WO2017031105A1 - Pharmaceutical formulations - Google Patents
Pharmaceutical formulations Download PDFInfo
- Publication number
- WO2017031105A1 WO2017031105A1 PCT/US2016/047148 US2016047148W WO2017031105A1 WO 2017031105 A1 WO2017031105 A1 WO 2017031105A1 US 2016047148 W US2016047148 W US 2016047148W WO 2017031105 A1 WO2017031105 A1 WO 2017031105A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- soft gelatin
- gelatin capsule
- ascomycin
- solvent
- acid
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title description 10
- 229940002612 prodrug Drugs 0.000 claims abstract description 27
- 239000000651 prodrug Substances 0.000 claims abstract description 27
- ZDQSOHOQTUFQEM-XCXYXIJFSA-N ascomycin Natural products CC[C@H]1C=C(C)C[C@@H](C)C[C@@H](OC)[C@H]2O[C@@](O)([C@@H](C)C[C@H]2OC)C(=O)C(=O)N3CCCC[C@@H]3C(=O)O[C@H]([C@H](C)[C@@H](O)CC1=O)C(=C[C@@H]4CC[C@@H](O)[C@H](C4)OC)C ZDQSOHOQTUFQEM-XCXYXIJFSA-N 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 239000007903 gelatin capsule Substances 0.000 claims abstract description 17
- 239000012453 solvate Substances 0.000 claims abstract description 16
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 82
- 239000002904 solvent Substances 0.000 claims description 81
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 57
- -1 ascomycin class compound Chemical class 0.000 claims description 42
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical group C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims description 41
- 229960001967 tacrolimus Drugs 0.000 claims description 32
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims description 32
- 239000013543 active substance Substances 0.000 claims description 25
- ZDQSOHOQTUFQEM-NURRSENYSA-N ascomycin Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](O)[C@H](OC)C1 ZDQSOHOQTUFQEM-NURRSENYSA-N 0.000 claims description 25
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 19
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- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 claims description 10
- 239000004014 plasticizer Substances 0.000 claims description 9
- BHIZVZJETFVJMJ-UHFFFAOYSA-N 2-hydroxypropyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(C)O BHIZVZJETFVJMJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 claims description 8
- 239000001856 Ethyl cellulose Substances 0.000 claims description 8
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 8
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- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 7
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- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 7
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- GHHURQMJLARIDK-UHFFFAOYSA-N 2-hydroxypropyl octanoate Chemical compound CCCCCCCC(=O)OCC(C)O GHHURQMJLARIDK-UHFFFAOYSA-N 0.000 claims description 6
- 229920002562 Polyethylene Glycol 3350 Polymers 0.000 claims description 6
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 claims description 5
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- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 claims description 4
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- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 3
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- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 3
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- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims description 2
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
Definitions
- agonist means a molecule such as a compound, a drug, an enzyme activator or a hormone that enhances the activity of another molecule or the activity of the target receptor.
- acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucohepton
- organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
- Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound.
- the ascomycin class compound can be the compound ascomycin, also known as FK520, with the IUFAC name of
- the present invention also provides prodrugs of an ascomycin and its analogues wherein the prodrug converts in vivo to ascomycin and its analogues.
- a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject.
- the suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art.
- Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001).
- Exemplary prodrugs are, for example, esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, wherein acyl has a meaning as defined herein.
- Suitable prodrugs are often pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters.
- amines have been masked as
- Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
- isotopes that can be incorporated into compounds as defined above include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as
- prodrugs thereof can generally be prepared by carrying out the synthetic procedures by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
- Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
- the compounds disclosed above, in free form may be converted into salt form, and vice versa, in a conventional manner understood by those skilled in the art.
- the compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallization.
- the compounds can be recovered from reaction mixtures and purified in a conventional manner.
- Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, de-acetone, de-DMSO.
- An ascomycin, or a pharmaceutically acceptable salt, solvate, analog, or prodrug thereof, that increases BMPR2 signaling can be administered to a patient for the treatment or prevention of PAH.
- Treatment or prevention of PAH as used herein encompasses one or more of the following:
- therapeutically effective amount can vary depending on the compound, the particular pulmonary hypertension condition to be treated, the severity of the condition, body weight and other parameters of the individual subject, and can be readily established without undue experimentation by the physician or clinician based on the disclosure herein. Typically, a therapeutically effective amount will be found in the range of about 0.1 to about 25 mg/day, for example about 0.5 to about IS mg/day, about 1 to about 10 mg/day, or about 0.S, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 6, about 7, about 8, about 9 or about 10 mg/day.
- the therapeutically effective amount can be
- the compound to increase BMPR2 signaling is ascomycin or a pharmaceutically acceptable solvate, salt, analog, or prodrug thereof, it can be administered at a dose and regimen that provides ascomycin whole blood concentration of about 0.05 ng/ml to about 30 ng/ml, such as about 0.1 ng/mL to about 0.5 ng/mL, about 0.15 ng/mL to about 0.3 ng/mL or about 0.1 -0.2 ng/mL.
- the exact dosing may vary between patients.
- Ascomycin or a pharmaceutically acceptable solvate, salt, analog, or prodrug thereof can be administered once, twice, or three or more times a day.
- the goal is to reach a whole blood level of about 0.2 ng/mL to about 30 ng/mL.
- an initial dose of 0.001 mg/kg day to 0.01 mg/kg day e.g., 0.002 mg kg /day to 0.05 mg/kg/day may be sufficient, and the does can be up-titrated according to the measured ascomycin whole blood level.
- the ascomycin may reach a whole blood concentration as low as 0.1-0.2 ng/ml (e.g., 0.10 to 0.12, 0.12 to 0.14, 0.14 to 0.16, 0.16 to 0.18 or 0.18 to 0.20), however whole blood a concentration in the range of 0.2 to 30 ng/ml, e.g., 0.2, 0.S, 1 and 2 ng/ml may be acceptable.
- ascomycin can reach a whole blood concentration as low as 0.1-0.2 ng/ml (e.g., 0.10 to 0.12, 0.12 to 0.14, 0.14 to 0.16, 0.16 to 0.18 or 0.18 to 0.20), however whole blood a concentration in the range of 0.2 to 30 ng/ml, e.g., 0.2, 0.S, 1 and 2 ng/ml may be acceptable.
- ascomycin can reach a whole blood concentration as low as 0.1-0.2 ng/ml (e.g., 0.10 to 0.12, 0.12 to 0.14, 0.14 to 0.16
- the active agent to increase BMPR2 signaling can be administered in
- an ascomycin, or a pharmaceutically acceptable salt, solvate, analog, or prodrug thereof can be administered alone or in combination with other active compounds.
- compounds that increase the signaling of the BMPR2 pathway can further be combined with other compounds that increase vasodilation such as compounds that target endothelin (Tracleer®, Opsumit®, and Letairis®), nitric oxide/PDE-5 (Revatio®, Adcirca®, avanafil, lodenafil, mirodenafil, udenafil, and zaprinast), prostacyclin (Remodulin®,
- the combined compounds can become more effective agents for the treatment of PAH, and may provide additive or synergistic results from the combined use of the compounds that increase the signaling of the BMPR2 pathway with compounds that target other pathways.
- Examples of drugs useful in combination therapy are classified and presented in several lists below. Some drugs are active at more than one target; accordingly certain drugs may appear in more than one list. Use of any listed drug in a combination is contemplated herein, independently of its mode of action.
- a suitable PDES inhibitor can illustratively be selected from the following list: sildenafil, tadalafil, vardenafil, avanafil, lodenafil, mirodenafil, udenafil, and zaprinast.
- a suitable ERA other than ambrisentan can illustratively be selected from the following list: atrasentan, ambrisentan, BMS 193884, bosentan, CI- 1020, darusentan, S-0139 SB-209670, sitaxsentan, TA-0201, tarasentan, TBC-3711, VML-588, and ZD-1611.
- a suitable diuretic can illustratively be selected from the following list:
- Organomercurials chlormerodrin, chlorothiazide, chlorthalidone, meralluride,
- mercaptomerin sodium mercumatilin, sodium mercurous, and chloride mersalyl
- Purines pamabrom, protheobromine, and theobromine
- Steroids canrenone, oleandrin, and spironolactone
- Sulfonamide derivatives acetazolamide, ambuside, azosemide, bumetanide, butazolamide, chloraminophenamide, clofenamide, clopamide, clorexolone, disulfamide, ethoxzolamide, furosemide, mefruside, methazolamide, piretanide, torsemide, tripamide, and xipamide
- Thiazides and analogs althiazide, bendroflumethiazide, benzthiazide,
- the diuretic if present comprises a thiazide or loop diuretic.
- Particularly suitable loop diuretics include bumetanide, furosemide, torsemide and combinations thereof.
- a suitable anticoagulant can illustratively be selected from the following list: acenocoumarol, ancrod, anisindione, bromindione, clorindione, coumetarol, cyclocumarol, dextran sulfate, sodium dicumarol, diphenadione, ethyl biscoumacetate, ethylidene dicoumarol, fluindione, heparin, hirudin, lyapolate, sodium pentosan, polysulfate
- the active agent to increase BMPR2 signaling can optionally be administered in combination therapy with one or more drugs targeting the underlying condition.
- the active agent and at least one drug can be administered at different times or at about the same time (at exactly the same time or directly one after the other in any order).
- the active agent and the second active drug can be formulated in one dosage form as a fixed-dose combination for administration at the same time, or in two or more separate dosage forms for administration at the same or different times.
- kits can optionally be co-packaged, for example in a single container or in a plurality of containers within a single outer package, or co-presented in separate packaging ("common presentation").
- a kit is contemplated comprising, in separate containers, active agent to increase BMPR2 signaling and at least one drug useful in combination with the active agent.
- the active agent and the at least one drug useful in combination therapy with the active agent are separately packaged and available for sale independently of one another, but are co-marketed or co-promoted for use according to the invention.
- the separate dosage forms can also be presented to a patient separately and independently, for use according to the invention.
- the compounds described above are preferably used to prepare a medicament, such as by formulation into pharmaceutical compositions for administration to a subject using techniques generally known in the art.
- a summary of such pharmaceutical compositions may be found, for example, in Remington's Pharmaceutical Sciences (the latest edition) Mack Publishing Co., Easton, PA.
- the compounds of the invention can be used singly or as components of mixtures.
- Preferred forms of the compounds are those for systemic administration as well as those for topical or transdermal administration.
- Formulations designed for timed release are also with the scope of the invention.
- Formulation in unit dosage form is also preferred for the practice of the invention.
- the formulation is divided into unit doses containing appropriate quantities of one or more compound.
- the unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packeted tablets or capsules, and powders in vials or ampoules.
- the compounds of the invention may be labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of
- chromophores or fluorescent moieties include chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
- compositions may be in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions.
- Suitable excipients or carriers are, for example, water, saline, dextrose, glycerol, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.
- these compositions may also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
- compositions comprising the compounds of the invention include formulating the derivatives with one or more inert, pharmaceutically acceptable carriers to form either a solid or liquid.
- Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
- Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
- a carrier of the invention can be one or more substances which also serve to act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, or tablet disintegrating agent.
- a carrier can also be an encapsulating material.
- Hard gelatin capsules can contain the compounds of the invention in
- a solid, pulverulent carrier such as, for example, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin.
- Soft gelatin capsules can be prepared in which capsules contain the compounds of the invention and/or non-aqueous, and/or water miscible solvents such as polyethylene glycol and the like.
- Hydrophilic solvents compatible with softgel capsules can include PEG400, PEG800, ethanol, glycerin, PPG, polysorbates, povidone (PVP), and the like containing up to about 5-8% water.
- the softgel capsules can optionally contain a buffer, a co-solvent, a lipophilic surfactant, a hydrophilic surfactant, a plasticizer, a bioavailability enhancer, or a fatty acid.
- composition or liquid formulation that may be used is a composition or liquid formulation in which the active agent is dissolved in a solvent component.
- a solvent component any solvent which has the desired effect may be used in which the therapeutic agent dissolves.
- the solvent can be aqueous or non-aqueous.
- An "aqueous solvent” is a solvent that contains at least about 50% water.
- Solvents for use in the liquid formulations can be determined by a variety of methods known in the art, including but not limited to (1) theoretically estimating their solubility parameter values and choosing the ones mat match with the therapeutic agent, using standard equations in the field; and (2) experimentally determining the saturation solubility of therapeutic agent in the solvents, and choosing the ones that exhibit the desired solubility.
- any concentration of solubilized active agent that has the desired effect can be used.
- the solvent component may be a single solvent or may be a mixture of solvents. Solvents and types of solutions are well known to those in drug delivery
- solvents may also serve as solubilizing agents.
- solvents for use in the invention include MaisineTM 35- 1 (glyceryl monolineate) that comprises long chain fatty acids, for example glyceryl linoleate, PEG400, PEG800, PEG 1200, PEG 3350, ethanol, glycerin, PPG, polysorbates, povidone (PVP), and Transcutol® HP (glycol monoethyl ether).
- Solvents that may be used include but are not limited to DMSO, ethanol, methanol, isopropyl alcohol, castor oil, propylene glycol, glycerin, polysorbate 80, benzyl alcohol, dimethyl acetamide (DMA), dimethyl formamide (DMF), triacetin, diacetin, corn oil, acetyl triethyl citrate (ATC), ethyl lactate, glycerol formal, ethoxy diglycol (Transcutol, Gattefosse), tryethylene glycol dimethyl ether (Triglyme), dimethyl isosorbide (DMT), ⁇ - butyrolactone, N-Memyl-2-pyrrolidinone (NMP), polyethylene glycol of various molecular weights, including but not limited to PEG 300 and PEG 400, and polyglycolated capryl glyceride (Labrasol, Gattefosse), combinations of any one or more of the foregoing, or analogs
- Phospholipid solvents can also be used, such as lecithin, phosphatidylcholine, or a mixture of various diglycerides of stearic, palmitic, and oleic acids, linked to the choline ester of phosphoric acid, hydrogenated soy phosphatidylcholine (HSPC),
- HSPC hydrogenated soy phosphatidylcholine
- solvents include, for example, components such as alcohols, propylene glycol, polyethylene glycol of various molecular weights, propylene glycol esters, propylene glycol esterified with fatty acids such as oleic, stearic, palmic, capric, linoleic, etc; medium chain mono-, di-, or triglycerides, long chain fatty acids, naturally occurring oils, and a mixture thereof.
- the oily components for the solvent system include commercially available oils as well as naturally occurring oils.
- the oils may further be vegetable oils or mineral oils.
- the oils can be characterized as non-surface active oils, which typically have no hydrophile lipophile balance value.
- Captex 100 Commercially available substances comprising medium chain triglycerides include, but are not limited to, Captex 100, Captex 300, Captex 355, Miglyol 810, Miglyol 812, Miglyol 818, Miglyol 829, and Dynacerin 660.
- Propylene glycol ester compositions that are commercially available encompass Captex 200 and Miglyol 840, and the like.
- the commercial product, Capmul MCM comprises one of many possible medium chain mixtures comprising monoglycerides and diglycerides.
- solvents include naturally occurring oils such as peppermint oil, and seed oils.
- exemplary natural oils include oleic acid, castor oil, saffiower seed oil, soybean oil, olive oil, sunflower seed oil, sesame oil, and peanut oil.
- Soy fatty acids may also be used.
- fully saturated non-aqueous solvents include, but are not limited to, esters of medium to long chain fatty acids (such as fatty acid triglycerides with a chain length of about Ce to about C24). Hydrogenated soybean oil and other vegetable oils may also be used.
- Mixtures of fatty acids may be split from the natural oil (for example coconut oil, palm kernel oil, babassu oil, or the like) and refined.
- natural oil for example coconut oil, palm kernel oil, babassu oil, or the like
- medium chain (about Cg to about C12) triglycerides such as caprilyic/capric triglycerides derived from coconut oil or palm seed oil, may be used.
- Medium chain mono- and diglycerides may also be used.
- Other fully saturated non-aqueous solvents include, but are not limited to, saturated coconut oil (which typically includes a mixture of lauric, myristic, palmitic, capric and caproic acids), including those sold under the MiglyolTM and bearing trade designations 810, 812, 829 and 840).
- Non-aqueous solvents include isopropyl myristate.
- synthetic oils include triglycerides and propylene glycol diesters of saturated or unsaturated fatty acids having 6 to 24 carbon atoms such as, for example hexanoic acid, octanoic (caprylic), nonanoic
- the non-aqueous solvent can comprise the mono-, di- and triglyceryl esters of fatty acids or mixed glycerides and/or propylene glycol mono- or diesters wherein at least one molecule of glycerol has been esterified with fatty acids of varying carbon atom length.
- a non-limiting example of a "non-oil" useful as a solvent is polyethylene glycol.
- Exemplary vegetable oils include cottonseed oil, corn oil, sesame oil, soybean oil, olive oil, fractionated coconut oil, peanut oil, sunflower oil, safflower oil, almond oil, avocado oil, palm oil, palm kernel oil, babassu oil, beechnut oil, linseed oil, rape oil and the like.
- Mono-, di-, and triglycerides of vegetable oils, including but not limited to corn, may also be used.
- Polyvinyl pyrrolidone may also be used as a solvent.
- Further solvents include but are not limited to C 6 -C 24 fatty acids, oleic acid, Imwitor 742, Capmul, F68, F68 (Lutrol), PLURONICS including but not limited to PLURONICS F108, F127, and F68, Poloxamers, Tetronics, F127, cyclodextrins such as ⁇ -cyclodextrin, - cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin (Captisol); CMC, polysorbitan 20, Cavitron, polyethylene glycol of various molecular weights including but not limited to PEG 300 and PEG 400. Beeswax and d-a-tocopherol (Vitamin E) may also be used as solvents.
- the solvent can be N-methylpyrrolidone (NMP), dimethyl-acetamine (DMA), dimethyl sulfoxide (DMSO), propylene glycol (PG), polyethylene glycol 600 (PEG 600), polyethylene glycol 400 (PEG 400), ethanol, or a mixture of one or more thereof.
- the solvent comprises a combination of solvents including N-methyl pyrrolidone (NMP), dimethyl-acetamine (DMA), or dimethyl sulfoxide (DMSO).
- the solvent comprises a combination of solvents including propylene glycol (PG), polyethylene glycol 600 (PEG 600), or polyethylene glycol 400 (PEG 400).
- the solvent can comprise a combination of at least two solvents.
- the solvent is polyethoxylated castor oil (e.g., Cremophor (PEG 35 castor oil)), monoglycerides and/or diglycerides of caprylic acid (e.g., Capmul MCM (C8)), nonionic polymer of the alkyl aryl polyether alcohol (e.g., tyloxapol (ethoxylated p-tert-octylphenol formaldehyde polymer)), Phosal® 50PG, ethanol, or a mixture of one or more thereof.
- the solvent can comprise a combination of at least two solvents.
- the at least two solvents comprising a first solvent such as polyethoxylated castor oil (e.g., Cremophor (PEG 35 castor oil)) or nonionic polymer of the alkyl aryl polyether alcohol (e.g., tyloxapol (ethoxylated p-tert- octylphenol formaldehyde polymer)) and a second solvent such as monoglycerides and/or diglycerides of caprylic acid (e.g., Capmul MCM (C8)).
- the solvent may further comprise 50% phosphatidylcholine in propylene glycol/ethanol carrier (e.g., Phosal® 50PG).
- the solvent is N-methylpyrrolidone (NMP), dimethyl- acetamine (DMA), dimethyl sulfoxide (DMSO), propylene glycol (PG), polyethylene glycol 600 (PEG 600), polyethylene glycol 400 (PEG 400), ethanol, or a mixture of one or more thereof.
- the solvent comprises a combination of solvents including N- methyl pyrrolidone (NMP), dimethyl-acetamine (DMA), or dimethyl sulfoxide (DMSO).
- the solvent comprises a combination of solvents including propylene glycol (PG), polyethylene glycol 600 (PEG 600), or polyethylene glycol 400 (PEG 400).
- the solvent may comprise a combination of at least two solvents.
- the at least two solvents comprising a first solvent such as N-methylpyrrolidone (NMP), dimethyl-acetamine (DMA), or dimethyl sulfoxide (DMSO) and a second solvent such as propylene glycol (PG), polyethylene glycol 600 (PEG 600), or polyethylene glycol 400 (PEG 400).
- NMP N-methylpyrrolidone
- DMA dimethyl-acetamine
- DMSO dimethyl sulfoxide
- PG propylene glycol
- PEG 600 polyethylene glycol 600
- PEG 400 polyethylene glycol 400
- the solvent is polyethoxylated castor oil (e.g., Cremophor (PEG 35 castor oil)), monoglycerides and/or diglycerides of caprylic acid (e.g., Capmul MCM (C8)), nonionic polymer of the alkyl aryl polyether alcohol (e.g., tyloxapol (ethoxylated p-tert-octylphenol formaldehyde polymer)), Phosal® 50PG, ethanol, or a mixture of one or more thereof.
- the solvent can comprise a combination of at least two solvents.
- the at least two solvents comprising a first solvent such as polyethoxylated castor oil (e.g., Cremophor (PEG 35 castor oil)) or nonionic polymer of the alkyl aryl polyether alcohol (e.g., tyloxapol (ethoxylated p-tert-octylphenol formaldehyde polymer)) and a second solvent such as monoglycerides and/or diglycerides of caprylic acid (e.g., Capmul MCM (C8)).
- the solvent may further comprise 50% phosphatidylcholine in propylene glycol/ethanol carrier (e.g., Phosal® SOPG), and the solvent can further comprise ethanol.
- Surfactants that can be used may be determined by mixing a therapeutic agent of interest with a putative solvent and a putative surfactant, and observing the characteristics of the formulation after exposure to a medium. Many surfactants are possible. Combinations of surfactants, including combinations of various types of surfactants, can also be used. For example, surfactants which are nonionic, anionic (i.e. soaps, sulfonates), cationic (i.e.
- CTAB zwitterionic, polymeric or amphoteric
- Examples of some surfactants, mixtures, and other equivalent compositions having an hydrophilic-lipophilic balance (HLB) less than or equal to 10 are propylene glycols, glyceryl fatty acids, glyceryl fatty acid esters, polyethylene glycol esters, glyceryl glycol esters, polyglycolyzed glycerides and polyoxyethyl steryl ethers.
- Propylene glycol esters or partial esters form the composition of commercial products, such as Lauroglycol FCC, which contains propylene glycol laureate.
- the surfactants or solubilizing agents that may be employed may be selected from solubilizing agents having a HLB of 8-18, HLB of 7-9 and HLB of 8-12, HLB of 13-15, polyoxyethanyl-tocopheryl-sebacate (PTS), polyoxyethanyl-sitosterol-sebacate (PSS), polyoxyethanyl-cholesterol-sebacate (PCS), polyoxyethanyl-ubiquinol-sebacate (PQS) and combinations or mixtures thereof.
- solubilizing agents having a HLB of 8-18, HLB of 7-9 and HLB of 8-12, HLB of 13-15, polyoxyethanyl-tocopheryl-sebacate (PTS), polyoxyethanyl-sitosterol-sebacate (PSS), polyoxyethanyl-cholesterol-sebacate (PCS), polyoxyethanyl-ubiquinol-sebacate (PQS) and combinations or
- the above solubilizing agent is selected from the group consisting of Poloxamer 188, Polysorbate 80, Polysorbate 20, Vitamin E- TPGS, Solutol HS 15, PEG-40 Hydrogenated castor oil (Cremophor RH40), PEG-35 Castor oil (Cremophor EL), PEG-8-glyceryl capylate/caprate (Labrasol), PEG-32-glyceryl laurate (Gelucire 44/14), PEG-32-glyceryl palmitostearate (Gelucire 50/13); Polysorbate 85, Polyglyceryl-6-dioleate (Caprol MPGO), Mixtures of high and low HLB emulsifiers;
- Sorbitan monooleate (Span 80), Capmul MCM, Maisine 35-1, Glyceryl monooleate, Glyceryl monolinoleate, PEG-6-glyceryl oleate (Labrafil M 1944 CS), PEG-6-glyceryl linoleate (Labrafil M 2125 CS), Oleic acid, Linoleic acid, Propylene glycol monocaprylate (e.g.
- Capmul PG-8 or Capryol 90 Propylene glycol monolaurate (e.g., Capmul PG-12 or Lauro glycol 90), Polyglyceryl-3 dioleate (Plurol Oleique CC497), Polyglyceryl-3
- Stabilizers may further comprise various other components such as stabilizers, for example.
- Stabilizers that may be used in the formulations described herein include but are not limited to agents that will (1) improve the compatibility of excipients with the encapsulating materials such as gelatin, (2) improve the stability (e.g. prevent crystal growth of a therapeutic agent such as tacrolimus or ascomycin) of a therapeutic agent such as tacrolimus ascomycin, or their prodrugs or derivatives, and/or (3) improve formulation stability. Note that there is overlap between components that are stabilizers and those that are solvents, solubilizing agents or surfactants, and the same component can carry out more than one role.
- Stabilizers may be selected from fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids,
- polyvinylpyrrolidones polyvinylethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, moisture-absorbing polymers, and combinations thereof.
- Amide analogues of the above stabilizers can also be used.
- the chosen stabilizer may change the hydrophobicity of the formulation (e.g. oleic acid, waxes), or improve the mixing of various components in the formulation (e.g. ethanol), control the moisture level in the formula (e.g. PVP), control the mobility of the phase (substances with melting points higher than room temperature such as long chain fatty acids, alcohols, esters, ethers, amides etc.
- waxes e.g. oleic acid or wax
- Some of these stabilizers may be used as solvents/co-solvents (e.g. ethanol).
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
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AU2016308568A AU2016308568A1 (en) | 2015-08-19 | 2016-08-16 | Pharmaceutical formulations |
EP22154078.4A EP4066822A1 (en) | 2015-08-19 | 2016-08-16 | Pharmaceutical formulations |
MX2018001989A MX2018001989A (en) | 2015-08-19 | 2016-08-16 | Pharmaceutical formulations. |
CA2994859A CA2994859A1 (en) | 2015-08-19 | 2016-08-16 | Pharmaceutical formulations |
US15/753,033 US20180243224A1 (en) | 2015-08-19 | 2016-08-16 | Pharmaceutical formulations |
EP16837688.7A EP3337463A4 (en) | 2015-08-19 | 2016-08-16 | Pharmaceutical formulations |
KR1020187007315A KR20180041704A (en) | 2015-08-19 | 2016-08-16 | Pharmaceutical preparation |
US16/220,292 US20190350864A1 (en) | 2015-08-19 | 2018-12-14 | Pharmaceutical formulations |
US16/893,998 US20210113477A1 (en) | 2015-08-19 | 2020-06-05 | Pharmaceutical formulations |
US17/470,437 US20210401759A1 (en) | 2015-08-19 | 2021-09-09 | Pharmaceutical formulations |
AU2022201340A AU2022201340A1 (en) | 2015-08-19 | 2022-02-26 | Pharmaceutical formulations |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US201562207324P | 2015-08-19 | 2015-08-19 | |
US62/207,324 | 2015-08-19 |
Related Child Applications (2)
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US15/753,033 A-371-Of-International US20180243224A1 (en) | 2015-08-19 | 2016-08-16 | Pharmaceutical formulations |
US16/220,292 Continuation US20190350864A1 (en) | 2015-08-19 | 2018-12-14 | Pharmaceutical formulations |
Publications (1)
Publication Number | Publication Date |
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WO2017031105A1 true WO2017031105A1 (en) | 2017-02-23 |
Family
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PCT/US2016/047148 WO2017031105A1 (en) | 2015-08-19 | 2016-08-16 | Pharmaceutical formulations |
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US (4) | US20180243224A1 (en) |
EP (2) | EP4066822A1 (en) |
KR (1) | KR20180041704A (en) |
AU (2) | AU2016308568A1 (en) |
CA (1) | CA2994859A1 (en) |
MX (2) | MX2018001989A (en) |
WO (1) | WO2017031105A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018209142A3 (en) * | 2017-05-10 | 2019-02-28 | Corcept Therapeutics, Inc. | Octahydro azadecalin formulations |
EP3793556A4 (en) * | 2018-03-19 | 2021-12-15 | Gemini Laboratories, LLC | Immunosuppressive dosage forms and methods of use |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020239086A1 (en) | 2019-05-31 | 2020-12-03 | Medical And Pharmaceutical Industry Technology And Development Center | Oral composition and methods for manufacturing the same and treatment |
US11185513B1 (en) * | 2021-05-07 | 2021-11-30 | King Abdulaziz University | Transfersome-containing transdermal film formulations and methods of use |
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-
2016
- 2016-08-16 EP EP22154078.4A patent/EP4066822A1/en active Pending
- 2016-08-16 CA CA2994859A patent/CA2994859A1/en active Pending
- 2016-08-16 WO PCT/US2016/047148 patent/WO2017031105A1/en active Application Filing
- 2016-08-16 KR KR1020187007315A patent/KR20180041704A/en not_active Application Discontinuation
- 2016-08-16 MX MX2018001989A patent/MX2018001989A/en unknown
- 2016-08-16 EP EP16837688.7A patent/EP3337463A4/en not_active Withdrawn
- 2016-08-16 US US15/753,033 patent/US20180243224A1/en not_active Abandoned
- 2016-08-16 AU AU2016308568A patent/AU2016308568A1/en not_active Abandoned
-
2018
- 2018-02-15 MX MX2022013450A patent/MX2022013450A/en unknown
- 2018-12-14 US US16/220,292 patent/US20190350864A1/en not_active Abandoned
-
2020
- 2020-06-05 US US16/893,998 patent/US20210113477A1/en not_active Abandoned
-
2021
- 2021-09-09 US US17/470,437 patent/US20210401759A1/en active Pending
-
2022
- 2022-02-26 AU AU2022201340A patent/AU2022201340A1/en not_active Abandoned
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US6555132B1 (en) * | 1993-09-28 | 2003-04-29 | Novartis Ag | Soft gelatin capsule manufacture |
WO2006062334A1 (en) * | 2004-12-06 | 2006-06-15 | Hanmi Pharm. Co., Ltd. | Oral micro-emulsion composition comprising tacrolimus |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018209142A3 (en) * | 2017-05-10 | 2019-02-28 | Corcept Therapeutics, Inc. | Octahydro azadecalin formulations |
EP3793556A4 (en) * | 2018-03-19 | 2021-12-15 | Gemini Laboratories, LLC | Immunosuppressive dosage forms and methods of use |
Also Published As
Publication number | Publication date |
---|---|
KR20180041704A (en) | 2018-04-24 |
CA2994859A1 (en) | 2017-02-23 |
AU2016308568A1 (en) | 2018-02-22 |
EP4066822A1 (en) | 2022-10-05 |
EP3337463A1 (en) | 2018-06-27 |
US20210113477A1 (en) | 2021-04-22 |
US20190350864A1 (en) | 2019-11-21 |
US20210401759A1 (en) | 2021-12-30 |
MX2022013450A (en) | 2022-11-16 |
EP3337463A4 (en) | 2019-04-03 |
AU2022201340A1 (en) | 2022-03-24 |
MX2018001989A (en) | 2018-06-19 |
US20180243224A1 (en) | 2018-08-30 |
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