc | Methods and compositions for the sustained release of chromium |
US9597404B2 (en) | 2007-03-13 | 2017-03-21 | Jds Therapeutics, Llc | Methods and compositions for sustained release of chromium |
US9119835B2 (en) | 2007-03-13 | 2015-09-01 | JDS Therapeautics, LLC | Methods and compositions for the sustained release of chromium |
US10363222B2 (en) | 2007-06-26 | 2019-07-30 | Jds Therapeutics, Llc | Multiple unit dosage form having a therapeutic agent in combination with a nutritional supplement |
US9421170B2 (en) | 2007-06-26 | 2016-08-23 | Jds Therapeutics, Llc | Multiple unit dosage form having a therapeutic agent in combination with a nutritional supplement |
US9005637B2 (en) | 2007-06-26 | 2015-04-14 | Jds Therapeutics, Llc | Multiple unit dosage form having a therapeutic agent in combination with a nutritional supplement |
US11241388B2 (en) | 2007-06-26 | 2022-02-08 | Jds Therapeutics, Llc | Multiple unit dosage form having a therapeutic agent in combination with a nutritional supplement |
US11801224B2 (en) | 2007-06-26 | 2023-10-31 | Jds Therapeutics, Llc | Multiple unit dosage form having a therapeutic agent in combination with a nutritional supplement |
US11850308B2 (en) | 2007-06-26 | 2023-12-26 | Bonafide Health, Llc | Multiple unit dosage form having a therapeutic agent in combination with a nutritional supplement |
WO2011017346A2 (en) | 2009-08-03 | 2011-02-10 | Emisphere Technologies, Inc. | Fast-acting naproxen composition with reduced gastrointestinal effects |
US8933022B2 (en) | 2011-03-01 | 2015-01-13 | Jds Therapeutics, Llc | Methods and compositions for the treatment and prevention Hypoglycemia and related disorders |
WO2012119007A1 (en) | 2011-03-01 | 2012-09-07 | N21 Acquisition Holding, Llc | Compositions of insulin and chromium for the treatment and prevention of diabetes, hypoglycemia and related disorders |
EP4070801A1 (de) | 2011-03-01 | 2022-10-12 | Nutrition 21, LLC | Zusammensetzungen aus insulin und chrom zur behandlung und vorbeugung von diabetes, hypoglykämie und verwandten erkrankungen |
AU2017209950B2 (en) * | 2016-01-19 | 2022-11-17 | Achromaz Pte. Ltd. | A cosmetic composition and the use thereof for regulating skin quality |
US11857553B2 (en) | 2016-02-11 | 2024-01-02 | Nutrition21, LLC | Chromium containing compositions for improving health and fitness |
US11865121B2 (en) | 2016-02-11 | 2024-01-09 | Nutrition21, LLC | Chromium containing compositions for improving health and fitness |
Also Published As
Publication number | Publication date |
---|---|
MXPA02004741A (es) | 2003-12-11 |
DE20022960U1 (de) | 2002-07-25 |
AU1594801A (en) | 2001-06-06 |
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