Classifications

• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
  • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
  • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
  • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4866—Organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/10—Antioedematous agents; Diuretics

Definitions

• U.S. Patent No. 4,620,974 (Hersh et al.) teaches a hard gelatin capsule comprising a telescoping two-piece cap with a lubricant comprising a polyethylene glycol of a molecular weight between about 200 and about 900 present in admixture with the composition at a concentration of from about 0.5 to about 25 weight percent.
• WO 96/40071 discloses methods and devices for producing minimal volume capsules.
• WO 96/41622 teaches suspensions suitable for encapsulation in gelatin capsules, particularly including a solid phase of solid particles and a liquid phase capable of suspending the solid phase.
• U.S. Patent No. 5,641,512 (Cimiluca) teaches soft gelatin encapsulated analgesics in which the shell contains a xanthine derivative, such as caffeine.
• U.S. Patent No. 4,578,391 (Kawata et al.) describes oily compositions for antitumor agents comprising at least one sparingly oil soluble or water-soluble antitumor drug, at least one fat or oil, and at least one solubilizing adjuvant in an oily vehicle, selected from crown ether, lecithin, polyethylene glycol, propylene glycol, vitamin E, polyoxyehtylene alkylether, and sucrose esters of fatty acids.
• EP 0 815 854 Al discloses a substantially translucent, semi-solid fill material for a soft gelatin capsule, the semi-solid material being sufficiently viscous that it cannot be expelled from the capsule with a syringe at room temperature.
• U.S. Patent No. 4,744,988 (Brox) teaches soft gelatin capsules comprising a shell of gelatin, a softener and a filling of a polyethylene glycol and a low polyhydric alcohol and at least one active substance, characterized in that the shell contains 4 to 40 percent sorbital or sorbitanes, at least half of the weight of polyethylene glycol used is a polyethylene glycol having a mean molecular weight of 600, and the capsule filling comprises up to 20% by weight of glycerol and or 1,2-propylene glycol.
• WO 95/19579 (Dhabhar) teaches a process for solubilizing difficulty soluble pharmaceutical agents in a mixture of polyethylene glycol and propylene glycol by using a polyvinylpyrrolidone with a specific viscosity average molecular weight of from about 5,000 to about 25,000.
• This invention provides orally administerable formulations for N-[4-(5H- pyrrolo[2,l-c][l,4]benzodiazepin-10(HH)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2- methylbenzamide, also known as VPA-985, or the pharmaceutically acceptable salts thereof, which has the structure:
• VPA-985 is a V2 receptor antagonist (vasopressin antagonist) with the ability to elicit the removal of water in mammals, without the excretion of necessary electrolytes.
• V2 receptor antagonist vasopressin antagonist
• NPA-985 can be seen as Example 482 in U.S. Patent No. 5,516,774.
• This compound is highly insoluble in both conventional, orally acceptable oils, such as safflower or sesame seed oils, and in aqueous systems. Therefore, its pharmaceutical formulation requires a novel approach.
• compositions of this invention comprise (by % w/w):
• PEG polyethylene glycols
• PVP polyvinylpyrrolidone
• Suitable pharmaceutically acceptable salts of N-[4-(5H-pyrrolo[2,l- c] [ 1 ,4]benzodiazepin- 10( 1 lH)ylcarbonyl)-3-chlorophenyl] -5-fluoro-2- methylbenzamide include those derived from organic and inorganic acids such as lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and similarly known acceptable acids.
• the polyethylene glycol component may be comprised of one or more PEG polymers, preferably commercially available PEG polymers between PEG 200 and
• PEG 4,000 i.e. those PEG polymers having an average molecular weight between about 190 and about 4800. More preferred are PEG polymers between average molecular weights of from about 190 to about 3450, most preferably between about 400 and 1540. Among the preferred PEG polymers are PEG 400, having an average molecular weight between about 380 and about 420, and PEG 1,000, having an average molecular weight between about 950 and about 1050. The ratio of high and low molecular weight PEG species within the PEG component is preferably from about 2.5:1 to about 1:2.5, more preferably about 1:1. As an example, a preferred blend of PEG polymers within this invention would include a 1 : 1 blend of PEG 400 and PEG 1000.
• Mixtures of final components which have a viscosity range of from about 140 to about 1500 centipoise at 37°C may be preferred, more preferably a range of from 300 to about 800 centipoise at 37°C.
• the surfactants that may be used with the present formulations include, but not limited to, polysorbate 20 (polyoxyethylene 20 sorbitan monolaurate), Polysorbate 60, Polysorbate 40, polysorbate 80, Span 80 Sorbitan Oleate, a product of ICI Americas, Wilmington, Delaware, polysorbate 81, polysorbate 85, polysorbate 120, bile acids and their salts defined by Martindale The Extra Pharmacopoeia Thirtieth Edition on pagel341-1342 such as Sodium taurocholates, Sodium deoxytaurocholates, Chenodeoxycholic acid, and ursodeoxycholic acid, and pluronic or poloxamers such as Pluronic F68, Pluronic L44, Pluronic LlOl, or combinations of one or more of the above. Polysorbate 80, by itself or in combination with one or more other surfactants, is preferred for use with this invention.
• sucrose fatty acid esters useful with this invention include those commercially available and art recognized esters useful for orally administered pharmaceutical compositions, including monoesters, diesters and triesters of sucrose, or mixtures or blends thereof.
• Specific examples of esters useful with this invention are sucrose monolaurate, sucrose monomyristate, sucrose monopalminate, sucrose monostearate, sucrose distearate, sucrose tristearate, sucrose trimyristate, and sucrose tripalmitate, or combinations thereof.
• other enhancing or protective pharmaceutically acceptable antioxidants or preservatives may be added to the compositions of this invention to comprise up to about 4% of the composition, by weight, more preferably up to about 3%.
• Examples may include ascorbyl palmitate, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), etc.
• BHA butylated hydroxyanisole
• BHT butylated hydroxytoluene
• examples of these components in the present formulations would include BHA at a concentration from about 0.3% to about 2.5% (% w/w) and BHT at a concentration from about 0.005% to about 0.15% (% w/w), preferably with a mixture of BHA and BHT within these ranges. Further embodiments include about 0.2% BHT.
• a formulation of this invention utilizing one or more of these antioxidants or preservatives comprises:
• PVP polyvinylpyrrolidone
• the formulations of this invention are enclosed in a sealed enclosure after manufacture, such as soft or hard gelatin capsules.
• the formulations of this invention may be created as a liquid or semi-liquid formulation and introduced into a capsule. Similarly, using an acceptable range of components and/or temperatures, the formulation may be made as a gel or solid prior to encapsulation.
• This invention also includes a method for producing the formulations disclosed herein.
• the process comprises the steps of:
• sucrose fatty acid ester(s) and or povidone preferably with stirring until the final pharmaceutical composition mixture is clear.
• optional antioxidants or preservatives such as BHA
• the PEG component such as a mixture of PEG 400 and PEG 1000
• the surfactant component such as Polysorbate 80
• a fluid or semi-solid composition may be produced with the more fluid PEG, surfactant and PVP species within the scope of this invention. More gel-like, viscous or semi-solid compositions may be produced with combinations of higher molecular weight PEG components and PVP components having higher K values. Moreover, the components may be cooled below their melting point if milling or other processing of the final composition is desired.
• a fluid composition of this invention may be sprayed onto a cooled Teflon®-coated surface to form small solid spheres, which may be individually coated or collected for further processing.
• polysorbate 80 in this formulation of Example 1, other polysorbate series such as Tween 20, 40 and 60 can also be used, alone or in combination with each other and/or polysorbate 80.
• step 4. Cool the solution in step 4. to 60 ⁇ 5 °C. 5. Add Povidone, USP, K-17 (Plasdone C-15, ISP) slowly to step 5, to prevent the formation of lumps.
• Example 3 50 mg/capsule
• Example 3 provides a formulation with a combination of two or more surfactants.
• Example 3 The formulation of Example 3 is manufactured the same as that of Example 1 (50 mg/capsule) with the exception that two surfactants, polysorbate 40 and poloxamer 188 were added in step 1 along with PEG 400 and PEG 1000.
• the encapsulation weight is 480 mg.
• Example 4 The formulation of Example 4 is produced in the same manner as that of 50 mg/capsule, above, with the exception that the heating temperature to solubilize VPA- 985 in step 3 is 115 ⁇ 5 °C, instead of 120 ⁇ 5 °C.
• the encapsulation weight is 455 mg.
• This formulation is produced with the same steps as the 50 mg/capsule, above, with the exception that the heating temperature to solubilize VPA-985 in step 3 is 145 ⁇ 5 °C, instead of 120 ⁇ 5 °C.
• the encapsulation weight is 650 mg in size 0 hard gelatin capsule.
• VPA-985 150 mg in Size 00 Capsule
• Inactive Ingredients PEG 1000, NF 26.3 239.33 4,786.60 Povidone USP K-17 15 136.50 2,730.00
• Example 6 This formulation of Example 6 is produced with the same steps as that of 50 mg/capsule with the exception of the heating temperature to solubilize VPA-985 in step 3 is 150 ⁇ 5 °C, instead of 145 ⁇ 5 °C.
• the encapsulation weight is 910 mg in size 00 hard gelatin capsule.
• Examples 12 through 32 were formulated by the methods herein using PEG 400, PEG 1000, PVP with a K value of 17, VPA-985, BHA and BHT as antioxidants or preservatives and the additional components listed as "other".
• Active Ingredient VPA-985 @100% 10.42 25 500.00

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Diabetes (AREA)
• Hematology (AREA)
• Urology & Nephrology (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

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• 2000
  • 2000-09-26 CZ CZ20021083A patent/CZ20021083A3/cs unknown
  • 2000-09-26 AU AU76150/00A patent/AU7615000A/en not_active Abandoned
  • 2000-09-26 WO PCT/US2000/026369 patent/WO2001022945A1/en not_active Application Discontinuation
  • 2000-09-26 BR BR0014351-0A patent/BR0014351A/pt not_active Application Discontinuation
  • 2000-09-26 IL IL14854100A patent/IL148541A0/xx unknown
  • 2000-09-26 HU HU0202972A patent/HUP0202972A3/hu unknown
  • 2000-09-26 CN CN00816008A patent/CN1391466A/zh active Pending
  • 2000-09-26 MX MXPA02003189A patent/MXPA02003189A/es not_active Application Discontinuation
  • 2000-09-26 JP JP2001526157A patent/JP2003510269A/ja active Pending
  • 2000-09-26 KR KR1020027003931A patent/KR20020039354A/ko not_active Application Discontinuation
  • 2000-09-26 EP EP00965430A patent/EP1216033A1/en not_active Withdrawn
  • 2000-09-26 AR ARP000105036A patent/AR025780A1/es unknown
  • 2000-09-26 PL PL00354282A patent/PL354282A1/xx not_active Application Discontinuation
  • 2000-09-26 CA CA002388474A patent/CA2388474A1/en not_active Abandoned
  • 2000-09-26 EA EA200200414A patent/EA200200414A1/ru unknown
• 2002
  • 2002-03-25 NO NO20021475A patent/NO20021475L/no not_active Application Discontinuation
  • 2002-04-25 ZA ZA200203312A patent/ZA200203312B/xx unknown
  • 2002-09-05 HK HK02106544.6A patent/HK1045109A1/zh unknown

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