Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • 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
  • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
  • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
• • 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
  • A61K9/0048—Eye, e.g. artificial tears

Definitions

• the present invention relates to pharmaceutical formulations comprising cyclodextrin or cyclodextrin derivatives, carboxy-containing polymers and therapeutic agents.
• the invention further relates to topical ophthalmic compositions comprising therapeutic agents, particularly, amino- substituted steroid therapeutic agents, lightly cross-linked carboxy-containing polymers and selected cyclodextrin derivatives.
• the invention further relates to methods of stabilizing and solubilizing amino-substituted steroid therapeutic agents in formulations using cyclodextrin derivatives, in combination with carboxy-containing polymers.
• Some valuable therapeutic agents are difficult to use because of their low stability in water or body fluids. Some therapeutic agents suffer from stability problems and they can cause irritation. Drug instability can limit the usefulness of pharmaceutical compositions containing them by shortening the shelf-life of the formulations and/or requiring stringent control of storage conditions. The insolubility of some therapeutic agents can seriously hamper efforts to utilize the compounds to their full potential because low solubility limits their bioavailability.
• Some aminosteroids illustrate these problems because they tend to be unstable and to have low solubility in aqueous environments such as body fluids. Instability of aminosteroids occurs primarily as a consequence of their antioxidative properties. Because they are potent antioxidants, the aminosteroids are especially sensitive to oxidative degradation.
• compositions comprising therapeutic drugs with agents that stabilize and solubilize the pharmaceutical compositions and ameliorate irritation.
• Providing compositions that deliver the therapeutic agent to a target site over a prolonged period of time is also an objective for many applications.
• compositions have been formulated to deliver drugs to the eye, skin and other parts of the body in a sustained manner.
• Sustained release ophthalmic formulations of an ophthalmic drug and a high molecular weight polymer to form a highly viscous gel, for instance, have been described in Schoenwald et al U.S. Patent No. 4,271 , 143, issued June 2, 1981 and Schoenwald et al U.S. Patent No. 4,407,792, issued October 4, 1983.
• Patent Application GB 2013084 A published August 8, 1979, describes an aqueous gel for application to the conjunctival sac of the eye comprising an ophthalmic drug and a polymer having carboxylic or anhydride functional groups and a molecular weight in excess of 1 ,000,000, such as carboxypolymethylene, carboxyvinyl and ethylene maleic anhydride polymers.
• lightly cross-linked polymers preferably ones prepared by suspension or emulsion polymerizing at least about 90% by weight of a carboxyl-containing monoethylenically unsaturated monomer such as acrylic acid with from about 0.1 % to about 5% by weight of a poly functional, and preferably difunctional, cross-linking agent such as divinyl glycol (3,4-dihydroxy-1,5-hexadiene), having a particle size of not more than about 50 ⁇ m in equivalent spherical diameter, with an ophthalmic medicament, e.g., the steroid fluorometholone, into suspensions in aqueous medium in which the amount of polymer ranges from about 0.1 % to about 6.5% by weight, based on the total weight of the aqueous suspension, the pH is from about 3.0 to about 6.5, and the osmotic pressure (osmolality or tonicity) is from about 10
• the '154 invention discloses methods and compositions for preventing or treating ophthalmic diseases or disorders in a human or other animal that is subject to intraocular damage (particularly oxidative intraocular damage) and in need of improved visual function or prevention of its loss from such damage, with an ophthalmically effective amount of certain amino-substituted steroids which function as a therapeutic agent (particularly an antioxidant agent) is in an inert vehicle, to arrest processes (particularly oxidation processes) damaging to the eye.
• Applicants' U.S. Patent No. 5,124, 154 further relates to formulations of aminosteroids with an appropriate inert vehicle or carrier for prevention or treatment of ophthalmic diseases or disorders. Topical, intraocular and systemic routes of administration are described.
• Topical formulations should generally include between 0.01 and 10% by weight, preferably between 0.1 and 5% by weight, of the amino-substituted steroid therapeutic agent in a suitable polymeric carrier.
• Polymeric carriers include lightly cross-linked carboxy-containing polymers (such as polycarbophil), dextran, cellulose derivatives, polyethyleneglycol 400 and other polymeric demulcents.
• Other additions taught as desirably included in the topical formulations include sodium chloride, EDTA (disodium edetate), surfactants, and preservatives such as BAK (benzalkonium chloride).
• Cyclodextrins are cyclic oligosaccharides.
• the most common cyclodextrins are ⁇ -cyclodextrin, which is composed of a ring of six glucose residues; ⁇ -cyclodextrin, which is composed of a ring of seven glucose residues; and ⁇ -cyclodextrin, which is composed of a ring of eight glucose units.
• the inside cavity of a cyclodextrin is lipophilic, while the outside of the cyclodextrin is hydrophilic; this combination of properties has led to widespread study of the natural cyclodextrins, particularly in connection with pharmaceuticals, and many inclusion complexes with drugs have been reported.
• ⁇ -Cyclodextrin has been of special interest because of its cavity size, but its relatively low aqueous solubility (about 1.8% w/v at 25 °C) and attendant nephrotoxicity have limited its use in the pharmaceutical field.
• Attempts to modify properties of the natural cyclodextrins have resulted in the development of heptakis (2,6-di-O-methyl)- ⁇ -cyclodextrin, heptakis (2,3,6-tri-O-methyl)- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin-epichlorohydrin polymer and others.
• the complexes enable the sex hormones to be successfully delivered to the systemic circulation via the sublingual or buccal route; the effectiveness of this delivery is believed to be due to "the high dissolution power of hydrophilic derivatives of cyclodextrins, the non-aggregated structure of their complexes with steroids,, and their low toxicity and irritancy of mouth tissue".
• Success with other cyclodextrins, including poly- ⁇ -cyclodextrin and hydroxypropyl- ⁇ -cyclodextrin have also been noted in the Pitha patent. See also Pitha et al, J. Pharm. Sci., Vol. 74, No. 9, September 1985, 987-990, concerning the same and related studies. Pitha et al also describe in the J.
• the patent describes the preparation of various substituted amorphous cyclodextrins, including hydroxypropyl- ⁇ -cyclodextrin and hydroxypropyl- ⁇ -cyclodextrin, the latter by analogous condensation of propylene oxide and ⁇ -cyclodextrin.
• compositions comprising inclusion compounds of drugs, which are unstable or only sparingly soluble in water, with partially etherified ⁇ -cyclodextrin derivatives having hydroxyalkyl and optionally additional alkyl groups.
• drugs include nonsteroidal anti-rheumatic agents, steroids, cardiac glycosides and derivatives of benzodiazepine, benzimidazole, piperidine, piperazine, imidazole and triazole.
• WO 85/02767 include oral, parenteral and topical formulations, with 4 to 10% solutions of cyclodextrin derivatives being used to solubilize various drugs.
• ⁇ -cyclodextrin derivatives which are ⁇ -cyclodextrin substituted with C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, carboxy C 1 -C 6 alkyl or C 1 - C 6 alkyloxycarbonyl C 1 -C 6 alkyl or mixed ethers thereof.
• specific derivatives named are hydroxypropyl- ⁇ -cyclodextrin and hydroxyethyl- ⁇ - cyclodextrin.
• Compositions comprising the cyclodextrin derivatives and a drug are also described. See also corresponding M ⁇ ller United States Patent No. 4,764,604, dated August 16, 1988.
• branched ⁇ -cyclodextrins are better solubilizers for poorly water-soluble drugs and have less hemolytic activity than ⁇ -cyclodextrin itself, and they suggest that glucosyl- ⁇ -cyclodextrin and maltosyl- ⁇ -cyclodextrin may be especially useful in parenteral preparations.
• Japanese Kokai 63-135402 (TOKUYAMA SODA KK), published June 7, 1988, describes compositions consisting of maltosyl- ⁇ -cyclodextrin and at least one of digitoxin, nifedipine, flurubiprophene, isosorbide nitrate, phenytoin, progesterone or testosterone.
• the compositions have improved water solubility and reduced erythrocyte destruction, are safe for humans and can be used as injections, eye drops, syrups, and for topical and mucous membrane application.
• Japanese Kokai 62-281855 (DAIKIN KOGYO KK), published
• Japanese Kokai 62-164701 (SHOKUHIN SANGYO BIO), published July 21, 1987, describes the preparation of diglucosyl- ⁇ -cyclodextrin and its general use in medicine.
• Japanese Kokai 62-003795 (TOKUYAMA SODA KK), published January 9, 1987, describes production of glucose and maltoligosaccharide (2-4 glucose units) derivatives of ⁇ -, ⁇ - and ⁇ -cyclodextrin and their use as stabilizers for pharmaceuticals.
• the redox system is a redox carrier system and the reduced, dihydropyridine form can be represented by the formula [D-DHC] wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal form of a dihydropyridine pyridinium salt redox carrier.
• centrally acting drug species is broadly defined and includes many classes of drugs, including steroids and, specifically, anti-inflammatory adrenal cortical steroids such as hydrocortisone, betamethesone, cortisone, dexamethasone, flumethasone, fluprednisolone, meprednisone, methyl prednisolone, prednisolone, prednisone, triamicinolone, cortodoxone, fludrocortisone, flurandrenolone acetonide (flurandrenolide), paramethasone and the like.
• steroids include steroids and, specifically, anti-inflammatory adrenal cortical steroids such as hydrocortisone, betamethesone, cortisone, dexamethasone, flumethasone, fluprednisolone, meprednisone, methyl prednisolone, prednisolone, prednisone, triamicinolone, cortodoxone, fludrocortisone, flurandrenol
• dihydropyridine carrier or “[DHC]” is defined as any non toxic carrier moiety comprising, containing or including the dihydropyridine nucleus, the only criterion being capacity for BBB penetration and in vivo oxidation to the corresponding quaternary pyridium salt.
• specific redox carrier drugs for complexation with cyclodextrins in accord with the Bodor patents are a number of steroid derivatives, including the derivatives of dexamethasone and hydrocortisone shown below:
• the redox derivative ha s about the same solubility in aqueous 50% hydroxypropyl- ⁇ -cyclodextrin as has the parent drug; in the case of norethindrone, the redox drug has less than 1 % of the solubility in aqueous 50% hydroxypropyl- ⁇ -cyclodextrin displayed by the parent drug.
• the parenteral solutions contain from about 20% to about 50% of the selected cyclodextrin(s).
• the drugs may be the dihydropyridine forms of dihydropyridine pyridinium salt redox systems (as noted above in connection with the Bodor '935 and '566 patents) or other poorly soluble or unstable drugs of many types, including steroids.
• Anti- inflammatory steroids such as dexamethasone, hydrocortisone and prednisolone are mentioned.
• HP ⁇ CD hydroxypropyl- ⁇ - cyclodextrin
• Solubility enhancement for many drugs in water has been accomplished by means of complexation with HP ⁇ CD.
• the solubility of dexamethasone was increased 5,500 times and intravenous administration of the dexamethasone-HP ⁇ CD complex gave higher initial plasma levels of dexamethasone than those obtained after dexamethasone phosphate dosing.
• the authors further note that transdermal/topical nonocclusive aqueous vehicle systems are suggested to avoid side-effects of occlusive systems, and that the improved water solubility of many lipophilic drugs in aqueo ⁇ s HP ⁇ CD solutions makes the nonocclusive systems possible.
• Transdermal delivery of the steroids 17 ⁇ - estradiol, hydrocortisone and testosterone in aqueous HP ⁇ CD solutions have been reported.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutic agent, an effective stabilizing amount of carboxy- containing polymer and cyclodextrin in an aqueous medium.
• the cyclodextrin is selected from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ , ⁇ and ⁇ -cyclodextrin, modified or nonmodified. It further provides a method for stabilizing and solubilizing a therapeutic agent in a pharmaceutical formulation, comprising combining the therapeutic agent in an aqueous medium with an effective stabilizing amount of carboxy-containing polymer and an amount of cyclodextrin sufficient to at least partially solubilize the therapeutic agent.
• the cyclodextrin is selected from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ , ⁇ - and ⁇ -cyclodextrin, modified or nonmodified.
• the present invention further provides a method for stabilizing and solubilizing an amino-substituted steroid therapeutic agent in a pharmaceutical formulation, comprising combining the therapeutic agent in an aqueous medium with an effective stabilizing amount of carboxy-containing polymer and an amount of cyclodextrin sufficient to at least partially solubilize the therapeutic agent.
• the cyclodextrin is selected from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ , ⁇ - and ⁇ -cyclodextrin, modified or nonmodified.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising an amino-substituted steroid therapeutic agent selected from the group consisting of the C 20 through C 26 aminosteroids of the formula XI hereinbelow, and the pharmaceutically acceptable salts, hydrates and solvates thereof, an effective stabilizing amount of a carboxy-containing polymer and an amount of cyclodextrin sufficient to at least partially solubilize said therapeutic agent, in an aqueous medium.
• the cyclodextrin being selected from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ , ⁇ - and ⁇ -cyclodextrin, modified or nonmodified.
• This invention comprises pharmaceutical preparations containing a combination of carboxy-containing polymers and a molecular inclusion chemical entity, cyclodextrin or a derivative of cyclodextrin, particularly ⁇ - hydroxypropyl cyclodextrin, as a vehicle for delivering therapeutic agents.
• Drugs used in the formulation can be hydrophobic organic compounds with little solubility and they may be labile.
• the drug can also be a peptide or protein from either a recombinant process or synthetic process, or a water soluble drug. The advantages of the invention are most apparent, however, in connection with drugs having low solubility in water or body fluids and/or instability problems.
• the combination of the present invention can be made without experiencing adverse consequences of incompatibility of the components.
• the improved solubility effect of the present invention might have been negated by the polymer competing for the drug.
• undersirable precipitation or agglomerated of particles may have occurred.
• the mechanism of the present invention is not fully understood and may be different for different therapeutic agents. It is believed, however, that stabilization of the drug may be achieved by cyclodextrin through molecular inclusion of the drug in the cyclodextrin ring or by ionic attractive forces between the drug and cyclodextrin.
• the polymer component of the present invention in most instances, provides the greatest stabilizing influence. For some drugs, particularly those that are positively charged, an ionic interaction may be formed between the drug and the polymer. This interaction may stabilize labile portions of the drug.
• the drug can be partially or completely solubilized by ⁇ -hydroxypropyl cyclodextrin and/or other modified and nonmodified cyclodextrins.
• partial solubilization refers to a degree of solubilization in excess of the normal solubility for the particular drug. Increasing the solubility of therapeutic agents typically also reduces irritation that would otherwise be experienced. The degree of solubilization can be controlled by the type and weight fraction of the cyclodextrin and the manufacturing procedures used and the formulation.
• the present invention may incorporate drugs that are highly soluble in water and body fluids, the fullest advantage of the solubilizing effect of cyclodextrin will be realized in connection with drugs that have low solubility in water or body fluids.
• Soluble drugs may be released from gels containing formulations of the present invention, through diffusion.
• Insoluble drugs can be solubilized by the cyclodextrin and diffused out of the polymeric gel or be released from it as the surrounding components of the formulation erode.
• the release profile of the drug from the delivery system can be modulated.
• cyclodextrin, carboxyl-containing polymer and drug may be varied to accommodate different applications. Other characteristics such as pH and osmolality may also be tailored to suit requirements of particular applications. In general, however, a stabilized, solubilized drug delivery system will be an aqueous suspension at a pH of from about 3 to about 9, preferably about 5 to about 8. For ophthalmic applications an 6 osmotic pressure of from about 10 to about 400 mOsM is desirable.
• formulations may contain up to about 10% , more preferably about 0.1 % to about 6.5% by weight, of the suspension, of a lightly cross-linked, carboxyl-containing polymer. Cyclodextrin may be present in amounts from about 1 % to about 50%. Suspensions of the present invention may have a wide range of viscosities, but many formulations may have a viscosity of from about 1 ,000 to about 100,000 centipoises. For ophthalmic applications the viscosity will preferably be about 1,000 to about 30,000 centipoises for drops and about 30,000 to about 100,000 centipoises for ribbons.
• Viscosities greater than about 100,000 centipoises are ordinarily appropriate for topical routes of administration other than ophthalmic, e.g. dermal and local routes such as nasal, buccal, rectal and vaginal, but viscosities for these applications may also, in some instances, be lower than 100,000 centipoises.
• the polymer ranges from about 0.1 to about 10% , preferably about 0.1 % to about
• the cyclodextrin preferably makes up about 1 to about 50%, more preferably about 5% to about 25%, depending on drug loading.
• Therapeutic agents (drugs) will ordinarily make up about .01 % to about 10% by weight of the composition, preferably about 0.1 % to about 5% of the composition.
• the lightly cross-linked carboxy-containing polymers for use in the present invention are lightly cross-linked polymers of acrylic acid or the like and are, in general, well-known in the art. See, for example, Robinson U.S. Patent No. 4,615,697, and International Publication No. WO 89/06964, referred to hereinabove. These polymers are also described in United States Patent 5,192,535.
• Suitable polymers are ones prepared from at least about 90% and preferably from about 95% to about 99.9% by weight, based on the total weight of monomers present, of one or more carboxyl-containing monoethylenically unsaturated monomers.
• Acrylic acid is the preferred carboxyl-containing monoethylenically unsaturated monomer, but other unsaturated, polymerizable carboxyl-containing monomers, such as methacrylic acid, ethacrylic acid, ⁇ -methylacrylic acid (crotonic acid), cis- ⁇ - methylcrotonic acid (angelic acid), trans- ⁇ -methylcrotonic acid (tiglic acid), ⁇ -butylcrotonic acid, ⁇ -phenylacrylic acid, ⁇ -benzylacrylic acid, ⁇ - cyclohexylacrylic acid, ⁇ -phenylacrylic acid (cinnamic acid), coumaric acid (o-hydroxycinnamic acid), umbellic acid (p-hydroxycoumaric acid), and
• the most preferred polymers are lightly cross-linked carboxy polymers. As will be understood from the present disclosure, however, soluble carboxy polymers that are not cross-linked may also be used. Examples of soluble polymers of the present invention that are not cross-linked include polyacrylic acid polymers and polymethacrylic acid polymers. Such polymers may be made by known methods.
• Preferred polymers are lightly cross-linked by using a small percentage, i.e., less than about 5%, such as from about 0.01 % to about 5%, and preferably from about 0.2% to about 3%, based on the total weight of monomers present, of a polyfunctional cross-linking agent.
• a polyfunctional cross-linking agent Included among such cross-linking agents are non-polyalkenyl polyether difunctional cross- linking monomers such as divinyl glycol; 3,4-dihydroxy-hexa-1,5-diene; 2,5- dimethyl-1,5-hexadiene; divinylbenzene; N,N-diallylacrylamide; N,N- diallylmethacrylamide and the like.
• Diolefinic non- hydrophilic macromeric cross-linking agents having molecular weights of from about 400 to about 8,000, such as insoluble di- and polyacrylates and methacrylates of diols and polyols, diisocyanate-hydroxyalkyl acrylate or methacrylate reaction products, and reaction products of isocyanate terminated prepolymers derived from polyester diols, polyether diols or polysiloxane diols with hydroxyalkylmethacrylates, and the like, can also be used as the cross- linking agents; see, e.g., Mueller et al U.S. Patents Nos. 4,192,827 and 4,136,250.
• the lightly cross-linked polymers can of course be made from a carboxyl-containing monomer or monomers as the sole monoethylenically unsaturated monomer present, together with a cross-linking agent or agents. They can also be polymers in which up to about 40%, and preferably from about 0% to about 20% by weight, of the carboxyl-containing monoethylenically unsaturated monomer or monomers has been replaced by one or more non-carboxyl-containing monoethylenically unsaturated monomers containing only physiologically (and, where appropriate, ophthalmologically) innocuous substituents, including acrylic and methacrylic acid esters such as methyl methacrylate, ethyl acrylate, butyl acrylate, 2-ethylhexylacrylate, octyl methacrylate, 2-hydroxyethyl-methacrylate, 3-hydroxypropylacrylate, and the like, vinyl acetate, N-vinylpyrrolidone, and the
• Patent No. 4,548,990 for a more extensive listing of such additional monoethylenically unsaturated monomers.
• Particularly preferred polymers are lightly cross-linked acrylic acid polymers wherein the cross-linking monomer is 2,3-dihydroxyhexa-1 ,5-diene or 2,5-dimethylhexa-1 ,5-diene.
• An especially preferred lightly cross-linked carboxy-containing polymer for use herein is polycarbophil, particularly NOVEON AA-1, a carboxyl- containing polymer prepared by suspension polymerizing acrylic acid and divinyl glycol.
• NOVEON AA-1 also called Carbopol 976
• Carbopol 974P A different preferred lightly cross-linked carboxy-containing polymer for use herein is Carbopol 974P which is prepared using a different polyfunctional cross-linking agent (of the polyalkenyl polyether type).
• the lightly cross-linked polymers used in practicing this invention are preferably prepared by suspension or emulsion polymerizing the monomers, using conventional free radical polymerization catalysts, to a dry particle size of not more than about 50 ⁇ m in equivalent spherical diameter; e.g., to provide dry polymer particles ranging in size from about 1 to about 30 ⁇ m, and preferably from about 3 to about 20 ⁇ m, in equivalent spherical diameter.
• such polymers will range in molecular weight estimated to be greater than about 250,000 and preferably greater than about 2,000,000.
• the cyclodextrins contemplated for use herein are hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -cyclodextrin and the corresponding derivatives of ⁇ -cyclodextrin.
• the hydroxyalkyl groupings may contain one or more hydroxyl groups, e.g. hydroxypropyl (2- hydroxypropyl, 3-hydroxypropyl), dihydroxypropyl and the like.
• the glucosyl, maltosyl and maltotriosyl derivatives may contain one or more sugar residues, e.g. glucosyl or diglucosyl, maltosyl or dimaltosyl.
• cyclodextrin derivatives for use herein include hydroxypropyl- ⁇ -cyclodextrin (HPCD or HPBCD), hydroxyethyl- ⁇ -cyclodextrin (HEBCD), hydroxypropyl- ⁇ -cyclodextrin (HPGCD), hydroxyethyl- ⁇ -cyclodextrin (HEGCD), dihydroxypropyl- ⁇ - cyclodextrin (2HPBCD), glucosyl- ⁇ -cyclodextrin (G 1 - ⁇ -CD or G 1 BCD), diglucosyl- ⁇ -cyclodextrin (2G 1 - ⁇ - CD or 2G 1 BCD), maltosyl- ⁇ -cyclodextrin (G 2 - ⁇ -CD or G 2 BCD), maltosyl- ⁇ -cyclodextrin (G 2 - ⁇ -CD or G 2 BCD), maltosyl- ⁇ -cyclodextrin (G 2 - ⁇ -CD or G 2 BCD),
• Hydroxypropyl- ⁇ - cyclodextrin for use in the compositions and methods of the present invention is commercially available. Alternatively, it can be prepared by known methods, especially by use of the optimized procedure of Pitha et al, International Journal of Pharmaceutics, 29, 73-82 (1986) or by modifications thereof as described in Bodor U.S. Patent No. 5,017,566 and related Bodor patents referred to hereinabove.
• the other hydroxyalkyl cyclodextrins intended for use herein can also be prepared by known procedures, e.g. as described by Pitha et al or Bodor.
• the cyclodextrins obtained in this manner are intrinsically amorphous mixtures; see Pitha et al, J. Pharm. Sci., Vol. 74, No. 9, September 1985, 987-990 and Pitha U.S.
• the other cyclodextrins intended for use in the present invention i.e. the glucosyl, maltosyl and maltotriosyl derivatives of ⁇ , ⁇ - and ⁇ - cyclodextrin, modified or nonmodified, are branched cyclodextrins which are highly soluble in water as compared to the parent cyclodextrins. These branched cyclodextrins can be produced by microbiological processes from the parent cyclodextrins.
• Glucosyl- ⁇ -cyclodextrins can be obtained from the mother liquor of a large-scale ⁇ - cyclodextrin synthesis with Bacillus ohbensis cyclomaltodextrin glucanotransferase; see Koizumi et al, Chem. Pharm. Bull., 35 (8), 3413-3418 (1987) and reference cited therein.
• Maltosyl and maltotriosyl ⁇ - and ⁇ -cyclodextrins can be prepared from the parent cyclodextrin and maltose or maltotriose through the reverse action of Pseudomonas isoamylase or Klebsiella aerogenes pullulanase, while glucosyl- ⁇ -cyclodextrin can be prepared by enzymatic hydrolysis of maltosyl- ⁇ - cyclodextrin; see Okada et al, Chem. Pharm. Bull., 36 (6), 2176-2185 (1988) and references cited therein.
• maltosyl- ⁇ -cyclodextrin by reacting maltose with ⁇ -cyclodextrin in the presence of pullulanase is also described in Japanese Kokai 61-287902, published Dec. 13, 1986, and Japanese Kokai 61-197602, published Sept. 1 , 1986.
• a mixture of maltosyl- ⁇ -cyclodextrin and various dimaltosyl- ⁇ -cyclodextrins may be conveniently employed. See also Kainuma et al U.S. Patent No. 4,668,626, issued May 26, 1987.
• a variety of drugs may be used in formulations of the present invention.
• Useful therapeutic agents include, but are not limited to: demulcents (for relief of "dry eye"), antibiotics, antivirals, steroids, amino- substituted steroids, including anti-inflammatory agents, peptides, polypeptides, cardiotonics, antihypertensives, or antioxidants, antiallergics, alpha- and betaadrenergic blocking agents, ophthalmic medicaments such as anticataract agents, collagenase inhibitors, antiglaucoma agents and ophthalmic antiinflammatory agents, ophthalmic lubricating agents, ophthalmic topical or regional anesthetic agents, antiretinopathy agents, etc.
• More specific therapeutic agents believed suitable for use in the present invention include drugs such as idoxuridine, carbachol, bethanechol, timolol, atenolol, labetolol, metoprolol, nadolol, oxprenolol, pindolol, sotalol, betaxolol, acebutolol, alprenolol, levobunolol, p-aminoclonidine, dipivefrin, epinephrine, phenylephrine, phospholine, aceclidine, demecarium, cyclopentolate, homatropine, scopolamine, pilocarpine, ethacrynic acid, furosemide, amiloride, bacitracin, neomycin, polymyxin, polymyxin B, gramicidin, gentamycin, penicillins, erythromycin, sulfacetamide,
• Topical or regional anesthetic agents include ones used during ophthalmic surgery or other ophthalmic procedures, such as lidocaine, cocaine, benoxinate, dibucaine, proparacaine, tetracaine, etidocaine, procaine, hexylcaine, bupivacaine, mepivacaine, prilocaine, chloroprocaine, benzocaine, tetracaine, and the like, as well as their acid forms.
• the drugs that may be administered include inorganic and organic drugs that can be transported across a vessel, for example, drugs acting on the central nervous system such as hypnotics and sedatives, mixtures thereof such as pentobarbital sodium, phenobarbital, secobarbital, thiopental, etc.; heterocyclic hypnotics such as dioxopiperidines, and glutarimides; hypnotics and sedatives such as amides and ureas exemplified by diethylisovaleramide and a bromo-isovaleryl urea; and hypnotic and sedative urethanes and disulfanes; narcotic antagonists such as naloxone and cyclazocine; psychic energizers such as isocarboxazid, nialamide, phenelzine, imipramine, tranylcypromine and paragylene; tranquilizers such as chloropromazine, promazine, fluphenazin
• R 6 is ⁇ -R 61 : ⁇ -R 62
• R 10 is ⁇ -R 101 : ⁇ -R 102
• R 7 is ⁇ -H: ⁇ -H, where one of R 61 and R 62 is -H, and the other is -H, -F, or C 1 -C 3 alkyl
• R 102 is -CH 3
• R 5 is ⁇ -R 53 : ⁇ -R 54
• R 6 is ⁇ -R 63 : ⁇ -R 64
• R 10 is a- R 103 : ⁇ - R 104 and R 7 is ⁇ -H: ⁇ -H, where one of R 63 and R 64 is -H, and the other taken together with one of R 53 and R 54 forms a second bond between C 5 and C 6
• R 104 is -CH 3
• R 103 and the other of R 53 and R 54 taken together are -(CH 2 ) 2 -
• R 5 is ⁇ -R 57 : ⁇ - R 58
• R 6 is ⁇ -R 67 : ⁇ - R 68
• R 7 is ⁇ -H: ⁇ -H
• R 6 is R 69 :R 610
• R 7 is R 79 :R 710
• R 10 is
• R 69 and R 610 is -H and the other taken together with one of R 79 and R 710 forms a second bond between C 6 and C 7 , and the other of R 79 and R 710 is -H, R 1010 is -CH 3 , R 109 and R 5 taken together are -(CH 2 ) 2 -
• R 11 is a-R 111 : ⁇ -R 112 , where one of R 111 and R 112 is taken together with R 9 to form a second bond between C 9 and C 11 and the other of
• R 111 and R 112 is -H
• (C-IV) R is -H or -F and R 11 is ⁇ -O-CO-R 117 : ⁇ -H, where R 117 is
• R 16 is R 161 :R 162 and R 17 is R 171 :R 172 , where one of R 161 and R 162 is -H or -CH 3 and the other taken together with one of R 171 and R 172 forms a second bond between C 16 and C 17 , and the other of R 171 and R 172 is -
• N-oxide thereof optionally substituted by 1 or 2 R 212 , being the same or different, where R 212 is
• R 214 is -H, C 1 -C 3 alkyl, or X 1 as defined above, where c and d are the same or different and are 0 through 2 with the proviso that the total number of ring carbon atoms is 4, 5 or 6, [a]
• Q is 2-pyridinyl where R 217 is -H or C 1 -C 3 alkyl and e is 0 through 3 (1)
• R 223 is -X 1 or -X 2 as defined above, or R 222 and R 223 are taken together with the attached nitrogen atom to form a saturated mono- nitrogen C 3 -C 6 heterocyclic ring and where m is as defined
• R 224 is phenyl substituted with 1 through 3 -OH, C 1 -C 3 alkoxy, -NR 225 R 226 where R 225 and R 226 are the same or different and are -H, C 1 -C 3 alkyl or are taken together with the attached nitrogen atom to form a C 4 -C 7 cyclic amino ring, [J]
• R 222 and R 223 are as defined above, [I]
• R 228 -CO-(CH 2 ) j - where R 228 is -X 1 , -NR 229 X 1 or 2-furanyl, where R 229 is -H or C 1 -C 3 alkyl, where j is 0 through 3 and X 1 is as defined above, [D]
• R 16 is ⁇ -R 163 : ⁇ -R 164 where one of R 163 and R 164 is -H and the other is -H, -F, -CH 3 or -OH, and R 11 is
• R 16 is ⁇ -R 165 : ⁇ -R 166 and R 17 is
• R 16 ⁇ or R 162 is taken together with one of R 171 or R 172 to form a second bond between C 16 and C 17 , only when R 10 is a-R 101 : ⁇ - R 102 , ⁇ -R 103 : ⁇ -R 104 , ⁇ -R 107 : ⁇ -R 108 or ⁇ -R 109 : ⁇ -R 1010 ,
• R 17 is -CH-(CH 2 ) p -NR 21 R 210 , only when R 10 is a- R 101 : ⁇ -R 102 , a-R 103 : ⁇ -R 104 , ⁇ -R 107 : ⁇ -R 108 or ⁇ -R 109 : ⁇ -R 1010 ,
• R 5 is ⁇ -R 57 : ⁇ -R 58 , only when R 17 is
• C 21 aminosteroids of formula XI especially those which inhibit lipid peroxidation.
• the 21- [4-(substituted-4-pyrimidinyl)-1-piperazinyl]-steroids such as U-74006 (21-[4- (2,6-dipyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 ⁇ -methylpregna-1,4,9(11)- triene-3,20-dione), and the 21-[4-(substituted-2-pyridinyl)-1-piperazinyl]- steroids, such as U-74500 (21-[4-[5,6-bis(diethylamino)-2-pyridinyl]-1- piperazinyl]-16 ⁇ -methylpregna-1,4,9(11)-triene-3,20-dione)and U-75412 (21- [4-(3-ethylamino-2-pyridinyl)-1-piperazoids
• a' is selected from the group 1,2-dihydro (saturated) and 1,2-dehydro (1,2- double bond);
• b' is selected from the group 6 ⁇ -H, 6 ⁇ -methyl and 6 ⁇ -flouro;
• c' is selected from the group 9,11-dihydro (saturated), 9(11)-dehydro
• d' is selected from the group 16 ⁇ -methyl-16 ⁇ -H-17 ⁇ -H, 16 ⁇ -methyl-16 ⁇ -H-
• a 17 ⁇ -OH group can be present instead of 17 ⁇ -H when d' is not 16-H-16,17-dehydro or 16-methyl-16, 17-dehydro; and where:
• X' is selected from the complex 21-amino substituents X1' and X2' where
• e' and f may be the same or different and are selected from the group: H,NHR1' and NR1'R2', where R1' and R2' are C1 to C3 lower alkyl or R1' and R2', taken together with N, constitute a heterocyclic ring; preferably 1-ethyleneimino, 1-trimethyleneimino, 1-pyrrolidinyl, 1- piperidinyl, 1-morpholinyl and 1-(4-methyl)pi ⁇ erazinyl.
• salts are those prepared by reacting the free base of the aminosteroid of formula (XI) with an approximately stoichiometrical amount of a pharmaceutically acceptable acid such as hydrochloric, hydroiodic, hydrobromic, phosphoric, sulfuric, acetic, citric, lactic, succinic, benzoic, pamoic, salicylic, cyclohexanesulfamic, methanesulfonic, p-toluenesulfonic, naphthalenesulfonic, malic, oxalic, fumaric or the like.
• Preferred salts are those of hydrochloric, methanesulfonic, maleic and fumaric acids.
• ком ⁇ онент (XI) and their pharmaceutically acceptable acid addition salts for the purposes of this invention are the pharmaceutically acceptable hydrates or solvates thereof, in which form they can be isolated.
• the aminosteroids can be administered by a variety of routes for the treatment or prevention of a variety of conditions, as noted in International Publication No. WO 87/01706. For particular routes of administration, certain characteristics of the lightly cross-linked polymers need to be carefully controlled.
• aqueous suspensions containing polymer particles prepared by suspension or emulsion polymerization whose average dry particle size is appreciably larger than about 50 ⁇ m in equivalent spherical diameter are less comfortable when administered to the eye than suspensions otherwise identical in composition containing polymer particles whose equivalent spherical diameters are, on the average, below about 50 ⁇ m.
• lightly cross-linked polymers of acrylic acid or the like prepared to a dry particle size appreciably larger than about 50 ⁇ m in equivalent spherical diameter and then reduced in size, e.g., by mechanically milling or grinding, to a dry particle size of not more than about 50 ⁇ m in equivalent spherical diameter do not work as well as polymers made by suspension or emulsion polymerization.
• the particles have a narrow particle size distribution within a 10 ⁇ m band of major particle size distribution which contains at least 80% , more preferably at least 90%, most preferably at least 95% of the particles. Also, there is no more than 20% , preferably no more than 10%, and most preferably no more than 5% particles of a size below 1 ⁇ m. The presence of large amounts of such fines has been found to inhibit the desired gelation upon eye contact. Apart from that, the use of a monodispersion of particles will give maximum viscosity and an increased eye residence time of the ophthalmic medicament delivery systems for a given particle size. Monodisperse particles having a particle size of 30 ⁇ m and below are most preferred.
• Aqueous solutions and suspensions for liquid oral administration will typically contain between about 0.05 and 5.0% by weight, preferably between 0.1 and 2.0% by weight of the amino-substituted steroid therapeutic agent; that suitable adjuvants which may be used as carriers to provide wetability and stability include propylene glycol, lightly cross-linked carboxy-containing polymers such as polycarbophil, ethyl cellulose, hydroxypropyl cellulose and methyl cellulose; and that other additives, including sodium edetate, methyl and propyl parabens, flavoring agents and colorants may also be employed, if desired.
• Examples 7 and 8 in the parent and grandparent applications detail the preparation of topical compositions containing the aminosteroid U-74006F,
• a stabilized sustained release aminosteroid delivery system comprises an aqueous suspension at a pH of from about 3 to about 9 (preferably 5 to 8) and an osmotic pressure of from about 10 to about 400 mOsM containing from about 0.1 % to about 6.5% by weight, based on the total weight of the suspension, of a lightly cross-linked, carboxyl-containing polymer prepared by polymerizing one or more carboxyl- containing monoethylenically unsaturated monomers and less than about 5 % by weight of a cross-linking agent, such weight percentages of monomers being based on the total weight of monomers polymerized.
• the suspension has an initial viscosity of from about 1,000 to about 30,000 centipoises and is administrable to the eye in drop form, or in the form of a ribbon at a viscosity of from about 30,000 to about 100,000 centipoises, but considerably higher viscosities are acceptable for topical routes of administration other than ophthalmic, e.g. dermal, and local routes such as nasal, buccal, rectal and vaginal.
• the polymer has an average particle size of not more than about 50 ⁇ m, preferably not more than about 30 ⁇ m, in equivalent spherical diameter.
• the pH of the suspension is from about 5 to about 9.
• the viscous gel can remain in the eye for a prolonged period of time so as to release the aminosteroid therapeutic agent contained therein in sustained fashion.
• the polymer is preferably prepared from at least about 50% by weight, more preferably at least about 90% by weight, of one or more carboxyl- containing monoethylenically unsaturated monomers.
• the polymer is prepared by suspension or emulsion polymerizing acrylic acid and a non- polyalkenyl polyether difunctional cross-linking agent to a particle size of not more than about 50 ⁇ m, preferably not more than about 30 ⁇ m, in equivalent spherical diameter.
• a preferred cross-linking agent is divinyl glycol.
• the osmotic pressure is preferably achieved by using a physiologically
• aminosteroid of formula (XI) may be present in desired therapeutic amount, preferably from about 0.01 % to about 10% by weight, based on the total weight of the suspension.
• Preferred aminosteroids include
• the foregoing suspensions are prepared and packaged at the desired viscosity of from 1,000 to about 30,000 centipoises, for administration to the eye in drop form.
• viscous gel remains in the eye for a prolonged period of time so as to release in a sustained fashion the aminosteroid entrapped therein.
• the present invention thus provides a stable ophthalmic delivery system that not only has the benefits of administration in drop form, but also does not suffer from breakdown limitations due to administration at a viscosity suitable for drops. Through administration at a viscosity such that the suspension can be reliably administered in drop form, but which actually increases when the suspension is so administered, controlled release of aminosteroid medicament is significantly enhanced.
• viscosities substantially over 30,000 cps are generally not suitable for drops; also, viscosities over 100,000 are generally not suitable as ribbons.
• the viscosities are substantially lower than 1,000 cps, the ability of the gel to sustain itself after contact with tears is impeded.
• a suspension at a pH of from about 3 to about 6.5 and an osmotic pressure of from about 10 to about 400 mOsM contacts the tear fluid there is an increased gelation with a pH change.
• tear fluid is at a higher pH of about 7.2 to about 7.4. With the pH increase, carboxylic acid (COOH) undergoes a sodium replacement (to COONa), and the sodium form dissociates, causing the polymer to expand.
• COOH carboxylic acid
• COONa sodium replacement
• the degree of cross-linking is necessarily high enough to avoid substantial dissolution of the polymer.
• the degree of cross-linking is necessarily low enough to permit gelation.
• the polymer particle size is too large, induced swelling can tend to fill voids between large particles that are in contact with one another, rather than causing gelation.
• particle size would be basically irrelevant. In a suspension, particle size can be relevant to comfort.
• the small particle size and light cross-linking synergistically yield rapid gelation to a substantially increased viscosity when the pH changes such as when compositions of the present invention contact tears fluid. In fact, above the 50 ⁇ m size this advantage of substantially increased viscosity is not realized. Moreover, at the 50 ⁇ m size, there is also reasonably good eye comfort.
• the particles are not only subject to the upper size limits described above, but also to a narrow particle size distribution.
• a monodispersion of particles which aids in good particle packing, yields a maximum increased viscosity upon contact of the suspension with the tears and increases eye residence time.
• At least about 80%, more preferably at least about 90% and most preferably at least about 95% , of the particles should be within a no more than about 10 ⁇ m band of major particle size distribution, and overall (i.e., considering particles both within and outside such band) there should be no more than about 20%, preferably no more than about 10% and most preferably no more than about 5% fines (i.e., particles of a size below 1 ⁇ m).
• the band of major particle size distribution be also narrowed, for example to 5 ⁇ m.
• Preferred sizes for particles within the band of major particle distribution are less than about 30 ⁇ m, more preferably less than about 20 ⁇ m, most preferably from about 1 ⁇ m to about 5 ⁇ m.
• the stable compositions obtained in accord with the foregoing detailed description provide for sustained release of the aminosteroid, by virtue of the fact that the aminosteroid is in suspension; prolonged retention at the site of application can also be readily provided by these compositions by virtue of their viscosity.
• immediate release of the aminosteroid and greater penetration e.g. through the cornea or skin, in the case of ophthalmic or dermal application, respectively
• the present invention provides for modification of the method and compositions described above in order to achieve these goals.
• the aminosteroid can be partially or completely solubilized in the aminosteroid/lightly cross-linked carboxy- containing polymer formulations by using an amount of cyclodextrin (as defined and discussed in detail hereinabove) sufficient to at least partially solubilize the aminosteroid. Addition of cyclodextrin reduces irritation topically and ocularly. Moreover, if desired, sufficient cyclodextrin can be utilized to substantially completely solubilize the aminosteroid. The degree of solubilization can be controlled and the mixed solution/suspension or complete solution which results is stable to degradation.
• the cyclodextrin used can be any of the hydroxyalkylated or branched derivatives of ⁇ - and ⁇ - cyclodextrins identified hereinabove. However, hydroxypropyl- ⁇ -cyclodextrin is presently preferred.
• compositions of the present invention are suspensions or formulations intended for administration to the eye, particle size and viscosity of the polymers, may be less important particularly when the therapeutic agent is completely solubilized.
• the cyclodextrin-containing compositions of the present invention can be adapted for topical treatment of skin and mucous membrane by local application to tissue in need of treatment, such as dermal, nasal, vaginal and rectal tissues.
• the dosage loading for compositions of the present invention may vary depending on the drug used, the route of administration selected and other factors familiar to those skilled at methods of formulating pharmaceutical compositions.
• the selected cyclodextrin e.g. hydroxypropyl- ⁇ -cyclodextrin
• the cyclodextrin is employed in an amount sufficient to solubilize at least a portion of the aminosteroid in the final formulation; the cyclodextrin is thus utilized in an amount which is generally from about 1.0 to about 20.0% or 30.0% by weight of the total composition, but much larger amounts of cyclodextrin (e.g.
• the weight ratio of cyclodextrin to aminosteroid can range from about 1 : 1 to about 500: 1.
• the selected polymer is generally used in an effective stabilizing amount of from about 0.1 % to about 2% by weight of the final composition, although additional polymer (up to about 6.5% by weight) can be present, if desired. This amount can also to expressed as a weight to weight ratio of polymer to aminosteroid from about 1: 10 to about 20: 1.
• the cyclodextrin is dissolved in water, then the polymer is slowly dispersed therein and stirred (typically, for a period of from about 15 minutes to 2 hours).
• Sodium chloride (from about 0 to 0.9% by weight) is added to adjust osmolality and, optionally, EDTA may be added to complex metal ions.
• the resultant mixture is generally heated (e.g. autoclaved) for a period of from about 30 to about 90 minutes, then cooled. It is preferred to adjust the pH of the mixture to be above about 6. This may be done by addition of a suitable base such as sodium hydroxide.
• the aminosteroid (from about 0.01 to about 10.0% by weight of the total composition) is dissolved in a strong acid solution (e.g. aqueous hydrochloric acid) and that solution is combined with the polymer/cyclodextrin solution, the pH is adjusted to around pH 6-7 with sodium hydroxide, and water is added as necessary to bring the total volume to 100%.
• a strong acid solution e.g. aqueous hydrochloric acid
• Compositions obtained in this manner can be solutions or mixed suspensions/solutions; the degree of solubilization is controlled by the concentration of the cyclodextrin component.
• a representative formulation prepared as described in EXAMPLE 1 hereinbelow, having a 1 % w/w concentration of the representative aminosteroid U-74006F which is approximately 75% solubilized, will be stable at room temperature and at 40°C over a three month storage period. There is no significant loss of aminosteroid concentration at either temperature. In this case, it is believed that stability results from the stability of the non-dissolved aminosteroid, the interaction of the aminosteroid with the polymer as discussed above in relation to the non-cyclodextrin compositions, and the molecular inclusion of the aminosteroid by the cyclodextrin. Solubilization is of course due primarily to the presence of cyclodextrin. The main reason the aminosteroid is stable in both formulations appears to be the presence of the cross-linked polymer and its ionic interaction with the aminosteroid.
• the aminosteroids of formula XI are useful in the treatment of a variety of medical conditions in warm-blooded animals, including humans.
• the present invention provides pharmaceutical compositions for administration in the treatment or prevention of the various conditions for which the aminosteroids are known to be useful, e.g. from International Publication No. WO 87/01706, and from U.S. Patent No. 5,124, 154.
• such conditions include spinal trauma; head injury (mild, moderate or severe); subarachnoid hemorrhage (including the associated cerebral vasospasm); skin graft rejection; ischemic stroke; excessive mucous secretion; asthma; muscular dystrophy; shock (hemorrhagic, septic or traumatic); cardiac toxicity induced by anti- cancer agents such as adriamycin; Parkinsonism, Alzheimer's disease and other neurological disorders of a degenerative nature; severe burns; ARDS; multiple sclerosis; organ damage occurring during reperfusion following transplant; osteoarthritis, rheumatoid arthritis and other inflammatory diseases; dermatological disorders such as inflammation and psoriasis; immunological nephrotic syndrome; allergic reactions; systemic lupus erythematosis; atherosclerosis; emphysema; metastases and tumor growth; cluster headaches, ulcers induced by stress; complications from radiation damage, brain tumors and damage after myocardial in
• the aminosteroids are further known to be useful in the prevention of damage following cardiopulmonary resuscitation, cardiac infarction and neurological or cardiovascular surgery; in the treatment and prevention of many of the conditions for which glucocorticoid pharmaceuticals are known to be useful (some of which are listed hereinabove); in the treatment or prevention of ophthalmic diseases or disorders such as cataracts, glaucoma or the risk of glaucoma associated with significantly elevated intraocular pressure, inflammatory eye disease, retinal eye disease, intraocular pressure rise due to uveitis, post-infarct ambolus, traumatic eye injury (such as blunt trauma, compression injury, hyphema, surgical trauma, etc.), neovascular or ischemic eye disease (conditions in the eye involving ischemia such as corneal edema from prolonged wearing of contact lenses and the like), bullous keratitis, dry eye including keratitis sicca, alkali burn and conditions arising from transplantation of ocular cells.
• Routes of administration, frequency of administration and dosage levels vary with the particular therapeutic agent selected, condition being treated, severity of the condition, size, weight and age of the patient and other well- known factors.
• Typical dosage ranges for intravenous or intramuscular injection of aminosteroids include from about 0.05 to about 100 mg/kg/day, one to four times daily.
• the dosages will vary, of course, with the compound selected.
• suspension and solutions can be administered by other routes as well including topical (e.g., ophthalmic, dermal or vaginal), introcular, nasal and rectal administration.
• Topical administration to the skin is generally preferred for the treatment of many dermatological conditions, particularly skin inflammation and psoriasis, but particularly serious dermal conditions may require systemic administration, alone or in conjunction with topical treatment.
• the specific dosages selected will vary somewhat depending on the drug selected and other factors noted above.
• topical administration is preferable when the target of the treatment is located in or near the anterior chamber of the eye.
• the flow of aqueous humor is from the ciliary body (behind the iris), forward towards the cornea before it exits through the trabecular meshwork and Schlemm's canal, penetration of drugs to the back of the eye when administered topically to the front of the eye occurs with some difficulty. It is therefore often more effective to administer drugs intended for the treatment of uveal and retinal diseases by the systemic route where access to the eye occurs through the choroid plexus, or by the intravitreal route.
• topical route is preferred for convenience of individual patient self- administration, and the intraocular and systemic routes are preferred for surgical and presurgical administration.
• the present invention also contemplates the treatment of an ophthalmic disease by administration of a therapeutically effective amount of amino-substituted steroid antioxidant agent (including salts, hydrates or solvates), by oral or intramuscular routes, in addition to the convenient topical route or by intraocular injection.
• Aqueous solutions, aqueous suspensions, ointments, and gels are preferably used for topical formulations, e.g. for ophthalmic or dermal administration.
• the aqueous formulations may also contain liposomes for creating a reservoir of dissolved amino-substituted steroid therapeutic agent for contact with the tear film.
• Topical formulations are gels, which enhance pre-corneal retention and protect the amino-substituted steroids from degradation without the inconvenience and impairment of vision associated with ointments.
• Topical formulations should generally include between 0.01 and 10% by weight, preferably between 0.1 and 5 % by weight, of the amino-substituted steroid therapeutic agent, together with the amounts of polymer and/or cyclodextrin noted hereinabove, in an aqueous medium.
• Other additives which are desirably included in the topical formulations include sodium chloride, EDTA (disodium edetate), pH adjusters, buffers, surfactants, and preservatives like BAK (benzalkonium chloride).
• Administration of the formulation to the eye or skin will typically be carried out between one and four times a day, depending on the particular problem being treated.
• Formulations for ocular injection, intramuscular injection, oral administration and other routes can be formulated in accord with techniques well-known to those skilled in the art of pharmaceutical formulations.
• the amounts of therapeutic agent, polymer and cyclodextrin as noted hereinabove may typically be included in an aqueous medium; and as in the case of topical formulations, other additives may be included just so long as they do not interfere with the stabilization (and solubilization, when desired) and are appropriate for the selected route of administration. See, for example applicants' parent application referenced hereinabove, and Remington's Pharmaceutical Sciences, seventeen edition, ed. Alfonso R.
• a 100 g batch of pharmaceutical composition may be prepared as described below:
• Polycarbophil 976 (Noveon AA-1) 1.0%
• the cyclodextrin (20 g) is dissolved in approximately 60 g of sterile water for injection.
• the polymer is dispersed in the cyclodextrin solution, then the mixture is stirred for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is added and stirred for 15 minutes.
• the mixture is autoclaved for 45 minutes at 121 °C, then allowed to cool to room temperature.
• the aminosteroid (1 g) is dissolved in 12.5 g of 0.2 N aqueous hydrochloric acid. The aminosteroid solution is added to the cyclodextrin/polymer mixture by sterile filtration.
• the pH is adjusted to about 7.2 with 2 N aqueous sodium hydroxide solution, the final weight of the formulation is adjusted to 100 g sterile water by sterile filtration.
• the formulation is sealed under a blanket of filtered nitrogen.
• the aminosteroid is extensively solubilized in the resultant composition, but about 25% of the steroid remained undissolved.
• the pH is physiological and the osmolality is slightly hypotonic.
• the resultant composition is of particular interest for topical treatment of ophthalmic conditions. Use of about 30 g of 2-hydroxypropyl- ⁇ - cyclodextrin in the above procedure is expected to substantially completely solubilize the aminosteroid.
• 1,4,9(11)-triene-3,20-dione methanesulfonate may be obtained from the description in Braughler et al, Biochemical Pharmacology 37:3856 (1988).
• a 100 g batch of pharmaceutical composition may be prepared as described below:
• BB-882 is a PAF-antagonist useful as an antiinflamatory therapeutic agent.
• BB-882 (.3 g) is dissolved in 12.5 g of 0.2 N hydrochloric acid.
• the BB-882 solution is added to the HPBC/polymer mixture by sterile filtration while mixing.
• the pH is adjusted to about 6.0 with 2 N sodium hydroxide solution and the final weight of the formulation is adjusted to 100 g with sterile water by sterile filtration.
• a 100 g batch of pharmaceutical composition may be prepared as described below:
• the HPBC (15 g) is dissolved in approximately 60 g of sterile water for injection.
• the polymer is dispersed in the HPBC solution, then the mixture is stirred for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is added and stirred for 15 minutes.
• the mixture is autoclaved for 20 minutes at 121 °C, then allowed to cool to room temperature.
• BB-94 is a collogenase inhibitor.
• the BB-94 (.3 g) is dissolved in 12.5 g of 0.2 N hydrochloric acid.
• the aminosteroid solution is added to the HPBC/polymer mixture by sterile filtration.
• the pH is adjusted to about 6.0 with 2 N sodium hydroxide solution.
• the final weight of the formulation is adjusted to 100 g with sterile water.
• a 100 g batch of pharmaceutical composition may be prepared as described below:
• the HPBC (15 g) is dissolved in approximately 60 g of sterile water for injection.
• the polymer is dispersed in the HPBC solution, then the mixture is stirred for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is added and stirred for 15 minutes.
• the mixture is autoclaved for 45 minutes at 121 °C, then allowed to cool to room temperature.
• Levobunolol HCl is an antiglaucoma therapeutic agent.
• the levobunolol HCl (1 g) is dissolved in
• a 100 g batch of pharmaceutical composition is prepared as described below:
• the polymer is dispersed in approximately 60 g of sterile water for injection, stured for 1 hour at 400 rpm. Then 0.1 g of EDTA is added and strrred for 15 minutes, 0.34 g of NaCl is added and stirred for 15 minutes, 1 g of sodium glycocholate is added to the mixture, and stined for 15 minutes. The mixture is autoclaved for 45 minutes at 12TC, then allowed to cool to room temperature. Dissolve HPBC (4 g) in 15 g of sterile water for injection, then add 1 g of CBT-101 to the HPBC solution. Add the CBT-lOl/HPBC solution to the polymer mixture by sterile filtration. The pH is adjusted to about 7-0 with 10 N.
• a 100 g batch of pharmaceutical composition may be prepared as described below:
• the cyclodextrin (20 g) is dissolved in approximately 60 g of sterile water for injection.
• the polymer is dispersed in the cyclodextrin solution, then the mixture is stined for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is added and stined for 15 minutes.
• the mixture is autoclaved for 45 minutes at 121 °C, then allowed to cool to room temperature.
• the aminosteroid (1 g) is dissolved in 12.5 g of 0.2 N aqueous hydrochloric acid.
• the aminosteroid solution is added to the cyclodextrin/polymer mixture by sterile filtration.
• the pH is adjusted to about 7.2 with 2 N aqueous sodium hydroxide solution, the final weight of the formulation is adjusted to 100 g sterile water by sterile filtration.
• the formulation is sealed under a blanket of filtered nitrogen.

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• 1993
  • 1993-12-01 EP EP94902482A patent/EP0674528A4/en not_active Withdrawn
  • 1993-12-01 CA CA002150554A patent/CA2150554A1/en not_active Abandoned
  • 1993-12-01 WO PCT/US1993/011651 patent/WO1994012217A1/en not_active Application Discontinuation
  • 1993-12-01 AU AU56841/94A patent/AU672862B2/en not_active Ceased
  • 1993-12-01 JP JP6513478A patent/JPH08503951A/ja active Pending
  • 1993-12-02 CN CN93120402A patent/CN1103316A/zh active Pending

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