Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Solid synthetic organic polymer
Reexamination Certificate
2000-09-25
2002-08-20
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Solid synthetic organic polymer
C514S966000, C424S464000, C424S474000, C424S480000, C424S485000
Reexamination Certificate
active
06437006
ABSTRACT:
This applications 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.
BACKGROUND OF THE INVENTION
The art describes many methods of producing liquid or semi-solid encapsulated pharmaceutical formulations. In Bull. Tech./Gattefosse Rep. (1996), 89, 27-38, authors Shah et al. describe hard gelatin capsule technology, particularly for use in enhancing the bioavailability of poorly soluble or poorly absorbed drugs.
U.S. Pat. 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 (Lamberti) discloses methods and devices for producing minimal volume capsules. WO 96/41622 (Tanner et al.) 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. Pat. 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 A1 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. Pat. 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. Pat. 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.
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:
U.S. Pat. No. 5,356,904 (Freidinger et al.) discloses methods of using oxytocin antagonist compounds of the formulae:
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 B1 (Ogawa et al.) teaches benzazepine derivatives of the
as vasopressin antagonists useful as vasodilators, hypotensive agents, water diuretics and platelet agglutination inhibitors.
U.S. Pat. No. 5,525,614 (Blankley et al.) teaches substituted 1,2,3,4-tetrahydroisoquinolines, having the general structure below:
as having angiotensin II receptor antagonist properties and as effective in treating disorders related to excessive vasopressin secretion.
U.S. Pat. No. 5,516,774 (Albright et al.) teaches tricyclic vasopressin compounds, including those having a pyrrolobenzodiazepine core. U.S. Pat. Nos. 5,700,796 and 5,719,278 provide other tricyclic benzazepine compounds useful as vasopressin antagonists. U.S. Pat. No. 5,654,297 teaches vasopressin antagonists having bicyclic non-peptide cores and U.S. Pat. No. 5,686,445 discloses similarly active compounds having pyridobenzoxazapine and pyridobenzothiazepine core structures.
SUMMARY OF THE INVENTION
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. Of particular interest is the use of the novel carrier systems in the formulation of encapsulated oral pharmaceutical compositions for mammalian use, preferably for human use.
In general, 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;
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%, 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 USPINF, or a combination of one or more sucrose fatty acid esters or PVP.
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. 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 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, Del., polysorbate 81, polysorbate 85, polysorbate 120, bile acids and salts defined by Martindale The Extra Pharmacopoeia Thirtieth Edition on page1341-1342 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.
The 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 sucros
Fawzi Mahdi
Saunders Richard W.
Yoon Joseph K.
American Cyanamid Company
Fubara Blessing
Nagy Michael R.
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