WO2008022032A2 - Compositions pharmaceutiques topiques contenant un bloqueur des canaux calciques et procédé d'utilisation - Google Patents

Compositions pharmaceutiques topiques contenant un bloqueur des canaux calciques et procédé d'utilisation Download PDF

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Publication number
WO2008022032A2
WO2008022032A2 PCT/US2007/075711 US2007075711W WO2008022032A2 WO 2008022032 A2 WO2008022032 A2 WO 2008022032A2 US 2007075711 W US2007075711 W US 2007075711W WO 2008022032 A2 WO2008022032 A2 WO 2008022032A2
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composition
weight
amount
water
oil
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PCT/US2007/075711
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English (en)
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WO2008022032A3 (fr
Inventor
Rajkumar Conjeevaram
Darius Dubash
Anil Salpekar
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Solvay Pharmaceuticals, Inc.
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Publication of WO2008022032A2 publication Critical patent/WO2008022032A2/fr
Publication of WO2008022032A3 publication Critical patent/WO2008022032A3/fr

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    • 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
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • Anal dilators have also been used in the treatment of anal fissure.
  • a dilator of medium size is coated with anesthetic jelly and inserted into the anal canal before the passage of stool to prevent exacerbation of the symptoms during defecations.
  • the procedure is inconvenient and success rate is low.
  • the most common treatment for chronic anal fissure is a lateral internal sphincterotomy, which involves surgery to the internal anal sphincter. This procedure, however, requires hospitalization and results in impairment of continence in many patients.
  • U.S. Patent Application Publication No. 2004/0028752 discloses topical diltiazem compositions said to be useful for treatment of anorectal disorder.
  • diltiazem is of low water solubility.
  • the HCl salt is soluble, both substances can re- crystallize when present in a topical formulation at therapeutically effective concentrations.
  • attempts to increase the solubility of Diltiazem HCl and concomitant prevention of recrystallization by adding additional water to such a formulation can lead to undesirable degradation products, for example Desacetyl diltiazem (DAD).
  • DAD Desacetyl diltiazem
  • topical pharmaceutical composition could be prepared comprising a therapeutically effective amount of a calcium-channel blocker of low water solubility, for example diltiazem, that addressed one or more of the above problems, significant advance in the art would result.
  • a calcium-channel blocker of low water solubility for example diltiazem
  • compositions comprising a drug of low water solubility, an oil phase, an aqueous phase, and a crystal formation inhibitor.
  • the composition further comprises an emulsifying agent.
  • the emulsifying agent is a component of the oil phase, for example as a self emulsifying compound.
  • the emulsifying agent is not a component of the oil phase, but the emulsifying agent is a component of the aqueous phase.
  • compositions prepared by processes of combining a drug of low water solubility, an oil phase, an aqueous phase and a crystal formation inhibitor represent further embodiments of the present disclosure, as do the processes for preparing such compositions. Methods of using such compositions in the treatment of various diseases and disorders are also provided.
  • Fig. 1 shows desacetyl diltiazem formation upon room temperature storage of comparator formulations CFl and CF2 for 12 months.
  • topically deliverable pharmaceutical composition comprising a drug of low water solubility as an active ingredient.
  • topical administration and related terms such as “topically administrable” and “topically deliverable” herein refer to any method of administration of a drug that involves placing the drug on the skin to achieve a therapeutic effect, whether or not the therapeutic effect is a local topical effect or a systemic effect resulting from penetration of the drug through the skin with subsequent absorption into the bloodstream.
  • drug of low water solubility refers to compounds that require, under ambient conditions, not less than about 100 parts of water for 1 part of solute, for dissolution.
  • at least a portion of the drug of low water solubility is in solubilized and/or dissolved form in a topically deliverable composition.
  • at least a therapeutically effective amount of the drug of low water solubility is in dissolved and/or solubilized form in a composition.
  • terapéuticaally effective amount refers to an amount of drug or agent that is sufficient to elicit the required or desired therapeutic and/or prophylactic response, as the particular treatment context may require.
  • the drug of low water solubility is a calcium-channel blocker.
  • the calcium-channel blocker is a diphenylpiperazine,
  • the drug of low water solubility is a calcium-channel blocker such as diltiazem shown in Formula I:
  • Non- limiting examples of additional calcium-channel blockers suitable for use in various embodiments described herein include nifedipine, amlodipine, verapamil, nicardipine, nisoldipine, diltiazem, isradipine, felodipine, lacidipine, lercanidipine, nimodipine and bepridil.
  • the drug of low water solubility can also be selected from the group of: corticosteroids, including but not limited to fluticasone propionate, clobetasol propionate, alclometasone dipropionate, prednicarbate, augmented betamethasone propionate, and mometasone furoate; antibiotics, including but not limited to mupirocin calcium cream, clindamycin, cortisporin, neomycin, polymixin-B sulfate & hydrocortisone acetate combination; anti-viral products, including but not limited to acyclovir and penciclovir; antifungal products such as econazole, ketoconazole, miconazole, oxiconazole and tioconazole; tri-cyclic antidepressants including but not limited to doxepin HCl as an anti-pruritic.
  • Other embodiments include various other creams such as tretinoin cream and cream
  • “Pharmaceutically acceptable salts,” or “salts,” include the salt of a drug of low water solubility (e.g. calcium-channel blocker) prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,
  • a drug of low water solubility e.g. calcium-channel blocker
  • acid addition salts are prepared from the free base forms using conventional methodology involving reaction of the free base with a suitable acid.
  • suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • an acid addition salt is reconverted to the free base by treatment with a suitable base.
  • the acid addition salts of the calcium-channel blockers are halide salts, which are prepared using hydrochloric or hydrobromic acids.
  • the basic salts are alkali metal salts, e.g., sodium salt.
  • the drug of low water solubility is present in a total amount not less than about 3%, by weight of the composition, or in a total amount of about 3% to about 12%, about 4% to about 12%, about 4% to about 10%, or about 7% to about 9%, by weight of the composition, for example about 4%, about 5%, about 6%, about 7% about 8% or about 9%.
  • at least a portion of the drug of low water solubility is in dissolved and/or solubilized form in the topically deliverable composition.
  • at least a substantial portion of the drug of low water solubility is in dissolved and/or solubilized form in the topically deliverable composition.
  • compositions are emulsions selected from creams, lotions, liniments, ointments, etc.
  • compositions are oil-in-water or water-in- oil emulsions.
  • suitable compositions comprise an aqueous phase and an oil phase.
  • the oil phase can comprise, inter alia, one or more oil phase suitable ingredients such as emollients, emulsifying agents, solvents, carbohydrates, proteins, high molecular weight alcohols, emulsifying waxes, etc.
  • emulsifying agent refers to an agent capable of lowering surface tension between a non-polar and polar phase and includes compounds defined elsewhere as “self emulsifying” agents.
  • Suitable emulsifying agents can come from any class of pharmaceutically acceptable emulsifying agents including carbohydrates, proteins, high molecular weight alcohols, wetting agents, waxes and finely divided solids.
  • the optional emulsifying agent if present, is present in a composition in a total amount of about 1% to about 15%, about 1% to about 12%, about 1% to about 10%, or about 1% to about 5% by weight of the composition.
  • Carbohydrates can also act as emulsifying agents.
  • Illustrative carbohydrate materials include naturally occurring acacia, tragacanth, agar, chondrus, pectin, and microcrystalline cellulose. These agents form hydrophilic colloids when added to water and generally produce oil-in-water emulsions.
  • One or more carbohydrates, if present, will be present in an amount of about 1% to about 30%, about 1% to about 25%, or about 1% to about 15%, about 1% to about 10%, or about 1% to about 5%, by weight of the composition.
  • Protein substances can also act as emulsifying agents.
  • Illustrative protein substances for use as emulsifying agents include gelatin, egg yolk, and casein.
  • One or more protein substances, if present, will be present in an amount of about 1% to about 30%, about 1% to about 25%, or about 1% to about 15%, about 1% to about 10%, or about 1% to about 5%, by weight of the composition.
  • High molecular weight alcohols can also act as emulsifying agents.
  • Illustrative high molecular weight alcohols include stearyl alcohol, cetyl alcohol, and glyceryl monostearate. Cholesterol and cholesterol derivatives may also be employed as emulsifying agents.
  • One or more high molecular weight alcohols, if present, will be present in an amount of about 1 % to about 30%, about 1% to about 25%, or about 1% to about 15%, about 1% to about 10%, or about 1% to about 5%, by weight of the composition.
  • wetting agents can also act as emulsifying agents. Suitable wetting agents may be anionic, cationic, or nonionic. In one embodiment, a wetting agent used as an emulsifying
  • agent is nonionic. These agents contain both hydrophilic and lipophilic groups, with the lipophilic portion of the molecule generally accounting for the surface-activity.
  • Nonionic emulsifiers include, without limitation, sorbitan esters and polyoxyethylene derivatives, for example as listed below.
  • One or more wetting agents, if present, will be present in an amount of about 1% to about 30%, about 1% to about 25%, or about 1% to about 15%, about 1% to about 10%, or about 1% to about 5%, by weight of the composition.
  • Finely divided solids can also act as emulsifying agents.
  • finely divided solids include colloidal clays such as bentonite, magnesium hydroxide, and aluminum hydroxide. These agents generally form oil-in-water emulsions when an insoluble material is added to an aqueous phase if there is a greater volume of the aqueous phase than of the oleaginous phase.
  • One or more finely divided solids, if present, will be present in an amount of about 1% to about 30%, about 1% to about 25%, or about 1% to about 15%, about 1% to about 10%, or about 1% to about 5%, by weight of the composition.
  • Non-limiting examples of suitable emulsifying agents include ethylene glycol distearate, sorbitan tristearate, propylene glycol monostearate, Triton X-15, X-45, or X-100 (Rohm and Haas, Philadelphia, PA), sorbitan monooleate, sorbitan monostearate, diethylene glycol monolaurate, sorbitan monopalmitate, sucrose dioleate, acacia, Amercol L-101, polyoxyethylene lauryl ether, gelatin, methylcellulose, polyoxyethylene monostearate, triethanolamine oleate, tragacanth, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, pluronic F 68, sodium oleate, potassium oleate, glyceryl monostearate, oleic acid, stearic acid, cetostearyl alcohol, cetyl
  • the emulsifying agent or agents have a hydrophile-lipophile balance (HLB) of about 1 to about 20, about 2 to about 18, about 3 to about 17, or about 4 to about 16, for example, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20.
  • HLB hydrophile-lipophile balance
  • a composition comprises a nonionic or cetrimide emulsifying wax as the emulsifying agent.
  • the emulsifying agent is cetomacrogel emulsifying wax. If present, an emuslifying wax will typically be present in a composition in a total amount of about 1 % to about 20%, about 2% to about 18%, or about 3% to about 15%, by weight.
  • One or more emulsifying agents as described above, if present, are present in an amount of about 1% to about 30%, about 2% to about 25%, or about 4% to about 15%, by weight, for example about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21% about 22% about 23% about 24% about 25%, about 26%, about 27%, about 28%, or about 29%, by weight.
  • the oil phase may optionally comprise one or more natural or synthetic oils, for example mineral oil.
  • one or more oils, if present, will be present in an amount of about 1% to about 30%, about 5% to about 25%, or about 7.5% to about 15%, by weight of the composition.
  • the oil phase may optionally also comprise one or more water immiscible solvents such as benzyl phenylformate, diethyl phthalate, ethyl oleate, glycerol, glycofurol, isopropylalcohol, isopropylmyristate, isopropyl palmitate, isosorbide, azone, DMSO, polyethylene glycol, propylene carbonate, and triacetin.
  • a water immiscible solvent will typically be present in a total amount of about 1% to about 50%, about 2% to about 30%, about 3% to about 20%, about 5 to about 18%, or about 10% to about 18%, by weight of the composition.
  • the water immiscible solvent comprises propylene glycol, and is present in a composition in an amount of about 5% to about 50%, about 10% to about 30%, or about 15% to about 30%, by weight of the composition, for example about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21% about 22%, about 23%, about 24%, about 25%, about 25%, about 27%, about 28%, about 29% or about 30%.
  • the aqueous phase comprises water and optionally one or more aqueous or water-miscible solvents or co-solvents.
  • solvents or co-solvents function as skin penetration enhancers.
  • the drug of low water solubility is soluble in the aqueous phase.
  • suitable solvents for the aqueous phase include water, propylene glycol, alcohol, glycerol, isopropylalcohol and polyethylene glycol.
  • water is present in a composition described herein in an amount of about 10% to about 80%, about 20% to about 60%, about 25% to about 55%, about 30% to about 50%, for example about 21%, about 22%, about 23%, about 24%, about 24%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37 %, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55%, by weight.
  • the aqueous phase prior to being mixed with the oil phase, comprises about 40% to about 95%, about 45% to about 95%, about 50% to about 95% or about 55% to about 90% water, by weight.
  • compositions described herein comprise a crystal formation inhibitor.
  • crystal formation inhibitor herein means any compound or ingredient that prevents, inhibits or slows formation of crystals from solubilized and/or dissolved drug. Without being bound by theory, the crystal formation inhibitor is believed to act to keep at least a portion of the solubilized and/or dissolved drug of low water solubility from forming crystals within the pharmaceutical composition.
  • a crystal formation inhibitor can comprise one or more of a variety of substances, including but not limited to cellulosic polymers, non- cellulosic polymers, and any number of classes of non-polymers such as non-ionic surfactants.
  • Non-limiting illustrative examples of suitable crystal formation inhibitors include polyvinylpyrrolidone (PVP), octylphenoxypolyethoxyethanol, the family of polysorbates, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene 20 sorbitan monooleate, sorbitan
  • PVP polyvinylpyrrolidone
  • octylphenoxypolyethoxyethanol the family of polysorbates
  • polyoxyethylene 20 sorbitan tristearate polyoxyethylene 20 sorbitan monopalmitate
  • polyoxyethylene 20 sorbitan monolaurate polyoxyethylene 20 sorbitan monooleate
  • sorbitan polyvinylpyrrolidone
  • the crystal formation inhibitor is present in an amount of about 1% to about 20%, about 1% to about 10%, or about 2% to about 8%, by weight of the composition.
  • the crystal formation inhibitor is present in an amount of about 1%, about 2% about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19% or about 20%, by weight of the composition.
  • the polyvinylpyrrolidone has a molecular weight of about 10,000 to about 15,000, for example about 10,100, about 10,200, about 10,300, about 10,400, about 10,500, about 10,600, about 10,700, about 10, 800, about 10,900, about 11,000, about 11,100, about 11,200, about 11,300, about 11,400, about 11,500, about 11,600, about 11,700, about 11,800, about 11,900, about 12,000, about 12,100, about 12,200, about 12,300, about 12,400, about 12,500, about 12,600, about 12,700, about 12,800, about 12,900, about 13,000, about 13,100, about 13,200, about 13,300, about 13,400, about 13,500, about 13,600, about 13,700, about 13,800, about 13,900, about 14,000, about 14,100, about 14,200, about 14,300, about 14,400, about 14,500, about 14,600, about 14,700, about 14,800, about 14,900, or about 15,000.
  • compositions described herein comprise one or more additional pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipient herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a unit dose of the composition, and that does not produce unacceptable toxicity or interaction with other components in the composition.
  • compositions described herein comprise one or more skin penetrating agents, for example sulfoxides, such as dimethyl sulfoxide (DMSO), amides, (DMA, DMF), pyrrolidones, organic solvents, laurocapram (AZONE), calcium thioglycollate, etc.
  • skin penetrating agents for example sulfoxides, such as dimethyl sulfoxide (DMSO), amides, (DMA, DMF), pyrrolidones, organic solvents, laurocapram (AZONE), calcium thioglycollate, etc.
  • skin penetrating agents are typically present in an amount of about 0.1% to about 20%, about 0.1% to about 10%, 0.1% to about 5%, or 0.1% to about 2.5%, by weight.
  • compositions described herein optionally comprises an emollient.
  • emollients include mineral oil, mixtures of mineral oil and lanolin alcohols, cetyl alcohol, cetostearyl alcohol, petrolatum, petrolatum and lanolin alcohols, cetyl esters wax, cholesterol, glycerin, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, lecithin, allyl caproate, althea officinalis extract, arachidyl alcohol, argobase EUC, Butylene glycol dicaprylate/dicaprate, acacia, allantoin, carrageenan, cetyl dimethicone, cyclomethicone, diethyl succinate, dihydroabietyl behenate, dioctyl adipate, ethyl laurate, ethyl palmitate, ethyl stearate, is
  • An emollient if present, is present in the compositions described herein in an amount of about 1% to about 30%, about 3% to about 25%, or about 5% to about 15%, by weight.
  • one or more emollients are present in a total amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, by weight.
  • a composition comprises an antimicrobial preservative.
  • anti-microbial preservatives include acids, including but not limited to benzoic acid, phenolic acid, sorbic acids, alcohols, benzethonium chloride, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium propionate, or thimerosal.
  • the anti-microbial preservative if present, is present in an amount of about 0.1% to about 5%, about 0.2% to about 3%, or about 0.3% to about 2%, by weight,
  • excipients and ingredients can have multiple roles as is known in the art. Thus, any categorization of excipients herein is not intended to be limiting in any manner. Excipients categorized in any way can also operate under various different categories of excipients as will be readily appreciated by one of ordinary skill in the art. For example, solvents may operated as skin penetration agents and vice versa.
  • compositions described herein upon storage in a closed container maintained at room temperature (ambient conditions), refrigerated (e.g. about 5 -10 0 C) temperature, or freezing temperature for a period of about 1 week, about 2 weeks, about 3 weeks, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months, contain at least about 90%, at least about 92.5%, at least about 95%, at least about 97.5%, or at least about 99% of the original active ingredient in non-degraded form.
  • compositions described herein upon storage in a closed container maintained at room temperature (ambient conditions), refrigerated (e.g. about 5 -10 0 C) temperature, or freezing temperature for a period of about 1 week, about 2 weeks, about 3 weeks, or about 1 , about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 1 , or about 12 months, contain at least about 90%, at least about 92.5%, at least about 95%, at least about 97.5%, or at least about 99% of the original active ingredient (e.g. calcium-channel blocker or salt thereof) in non-crystallized form.
  • the original active ingredient e.g. calcium-channel blocker or salt thereof
  • compositions described herein comprising diltiazem HCl (or other salt), upon storage in a closed container maintained under ambient conditions,
  • 1407465.1 07095168 12 refrigerated ⁇ e.g. about 5 -10 0 C) temperature, or freezing temperature for a period of about 1 week, about 2 weeks, about 3 weeks, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months, not more than about 1% of the diltiazem HCl (or other salt) present is in the form of, or has converted to, desacetyl diltiazem HCl (or other salt).
  • compositions described herein comprising diltiazem HCl (or other salt) upon storage in a closed container maintained under ambient conditions, refrigerated ⁇ e.g. about 5 -10 °C) temperature, or freezing temperature for a period of about 1 week, about 2 weeks, about 3 weeks, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 1, or about 12 months, not more than about 0.8% of the diltiazem HCl (or other salt) present is in the from of, or has converted to, desacetyl diltiazem HCl (or other salt).
  • compositions described herein comprising diltiazem HCl (or other salt) upon storage in a closed container maintained under ambient conditions, refrigerated ⁇ e.g. about 5 -10 0 C) temperature, or freezing temperature for a period of about 1 week, about 2 weeks, about 3 weeks, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months, not more than about 0.5% of the diltiazem HCl (or other salt) present is in the form of, or has converted to, desacetyl diltiazem HCl (or other salt).
  • compositions described herein comprising diltiazem HCl, upon storage in a closed container maintained under ambient conditions, refrigerated ⁇ e.g. about 5 -10 0 C) temperature, or freezing temperature for a period of about 1 week, about 2 weeks, about 3 weeks, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months, not more than about 0.4% of the diltiazem HCl (or other salt) present is in the form of, or has converted to, desacetyl diltiazem HCl (or other salt).
  • compositions described herein comprising diltiazem HCl (or other salt) upon storage in a closed container maintained under ambient conditions, refrigerated ⁇ e.g. about 5 -10 0 C) temperature, or freezing temperature for a period of about 1 week, about 2 weeks, about 3 weeks, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months, not more than about 0.35%
  • compositions described herein comprising diltiazem HCl, upon storage in a closed container maintained under ambient conditions, refrigerated (e.g. about 5 -10 0 C) temperature, or freezing temperature for a period of about 1 week, about 2 weeks, about 3 weeks, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 months, not more than about 0.25% of the diltiazem HCl (or other salt) present is in the form of, or has converted to, desacetyl diltiazem HCl (or other salt).
  • compositions described herein are suitable for topical administration.
  • topically administrate compositions are adapted for topical administration in and/or around the anal canal and may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, foam, oils, aerosols, suppositories or enemas.
  • compositions that comprise an oil phase and an aqueous phase.
  • a composition can be prepared in any suitable manner.
  • the composition is prepared by separately preparing an aqueous phase and an oil phase, and then combining the two phases, for example with homogenization.
  • the first and second phases can be prepared in any order or substantially simultaneously.
  • the aqueous phase is made by mixing, in a first vessel, water and the water-miscible solvent (penetration enhancer) to form an aqueous pre-mix.
  • the aqueous pre-mix is heated, for example to a temperature of about 50 0 C to about 80 0 C, about 55 0 C to about 75 0 C or about 60 0 C to about 70 0 C, for example about 65 0 C.
  • the aqueous pre-mix is heated to a temperature higher than the melting point of any component of the oil phase.
  • the components of the aqueous pre-mix can be individually heated prior to being mixed together.
  • the crystal formation inhibitor is added to the aqueous pre-mix prior to, during or after it or the individual components are heated to the desired temperature.
  • the oil phase is prepared by adding to a second vessel one or more emulsifying agents and optionally an oil and or an emollient.
  • the emulsifying agent and optional oil and/or emollient are heated to a desired temperature and at a rate sufficient to form a substantially uniform oil phase.
  • the desired temperature is about 60 0 C to about 90 0 C, about 65 0 C to about 80 0 C or about 67 0 C to about 75°C, for example about 70 °C.
  • the oil phase is cooled to substantially the same temperature as the aqueous phase and the two phases are combined to form a mixture.
  • the mixture is homogenized to form a substantially homogenous composition.
  • compositions described herein can be used to treat and/or prevent numerous medical conditions.
  • One embodiment provides topical compositions comprising a calcium- channel blocker useful for treating and/or preventing disorders of the distal anal canal, including but not limited to acute and chronic anal fissures or ulcers.
  • Such compositions can be applied between once and several times per day.
  • the term "several times per day” herein means more than one but less than about 10.
  • "several times per day” in the present context could illustratively represent about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 dosage compartments or any increment within the range of 2 to 10.
  • Each application will generally provide about 2 mg to about 20 mg, about 4 mg to about 15 mg, or about 6 mg to about 10 mg, for example 8 mg of active agent, for example, diltiazem.
  • Total daily doses of diltiazem of about 2 mg to about 120 mg, illustratively about 4 mg, about 6 mg about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 52 mg, about 54 mg, about 56 mg, about 58 mg, about 60 mg, about 62 mg, about 64 mg, about 66 mg, about 68 mg, about 70 mg, about 72 mg, about 74 mg, about 76 mg, about 78 mg, about 80 mg, about 82 mg, about 84
  • any ranges, ratios and ranges of ratios that can be formed by any of the numbers or data present herein represent further embodiments of the present invention. This includes ranges that can be formed that do or do not include a finite upper and/or lower boundary.
  • Table 4 shows, inter alia, the amounts of diltiazem HCl , phenoxyethanol, and desacetyl diltiazem HCl formed after storage of a diltiazem HCl composition for 0, 1 and 2 months.
  • one embodiment of the present invention is a diltiazem HCl compositions that, upon storage under refrigerated conditions for a period of 1 month, exhibits a diltiazem HCkdesacetyl diltiazem HCl ratio of about 428 (102.9/0.24), greater than about 428, or less than about 428 as is shown in Table 4.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 1 was prepared according to the procedure set forth below.
  • composition of a topical cream 1407465 1 07095168 16 Table 1.
  • the aqueous phase was prepared by heating, in a first vessel, water and propylene glycol to 65 °C. PVP was then added to the vessel with mixing until dissolved. Diltiazem HCl was then added to the vessel. Next, phenoxyethanol was added to the vessel with mixing.
  • the oil phase was prepared by melting cetomacrogol emulsifying wax, glyceryl monostearate and mineral oil at 70 °C with slow mixing. Once a substantially uniform mixture was formed, the temperature was reduced to 65 0 C. The aqueous phase and the oil phase were then slowly homogenized at high shear to form a dense, homogenous cream.
  • CFl and CF2 were stored at room temperature for a period of 12 months. Formation of Desacetyl Diltiazem was measured at month 1, month 3, month 6, month 9 and month 12. Data are shown in Fig. 1. As can be seen from Fig. 1, after 12 months of storage for each of formulations CF 1 and CF2, more than 5% of the total diltiazem content was desacetyl diltiazem.
  • Formulations Fl - F6 were maintained under accelerated 2 month freeze- thaw cycles as follows. Each cycle consisted of the following: the formulations, after preparation, were first stored in a freezer at -20 C for 4 days. After 4 days, the formulations were removed from the freezer and stored at 25 0 C and 60% relative humidity for 3 days. This cycling was repeated throughout the storage period. Formulations F3 and F6 exhibited no crystal growth after two months of freeze-thaw storage cycles.
  • a batch of Formulation F3 was prepared and was maintained under refrigerated conditions for a period of 2 months. After two months of storage, diltiazem HCl concentration, phenoxyethanol concentration, and desacetyl diltiazem (DAD) HCl concentration were measured (as % label claim). Results are shown in Table 4.
  • formulation F3 is stable throughout the two month storage period.
  • Example 4 is stable throughout the two month storage period.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 5 can be prepared according to the process described herein.
  • Table 5 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 6 can be prepared according to the process described herein.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 7 can be prepared according to the process described herein.
  • Table 7 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 8 can be prepared according to the process described herein.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 9 can be prepared according to the process described herein.
  • Table 9 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 10 can be prepared according to the process described herein.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 11 can be prepared according to the process described herein.
  • Table 11 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 12 can be prepared according to the process described herein.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 13 can be prepared according to the process described herein.
  • Table 13 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 14 can be prepared according to the process described herein.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 15 can be prepared according to the process described herein.
  • Table 15 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 16 can be prepared according to the process described herein.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 17 can be prepared according to the process described herein.
  • Table 17 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 18 can be prepared according to the process described herein.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 19 can be prepared according to the process described herein.
  • Table 19 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 20 can be prepared according to the process described herein.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 21 can be prepared according to the process described herein.
  • Table 21 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 22 can be prepared according to the process described herein.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 23 can be prepared according to the process described herein.
  • Table 23 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 24 can be prepared according to the process described herein.
  • composition of a topical cream Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 25 can be prepared according to the process described herein.
  • Table 25 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 26 can be prepared according to the process described herein.
  • composition of a topical cream Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 27 can be prepared according to the process described herein.
  • Table 27 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 28 can be prepared according to the process described herein.
  • composition of a topical cream Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 29 can be prepared according to the process described herein.
  • Table 29 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 30 can be prepared according to the process described herein.
  • composition of a topical cream Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 31 can be prepared according to the process described herein.
  • Table 31 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 32 can be prepared according to the process described herein.
  • composition of a topical cream Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 33 can be prepared according to the process described herein.
  • Table 33 Composition of a topical cream.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 34 can be prepared according to the process described herein.
  • a pharmaceutical composition in the form of a topical cream as shown in Table 35 can be prepared according to the process described herein.
  • Table 35 Composition of a topical cream.
  • the amount of broadening from the strict numerical boundary depends upon many factors. For example, some of the factors which may be considered include the criticality of the element and/or the effect a given amount of variation will have on the performance of the claimed subject matter, as well as other considerations known to those of skill in the art. As used herein, the use of differing amounts of significant digits for different numerical values is not meant to limit how the use of the words "about” or “approximately" will serve to broaden a particular numerical value.

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Abstract

La présente invention concerne des compositions pharmaceutiques susceptibles d'être administrées selon un mode topique, qui contiennent un médicament faiblement hydrosoluble et un inhibiteur de formation de cristaux. Dans un mode de réalisation, le médicament faiblement hydrosoluble est un agent de blocage des canaux calciques ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2007/075711 2006-08-11 2007-08-10 Compositions pharmaceutiques topiques contenant un bloqueur des canaux calciques et procédé d'utilisation WO2008022032A2 (fr)

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US9700549B2 (en) 2013-10-03 2017-07-11 David Wise Compositions and methods for treating pelvic pain and other conditions
US11766428B2 (en) 2018-06-01 2023-09-26 Tavanta Therapeutics Hungary Incorporated Topical amlodipine salts for the treatment of anorectal diseases
WO2024016630A1 (fr) * 2022-07-22 2024-01-25 上海奥全生物医药科技有限公司 Composition pharmaceutique de chlorhydrate de diltiazem, son procédé de préparation et son utilisation

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9700549B2 (en) 2013-10-03 2017-07-11 David Wise Compositions and methods for treating pelvic pain and other conditions
US10543201B2 (en) 2013-10-03 2020-01-28 David Wise Compositions and methods for treating pelvic pain and other conditions
US11766428B2 (en) 2018-06-01 2023-09-26 Tavanta Therapeutics Hungary Incorporated Topical amlodipine salts for the treatment of anorectal diseases
WO2024016630A1 (fr) * 2022-07-22 2024-01-25 上海奥全生物医药科技有限公司 Composition pharmaceutique de chlorhydrate de diltiazem, son procédé de préparation et son utilisation
US12102683B2 (en) 2022-07-22 2024-10-01 Auson Pharmaceuticals Inc. Pharmaceutical composition of diltiazem hydrochloride, preparation method therefor, and application thereof

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