Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • 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

Definitions

• This application concerns new formulations for pharmaceutical carriers, excipients or pharmaceutical media which are useful in formulating pharmaceutical compositions for biologically active compounds having poor oil and water solubility and/or poor biological absorption properties.
• the invention particularly relates to orally administered formulations of these compounds.
• 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.
• 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.
• 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.
• an oily vehicle selected from crown ether, lecithin, polyethylene glycol, propylene glycol, vitamin E, polyoxyehtylene alkylether, and sucrose esters of fatty acids.
• WO 98/24430 (Gautier et al.) teaches an anhydrous solubilizing/stabilizing system, emulsifiable or microemulsifiable in water, for solubilizing hydrophobic N- sulphonyl indolin derivatives of the structure:
• WO 95/03305 discloses nitrogenous aromatic 5-membered fused benzazepine derivatives, having the structure below, which are pharmacologically useful as arginine vasopressin antagonists.
• EP 0 514 667 Bl (Ogawa et al.) teaches benzazepine derivatives of the structure below:
• vasopressin antagonists useful as vasodilators, hypotensive agents, water diuretics and platelet agglutination inhibitors.
• angiotensin II receptor antagonist properties as having angiotensin II receptor antagonist properties and as effective in treating disorders related to excessive vasopressin secretion.
• U.S. Patent No. 5,516,774 (Albright et al.) teaches tricyclic vasopressin compounds, including those having a pyrrolobenzodiazepine core.
• U.S. Patents Nos. 5,700,796 and 5,719,278 provide other tricyclic benzazepine compounds useful as vasopressin antagonists.
• U.S. Patent No. 5,654,297 teaches vasopressin antagonists having bicyclic non-peptide cores and U.S. Patent No. 5,686,445 discloses similarly active compounds having pyridobenzoxazapine and pyridobenzothiazepine core structures.
• This invention provides new pharmaceutical carrier or excipient systems useful in the formulation of biologically active compounds and formulations produced using the carrier system, as well as processes for producing the carrier systems and formulations.
• novel carrier systems are useful in the formulation of encapsulated oral pharmaceutical compositions for mammalian use, preferably for human use.
• the carrier systems of this invention comprise, by weight percentage, a composition having the components: a) from about 1% to about 20%, preferably from about 5% to about 12%, of a surfactant component, more preferably from about 9% to about 14% or from about 10.5% to about 13% surfactant; b) from about 55% to about 93%, preferably from about 60% to about 85%, of a component of one or more polyethylene glycols (PEG) with an average molecular weight range of from about 190 to about 3450, preferably 400 to 1540; and c) from about 1% to about 25%, preferably from about 5% to about 15%, more preferably from about 9% to about 14% or from about 10% to about 13% of one or more sucrose fatty acid esters or polyvinylpyrrolidone (PVP) with a K value between about 15 and about 90, preferably with a K value of from about 16 to about 18, most preferably about 17, as defined in USP/NF, or a combination of one or more sucrose
• 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.
• a preferred blend of PEG polymers within this invention would include a 1 : 1 blend of PEG 400 and PEG 1000. It may be preferable to choose a mixture of PEG components which will have a melting point at or near the physiological temperature of the mammal to receive the formulation. 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 polyethylene glycol component may suitably be from about 32% to about 36% of PEG 1000 and from about 35% to about 46% PEG 400 or from about 33% to about 35% PEG 1000 and from about 37.5% to about 43% PEG 400.
• 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 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 L101, 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.
• antioxidants or preservatives may be added to the compositions of this invention, preferably accounting for from about 0.1% to about 4% by weight of the composition, more preferably from about 0.1% to about 3% of the composition.
• examples may include ascorbyl palmitate, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), etc.
• BHA butylated hydroxyanisole
• BHT butylated hydroxytoluene
• 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.
• BHA are from about 0.5% to about 2.0% or from about 0.75% to about 1.5%.
• Preferred amounts of BHT are from about 0.005% to about 0.02% or from about 0.075% to about 1.5%. Further embodiments are those wherein about 0.2% BHT is included.
• One embodiment of a pharmaceutically useful carrier or excipient system of this invention comprises, as compared by % weight/weight:
• the percentages of the BHT and BHA in components e) and f) can understandably be increased relative to each other to create an antioxidant/preservative component of up to about 4%.
• the percentages of the compounds in each of the formulations of these carrier or excipient systems will equal 100%, without taking into account an active pharmacological agent or other pharmacological components, such as coloring agents, fillers, pharmaceutically acceptable adjuvants, encapsulating or coating components, etc.
• the carrier system above is combined with a pharmacologically active agent and then encapsulated, such as with a hard or soft gelatin capsule.
• Another preferred embodiment of this invention includes a carrier or excipient system useful for pharmaceutical compositions comprising on a weight per weight percentage basis:
• PEG 400 polyethylene glycol 400
• BHT butylated hydroxytoluene
• BHA Butylated Hydroxyanisole
• the carrier or excipient systems of this invention may be used to formulate pharmaceutical compositions for numerous classes of compounds. These include those chemical compounds produced around various bicyclic and tricyclic core molecules, including bi- and tricyclic heterocycles. Examples of the compounds in question include those disclosed in U.S. Patents Nos. 5,516,774; 5,654,297; 5,686,445; 5,700,796; and 5,719,278, each of which is fully included herein by reference. Also incorporated herein by reference for use with the present carrier systems are the compounds disclosed in WO 98/24430 (Gautier et al.), U.S. Patent No.
• 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
• the synthesis of this compound and its salts is disclosed in U.S. Patent No. 5,516,774 (Albright et al.), which is incorporated herein by reference.
• Formulations using this compound are useful in methods for treating in humans or other mammals diseases, conditions or disorders in which vasopressin agonist activity is desired.
• These methods of treatment include those for diseases, conditions or disorders which make it desirable to release factor VIII and von Willebrand factor into the circulatory system, release tissue-type plasminogen activator (t-PA) in the blood circulation, or affect the renal conservation of water and urine concentration.
• Such methods of treatment include, but are not limited to, treatments for diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, or bleeding and coagulation disorders in humans or other mammals, including hemophilia.
• the methods herein for which the formulations may be used also include facilitation in humans or other mammals of temporary delay of urination, which may also be described as controlling or treating the inability to temporarily delay urination, whenever desirable.
• This method is understood to include treatments facilitating the temporary delay of urination which are separate from and not included in the treatment of the conditions known as nocturnal enuresis and nocturia.
• Oxalyl chloride (2.60 g) was added to a suspension of 2-chloro-4- fluorobenzoic acid (3.44 g) in dichloromethane (50 ml). Two drops of dimethylformamide were added and the mixture was stirred for 18 hours at room temperature. The resultant solution was evaporated to give the crude 2-chloro-4- fluorobenzoyl chloride as a viscous oil (3.72 g).
• a composition of the invention is in the form of a unit dose.
• Suitable unit dose forms preferably include tablets or capsules, though one skilled in the art will understand semi-solids or gels of this invention are also readily made and useful.
• Such unit dose forms may contain from 0.1 to 1000 mg of an active ingredient compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a pharmaceutically active compound of the present invention.
• formulations of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg of active ingredient or preferably at a dose range of 0.1 to
• compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
• compositions of the invention may be formulated with other conventional carriers or excipients such as fillers, disintegrating agents, adjuvants, binders, lubricants, flavoring agents and the like.
• 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.
• the formulation may be made as a gel or solid prior to encapsulation.
• the carrier system of this invention may also be used in pharmaceutical compositions containing as active pharmaceutical agents or ingredients other poorly soluble compounds including, but not limited to, the compounds disclosed in EP 0709386 (Yamanouchi Pharmaceutical Company, Ltd), including the compound N- [l, -biphenyl]-2-yl-4-[(4,5-dihydro-2-mehtylimidazo[4,5-d][l]benzazepin-6(lH)- yl)carbonyl]-benzamide (CAS Reg. No. 179528-39-3 YM 087), or pharmaceutically acceptable salts thereof.
• This invention also includes methods for producing the formulations using the biologically and pharmacologically active ingredients of the type described herein.
• a process of this invention comprises the steps of:
• sucrose fatty acid ester(s) and/or povidone adding the amount of sucrose fatty acid ester(s) and/or povidone to create a final pharmaceutical composition mixture, preferably with stirring until the final pharmaceutical composition mixture is clear.
• the PEG component such as a mixture of PEG 400 and PEG 1000
• the surfactant component such as Polysorbate 80
• sucrose fatty acid ester(s) and/or povidone adding the amount of sucrose fatty acid ester(s) and/or povidone to create a final pharmaceutical composition mixture, preferably with stirring until the final pharmaceutical composition mixture is clear.
• 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. To create a more pelletized initial composition, 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.
• Example 2 50 mg/capsule; Oral Formulation at 10 % Drug Loading
• This formulation is manufactured the same as that of the formula of Example 1 (50 mg/capsule) with the exception that 12 % of poloxamer was used in place of the polysorbate 80 in this formulation.
• the encapsulation weight is 480 mg.
• Example 4 provides a formulation with a combination of two or more surfactants. (% w/w) per capsule (mg) 20,000 capsule batch (g) active ingredient 10.64 51.07 1,021.44
• 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 the active ingredient 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 the active ingredient in step 3 is 145 ⁇ 5 °C, instead of 120 ⁇ 5 °C.
• the encapsulation weight is 650 mg in size 0 hard gelatin capsule.
• 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 the active ingredient 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 may be formulated by the methods herein using PEG 400, PEG 1000, PVP with a K value of 17, active ingredient, BHA and BHT as antioxidants or preservatives and the additional components listed as "other".

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Inorganic Chemistry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Citations (3)

• 2000
  • 2000-09-26 MX MXPA02003190A patent/MXPA02003190A/es unknown
  • 2000-09-26 EP EP00966880A patent/EP1216029A1/en not_active Withdrawn
  • 2000-09-26 BR BR0014308-1A patent/BR0014308A/pt not_active Application Discontinuation
  • 2000-09-26 AR ARP000105037A patent/AR025867A1/es unknown
  • 2000-09-26 KR KR1020027003934A patent/KR20020064289A/ko not_active Application Discontinuation
  • 2000-09-26 WO PCT/US2000/026381 patent/WO2001022942A1/en not_active Application Discontinuation
  • 2000-09-26 IL IL14854300A patent/IL148543A0/xx unknown
  • 2000-09-26 EA EA200200415A patent/EA200200415A1/ru unknown
  • 2000-09-26 PL PL00354331A patent/PL354331A1/xx not_active Application Discontinuation
  • 2000-09-26 AU AU77161/00A patent/AU7716100A/en not_active Abandoned
  • 2000-09-26 CZ CZ20021082A patent/CZ20021082A3/cs unknown
  • 2000-09-26 HU HU0202652A patent/HUP0202652A3/hu unknown
  • 2000-09-26 CN CN00816307A patent/CN1399542A/zh active Pending
  • 2000-09-26 JP JP2001526154A patent/JP2003510267A/ja active Pending
  • 2000-09-26 CA CA002388471A patent/CA2388471A1/en not_active Abandoned
• 2002
  • 2002-03-25 NO NO20021476A patent/NO20021476L/no not_active Application Discontinuation
  • 2002-04-25 ZA ZA200203311A patent/ZA200203311B/xx unknown
  • 2002-08-23 HK HK02106196.7A patent/HK1044485A1/zh unknown

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