WO2017192675A1 - Pharmaceutical ophthalmic compositions and methods for fabricating thereof - Google Patents
Pharmaceutical ophthalmic compositions and methods for fabricating thereof Download PDFInfo
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- WO2017192675A1 WO2017192675A1 PCT/US2017/030772 US2017030772W WO2017192675A1 WO 2017192675 A1 WO2017192675 A1 WO 2017192675A1 US 2017030772 W US2017030772 W US 2017030772W WO 2017192675 A1 WO2017192675 A1 WO 2017192675A1
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- 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
- A61K31/47—Quinolines; Isoquinolines
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- 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
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- 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
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
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- 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
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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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
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the present invention relates generally to the field of ophthalmology and more specifically to injectable ophthalmological compositions having anti-bacterial and antiinflammatory properties, and to methods of preparing such compositions.
- pre- and post-operative eye drops are frequently used by the patients to eliminate or alleviate negative post-surgery complications such as infections, inflammation, and tissue edema. It has been reported that as many as 8% of all ocular surgery patients may suffer from infections, including the potentially catastrophic endophthalmitis, and various negative sight threatening side effects after surgery, such as inflammatory uveitis, corneal edema, and cystoid macular edema.
- the topical postoperative medications are prescribed for at-home use starting before and then after cataract surgery, and are typically self-administered, unless requiring a caregiver or family assistance.
- One such alternative procedure includes the intraoperative intravitreal injection by an atraumatic transzonular route that can achieve patient outcomes that are as good as, or better than, the current at-home eye drop regimen, removing the issues of compliance and medication administration accuracy.
- This patent specification discloses pharmaceutical compositions suitable for intraoperative ocular injections that can achieve such positive patient outcomes, and methods of fabricating and administering the same.
- an ophthalmic pharmaceutical composition comprising a therapeutic component consisting essentially of a therapeutically effective quantity of an anti-bacterial agent and a
- composition is suitable for delivery via intraocular injection or via eye drops.
- an anti-bacterial agent described herein can be a compound selected from the group of quinolone (including a fluorinated quinolone), e.g., moxifloxacin, and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof.
- an anti-inflammatory agent described herein can be a corticosteroid, e.g., triamcinolone, and pharmaceutically acceptable salts, hydrates, solvates, ethers, esters, acetals and ketals thereof.
- a corticosteroid e.g., triamcinolone
- pharmaceutically acceptable salts, hydrates, solvates, ethers, esters, acetals and ketals thereof e.g., triamcinolone, and pharmaceutically acceptable salts, hydrates, solvates, ethers, esters, acetals and ketals thereof.
- compositions described herein further include at least two solubilizing and suspending agents of which one is any of non-ionic polyoxyethlene-polyoxypropylene block copolymers, e.g., Poloxamer 407 ® , and the other is any of water-soluble derivatives of cellulose (e.g., carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, or hydroxypropyl cellulose), non-cross-linked or partially cross-linked polyacrylates, polyoxyethylene sorbitan monolaurates, polyoxyethylene sorbitan monopalmitates, polyoxyethylene sorbitan monostearates, polyoxyethylene sorbitan monooleates or combinations thereof.
- cellulose e.g., carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, or hydroxypropyl cellulose
- non-cross-linked or partially cross-linked polyacrylates polyoxyethylene sorbitan monolaurates, polyoxyethylene sorbitan monopalmitate
- the pharmaceutical compositions described herein may be intravitreally transzonularly injected into a mammalian subject as a part of the process of treatment of a variety of ophthalmological diseases, conditions or pathologies associated with intraocular surgery, such as cataracts, retinal and glaucoma disease.
- “About” as used herein means that a number referred to as “about” comprises the recited number plus or minus 1 -10% of that recited number. For example, “about” 100 degrees can mean 95-105 degrees or as few as 99-101 degrees depending on the context. Whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; i.e., meaning only 1, only 2, only 3, etc., up to and including only 20.
- composition is defined as a chemical or a biological compound or substance, or a mixture or combination of two or more such compounds or substances, intended for use in the medical diagnosis, cure, treatment,
- intraocular injection refers to an injection that is administered by entering the eyeball of the patient.
- peri-ocular injection refers to an injection that is administered behind the eye but outside the eye wall.
- transzonular refers to an injection administered through the ciliary zonule which is a series of fibers connecting the ciliary body and lens of the eye.
- injection refers to an injection administered through an eye of the patient, directly into the inner cavity of the eye.
- intraoperative is defined as an action occurring or carried during, or in the course of, surgery.
- phase is defined for the purposes of the present application as a two-phase dispersion system having a first phase and a second phase. It is further specifically provided that dispersion systems having three, four or more phases are not within the meaning of "suspension" for the purposes of the instant application.
- the above mentioned first phase of the suspension consists of a multitude of solid particles and is designated and defined as the "dispersed phase”, and the above mentioned second phase of the suspension is a liquid and is designated and defined as the “dispersion medium”, or, interchangeably and synonymously, the "continuous phase”.
- dispersed phase is dispersed in the above mentioned dispersion medium, and the term “dispersed” is defined as meaning that the dispersed phase is statistically evenly distributed throughout the entire volume of the suspension, with no statistically meaningful deviations in the concentrations of the dispersed phase in different portions of the suspension.
- keratomileusis refers to a surgical procedure whereby
- corneal refractive surgical procedures that are encompassed by the term “keratomileusis” include, without limitations,
- SMILE corneal lenticular surgery
- anti-inflammatory refers to substances or compounds that counteract or suppress inflammation via any mechanism or route.
- quinolone for the purposes of this application refers to a genus of antibacterial compounds that are derivatives of benzopyridine and in some embodiments include fluorine atom, such as in the following structure (“fluoroquinolone”):
- corticosteroid and closely related "glucocorticoid” are defined as compounds belonging to a sub-genus of steroids that are derivatives of corticosterone, the latter having the chemical structure:
- salt refers to an ionic compound which is a product of the neutralization reaction of an acid and a base.
- solvate and "hydrate” are used herein to indicate that a compound or a substance is physically or chemically associated with a solvent for “solvates” such as water (for “hydrates”).
- ether refers to a chemical compound containing the structure R-O-Ri, where two organic fragments R and Ri are connected via oxygen.
- ester refers to a chemical compound containing the ester group
- R-0-C(0)-Ri connecting two organic fragments R and Ri.
- acetal and “ketal” refer to a chemical compound containing the functional group R-C(Ri)(OR2)2, where R and R2 are organic fragments and Ri is hydrogen atom (for acetals), and is inclusive of "hemiacetals” where one R2 (but not the other) is hydrogen atom; or where none of R, Ri and R2 is a hydrogen atom and each is an organic fragment (for ketals).
- non-steroid anti-inflammatory drug or “NSAID” refer to substances or compounds that are free of steroid moieties and provide analgesic, antipyretic and/or antiinflammatory effects.
- carrier refers to a substance that serves as a vehicle for improving the efficiency of delivery and the effectiveness of a pharmaceutical composition.
- excipient refers to a pharmacologically inactive substance that is formulated in combination with the pharmacologically active ingredient of the
- composition and is inclusive of bulking agents, fillers, diluents and products used for facilitating drug absorption or solubility or for other pharmacokinetic considerations.
- solubilizing agent for the purposes of the instant application refers broadly to chemical compounds that improve the process of incorporating the solubilizate (i.e., active components described herein) into micelles; in other words, the presence of a solubilizing agent makes the process of solubilization faster, easier, and/or more complete compared with compositions without it.
- sustained agent for the purposes of the instant application refers broadly to chemical compounds that help active pharmaceutical ingredients stay suspended in the formulation and prevents and/or reduces the phase separation of two-phase dispersion systems described herein.
- terapéuticaally effective amount is defined as the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, medical doctor or other clinician.
- pharmaceutically acceptable is defined as a carrier, whether diluent or excipient, that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- administration of a composition or “administering a composition” is defined to include an act of providing a compound of the invention or pharmaceutical composition to the subject in need of treatment.
- compositions intended to prevent and/or treat inflammation and/or infections include an active component comprising, consisting essentially of, or consisting of a therapeutically effective quantity of an anti-bacterial agent (i.e., an antibiotic) and a therapeutically effective quantity of an anti-inflammatory agent (e.g., a corticosteroid).
- an active component comprising, consisting essentially of, or consisting of a therapeutically effective quantity of an anti-bacterial agent (i.e., an antibiotic) and a therapeutically effective quantity of an anti-inflammatory agent (e.g., a corticosteroid).
- an anti-bacterial agent i.e., an antibiotic
- an anti-inflammatory agent e.g., a corticosteroid
- the pharmaceutical compositions can be used for intraocular injections.
- the pharmaceutical compositions can be used for intra-articular or intra-lesional use.
- the pharmaceutical compositions can be used for delivery via eye drops.
- the compositions further include one or several pharmaceutically acceptable excipient(s) and one or
- the concentration of the anti-bacterial agent in the pharmaceutical composition may be between about O.Olmg/mL and about 50.0 mg/mL, such as between about 0.5 mg/mL and about 10 mg/mL, for example, about 1.0 mg/mL.
- the concentration of the antiinflammatory agent in the pharmaceutical composition may be between about 0.1 mg/mL and about 100.0 mg/mL, such as between about 5.0 mg/mL and about 50.0 mg/mL, for example, about 15.0 mg/mL.
- the anti-bacterial agent to be employed in the active component of the composition may be selected from the group of quinolones, including fluoroquinolones, and suitable derivatives of the same, such as pharmaceutically acceptable salts, hydrates or solvates thereof.
- the fluoroquinolone that may be so employed is moxifloxacin (chemically, l-cyclopropyl-7-[(l S,6S)-2,8- diazabicyclo-[4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid), which is available, e.g., under trade name Avelox® from Bayer Healthcare Corp. of Wayne, New Jersey, and under other trade names from other suppliers such as Alcon Corp. and Bristol- Myers Squibb Co., and has the following chemical structure:
- a non-limiting example of a possible alternative fluoroquinolone antibiotic that may be used instead of, or in combination with, moxifloxacin is gatifloxacin.
- one or several glycopeptide antibiotic(s), or a combination of some or all of them may be optionally used as a part of the anti-bacterial agent, in combination with (i.e., in addition to) moxifloxacin.
- an acceptable additional glycopeptide antibiotic is vancomycin, which can be introduced into the pharmaceutical composition at a concentration between about 1.0 mg/mL and about 100.0 mg/mL, such as between about 5.0 mg/mL and about 50.0 mg/mL, for example, about 10.0 mg/mL. Vancomycin is available under the trade name Vancocin® from Eli Lilly & Co. of Indianapolis, Indiana.
- additional glycopeptide antibiotics that may be so optionally used include teicoplanin, telavancin, decaplanin, ramoplanin, gentamicin, tobramycin, amikacin, cefuroxime, polymyxin B sulfate, and trimethoprim.
- the anti-inflammatory agent to be employed in the active component of the composition may be selected from the group of corticosteroids, such as derivatives of corticosterone, and pharmaceutically acceptable salts, hydrates, solvates, ethers, esters, acetals and ketals thereof.
- a product obtained as a result of a chemically reasonable substitution of any hydrogen and/or hydroxyl group in the molecule of corticosterone may be used.
- a corticosteroid that can be so utilized is triamcinolone (chemically, (l i , 16a)-9-fluoro-l l, 16, 17,21 -tetrahydroxypregna- l,4-diene-3,20-dione), having the following chemical formula:
- a corticosteroid that can be so utilized is triamcinolone acetonide (chemically, (4aS,4bR,5S,6aS,6bS,9aR, 10aS,10bS)-4b-fluoro-6b-glycoloyl-5- hy droxy-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a, 10, 10a, 1 Ob, 11 , 12-dodecahy dro-2H- naphtho[2', l':4,5]indeno[l ,2-d] [l ,3]dioxol-2-one), which is a ketal derivative of
- triamcinolone available, e.g., under the trade name Kenalog® from Bristol-Myers Squibb Co. of Princeton, New Jersey, and under other trade names from other suppliers, and having the following chemical formula:
- corticosteroids may be used instead of all or a portion of triamcinolone and/or of all or a portion of triamcinolone acetonide.
- Some non-limiting examples of such acceptable other corticosteroids or glucocorticoids include triamcinolone diacetate, triamcinolone benetonide, triamcinolone furetonide, triamcinolone hexacetonide, betamethasone acetate, dexamethasone,
- fiuorometholone and fluocinolone acetonide prednisone, prednisolone, methylprednisone, corticol, cortisone, fluorocortisone, deoxycorticosterone acetate, aldosterone, budesonide and derivatives, analogs or combinations thereof.
- corticosteroids e.g., without limitation, prednisone, prednisolone, dexamethasone, or methylprednisone are considered particularly suitable in methods for performing a keratomileusis or corneal refractive surgery (e.g., LASIK surgery) described below in more detail.
- LASIK surgery a keratomileusis or corneal refractive surgery
- compositions described herein may further optionally include pharmaceutically effective quantities of one or several nonsteroid anti-inflammatory drug(s) or NSAID(s).
- concentration of NSAID(s) in the pharmaceutical composition may be between about O. lmg/mL and about 100.0 mg/rriL, such as between about 5.0 mg/mL and about 50.0 mg/mL, for example, about 15.0 mg/mL.
- compositions disclosed herein do include NSAID(s), it is envisioned that some compositions should be free of the specific NSAID, bromfenac. In other embodiments, however, bromfenac may be used as well as such NSAID(s) as any of ketorolac, etodolac, sulindac, diclofenac, aceclofenac, nepafenac, tolmetin, indomethacin, nabumetone, ketoprofen, dexketoprofen, ibuprofen, flurbiprofen, dexibuprofen, fenoprofen, loxoprofen, oxaprozin, naproxen, aspirin, salicylic acid, diflunisal, salsalate, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam, piroxicam, temoxicam,
- the pharmaceutical composition that is the subject matter of the instant application may further optionally include one or several pharmaceutically acceptable excipient(s).
- suitable excipient(s) it is worth mentioning that when moxifloxacin is used in
- a stable suspension of another product e.g., a corticosteroid such as triamcinolone acetonide
- a corticosteroid such as triamcinolone acetonide
- difficulties in obtaining the stable suspension are believed to be caused by moxifloxacin' s tendency to deactivate many suspending agents resulting in unacceptable coagulation, clumping and flocculation.
- normal delivery through a typical 27-29 gage cannula is often difficult or even impossible.
- present embodiments teach that combinations of at least two solubilizing and suspending agents, i.e., a first solubilizing and suspending agent and a second solubilizing and suspending agent, can be used to formulate the excipients to be used in the compositions of the present invention.
- at least one first solubilizing and suspending agent and at least one second solubilizing and suspending agent are present in the compositions.
- an excipient that can be used as the first solubilizing and stabilizing agent to overcome the above-described difficulties, and thus to obtain a stable suspension of the corticosteroid such as triamcinolone acetonide or prednisolone may be a non-ionic polyoxyethlene-polyoxypropylene block copolymer having the following general structure:
- a non-ionic polyoxyethlene-polyoxypropylene block copolymer when used as the first solubilizing and stabilizing agent in the pharmaceutical compositions of the instant invention, its contents in the overall composition may be between about 0.01 mass % and about 10.0 mass %, such as between about 1.0 mass % and about 8 mass %, for example, about 5.0 mass %.
- Non-limiting example of a specific non-ionic polyoxyethlene- polyoxypropylene block copolymer that can be used as the first solubilizing and stabilizing agent in the pharmaceutical compositions of the instant invention is the product known under the trade name Poloxamer 407 ® (poly(ethylene glycol)-block-poly(propylene glycol)-block- poly(ethylene glycol)) available from Sigma- Aldrich Corp. of St. Louis, Missouri, with the molecular weight of the polyoxypropylene portion of about 4,000 Daltons, about a 70% poly oxy ethylene content, the overall molecular weight of between about 9,840 Daltons and about 14,600 Daltons and having the following chemical structure:
- An excipient that can be used as the second solubilizing and stabilizing agent can be a water-soluble derivative of cellulose, water-soluble, optionally partially cross-linked polyacrylates, and products of Polysorbate family, or combinations thereof.
- Suitable water-soluble derivatives of cellulose include, without limitations, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose available, among other sources, from The Dow Chemical Company of Midland, Michigan.
- Examples of acceptable water-soluble, partially cross-linked, polyacrylates that may be used include, without limitations, such polymers of the Carbopol® family available from The Lubrizol Corporation of Wickliffe, Ohio.
- the cross- linking agents that may be used to cross-link such polyacrylates are allyl sucrose or allyl pentaerythritol.
- Suitable products of the Polysorbate family i.e., ethoxylated sorbitan esterified with fatty acids
- Suitable products of the Polysorbate family include, without limitations, poly oxy ethylene sorbitan monolaurates, polyoxy ethylene sorbitan monopalmitates, polyoxy ethylene sorbitan monostearates, or poly oxy ethylene sorbitan monooleates, some of which are also known as Tween® products, such as Polysorbate 80®, can be used as the second solubilizing and stabilizing agent.
- Tween® products such as Polysorbate 80®
- Non-limiting examples of some other excipients and carriers that may be used in preparing in the pharmaceutical compositions of the instant invention include edetate calcium disodium (EDTA, a chelating agent), hydrochloric acid (the pH adjuster) and sterile water.
- EDTA edetate calcium disodium
- hydrochloric acid the pH adjuster
- the pharmaceutical compositions described herein are formulated as stable two-phase suspensions, as defined above. More specifically, according to these embodiments, the suspensions at issue consist of two phases, i.e., a dispersed phase that is dispersed within the dispersion medium.
- the dispersed phase consists of solid particles consisting of a therapeutically effective quantity of a corticosteroid. No compounds other than the corticosteroids described hereinabove are present within the solid particles that form the dispersed phase.
- the dispersion medium is a liquid that includes all other compounds that are present in the pharmaceutical compositions described in the application.
- the application envisions no embodiment where a corticosteroid can be used outside the dispersed phase such as in the dispersion medium.
- the dispersion medium includes the following components (a)-(e):
- At least one anti-bacterial agent of the quinolone group i.e., quinolone, a fluorinated quinolone and derivatives as described
- At least one glycopeptide antibiotic i.e., vancomycin, or other antibiotic(s) described hereinabove
- the use of this component in the dispersion medium is optional;
- At least one non-steroid anti-inflammatory drug such as bromfenac or other NSAIDs described hereinabove; and (e) a carrier.
- a one-batch formulation method may be used, where the components of the pharmaceutical formulation can be combined in single container; the components may be added to the container simultaneously or consecutively.
- the process of preparing the pharmaceutical compositions described hereinabove may commence by forming the aqueous dispersion medium.
- a quantity of an anti-bacterial agent such as moxifloxacin may be put into a mixing container followed by adding a quantity of sterile water and hydrochloric acid to obtain a slightly acidic mixture (e.g., having a pH of about 6.5), which can be stirred until a clear solution is obtained.
- a slightly acidic mixture e.g., having a pH of about 6.5
- the solution is stable, allowing the formulation to remain closed system thus preventing contamination and the loss of sterility.
- a quantity of Poloxamer 407® and/or a quantity of polysorbate 80 may all be added to the same container with the already prepared moxifloxacin/HCl solution.
- a quantity of Poloxamer 407® and/or a quantity of polysorbate 80 may all be added to the same container with the already prepared moxifloxacin/HCl solution.
- an antibiotic e.g., vancomycin
- an NSAID e.g., bromfenac
- a quantity of corticosteroid such as micronized triamcinolone acetonide can be added to the above described solution, followed by stirring everything together (e.g., by spinning) for a period of time, e.g., about 6 hours, until a homogenous suspension has been obtained.
- a period of time e.g., about 6 hours
- compositions prepared as described above can be used to prevent complications that may arise after ophthalmic surgical operations and procedure.
- the formulations can be used during any intraocular surgery, such as cataract surgery, planned vitrectomy or glaucoma procedures, to prevent or at least substantially reduce the risk of post-surgery complications, such as the development of endophthalmitis or cystoid macular edema (CME), without having the patient use pre- or post-operative topical ophthalmic drops.
- intraocular surgery such as cataract surgery, planned vitrectomy or glaucoma procedures
- CME cystoid macular edema
- Individuals with evidence of endophthalmitis from prior surgical procedures or traumatic ocular penetration will benefit from concurrent injection of these formulations to sterilize infection and reduce damaging inflammation.
- compositions described herein can be delivered via intraocular intravitreal injection which can be transzonular, or, if desired not transzonular.
- Intraocular intravitreal injection of this formulation whether done via transzonular or via direct pars plana (trans-scleral) injection, delivers potent broad spectrum antibiotics directly into the suppurative tissue without requiring the urgent compounding of multiple individual medications or multiple individual injections into the eye.
- a pharmaceutical composition described above will be intraocularly administered to a mammalian subject (e.g., humans, cats, dogs, other pets, domestic, wild or farm animals) in need of emergent, urgent or planned ophthalmic surgery treatment.
- a mammalian subject e.g., humans, cats, dogs, other pets, domestic, wild or farm animals
- the effect achieved by such use of pharmaceutical composition described above may last up to four weeks.
- the composition is to be injected intravitreally and trans-zonularly using methods and techniques known to those having ordinary skilled in the art of ophthalmology.
- the injection can be intraoperative.
- the delivery through a typical 27 gauge cannula can be employed utilizing a 1 mL TB syringe, with attention to re-suspending the formulation using momentary flicks and shake just prior to injection.
- the medicinal volume (i.e., dosage) required of this formulation varies based on the type of intraocular procedure, the degree of postoperative inflammation induced or anticipated, the risk assessment for postoperative infection, and anatomic considerations regarding the available volume for the injection being added to a closed intraocular space.
- intracameral (that is, anterior chamber) injections are within the scope of the instant invention, such injections instead of posterior chamber (intravitreal) injection may not be satisfactory in some cases, as the suspension clogs the trabecular meshwork and aggravates intraocular drainage, resulting in a postoperative rise in intraocular pressure. This may be avoided with intravitreal injection, in addition to retaining the formulation components into the protein matrix of the vitreous of a greater
- Anterior chamber wash out occurs over hours (antibiotic in solution) and days (steroid in suspension), while intravitreal injection is retained for weeks.
- the formulations may also be delivered in the form of eye drops or eye sprays, as well as via subconjunctival injection, intraocular intracameral injection, sub-tenon injection, intra-articular injection or intra- lesional injection, particularly, in, but not limited to, some cases when necessary to deliver additional medication when local ocular inflammation and extra-ocular infection need suppression.
- Intravitreal delivery of steroid has historically been used to treat clinically significant cystoid macular edema (CME); the application of this formulation into the vitreous during routine intraocular procedures brings more aggressive prophylaxis against CME occurrence.
- CME cystoid macular edema
- the suspension of this formulation is useful for staining vitreous during planned and unplanned vitrectomies, improving visualization of this otherwise transparent intraocular tissue, improving vitrectomy outcomes and reducing complications resulting from inadequate or tractional vitreous removal.
- intra-canalicular delivery i.e., delivery via a lacrimal canaliculus implant.
- the formulation may be also delivered via anterior chamber injection or capsular bag placement of medication.
- a solution could be also added to the irrigating solution that is used during cataract surgery which could allow for the bottles, tubing, etc. to become "sterilized" during surgery.
- Intracomeal delivery through laser created corneal channels that could hold medication can be also used, if desired.
- compositions comprising both anti-bacterial and anti-inflammatory agents
- consecutive injections may be used instead, if desired.
- triamcinolone or prednisolone may be injected first, immediately followed by the injection of moxifioxacin or vice versa.
- the pharmaceutical applications described hereinabove may be used before or after performing corneal refractive surgery or a keratomileusis surgery such as LASIK surgery.
- a pharmaceutical composition to be used for these purposes may include any corticosteroid and any anti-bacterial agent described above, to be selected by the skilled practitioner.
- prednisone, prednisolone or methylprednisone may be chosen as the former and moxifioxacin as the latter.
- the formulations used in conjunction with a keratomileusis surgery may have the concentration of the anti-bacterial agent such as moxifloxacin between about O.Olmg/mL and about 50.0 mg/mL, such as between about 0.5 mg/mL and about 10 mg/mL, for example, about 1.0 mg/mL; and the concentration of the corticosteroid such as prednisone between about O. lmg/mL and about 100.0 mg/mL, such as between about 5.0 mg/mL and about 50.0 mg/mL, for example, about 15.0 mg/mL.
- the anti-bacterial agent such as moxifloxacin
- concentration of the corticosteroid such as prednisone between about O. lmg/mL and about 100.0 mg/mL, such as between about 5.0 mg/mL and about 50.0 mg/mL, for example, about 15.0 mg/mL.
- kits are provided.
- the kit includes a sealed container approved for the storage of pharmaceutical compositions, the container containing one of the above-described pharmaceutical compositions.
- An instruction for the use of the composition and the information about the composition are to be included in the kit.
- a pharmaceutical composition was prepared as described below. The following components were used in the amounts and concentrations specified:
- Moxifloxacin hydrochloride was placed into a de-pyrogenated beaker with a spin bar. Sterile water for injection was added to about 1/3 of the volume of the beaker. While spinning, moxifloxacin was dissolved by adding hydrochloric acid until a clear solution having the final pH of about 6.5 was obtained.
- the suspension was transferred into de-pyrogenated, single dose vials (2mL size), capped and sealed, followed by autoclaving and shaking the vials until cool. Complete sterility and endotoxin testing was performed by an outside laboratory to ensure safety.
- a pharmaceutical composition was prepared as described in Example 1, supra.
- the composition was autoclaved and sonicated for about 60 minutes and about 96 mL of the composition were combined with about 4 mL of vancomycin at a concentration of about 250 mg/mL.
- the pH of the mixture was adjusted to about 6.0-6.5 using hydrochloric acid.
- the product was then transferred into vials (at about 1 mL plus 5 drops per vial) and frozen. The product has kept its stability and potency for at least six months.
- a pharmaceutical composition was prepared as described below. The following components were used in the amounts specified:
- the solution was combined with micronized prednisolone acetate, Poloxamer 407 ® , edetate calcium disoudium and polysorbate 80 and allowed to spin until a hydrated and homogenous product was obtained. It is expected that the particle sizes and their distribution are similar to those described in Example 1, above.
- the product was then transferred into de- pyrogenated, single dose vials (about 1 mL of the product in 3mL size vial), capped and sealed, followed by autoclaving, shaking and sonicating the vials for about 1 hour.
- Prednisolone based composition obtained as described in this Example can then be administered to a patient by ordinarily skilled ophthalmologists as eye drops after performing a keratomileusis surgery such as LASIK surgery, e.g., as follow-up care.
- Example 5 Preparing a Pharmaceutical Composition Containing NSAID Bromfenac
- a pharmaceutical composition was prepared as described below. The following components were used in the amounts specified:
- Moxifloxacin hydrochloride was placed into a de-pyrogenated beaker with a spin bar. Sterile water for injection was added, about 60% of the total volume of water. While spinning, moxifloxacin was dissolved by adding sodium hydroxide to adjust the pH to about 7.4 to 7.8, followed by additional stirring for about 5 minutes, until a clear solution was obtained. Bromfenac was then added, with continued stirring, until completely dissolved which is indicated by the solution being visibly clear. The pH then was adjusted again to maintain it in the range of 7.4 to 7.8.
- the product was then transferred into pre-sterilized de-pyrogenated, 100 mL vials, capped and sealed, followed by autoclaving (about 121°C and about 15.0 psi of pressure for about 30 minutes) shaking and sonicating the vials for about 30 minutes.
- composition obtained as described in this Example can then be administered to a patient by ordinarily skilled ophthalmologists as eye drops after performing a
- keratomileusis surgery such as LASIK surgery, e.g., as follow-up care.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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US15/552,450 US20190111045A1 (en) | 2016-05-06 | 2017-05-03 | Pharmaceutical ophthalmic compositions and methods for fabricating thereof |
CA3023243A CA3023243C (en) | 2016-05-06 | 2017-05-03 | Pharmaceutical ophthalmic compositions and methods for fabricating thereof |
JP2018558268A JP6694525B2 (en) | 2016-05-06 | 2017-05-03 | Pharmaceutical ophthalmic composition and method for producing the same |
EP17793224.1A EP3452033A4 (en) | 2016-05-06 | 2017-05-03 | Pharmaceutical ophthalmic compositions and methods for fabricating thereof |
KR1020197027514A KR20190109604A (en) | 2016-05-06 | 2017-05-03 | Pharmaceutical ophthalmic compositions and methods for fabricating thereof |
AU2017260327A AU2017260327B2 (en) | 2016-05-06 | 2017-05-03 | Pharmaceutical Ophthalmic compositions and methods for fabricating thereof |
KR1020187033036A KR20180126087A (en) | 2016-05-06 | 2017-05-03 | Pharmaceutical ophthalmic compositions and methods for making the same |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US15/148,574 US20160243031A1 (en) | 2013-07-22 | 2016-05-06 | Pharmaceutical ophthalmic compositions and methods for fabricating thereof |
US15/148,574 | 2016-05-06 | ||
US15/178,812 US20160279055A1 (en) | 2013-07-22 | 2016-06-10 | Pharmaceutical ophthalmic compositions for intraocular administration and methods for fabricating thereof |
US15/178,812 | 2016-06-10 |
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WO2017192675A1 true WO2017192675A1 (en) | 2017-11-09 |
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PCT/US2017/030772 WO2017192675A1 (en) | 2016-05-06 | 2017-05-03 | Pharmaceutical ophthalmic compositions and methods for fabricating thereof |
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EP (1) | EP3452033A4 (en) |
JP (1) | JP6694525B2 (en) |
KR (2) | KR20180126087A (en) |
AU (1) | AU2017260327B2 (en) |
CA (1) | CA3023243C (en) |
WO (1) | WO2017192675A1 (en) |
Cited By (3)
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---|---|---|---|---|
JP2020535217A (en) * | 2017-09-01 | 2020-12-03 | マリー アンド プール エンタープライゼズ,リミテッド | Methods and compositions for treating ocular conditions |
US11071724B2 (en) | 2019-05-17 | 2021-07-27 | Ocular Science, Inc. | Compositions and methods for treating presbyopia |
WO2021252054A1 (en) * | 2020-06-10 | 2021-12-16 | Ocular Science, Inc. | Compositions and uses in method for post-operative ocular care |
Families Citing this family (1)
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WO2022092868A1 (en) * | 2020-10-29 | 2022-05-05 | 주식회사태준제약 | Ophthalmic composition |
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UA119324C2 (en) * | 2013-04-02 | 2019-06-10 | Теміс Медікер Лімітед | Compositions of pharmaceutical actives containing diethylene glycol monoethyl ether or other alkyl derivatives |
US20150164882A1 (en) * | 2013-07-22 | 2015-06-18 | Imprimis Pharmaceuticals, Inc. | Pharmaceutical compositions for intraocular administration and methods for fabricating thereof |
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EP3024475B8 (en) * | 2013-07-22 | 2020-11-18 | Novel Drug Solutions LLC | Pharmaceutical compositions for intraocular administration comprising an antibacterial agent and an antiinflammatory agent |
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2017
- 2017-05-03 CA CA3023243A patent/CA3023243C/en not_active Expired - Fee Related
- 2017-05-03 EP EP17793224.1A patent/EP3452033A4/en not_active Withdrawn
- 2017-05-03 KR KR1020187033036A patent/KR20180126087A/en active Application Filing
- 2017-05-03 KR KR1020197027514A patent/KR20190109604A/en not_active Application Discontinuation
- 2017-05-03 WO PCT/US2017/030772 patent/WO2017192675A1/en unknown
- 2017-05-03 JP JP2018558268A patent/JP6694525B2/en active Active
- 2017-05-03 AU AU2017260327A patent/AU2017260327B2/en not_active Ceased
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US20070148192A1 (en) * | 2003-02-21 | 2007-06-28 | Laddha Ritu N | Stable ophthalmic composition |
US20070077209A1 (en) * | 2003-05-30 | 2007-04-05 | 3M Innovative Properties Company | Stabilized particle dispersions containing nanoparticles |
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JP2020535217A (en) * | 2017-09-01 | 2020-12-03 | マリー アンド プール エンタープライゼズ,リミテッド | Methods and compositions for treating ocular conditions |
US11071724B2 (en) | 2019-05-17 | 2021-07-27 | Ocular Science, Inc. | Compositions and methods for treating presbyopia |
WO2021252054A1 (en) * | 2020-06-10 | 2021-12-16 | Ocular Science, Inc. | Compositions and uses in method for post-operative ocular care |
GB2613469A (en) * | 2020-06-10 | 2023-06-07 | Ocular Science Inc | Compositions and uses in method for post-operative ocular care |
Also Published As
Publication number | Publication date |
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KR20190109604A (en) | 2019-09-25 |
KR20180126087A (en) | 2018-11-26 |
AU2017260327B2 (en) | 2018-12-20 |
JP2019514975A (en) | 2019-06-06 |
EP3452033A1 (en) | 2019-03-13 |
CA3023243A1 (en) | 2017-11-09 |
AU2017260327A1 (en) | 2018-11-29 |
EP3452033A4 (en) | 2020-02-12 |
CA3023243C (en) | 2020-01-21 |
JP6694525B2 (en) | 2020-05-13 |
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