US20130186391A1 - Device for intranasal administration of ketorolac - Google Patents
Device for intranasal administration of ketorolac Download PDFInfo
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- US20130186391A1 US20130186391A1 US13/791,780 US201313791780A US2013186391A1 US 20130186391 A1 US20130186391 A1 US 20130186391A1 US 201313791780 A US201313791780 A US 201313791780A US 2013186391 A1 US2013186391 A1 US 2013186391A1
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- ketorolac
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- OZWKMVRBQXNZKK-UHFFFAOYSA-N O=C(C1=CC=CC=C1)C1=CC=C2C(C(=O)O)CCN12 Chemical compound O=C(C1=CC=CC=C1)C1=CC=C2C(C(=O)O)CCN12 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 2
- RARYMXYCNAQQGV-UHFFFAOYSA-N CCN(CC)CC(=O)CC1=C(C)C=CC=C1C Chemical compound CCN(CC)CC(=O)CC1=C(C)C=CC=C1C RARYMXYCNAQQGV-UHFFFAOYSA-N 0.000 description 1
- NFKBMHXYCKRXPQ-UHFFFAOYSA-N O=C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 Chemical compound O=C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 NFKBMHXYCKRXPQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/08—Inhaling devices inserted into the nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
- A61M11/02—Sprayers or atomisers specially adapted for therapeutic purposes operated by air or other gas pressure applied to the liquid or other product to be sprayed or atomised
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K47/02—Inorganic 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- 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
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B5/00—Packaging individual articles in containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, jars
- B65B5/04—Packaging single articles
- B65B5/045—Packaging single articles in bags
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B7/00—Closing containers or receptacles after filling
- B65B7/02—Closing containers or receptacles deformed by, or taking-up shape, of, contents, e.g. bags, sacks
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D47/00—Closures with filling and discharging, or with discharging, devices
- B65D47/04—Closures with discharging devices other than pumps
- B65D47/06—Closures with discharging devices other than pumps with pouring spouts or tubes; with discharge nozzles or passages
- B65D47/18—Closures with discharging devices other than pumps with pouring spouts or tubes; with discharge nozzles or passages for discharging drops; Droppers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D65/00—Wrappers or flexible covers; Packaging materials of special type or form
- B65D65/02—Wrappers or flexible covers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D77/00—Packages formed by enclosing articles or materials in preformed containers, e.g. boxes, cartons, sacks or bags
- B65D77/04—Articles or materials enclosed in two or more containers disposed one within another
- B65D77/0406—Rigid containers in preformed flexible containers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B31/00—Packaging articles or materials under special atmospheric or gaseous conditions; Adding propellants to aerosol containers
Definitions
- each vial comprises a head space with reduced oxygen content.
- Ketorolac has been known for several years (U.S. Pat. No. 4,089,969) and is used in human therapy as an analgesic and an anti-inflammatory as the tromethamine salt.
- U.S. Pat. No. 4,089,969 is incorporated herein by reference in its entirety.
- ketorolac A review of its pharmacodynamic and pharmacokinetic properties and its therapeutic potential”, Drugs 39(1): 86-109, 1990. It is described as a drug with considerably higher analgesic activity than many other non-steroidal anti-inflammatory drugs. Most significantly, it has analgesic activity comparable to that of the opiates, such as morphine, without the well-known side effects of the latter.
- ketorolac can be formulated as a nasally administrable composition. See U.S. Pat. No. 6,333,044 to Recordati, and U.S. Patent Application Publication No. 2009/0042968, which are incorporated herein by reference in their entirety.
- ketorolac tromethamine nasally has certain advantages over administering the compound by injection or orally. These are discussed in prior art references U.S. Pat. No. 6,333,044 and U.S. Patent Publication 2009/0042968. The latter reference teaches that ketorolac tromethamine is successfully combined with a local anesthetic, e.g. lidocaine hydrochloride, to reduce the stinging effect that some patients experience with the nasal administration of ketorolac tromethamine alone.
- a local anesthetic e.g. lidocaine hydrochloride
- this invention provides a vial capped with a spray system, the vial comprising: a solution, a dip tube attached to the spray system and dipping into the solution, and a head space above the solution, wherein the head space comprises no more than about 10% v/v oxygen.
- this invention provides a nasal spray device, comprising: a vial and a nasal spray system capped to the vial wherein the vial comprises a solution, a dip tube attached to the nasal spray system and dipping into the solution, and a head space above the solution, wherein the head space comprises no more than about 10% volume to volume (v/v) oxygen.
- this invention provides a high recovery vial capped with a spray system, comprising a concave or V shaped inner bottom.
- the high recovery vial further comprises a head space above the solution, wherein the head space comprises equal to or less than about 10% v/v oxygen.
- the vial or device of this invention is placed in a sealed pouch comprising an oxygen-impermeable film.
- the sealed pouch comprises an inside space having an oxygen content of equal to or less than about 10% v/v.
- FIG. 1 illustrates an example of a vial, preferably with a head space comprising equal to or less than about 10% v/v oxygen.
- FIG. 2 illustrates an example of a high recovery vial, preferably with a head space comprising equal to or less than about 10% v/v oxygen.
- FIG. 3 illustrates an example of a conventional oxygen reduction device.
- FIG. 4 illustrates a tube used in the conventional oxygen reduction device.
- FIG. 5 illustrates a tube used in the improved oxygen reduction device.
- FIG. 6 illustrates an example of frequency modulation signals from oxygen absorption.
- the peak to peak amplitude of each spectrum is proportional to oxygen concentration (noted to the right of each scan).
- FIG. 7 illustrates an example of a vial of this invention placed in a sealed pouch comprising an oxygen-impermeable film and having an inside space comprising equal to or less than about 10% v/v oxygen.
- a pharmaceutically acceptable salt includes a plurality of pharmaceutically acceptable salts, including mixtures thereof.
- compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
- Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
- Consisting of shall mean excluding more than trace amount of elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
- Ketorolac refers to the chemical compound of 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid which has the following Formula (I):
- ketorolac encompasses individually or collectively the racemic mixture, a scalemic (or enantiomerically enriched) mixture, or optically active compound as well as tautomers thereof, and includes the pharmaceutically acceptable salts of ketorolac, particularly the tromethamine salt.
- a racemic mixture of ketorolac is a mixture having equal amounts of the two enantiomers of Formula (I).
- a scalemic or enantiomerically enriched mixture of ketorolac is a mixture where the amount of one of the enantiomers of Formula (I) is larger than the other enantiomer.
- An optically active compound may include enantiomerically enriched or enantiomerically pure compound.
- Enantiomerically pure compound refers to ketorolac having more than 99%, e.g. 99.5%, or 99.9% of one of the enantiomers relative to the total amount of ketorolac.
- Lidocaine refers to the chemical compound of 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide, which has the Formula (II):
- lidocaine many pharmaceutically acceptable salts of lidocaine are known. Non-limiting examples of such salts are lidocaine hydrochloride and lidocaine methanesulphonate.
- lidocaine hydrochloride and lidocaine methanesulphonate.
- lidocaine refers to the compound or any of its pharmaceutically acceptable salts, unless otherwise indicated.
- subject refers to a human.
- pharmaceutically acceptable salt refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tromethamine and tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate(methanesulfonate), acetate, maleate, and oxalate.
- Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.
- oxygen-impermeable film refers to a thin membranous material that has no or very limited oxygen permeability, for example, a oxygen permeability of about 0.03 mL/100 square inches(si)/day or less.
- Materials suitable for oxygen-impermeable film include, but are not limited to, polyester films, including polyethylene terphthalate and copolymers, polyvinyl alcohol, polypropylene or mixture thereof, such as biaxially-oriented polyethylene terephthalate (BOPET, a polyester film made from stretched polyethylene terephthalate (PET)) films, cast polypropylene (CPP) films, including polyethylene terphthalate and copolymers and including multilayer polypropylene films, bi-axially oriented polypropylene (BOPP) films and thermal lamination films, available from UFLEX Ltd., India.
- BOPET biaxially-oriented polyethylene terephthalate
- PET stretched polyethylene terephthalate
- CPP cast polypropylene
- BOPP
- the films may be optionally metallized, such as the metallized polyester films, metallized bi-axially oriented polypropylene (BOPP) films, and metalized cast polypropylene (CPP) films, and plasma metallized films, such as plasma metallized polyester films, available from UFLEX Ltd., India.
- metallized polyester films such as metallized bi-axially oriented polypropylene (BOPP) films, and metalized cast polypropylene (CPP) films
- plasma metallized films such as plasma metallized polyester films, available from UFLEX Ltd., India.
- sealed oxygen-impermeable pouch refers to a container that has no opening that allows free exchange of air and that is made of an oxygen-impermeable film.
- the pouch has an inside space that is sufficient to enclose the device of this invention or about 40-50 mL when inflated.
- the oxygen permeability of the pouch is less than 0.005 mL/package/day, for example less than 0.0048 mL/package/day.
- One aspect of this invention is a device, such as a vial, comprising a volume of about 10 mL or less associated with a spray system for delivering a medicament to a subject from a solution containing the medicament.
- a vial will generally be capped with the spray system and will have a headspace between the surface of the solution and the cap.
- the content of the gas occupying the headspace above the solution where the medicament is ketorolac need to be kept below 10% v/v oxygen to ensure the long term stability of the ketorolac solution without the need of refrigeration.
- ketorolac can produce several degradation products, such as the 1-keto analog having Formula (III) and the chemical name of 5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-one (or 5-benzoyl-1-keto-2,3-dihydro 1H-pyrrolizine, in racemic or optically active form), in solution.
- the 1-keto analog forms when ketorolac is oxidized by too much oxygen in the headspace of the device.
- We have found that the formation of the 1-keto analog is especially problematic for the intranasal compositions with a high concentration of ketorolac.
- ketorolac Prior to the discovery of intranasally administered ketorolac, it has been available for parenteral administration at a much lower concentration in the order of about 3% or 1.5% or less. A lower concentration is used because a larger volume can be administered over time. At this lower concentration, the amount of 1-keto analog formed is within an acceptable level.
- ketorolac is required, which we found can result in a concentration of the 1-keto analog that can be outside the acceptable level, which may cause safety concerns. It has been discovered that by ensuring that there is less than 10% v/v oxygen in the head space of the vial containing a highly concentrated ketorolac tromethamine solution, the shelf life of the final product is extended without the need for refrigeration.
- the unique product of this invention may be obtained by a manual process, as discussed hereinafter, or by a unique oxygen reduction device provided herein that reduces the level of oxygen content in the vial containing the intranasal formulation thereby reducing the level of the ketorolac degradative products and resulting in a device providing a level of stability that allows the formulation to be stored at room temperatures for two years or more.
- the ketorolac solution for intranasal administration is contained and stored in a container, referred to herein as a vial.
- a vial Owing to a limited volume of the solution in the vial, there is often head space left in the vial. Typically, this head space is filled with air having about 20% v/v oxygen.
- air having about 20% v/v oxygen.
- the head space increases as the medicament is expelled from the vial.
- the head space volume is typically determined by the following factors:
- the minimum head space is dictated by the size of the vial and the volume of the solution contained therein and generally about 1 mL, 3 mL, 4 mL or larger, which, if filled with air will contain an oxygen amount that may cause significant degradation of the drug contained in the vial.
- the headspace is no more than 80% of the total volume of the vial.
- the invention based on this line of discoveries and observations of the inventor, comprises several aspects.
- One aspect is a product for nasal administration of a solution of ketorolac, and optionally lidocaine, which is contained in a vial fitted with an atomizer and having a headspace that contains less than 10% v/v oxygen.
- Another aspect of this invention is a method of administering ketorolac, alone or in combination with lidocaine, by nasal administration using the product.
- Another aspect of the invention is a method of making the product of the invention by placing a solution of ketorolac, and optionally lidocaine, into a vial containing a suitable amount of the solution for nasal administration, ensuring that the headspace of the vial has less than 10% v/v of oxygen, and capping the vial.
- Still another aspect of the invention is a system for treating pain or inflammation in a human that comprises the product in combination with labeling instructions for such use.
- Other aspects of the invention will apparent to one of ordinary skill in the art upon reading this application in its entirety.
- a vial capped with a spray system comprising: a solution, a dip tube attached to the spray system and dipping into the solution, and a head space above the solution, wherein the head space comprises equal to or less than about 10% v/v oxygen.
- FIG. 1 An example of the vial capped with a spray system, is illustrated in FIG. 1 .
- the vial 100 in FIG. 1 is shown for illustration purposes only and it is to be understood that any variation in the size, shape, or design of the vial is well within the scope of the present invention.
- the vial 100 may be made of glass, polymer, or any other suitable material known in the art.
- the vial 100 comprises a cap 101 which is a spray system.
- the spray system is a nasal spray system.
- the nasal spray system is a metered nasal spray system.
- the vial 100 comprises a solution 102 in the vial.
- the solution 102 is a medicament.
- the medicament comprises a ketorolac solution as described in one or more of U.S. Pat. No. 6,333,044, U.S. Patent Application Publication No. 2009/0042968 and 2010/0016402 A1, both of which are incorporated herein by reference in their entirety.
- the vial contains multiple unit doses of the ketorolac solution. In some embodiments, the vial contains up to 8 unit doses of the ketorolac solution.
- the vial 100 comprises a dip tube 103 in the vial that is attached to the spray system at one end and is dipping in the solution at the other end.
- the vial 100 also comprises a head space 104 in the vial where the head space comprises an inert gas with no more than about 10% v/v oxygen.
- the head space comprises an inert gas with no more than about 8% v/v oxygen; or more preferably no more than about 5% v/v oxygen.
- the head space comprises an inert gas having between about 5% to about 10% v/v oxygen; or between about 3% to about 8% v/v oxygen; or between about 2% to about 5% v/v oxygen.
- stable describes a state that the solution remains substantially unchanged in the percentage of active ingredient in solution so that it is suitable for its intended use during the relevant period of time.
- the solution is a medicament
- the solution is in a stable state if it meets the standard for being used as a medicament as requested by a New Drug Application applicant and required by the relevant regulatory agency, such as the United States Food and Drug Administration.
- a stable solution may comprise certain minor degree of degradation, so long as the degree of degradation is not significant enough to make it unusable for its intended use, e.g., fall below the standard for use as a medicament.
- the solution in the vial can be stored in the vial for about two years at room temperature. In some embodiments, no more than about 10% v/v oxygen in the head space increases the shelf life of the solution as compared to the vial containing an ambient atmosphere.
- the vial contains highly concentrated ketorolac solution, e.g., 12-38% or 15-35% w/v
- storing the ketorolac composition under a gaseous atmosphere that has reduced oxygen content for example, no more than about 10% v/v of oxygen, allows the composition to be stored at room temperatures for a sufficiently long period of time, such as two years, without significant degradation.
- a regularly shaped vial such as the one shown in FIG. 1 , has a substantially flat inner bottom. Further, there is typically a space between the tip of the dip tube 103 and the bottom of the vial to allow liquid to flow into the dip tube. This presents multiple issues such as the need to use excess solution to ensure that adequate amounts can be delivered in each dosing for a multiple dose container as well as potential introduction of air into the dip tube thereby providing less than the desired dose.
- a high recovery vial for nasal spray which reduces the likelihood of air being introduced into the dip tube during administration while also reducing the amount of solution required to provide adequate dosing. High recovery vials are especially beneficial where the drug composition is expensive.
- the inner bottom of the high recovery vial 200 comprises a concave or “V” shaped bottom 201 so that residue drug solution (represented by the dashed line 202 , while the dashed line 203 represents the amount of drug solution prior to use) is collected in the tip of the concave or “V” shaped bottom 201 .
- the vial also comprises a dip tube 204 having a notch 205 to allow the solution to go into the dip tube 204 .
- the dip tube is a stiff-notched dip tube.
- the vial comprises a head space 104 , which preferably has less than 10% v/v oxygen.
- a nasal spray device comprising: a vial having a volume of no more than 10 mL and a nasal spray system capped to the vial wherein the vial comprises a solution, a dip tube attached to the nasal spray system and dipping into the solution, and a head space above the solution, wherein the head space comprises no more than about 10% v/v oxygen.
- the nasal spray device comprises the vial as described above.
- the amount of oxygen in the head space is as provided above.
- a nasal spray device is one designed for the exit tip to be inserted into a patient's nostril to spray a defined amount of the solution into the nostril.
- the nasal spray device is further equipped with a metering chamber to measure a desired amount of the composition to be sprayed into the patient's nasal passage.
- the metering chamber is coupled with the spraying device so that a patient can simultaneously measure and spray a desired amount (e.g. a unit dose) of the composition.
- the metering chamber is able to deliver a predetermined amount of about 50 to about 125 microliters of liquid.
- the metering chamber is able to deliver from about 50 to about 100 microliters of liquid.
- the metering chamber having different volume deliveries can be used.
- the metering chamber is able to measure about 50 microliters of liquid.
- the metering chamber is able to measure about 100 microliters of liquid.
- Appropriate vials and spray devices with or without a metering chamber are available to one of skill in the art by referring to “Remington's Pharmaceutical Sciences.”
- One source for such vessels is Ing. Erich Pfeiffer GmbH, Radolfzell, Germany.
- Another source is Valois, 50 avenue de l'Europe, 78164 MARLY-LE-ROI, France.
- the vial or nasal spray device of this invention is in combination with labeling instructions for use in treating a pain or inflammation in a human subject.
- the pain is the result of a trauma inflicted on the subject.
- the pain is the result of a medical operation performed on the subject.
- the pain is pathological.
- the pain is neuropathic.
- the pain is migraine or other headache pain.
- the vial, or the nasal spray device of this invention further comprises a sealed oxygen-impermeable pouch covering the vial, which pouch comprises an inside space having an oxygen content of equal to or less than about 10% v/v.
- the oxygen content of the inside space of the sealed pouch is capable of being maintained at a level of equal to or less than about 10% v/v for at least 2 years.
- the oxygen content in the inside space of the pouch is at least equal to or less than about 5% v/v. In some embodiments, the oxygen content in the inside space of the pouch is capable of being maintained at equal to or less than about 10% v/v for at least two years, for example equal to or less than about 8% v/v for at least two years. In some embodiments, the inside space comprises an initial oxygen content of about 2% v/v. In some embodiments, the oxygen permeability of the pouch is less than 0.005 mL/package/day, or less than 0.0048 mL/package/day.
- the sealed pouch has a dimension of about 5-8 centimeters by 12-15 centimeters, for example a dimension of about 6-6.5 centimeters by 14-15 centimeters.
- the sealed wrap has a dimension of about 6.2 centimeters by 14.5 centimeters.
- the sealed pouch has an inside volume of about 40-50 mL, more specifically about 45 mL.
- the pouch is made from a polyester film, including polyethylene terphthalate and copolymers, a polyvinyl alcohol film, or a film comprising polyester and polyvinyl alcohol.
- the film is selected from the group consisting of biaxially-oriented polyethylene terephthalate (BOPET, a polyester film made from stretched polyethylene terephthalate (PET)) films, cast polypropylene (CPP) films, including copolymer and terpolymer, multilayer polypropylene films, bi-axially oriented polypropylene (BOPP) films and thermal lamination films.
- BOPET biaxially-oriented polyethylene terephthalate
- PET stretched polyethylene terephthalate
- CPP cast polypropylene
- multilayer polypropylene films multilayer polypropylene films
- bi-axially oriented polypropylene (BOPP) films bi-axially oriented polypropylene
- the film is metallized, such as the metallized polyester films (including polyethylene terphthalate and copolymers), metallized bi-axially oriented polypropylene (BOPP) films, and metalized cast polypropylene (CPP) films (including copolymers and terpolymer), and plasma metallised films, such as plasma metallized polyester films.
- metallized polyester films including polyethylene terphthalate and copolymers
- BOPP metallized bi-axially oriented polypropylene
- CCP metalized cast polypropylene
- plasma metallised films such as plasma metallized polyester films.
- Processes and equipment for preparing sealed bags for food packaging may be used to prepare the pouch.
- a vial of this invention comprising a ketololac composition and a head space with an equal to or less than 10% v/v oxygen is placed in the pouch with an opening.
- the pouch is then flushed with an inert gas, such as nitrogen and argon, which is sufficient to reduce the oxygen content of the inside space to below 10%, preferably below 5%, and more prefereably at or below 2%.
- the pouch is then sealed.
- the production speed is about 200 per minute.
- the sealed pouch is in a fin seal flow wrap style with scalloped end seals.
- Other methods of sealing are well known in the art. It is to be understood that the specific manner of sealing is non-essential so long as the pouch is sealed to prevent oxygen from entering into the pouch through any opening of the pouch, or to minimize the ingress of oxygen in accordance with the teachings of this disclosure.
- FIG. 7 illustrates an example of the vial 100 of this invention in a sealed pouch 601 .
- the sealed pouch comprises an inside space 602 having an oxygen content of equal to or less than about 10% v/v.
- a method of preparing a nasal spray device comprising: a vial having a volume of no more than 10 mL and a nasal spray system capped to the vial wherein the vial comprises a solution, a dip tube attached to the nasal spray system and dipping into the solution, and a head space above the solution, the process comprising:
- the inert gas is nitrogen. In some embodiments, the inert gas is a noble gas, such as argon.
- the following describes an efficient process to purge air from the vials, especially in a contemplated manufacturing context.
- an oxygen reduction device 300 is used for purging air out of a vial containing a solution before capping of the vial, for example 100 or 200, with, for example, a cap or a spray system.
- a stream of an inert gas such as argon or nitrogen, may be passed over the vial using a tube 301 , also referred to as purge bar, attached to the oxygen reduction device 300 .
- the tube 301 as attached to the oxygen reduction device 300 can be seen partially in FIG. 3 .
- the tube 301 is illustrated fully in FIG. 4 .
- the tube 301 comprises an inlet 401 and an outlet 402 and a number of holes 403 at various points on the tube 301 .
- the nitrogen enters from the inlet 401 and passes through the tube 301 to exit through outlet 402 .
- the holes 403 pass a stream of inert gas, such as nitrogen or argon, over the vials. Typically, in a manufacturing process, nitrogen is preferred due to cost consideration. However, the holes 403 pass the inert gas around the vials and not into the vials.
- the tube 301 is attached to the oxygen reduction device 300 in such a way that the inert gas may not pass directly into the mouth of the vials but may instead be around them.
- this diffusion of the nitrogen around the vials is further coupled with the fact that the nitrogen being lighter than the air will not replace the air in the vials.
- This incomplete purging may be more pronounced in an aseptic environment due to rapid air flow in that situation.
- a lid or a spray system is snapped on the vial to cap the vial, a significant amount of air may remain in the vial which may lead to the degradation of the solution, such as a medicament, in the vial.
- an improved oxygen reduction device for purging air from a vial where the vial comprises a solution and a head space
- the improved oxygen reduction device comprises a tube with one or more purging outlets that flow an inert gas such as nitrogen directly over and into the vial to purge the air out of the vial, although other inert gases such as argon can be used.
- an inert gas such as nitrogen directly over and into the vial to purge the air out of the vial, although other inert gases such as argon can be used.
- nitrogen uses nitrogen to illustrate the device and process for brevity.
- the tube 500 in the improved oxygen reduction device 300 is as illustrated in FIG. 5 .
- the tube 500 comprises an inlet 401 and an outlet 402 .
- the nitrogen enters from the inlet 401 and passes through the tube 500 to exit through outlet 402 .
- the tube 500 optimally may comprise two brackets 501 and 502 for attaching the tube 500 to other components of the oxygen reduction device 300 .
- the tube 500 comprises one or more purging outlets 503 (also called bar nozzles) that direct the nitrogen directly on the mouth of the vial thereby effectively purging the air out of the vial.
- FIG. 5 comprises four such purging outlets 503 which is for illustration purposes only.
- the number of the purging outlets 503 can vary depending on, for example, the oxygen reduction device 300 and the length of the assembly line carrying the vials along the device, etc. It is also to be understood that the design of the tube 500 , inlet 401 and outlet 402 , brackets 501 and 502 and purging outlets 503 in FIG. 5 is for illustration purposes only. It is contemplated that the purging outlet 503 can have different configurations so long as it can deliver nitrogen directly onto the mouth of the vial. It is also contemplated that the length and size of the purging outlet 503 and/or the position of the vial may be adjusted so that the distance between the tip of the purging outlet 503 and the mouth of the vial can be optimal for delivering nitrogen inside the vial.
- the tube 500 has at least two purging outlets 503 . In some embodiments, the tube 500 has at least three purging outlets 503 . In some embodiments, the tube 500 has four purging outlets 503 .
- the tube 500 can be made of materials well known in the art. For example, the tube 500 can be made of stainless steel. In some embodiments, the tube 500 is made of plated metal. It is important that the purging outlets 503 are oriented in such a manner that the distal end of the purging outlet 503 is placed over the mouth of the vial.
- At least one purging outlet 503 of the tube 500 is close to a last station where a capping of the vial with the spray system takes place in order to minimize oxygen reentry into the gaseous atmosphere in the vial.
- the orientation of the purging outlet 503 should be combined with a capping system such that capping occurs within 1 second of purging and preferably within 0.6 seconds of purging and even more preferably from 0.3 seconds to 0.5 seconds, and most preferably 0.4 second.
- the one or more purging outlets 503 of the tube 500 in the oxygen reduction device 300 flow nitrogen directly over and into the vial to purge the air out of the vial thereby reducing an oxygen content in the head space of the vial to equal to or less than about 10% v/v oxygen.
- the reduction in the oxygen content in the head space of the vial to equal to or less than about 10% v/v oxygen is an improvement over a conventional oxygen reduction device wherein the reduction in the oxygen content in the head space of the vial is more than about 10% v/v oxygen.
- the reduction in the oxygen content in the head space of the vial is equal to or less than about 8% v/v oxygen; equal to or less than about 5% v/v oxygen. In some embodiments, the reduction in the oxygen content in the head space of the vial is in the range of about 5-10%, 3-8% or 2-5% v/v.
- the improvement in the oxygen reduction device further comprises adjusting a flow rate of the nitrogen to reduce the oxygen content in the vial.
- the flow rate of the nitrogen can be increased or decreased depending on the purging of the air out of the vial. This adjustment of the nitrogen flow can help reduce the oxygen content in the vial.
- the nitrogen flow rate is about 20 liters per minute (L/min) to about 80 L/min. In some embodiments, the nitrogen flow rate is about 40 L/min to 60 L/min. In some embodiments, the nitrogen flow rate is about 50 L/min.
- the improvement in the oxygen reduction device further comprises adjusting a speed of a capping of the vial, such as with a nasal spray system.
- the capping rate is selected to permit purging of from about 100 vials per minute to about 210 vials per minute.
- the capping rate is about 150 vials per minute to about 210 vials per minute.
- the capping rate is selected to permit purging of about 150 vials per minute.
- the adjustment of the speed of the capping may also comprise attaching a purging outlet 503 in FIG. 5 closer to the last station where the capping of the vial takes place.
- the time lag between the vial leaving the assembly line and reaching the capping end can be reduced thereby reducing the amount of time the vial is exposed to air.
- the nitrogen is blown into the vial simultaneously with capping the vial. This improvement can further reduce the oxygen content in the vial.
- a process to purge air from a vial, especially in an aseptic environment, the vial comprising a solution and a head space comprising: flowing an inert gas, such as nitrogen or argon, directly over and into the vial to purge the air out of the vial using an improved oxygen reduction device wherein the device comprises a tube with one or more purging outlets that flow the inert gas directly over and into the vial to purge the air out of the vial, wherein the process reduces an oxygen content in the head space of the vial to equal to or no more than about 10% v/v oxygen.
- an inert gas such as nitrogen or argon
- a nasal spray device especially in an aseptic environment
- the nasal spray device comprising: a vial and a nasal spray system capped to the vial wherein the vial comprises a solution, a dip tube attached to the nasal spray system and dipping into the solution, and a head space above the solution, the process comprising:
- the improved oxygen reduction device comprises a tube with one or more purging outlets that flow nitrogen directly over and into the vial to purge the air out of the vial;
- the inert gas is nitrogen. In some embodiments, the inert gas is a noble gas. In some embodiments, the inert gas is argon. In some embodiments, the rate of capping is selected to be fast enough to ensure that minimal atmospheric change occurs in the vial between completion of the purging and capping and slow enough to ensure that the purging process is effective. In some embodiments, capping occurs within about 0.28 to 1 second after purging so as to provide for 60 to 210 vials capped per minute; preferably within about 0.28 to 0.4 seconds (150 to 210 vials capped per minute).
- all or a selected number of the treated and capped vials are passed through spectrometry analysis to measure the oxygen content and/or further remove the vials with unacceptable oxygen content.
- the solution inside the vial is an intranasal formulation of ketorolac or a pharmaceutically acceptable salt thereof.
- the bacterial load in the solution is less than about 100 colony forming units (CFU).
- the intranasal formulation comprises concentrations of ketorolac, or a pharmaceutically acceptable salt, ranging from about 12.5 to 38% weight to volume (w/v), for example about 15%, 20%, 25%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, or 38% w/v, based on the final formulation.
- the intranasal formulation comprises:
- ketorolac (a) about 12.5% w/v to about 38% w/v of ketorolac or a pharmaceutically acceptable salt thereof, and
- the composition further comprises a local anesthetics, such as lidocaine, or a pharmaceutically acceptable salt, ranging from about 4% to 10%, for example about 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/v.
- a local anesthetics such as lidocaine, or a pharmaceutically acceptable salt
- lidocaine is a local anesthetic that is known to cause numbness
- such numbness is substantially absent or reduced when lidocaine is combined with ketorolac.
- combination of 5 to 6% of lidocaine with ketorolac have been found to decrease the Tmax for ketorolac to reach its Cmaxin a subject's plasma, providing a subject with faster and better pain relief. It is contemplated that when the concentration of ketorolac is increased to up to about 38%, the amount of lidocaine can be maintained at a level of 4-10% or preferably 5-6% and yet still inhibits the stinging sensation of ketorolac.
- the intranasal formulation comprises:
- ketorolac (a) about 12.5% w/v to about 38% w/v of ketorolac or a pharmaceutically acceptable salt thereof,
- ketorolac is as a racemic mixture.
- the pharmaceutically acceptable salt of ketorolac is ketorolac tromethamine.
- the intranasal formulation comprises about 13% to 20% w/v of ketorolac tromethamine.
- the intranasal formulation comprises about 15% w/v of ketorolac tromethamine.
- the intranasal formulation comprises about 25% to 35% w/v of ketorolac tromethamine.
- the intranasal formulation comprises about 28% to 32% w/v of ketorolac tromethamine.
- the intranasal formulation comprises about 30% w/v of ketorolac tromethamine.
- the intranasal formulation comprises lidocaine hydrochloride. In some embodiments, the intranasal formulation comprises about 5-6% lidocaine hydrochloride.
- the intranasal formulation comprises about 6% lidocaine hydrochloride.
- the intranasal formulation further comprises a chelator, i.e. a substance that binds primarily di- or tri valent metallic ions (e.g. calcium) that might interfere with the stability or activity of the active ingredient.
- a chelator i.e. a substance that binds primarily di- or tri valent metallic ions (e.g. calcium) that might interfere with the stability or activity of the active ingredient.
- Chelators are known to those of skill in the art by referring to the recent edition of “Remington's Pharmaceutical Sciences.”
- a preferred chelator is sodium ethylenediamine tetraacetic acid (sodium EDTA), USP.
- the chelator is disodium edetate. The amount of may be from about 0.01% w/v to about 0.1% w/v, for example, 0.02, 0.05, 0.075, and 0.10 w/v.
- the pH of the intranasal formulation is about 4.5 to 8. In some embodiments, the pH is about 4.8 to 7.5. In some embodiments, the pH is about 7.2.
- the pH is adjusted by a pharmaceutically acceptable base.
- the pharmaceutically acceptable base is sodium hydroxide.
- a pharmaceutically acceptable buffer may be present in order to create optimum pH conditions for both product stability and tolerance (pH range about 4 to about 8; preferably about 6.0 to 7.5).
- Suitable buffers include without limitation tris(tromethamine) buffer, phosphate buffer, etc.
- potassium phosphate NF is used to adjust the pH to 7.2.
- the composition comprises up to about 2% of a phosphate buffer, such as potassium phosphate monobasic, potassium phosphate dibasic.
- the composition comprises about 0.6 to 0.8% w/v of potassium phosphate monobasic.
- the composition comprises about 0.68% w/v of potassium phosphate monobasic.
- the intranasal formulation is a sprayable liquid.
- the pharmaceutically acceptable carrier is water.
- the intranasal formulation comprises:
- the intranasal formulation comprises:
- the intranasal formulation comprises:
- the intranasal formulation comprises:
- the intranasal formulation may optionally comprise one or more pharmaceutically acceptable excipients.
- the preferred diluent for the formulations is water, and other excipients may be added if desired.
- excipients include chemical enhancers such as absorption promoters. These include fatty acids, bile acid salts and other surfactants, fusidic acid, lysophosphatides, cyclic peptide antibiotics, preservatives, carboxylic acids (ascorbic acid, amino acids), glycyrrhetinic acid, o-acylcarnitine.
- Preferred promoters are diisopropyladipate, POE(9) lauryl alcohol, sodium glycocholate and lysophosphatidyl choline which proved to be particularly active.
- excipients such as oil, gel, chemical enhancers, including abosorption promoters, etc. should be in an amount that does not adversely affect the homogeneity and sprayability of the solution.
- the intranasal formulation can also contain a compatible preservative that ensures the microbiological stability of the active ingredient.
- Suitable preservatives include without limitation, methyl paraoxybenzoate (methyl paraben), propyl paraoxybenzoate (propyl paraben), sodium benzoate, benzyl alcohol, and chlorobutanol.
- the intranasal ketorolac formulation does not contain a preservative.
- Illustrative formulations may contain the following ingredients and amounts (w/v) in addition to ketorolac, lidocaine and water.
- Headspace oxygen concentrations were measured using a Lighthouse Instruments FMS-760 Headspace Oxygen Analyzer. The measurements were made to assess the performance of a nondestructive measurement method for headspace oxygen analysis.
- Laser absorption spectroscopy is an optical measurement method for rapid and non-invasive headspace gas analysis of containers, such as parenteral containers or containers for intranasal spray.
- the technique can measure a number of physical parameters within the headspace of the container, including gas concentrations and total headspace pressures.
- Light from a near-infrared semiconductor laser is tuned to match the internal vibrational frequency of the target molecule.
- the light is passed through the headspace region of a container, scanned in frequency and detected by a photodetector.
- the amount of light absorbed is proportional to the target molecule concentration.
- the instruments incorporate a high sensitivity detection method known as frequency modulation spectroscopy.
- the oxygen A-band is a series of rotational transitions within the 0-0 vibrational band of the X 3 ⁇ ⁇ g ⁇ b 1 ⁇ + g magnetic dipole transition.
- the amount of laser light absorbed by an individual transition in the oxygen A-band is proportional to the oxygen concentration in the headspace of a parenteral or nasal spray container.
- the laser frequency is repeatedly scanned over the absorption feature and successive scans are averaged to improve the signal to noise ratio.
- the averaged light absorption signal (an example shown in FIG. 6 ) and the total power are then multiplied by a calibration constant to yield the headspace oxygen concentration.
- An instrument calibration constant, k is determined using a vial filled with a known concentration of oxygen.
- Oxygen standards are prepared using certified gas mixtures of oxygen and nitrogen. A 20% oxygen/80% nitrogen standard is used for FMS-760 calibration.
- a calibration standard is inserted to the instrument, the system response (signal amplitude, S, and power, P) is measured and a calibration constant is computed.
- the instrument calibration procedure is fully automated and controlled by the instrument computer. Once the user inputs the calibration vial and initiates the calibration routine the instrument begins to record data and using the known concentration computes a calibration constant k,
- P is the detected laser power
- S is the peak to peak absorption signal (see FIG. 6 for oxygen example)
- Known Concentration is the concentration in the calibration vial.
- the measured values of P and S are the average of 1000 scans (10 s acquisition time). The system stores the calibration constant and uses it for subsequent sample measurements.
- the instrument data acquisition system uses the stored calibration constant to determine the headspace oxygen concentration in a sample.
- the system measures the absorption signal and laser power and multiplies by the calibration constant to determine the headspace oxygen or water vapor concentration.
- S m is the sample signal amplitude
- P m is the laser power transmitted through the sample
- P c is the calibration power
- S c is the calibration signal amplitude
- % Oxygen in Standard is the known amount of oxygen in the calibration vial.
- Headspace oxygen measurements were performed using a Lighthouse Instruments FMS-760 Headspace Oxygen Analyzer (SN 760-104). The instrument was turned on and allowed to warm up for thirty minutes. Calibration was performed using a 21% oxygen standard. The headspace oxygen concentration in each sample was measured three times.
- a suitable length of a tubing preferably made of a chemical resistant polymer and preferably free from contamination, is connected to an argon or nitrogen gas tank at one end.
- the other end of the tubing is inserted in the mouth of a vial having a ketorolac solution and an about 2 mL head space, preferably the tubing does not touch the ketorolac solution inside the vial.
- Argon or nitrogen is passed through the tubing into the vial for a sufficient amount of time so that the oxygen content in the head space of the vial is less than 10%.
- the tubing is removed from the vial and the vial is capped with a nasal spray system and stored at room temperature.
- Vials were processed using a conventional oxygen reduction device having a tube with purging holes. Other conditions are the same as described in Example 4 below.
- the oxygen content of the following five sets of glass vials were tested using the above described protocol of Example 1. The individual results were recorded and averaged and mean concentration and standard deviation were computed. The results of the samples tested are summarized below.
- the individual headspace oxygen measurements of the five samples varied from between 17.8% to 20.5%, and the average headspace oxygen concentrations of the each of the five samples varied between 18.3% and 20.2%, with a mean of 19.0% and a standard deviation of 0.80%.
- the individual headspace oxygen measurements of the five samples varied from between 20.2% to 21.7%, and the average headspace oxygen concentrations of each of the five samples varied between 20.6% and 21.1%, with a mean of 20.8% and a standard deviation of 0.20%.
- Set 3 is a repeat of Set 1, except that in Set 3 the samples were collected after stopping the capper (simulated line stoppage) for 5 minutes and resuming the capping operation.
- the individual headspace oxygen measurements of the five samples varied from between 18.2% to 22.0%, and the average headspace oxygen concentrations of each of the five samples varied between 18.7% and 21.4%, with a mean of 19.5% and a standard deviation of 1.11%.
- the individual headspace oxygen measurements of the five samples varied from between 20.5% to 21.9%, and the average headspace oxygen concentrations of each of the five samples varied between 18.4% and 21.8%, with a mean of 19.9% and a standard deviation of 1.46%.
- the individual headspace oxygen measurements of the five samples varied from between 18.1% to 21.7%, and the average headspace oxygen concentrations of each of the five samples varied between 21.1% and 21.4%, with a mean of 21.3% and a standard deviation of 0.12%.
- the experiment was conducted using 20 mm Hi-Recovery vials (4 mL) and snap-on metering pump.
- the vials were filled with about 1.8 mL of injection quality water (WFI) while purged with nitrogen having varying flow rates.
- WFI injection quality water
- the experiment was repeated with a similar oxygen reduction device having GMP quality. Twenty vials from each fill speed and flow rate combination were sampled and tested. Result summaries are shown in the following tables 1 and 2.
- capping speeds would directly affect the amount of retention time each vial has under the oxygen reduction device bar nozzles.
- at the high machine speed 210 vials per minute
- frequent pauses were observed as the pump bowl was not supplying pumps at the same rate. This may have caused the high oxygen contents in some of the vials prepared at a rate of 210 vials per minute. It is anticipated that adjusted operation of the pump bowl would reduce the frequency and duration of the pauses, which would result in tighter oxygen level results.
- Another solution is to reject vials after machine stoppage.
- Residual oxygen contents for 80 L/min at both speeds were slightly higher than those observed at the 60 L/min flow. As flow rate gets higher, the volume that can be displaced is higher, but the flow also grows more turbulent, possibly entraining ambient air with the purge air.
Abstract
Description
- This application is a continuation-in-part application of U.S. patent application Ser. No. 12/404,250, filed Mar. 13, 2009, which is incorporated hereby by reference in its entirety.
- Disclosed herein are vials and methods for preserving a ketorolac composition where each vial comprises a head space with reduced oxygen content.
- Ketorolac has been known for several years (U.S. Pat. No. 4,089,969) and is used in human therapy as an analgesic and an anti-inflammatory as the tromethamine salt. U.S. Pat. No. 4,089,969 is incorporated herein by reference in its entirety.
- Ample literature is available on ketorolac (for instance, “Ketorolac—A review of its pharmacodynamic and pharmacokinetic properties and its therapeutic potential”, Drugs 39(1): 86-109, 1990). It is described as a drug with considerably higher analgesic activity than many other non-steroidal anti-inflammatory drugs. Most significantly, it has analgesic activity comparable to that of the opiates, such as morphine, without the well-known side effects of the latter.
- It is known that ketorolac can be formulated as a nasally administrable composition. See U.S. Pat. No. 6,333,044 to Recordati, and U.S. Patent Application Publication No. 2009/0042968, which are incorporated herein by reference in their entirety.
- Administering ketorolac tromethamine nasally has certain advantages over administering the compound by injection or orally. These are discussed in prior art references U.S. Pat. No. 6,333,044 and U.S. Patent Publication 2009/0042968. The latter reference teaches that ketorolac tromethamine is successfully combined with a local anesthetic, e.g. lidocaine hydrochloride, to reduce the stinging effect that some patients experience with the nasal administration of ketorolac tromethamine alone.
- In one aspect, this invention provides a vial capped with a spray system, the vial comprising: a solution, a dip tube attached to the spray system and dipping into the solution, and a head space above the solution, wherein the head space comprises no more than about 10% v/v oxygen.
- In another aspect, this invention provides a nasal spray device, comprising: a vial and a nasal spray system capped to the vial wherein the vial comprises a solution, a dip tube attached to the nasal spray system and dipping into the solution, and a head space above the solution, wherein the head space comprises no more than about 10% volume to volume (v/v) oxygen.
- In still another aspect, this invention provides a high recovery vial capped with a spray system, comprising a concave or V shaped inner bottom. In some embodiments, the high recovery vial further comprises a head space above the solution, wherein the head space comprises equal to or less than about 10% v/v oxygen.
- In still another aspect, the vial or device of this invention is placed in a sealed pouch comprising an oxygen-impermeable film. In some embodiments, the sealed pouch comprises an inside space having an oxygen content of equal to or less than about 10% v/v.
- These and the other embodiments are further described in the text that follows.
- This invention will be further described with reference being made to the accompanying drawings.
-
FIG. 1 illustrates an example of a vial, preferably with a head space comprising equal to or less than about 10% v/v oxygen. -
FIG. 2 illustrates an example of a high recovery vial, preferably with a head space comprising equal to or less than about 10% v/v oxygen. -
FIG. 3 illustrates an example of a conventional oxygen reduction device. -
FIG. 4 illustrates a tube used in the conventional oxygen reduction device. -
FIG. 5 illustrates a tube used in the improved oxygen reduction device. -
FIG. 6 illustrates an example of frequency modulation signals from oxygen absorption. The peak to peak amplitude of each spectrum is proportional to oxygen concentration (noted to the right of each scan). These spectra were taken through 1 inch diameter glass containers filled with certified gas mixtures of oxygen in nitrogen. -
FIG. 7 illustrates an example of a vial of this invention placed in a sealed pouch comprising an oxygen-impermeable film and having an inside space comprising equal to or less than about 10% v/v oxygen. - Before the various aspects of this invention are described, it is to be understood that the invention is not limited to the particular methodologies, protocols, and reagents described, as these may vary. It is also to be understood that the terminology used herein is intended to describe particular embodiments of the present invention, and is in no way intended to limit the scope of the present invention as set forth in the appended claims.
- Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
- In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
- The term “about” when used before a numerical designation, e.g., pH, temperature, amount, concentration, and molecular weight, including range, indicates approximations which may vary by (+) or (−) 5%, 1% or 0.1%.
- As used in the specification and claims, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a pharmaceutically acceptable salt” includes a plurality of pharmaceutically acceptable salts, including mixtures thereof.
- As used herein, the term “comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consisting essentially of” when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. “Consisting of” shall mean excluding more than trace amount of elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
- “Ketorolac” refers to the chemical compound of 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid which has the following Formula (I):
- or a pharmaceutically acceptable salt thereof.
- For purposes of this application, the name ketorolac encompasses individually or collectively the racemic mixture, a scalemic (or enantiomerically enriched) mixture, or optically active compound as well as tautomers thereof, and includes the pharmaceutically acceptable salts of ketorolac, particularly the tromethamine salt. As used herein, a racemic mixture of ketorolac is a mixture having equal amounts of the two enantiomers of Formula (I). A scalemic or enantiomerically enriched mixture of ketorolac is a mixture where the amount of one of the enantiomers of Formula (I) is larger than the other enantiomer. An optically active compound may include enantiomerically enriched or enantiomerically pure compound. Enantiomerically pure compound refers to ketorolac having more than 99%, e.g. 99.5%, or 99.9% of one of the enantiomers relative to the total amount of ketorolac.
- “Lidocaine” refers to the chemical compound of 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide, which has the Formula (II):
- or a pharmaceutically acceptable salt thereof.
- Many pharmaceutically acceptable salts of lidocaine are known. Non-limiting examples of such salts are lidocaine hydrochloride and lidocaine methanesulphonate. As used herein, the term “lidocaine” refers to the compound or any of its pharmaceutically acceptable salts, unless otherwise indicated.
- The term “subject,” “individual” or “patient” is used interchangeably herein, and refers to a human.
- The term “pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tromethamine and tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate(methanesulfonate), acetate, maleate, and oxalate. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.
- The term “oxygen-impermeable film” refers to a thin membranous material that has no or very limited oxygen permeability, for example, a oxygen permeability of about 0.03 mL/100 square inches(si)/day or less. Materials suitable for oxygen-impermeable film include, but are not limited to, polyester films, including polyethylene terphthalate and copolymers, polyvinyl alcohol, polypropylene or mixture thereof, such as biaxially-oriented polyethylene terephthalate (BOPET, a polyester film made from stretched polyethylene terephthalate (PET)) films, cast polypropylene (CPP) films, including polyethylene terphthalate and copolymers and including multilayer polypropylene films, bi-axially oriented polypropylene (BOPP) films and thermal lamination films, available from UFLEX Ltd., India. The films may be optionally metallized, such as the metallized polyester films, metallized bi-axially oriented polypropylene (BOPP) films, and metalized cast polypropylene (CPP) films, and plasma metallized films, such as plasma metallized polyester films, available from UFLEX Ltd., India.
- The term “sealed oxygen-impermeable pouch” refers to a container that has no opening that allows free exchange of air and that is made of an oxygen-impermeable film. In some embodiments, the pouch has an inside space that is sufficient to enclose the device of this invention or about 40-50 mL when inflated. In some embodiments, the oxygen permeability of the pouch is less than 0.005 mL/package/day, for example less than 0.0048 mL/package/day.
- One aspect of this invention is a device, such as a vial, comprising a volume of about 10 mL or less associated with a spray system for delivering a medicament to a subject from a solution containing the medicament. Such a vial will generally be capped with the spray system and will have a headspace between the surface of the solution and the cap. We have found that the content of the gas occupying the headspace above the solution where the medicament is ketorolac need to be kept below 10% v/v oxygen to ensure the long term stability of the ketorolac solution without the need of refrigeration.
- Our ambient atmosphere (air) contains about 20% v/v oxygen, 78% v/v nitrogen, 1% v/v argon, and a number of other components. It has been found that high oxygen content can degrade certain medicament solutions (e.g. ketorolac tromethamine) in the vial thereby reducing the shelf life of the medicament. Under such circumstances, the solution-containing vial is often kept refrigerated to maintain stability of the solution over the desired shelf life of the product. The need for refrigeration can increase the cost of handling and storing of the product.
- We have found that ketorolac can produce several degradation products, such as the 1-keto analog having Formula (III) and the chemical name of 5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-one (or 5-benzoyl-1-keto-2,3-dihydro 1H-pyrrolizine, in racemic or optically active form), in solution.
- The 1-keto analog forms when ketorolac is oxidized by too much oxygen in the headspace of the device. We have found that the formation of the 1-keto analog is especially problematic for the intranasal compositions with a high concentration of ketorolac. Prior to the discovery of intranasally administered ketorolac, it has been available for parenteral administration at a much lower concentration in the order of about 3% or 1.5% or less. A lower concentration is used because a larger volume can be administered over time. At this lower concentration, the amount of 1-keto analog formed is within an acceptable level. However, due to the limited volume that can be administered intranasally, a much higher concentration of ketorolac is required, which we found can result in a concentration of the 1-keto analog that can be outside the acceptable level, which may cause safety concerns. It has been discovered that by ensuring that there is less than 10% v/v oxygen in the head space of the vial containing a highly concentrated ketorolac tromethamine solution, the shelf life of the final product is extended without the need for refrigeration. The unique product of this invention may be obtained by a manual process, as discussed hereinafter, or by a unique oxygen reduction device provided herein that reduces the level of oxygen content in the vial containing the intranasal formulation thereby reducing the level of the ketorolac degradative products and resulting in a device providing a level of stability that allows the formulation to be stored at room temperatures for two years or more.
- The ketorolac solution for intranasal administration is contained and stored in a container, referred to herein as a vial. Owing to a limited volume of the solution in the vial, there is often head space left in the vial. Typically, this head space is filled with air having about 20% v/v oxygen. In many cases, it is not practical to reduce the head space volume to an extent that the amount of air is not a substantial issue to the stability of the medicament inside the vial. In most cases, the head space increases as the medicament is expelled from the vial. For example, in the case of a vial containing an intranasal composition, the head space volume is typically determined by the following factors:
-
- (1) The size of the vial: Due to the presence of the spray system on the vial in order to deliver the composition by intranasal spray, the minimum size of the vial needs to be able to balance the weight of the spray system in order to stabilize the vial when the vial is stored. If the vial is too small, the vial will tend to tip over and fall due to the weight of the spray system. Preferably the minimum volume of the vial is about 3.5 mL. Preferably, the maximum volume of the vial is about 10 mL, more preferably 5 mL.
- (2) The volume of the composition inside: In a preferred embodiment, the amount of drug solution that may be contained in a single vial is about 0.4-4 mL; more preferably about 0.6-3 mL; and even more preferably about 0.8-2 mL. In one embodiment the volume is about 1 mL and up to about 1.8 mL. In another embodiment the volume is not less than about 1.6 mL and up to about 1.8 mL.
- Accordingly, the minimum head space is dictated by the size of the vial and the volume of the solution contained therein and generally about 1 mL, 3 mL, 4 mL or larger, which, if filled with air will contain an oxygen amount that may cause significant degradation of the drug contained in the vial. Generally, the headspace is no more than 80% of the total volume of the vial.
- Thus it can be seen that the invention, based on this line of discoveries and observations of the inventor, comprises several aspects. One aspect is a product for nasal administration of a solution of ketorolac, and optionally lidocaine, which is contained in a vial fitted with an atomizer and having a headspace that contains less than 10% v/v oxygen. Another aspect of this invention is a method of administering ketorolac, alone or in combination with lidocaine, by nasal administration using the product. Another aspect of the invention is a method of making the product of the invention by placing a solution of ketorolac, and optionally lidocaine, into a vial containing a suitable amount of the solution for nasal administration, ensuring that the headspace of the vial has less than 10% v/v of oxygen, and capping the vial. Still another aspect of the invention is a system for treating pain or inflammation in a human that comprises the product in combination with labeling instructions for such use. Other aspects of the invention will apparent to one of ordinary skill in the art upon reading this application in its entirety.
- Accordingly, in one aspect, there is provided a vial capped with a spray system, the vial comprising: a solution, a dip tube attached to the spray system and dipping into the solution, and a head space above the solution, wherein the head space comprises equal to or less than about 10% v/v oxygen.
- An example of the vial capped with a spray system, is illustrated in
FIG. 1 . Thevial 100 inFIG. 1 is shown for illustration purposes only and it is to be understood that any variation in the size, shape, or design of the vial is well within the scope of the present invention. Thevial 100 may be made of glass, polymer, or any other suitable material known in the art. Thevial 100 comprises acap 101 which is a spray system. In some embodiments, the spray system is a nasal spray system. In some embodiments, the nasal spray system is a metered nasal spray system. - The
vial 100 comprises asolution 102 in the vial. In some embodiments, thesolution 102 is a medicament. In some embodiments, the medicament comprises a ketorolac solution as described in one or more of U.S. Pat. No. 6,333,044, U.S. Patent Application Publication No. 2009/0042968 and 2010/0016402 A1, both of which are incorporated herein by reference in their entirety. In some embodiments, the vial contains multiple unit doses of the ketorolac solution. In some embodiments, the vial contains up to 8 unit doses of the ketorolac solution. - The
vial 100 comprises adip tube 103 in the vial that is attached to the spray system at one end and is dipping in the solution at the other end. Thevial 100 also comprises ahead space 104 in the vial where the head space comprises an inert gas with no more than about 10% v/v oxygen. In some embodiments, the head space comprises an inert gas with no more than about 8% v/v oxygen; or more preferably no more than about 5% v/v oxygen. In some embodiments, the head space comprises an inert gas having between about 5% to about 10% v/v oxygen; or between about 3% to about 8% v/v oxygen; or between about 2% to about 5% v/v oxygen. - Keeping the percentage of oxygen the head space to 10% or less keeps the solution stable for about two years. It is to be understood that “stable” describes a state that the solution remains substantially unchanged in the percentage of active ingredient in solution so that it is suitable for its intended use during the relevant period of time. For example, if the solution is a medicament, the solution is in a stable state if it meets the standard for being used as a medicament as requested by a New Drug Application applicant and required by the relevant regulatory agency, such as the United States Food and Drug Administration. Thus, a stable solution may comprise certain minor degree of degradation, so long as the degree of degradation is not significant enough to make it unusable for its intended use, e.g., fall below the standard for use as a medicament. In some embodiments, the solution in the vial can be stored in the vial for about two years at room temperature. In some embodiments, no more than about 10% v/v oxygen in the head space increases the shelf life of the solution as compared to the vial containing an ambient atmosphere. Where the vial contains highly concentrated ketorolac solution, e.g., 12-38% or 15-35% w/v, storing the ketorolac composition under a gaseous atmosphere that has reduced oxygen content, for example, no more than about 10% v/v of oxygen, allows the composition to be stored at room temperatures for a sufficiently long period of time, such as two years, without significant degradation.
- A regularly shaped vial, such as the one shown in
FIG. 1 , has a substantially flat inner bottom. Further, there is typically a space between the tip of thedip tube 103 and the bottom of the vial to allow liquid to flow into the dip tube. This presents multiple issues such as the need to use excess solution to ensure that adequate amounts can be delivered in each dosing for a multiple dose container as well as potential introduction of air into the dip tube thereby providing less than the desired dose. In another embodiment of this invention, there is provided a high recovery vial for nasal spray which reduces the likelihood of air being introduced into the dip tube during administration while also reducing the amount of solution required to provide adequate dosing. High recovery vials are especially beneficial where the drug composition is expensive.FIG. 2 illustrates an example of ahigh recovery vial 200. As shown inFIG. 2 , the inner bottom of thehigh recovery vial 200 comprises a concave or “V” shapedbottom 201 so that residue drug solution (represented by the dashedline 202, while the dashedline 203 represents the amount of drug solution prior to use) is collected in the tip of the concave or “V” shapedbottom 201. The vial also comprises adip tube 204 having anotch 205 to allow the solution to go into thedip tube 204. In one embodiment, the dip tube is a stiff-notched dip tube. The vial comprises ahead space 104, which preferably has less than 10% v/v oxygen. - In another aspect, there is provided a nasal spray device, comprising: a vial having a volume of no more than 10 mL and a nasal spray system capped to the vial wherein the vial comprises a solution, a dip tube attached to the nasal spray system and dipping into the solution, and a head space above the solution, wherein the head space comprises no more than about 10% v/v oxygen. In some embodiments, the nasal spray device comprises the vial as described above. In preferred embodiments, the amount of oxygen in the head space is as provided above. A nasal spray device is one designed for the exit tip to be inserted into a patient's nostril to spray a defined amount of the solution into the nostril.
- In some embodiments, the nasal spray device is further equipped with a metering chamber to measure a desired amount of the composition to be sprayed into the patient's nasal passage. In one embodiment, the metering chamber is coupled with the spraying device so that a patient can simultaneously measure and spray a desired amount (e.g. a unit dose) of the composition. In one embodiment, the metering chamber is able to deliver a predetermined amount of about 50 to about 125 microliters of liquid. In one embodiment, the metering chamber is able to deliver from about 50 to about 100 microliters of liquid. In one embodiment, the metering chamber having different volume deliveries can be used. In one embodiment, the metering chamber is able to measure about 50 microliters of liquid. In one embodiment, the metering chamber is able to measure about 100 microliters of liquid. Appropriate vials and spray devices with or without a metering chamber are available to one of skill in the art by referring to “Remington's Pharmaceutical Sciences.” One source for such vessels is Ing. Erich Pfeiffer GmbH, Radolfzell, Germany. Another source is Valois, 50 avenue de l'Europe, 78164 MARLY-LE-ROI, France.
- In another aspect, the vial or nasal spray device of this invention is in combination with labeling instructions for use in treating a pain or inflammation in a human subject. In some embodiments, the pain is the result of a trauma inflicted on the subject. In some embodiments, the pain is the result of a medical operation performed on the subject. In some embodiments, the pain is pathological. In some embodiments, the pain is neuropathic. In some embodiments, the pain is migraine or other headache pain.
- In another aspect, the vial, or the nasal spray device of this invention further comprises a sealed oxygen-impermeable pouch covering the vial, which pouch comprises an inside space having an oxygen content of equal to or less than about 10% v/v. In some embodiments, the oxygen content of the inside space of the sealed pouch is capable of being maintained at a level of equal to or less than about 10% v/v for at least 2 years.
- In some embodiments, the oxygen content in the inside space of the pouch is at least equal to or less than about 5% v/v. In some embodiments, the oxygen content in the inside space of the pouch is capable of being maintained at equal to or less than about 10% v/v for at least two years, for example equal to or less than about 8% v/v for at least two years. In some embodiments, the inside space comprises an initial oxygen content of about 2% v/v. In some embodiments, the oxygen permeability of the pouch is less than 0.005 mL/package/day, or less than 0.0048 mL/package/day.
- In some embodiments, the sealed pouch has a dimension of about 5-8 centimeters by 12-15 centimeters, for example a dimension of about 6-6.5 centimeters by 14-15 centimeters. In a specific embodiment, the sealed wrap has a dimension of about 6.2 centimeters by 14.5 centimeters. In some embodiments, the sealed pouch has an inside volume of about 40-50 mL, more specifically about 45 mL. In some embodiments, the pouch is made from a polyester film, including polyethylene terphthalate and copolymers, a polyvinyl alcohol film, or a film comprising polyester and polyvinyl alcohol. In some embodiments, the film is selected from the group consisting of biaxially-oriented polyethylene terephthalate (BOPET, a polyester film made from stretched polyethylene terephthalate (PET)) films, cast polypropylene (CPP) films, including copolymer and terpolymer, multilayer polypropylene films, bi-axially oriented polypropylene (BOPP) films and thermal lamination films. In some embodiments, the film is metallized, such as the metallized polyester films (including polyethylene terphthalate and copolymers), metallized bi-axially oriented polypropylene (BOPP) films, and metalized cast polypropylene (CPP) films (including copolymers and terpolymer), and plasma metallised films, such as plasma metallized polyester films.
- Processes and equipment for preparing sealed bags for food packaging may be used to prepare the pouch. A vial of this invention comprising a ketololac composition and a head space with an equal to or less than 10% v/v oxygen is placed in the pouch with an opening. The pouch is then flushed with an inert gas, such as nitrogen and argon, which is sufficient to reduce the oxygen content of the inside space to below 10%, preferably below 5%, and more prefereably at or below 2%. The pouch is then sealed. Such processes are well known in the art. In some embodiments, the production speed is about 200 per minute.
- In some embodiments, the sealed pouch is in a fin seal flow wrap style with scalloped end seals. Other methods of sealing are well known in the art. It is to be understood that the specific manner of sealing is non-essential so long as the pouch is sealed to prevent oxygen from entering into the pouch through any opening of the pouch, or to minimize the ingress of oxygen in accordance with the teachings of this disclosure.
-
FIG. 7 illustrates an example of thevial 100 of this invention in a sealedpouch 601. The sealed pouch comprises aninside space 602 having an oxygen content of equal to or less than about 10% v/v. - In yet another aspect, there is provided a method of preparing a nasal spray device, the nasal spray device comprising: a vial having a volume of no more than 10 mL and a nasal spray system capped to the vial wherein the vial comprises a solution, a dip tube attached to the nasal spray system and dipping into the solution, and a head space above the solution, the process comprising:
- a) adding a pharmaceutical composition susceptible to degradation by oxygen;
- b) flowing an inert gas into the vial to purge the air out of the vial; and
- c) capping the vial with a nasal spray system,
- wherein the process results in an oxygen content in the head space of the vial equal to or less than about 10% v/v oxygen after the capping of the vial with the nasal spray system.
- In some embodiments, the inert gas is nitrogen. In some embodiments, the inert gas is a noble gas, such as argon.
- The following describes an efficient process to purge air from the vials, especially in a contemplated manufacturing context.
- In a conventional manufacturing facility, an
oxygen reduction device 300, as shown inFIG. 3 , is used for purging air out of a vial containing a solution before capping of the vial, for example 100 or 200, with, for example, a cap or a spray system. In order to purge air out of the vial, a stream of an inert gas, such as argon or nitrogen, may be passed over the vial using atube 301, also referred to as purge bar, attached to theoxygen reduction device 300. Thetube 301 as attached to theoxygen reduction device 300 can be seen partially inFIG. 3 . - This
tube 301 is illustrated fully inFIG. 4 . Thetube 301 comprises aninlet 401 and anoutlet 402 and a number ofholes 403 at various points on thetube 301. The nitrogen enters from theinlet 401 and passes through thetube 301 to exit throughoutlet 402. It is to be understood that theinlet 401 andoutlet 402 can be interchanged depending on the configuration of the attachedtube 301 with theoxygen reduction device 300. Theholes 403 pass a stream of inert gas, such as nitrogen or argon, over the vials. Typically, in a manufacturing process, nitrogen is preferred due to cost consideration. However, theholes 403 pass the inert gas around the vials and not into the vials. Additionally, thetube 301 is attached to theoxygen reduction device 300 in such a way that the inert gas may not pass directly into the mouth of the vials but may instead be around them. In the case of nitrogen, this diffusion of the nitrogen around the vials is further coupled with the fact that the nitrogen being lighter than the air will not replace the air in the vials. This can lead to the incomplete purging of the air from the vials. This incomplete purging may be more pronounced in an aseptic environment due to rapid air flow in that situation. After the last station, where a lid or a spray system is snapped on the vial to cap the vial, a significant amount of air may remain in the vial which may lead to the degradation of the solution, such as a medicament, in the vial. - In one aspect, there is provided an improved oxygen reduction device for purging air from a vial where the vial comprises a solution and a head space, the improved oxygen reduction device comprises a tube with one or more purging outlets that flow an inert gas such as nitrogen directly over and into the vial to purge the air out of the vial, although other inert gases such as argon can be used. The following description uses nitrogen to illustrate the device and process for brevity.
- The
tube 500 in the improvedoxygen reduction device 300 is as illustrated inFIG. 5 . Thetube 500 comprises aninlet 401 and anoutlet 402. The nitrogen enters from theinlet 401 and passes through thetube 500 to exit throughoutlet 402. It is to be understood that theinlet 401 andoutlet 402 can be interchanged depending on the configuration of the attachedtube 500 with the oxygen reduction device. Thetube 500 optimally may comprise twobrackets tube 500 to other components of theoxygen reduction device 300. Thetube 500 comprises one or more purging outlets 503 (also called bar nozzles) that direct the nitrogen directly on the mouth of the vial thereby effectively purging the air out of the vial.FIG. 5 comprises four such purgingoutlets 503 which is for illustration purposes only. It is well understood that the number of the purgingoutlets 503 can vary depending on, for example, theoxygen reduction device 300 and the length of the assembly line carrying the vials along the device, etc. It is also to be understood that the design of thetube 500,inlet 401 andoutlet 402,brackets outlets 503 inFIG. 5 is for illustration purposes only. It is contemplated that thepurging outlet 503 can have different configurations so long as it can deliver nitrogen directly onto the mouth of the vial. It is also contemplated that the length and size of thepurging outlet 503 and/or the position of the vial may be adjusted so that the distance between the tip of thepurging outlet 503 and the mouth of the vial can be optimal for delivering nitrogen inside the vial. - In some embodiments, the
tube 500 has at least two purgingoutlets 503. In some embodiments, thetube 500 has at least three purgingoutlets 503. In some embodiments, thetube 500 has four purgingoutlets 503. Thetube 500 can be made of materials well known in the art. For example, thetube 500 can be made of stainless steel. In some embodiments, thetube 500 is made of plated metal. It is important that the purgingoutlets 503 are oriented in such a manner that the distal end of thepurging outlet 503 is placed over the mouth of the vial. In some embodiments, at least onepurging outlet 503 of thetube 500 is close to a last station where a capping of the vial with the spray system takes place in order to minimize oxygen reentry into the gaseous atmosphere in the vial. The orientation of thepurging outlet 503 should be combined with a capping system such that capping occurs within 1 second of purging and preferably within 0.6 seconds of purging and even more preferably from 0.3 seconds to 0.5 seconds, and most preferably 0.4 second. - The one or more purging
outlets 503 of thetube 500 in theoxygen reduction device 300, as illustrated inFIG. 5 , flow nitrogen directly over and into the vial to purge the air out of the vial thereby reducing an oxygen content in the head space of the vial to equal to or less than about 10% v/v oxygen. In some embodiments, the reduction in the oxygen content in the head space of the vial to equal to or less than about 10% v/v oxygen is an improvement over a conventional oxygen reduction device wherein the reduction in the oxygen content in the head space of the vial is more than about 10% v/v oxygen. In some embodiments, the reduction in the oxygen content in the head space of the vial is equal to or less than about 8% v/v oxygen; equal to or less than about 5% v/v oxygen. In some embodiments, the reduction in the oxygen content in the head space of the vial is in the range of about 5-10%, 3-8% or 2-5% v/v. - In some embodiments, the improvement in the oxygen reduction device further comprises adjusting a flow rate of the nitrogen to reduce the oxygen content in the vial. The flow rate of the nitrogen can be increased or decreased depending on the purging of the air out of the vial. This adjustment of the nitrogen flow can help reduce the oxygen content in the vial. In some embodiments, the nitrogen flow rate is about 20 liters per minute (L/min) to about 80 L/min. In some embodiments, the nitrogen flow rate is about 40 L/min to 60 L/min. In some embodiments, the nitrogen flow rate is about 50 L/min.
- In some embodiments, the improvement in the oxygen reduction device further comprises adjusting a speed of a capping of the vial, such as with a nasal spray system. In some embodiments, the capping rate is selected to permit purging of from about 100 vials per minute to about 210 vials per minute. In some embodiments, the capping rate is about 150 vials per minute to about 210 vials per minute. In some embodiments, the capping rate is selected to permit purging of about 150 vials per minute. The adjustment of the speed of the capping may also comprise attaching a
purging outlet 503 inFIG. 5 closer to the last station where the capping of the vial takes place. By attaching thepurging outlet 503 closer to the last station, the time lag between the vial leaving the assembly line and reaching the capping end can be reduced thereby reducing the amount of time the vial is exposed to air. In some embodiments, the nitrogen is blown into the vial simultaneously with capping the vial. This improvement can further reduce the oxygen content in the vial. - Provided herein is also a process to purge air from a vial, especially in an aseptic environment, the vial comprising a solution and a head space, the process comprising: flowing an inert gas, such as nitrogen or argon, directly over and into the vial to purge the air out of the vial using an improved oxygen reduction device wherein the device comprises a tube with one or more purging outlets that flow the inert gas directly over and into the vial to purge the air out of the vial, wherein the process reduces an oxygen content in the head space of the vial to equal to or no more than about 10% v/v oxygen.
- Provided herein is also a process to manufacture a nasal spray device, especially in an aseptic environment, the nasal spray device comprising: a vial and a nasal spray system capped to the vial wherein the vial comprises a solution, a dip tube attached to the nasal spray system and dipping into the solution, and a head space above the solution, the process comprising:
- a) providing the vial to an improved oxygen reduction device wherein the improved oxygen reduction device comprises a tube with one or more purging outlets that flow nitrogen directly over and into the vial to purge the air out of the vial;
- b) flowing an inert gas, directly over and into the vial to purge the air out of the vial; and
- c) capping the vial with a nasal spray system;
- wherein the process reduces an oxygen content in the head space of the vial to equal to or less than about 10% v/v oxygen after the capping of the vial with the nasal spray system.
- In some embodiments, the inert gas is nitrogen. In some embodiments, the inert gas is a noble gas. In some embodiments, the inert gas is argon. In some embodiments, the rate of capping is selected to be fast enough to ensure that minimal atmospheric change occurs in the vial between completion of the purging and capping and slow enough to ensure that the purging process is effective. In some embodiments, capping occurs within about 0.28 to 1 second after purging so as to provide for 60 to 210 vials capped per minute; preferably within about 0.28 to 0.4 seconds (150 to 210 vials capped per minute).
- In some embodiments, all or a selected number of the treated and capped vials are passed through spectrometry analysis to measure the oxygen content and/or further remove the vials with unacceptable oxygen content.
- In some embodiments, the solution inside the vial is an intranasal formulation of ketorolac or a pharmaceutically acceptable salt thereof. In some embodiments, the bacterial load in the solution is less than about 100 colony forming units (CFU).
- In some embodiments, the intranasal formulation comprises concentrations of ketorolac, or a pharmaceutically acceptable salt, ranging from about 12.5 to 38% weight to volume (w/v), for example about 15%, 20%, 25%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, or 38% w/v, based on the final formulation.
- In some embodiments, the intranasal formulation comprises:
- (a) about 12.5% w/v to about 38% w/v of ketorolac or a pharmaceutically acceptable salt thereof, and
- (b) a pharmaceutically acceptable carrier.
- In some embodiments, the composition further comprises a local anesthetics, such as lidocaine, or a pharmaceutically acceptable salt, ranging from about 4% to 10%, for example about 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/v. As disclosed in US Patent Application Publication No. 2009/0042968, which is incorporated herein by reference in its entirety, the addition of lidocaine to the 15% ketorolac composition has been found to provide unexpected advantageous synergistic effects. First, the combination substantially reduces the stinging sensation caused by ketorolac. Second, while lidocaine is a local anesthetic that is known to cause numbness, such numbness is substantially absent or reduced when lidocaine is combined with ketorolac. Third, combination of 5 to 6% of lidocaine with ketorolac have been found to decrease the Tmax for ketorolac to reach its Cmaxin a subject's plasma, providing a subject with faster and better pain relief. It is contemplated that when the concentration of ketorolac is increased to up to about 38%, the amount of lidocaine can be maintained at a level of 4-10% or preferably 5-6% and yet still inhibits the stinging sensation of ketorolac.
- In some embodiments, the intranasal formulation comprises:
- (a) about 12.5% w/v to about 38% w/v of ketorolac or a pharmaceutically acceptable salt thereof,
- (b) about 4% w/v to about 10% w/v of lidocaine or a pharmaceutically acceptable salt thereof, and
- (c) a pharmaceutically acceptable carrier.
- In some embodiments, ketorolac is as a racemic mixture. In some embodiments, the pharmaceutically acceptable salt of ketorolac is ketorolac tromethamine. In some embodiments, the intranasal formulation comprises about 13% to 20% w/v of ketorolac tromethamine. In some embodiments, the intranasal formulation comprises about 15% w/v of ketorolac tromethamine. In some embodiments, the intranasal formulation comprises about 25% to 35% w/v of ketorolac tromethamine. In some embodiments, the intranasal formulation comprises about 28% to 32% w/v of ketorolac tromethamine. In some embodiments, the intranasal formulation comprises about 30% w/v of ketorolac tromethamine.
- In some embodiments, the intranasal formulation comprises lidocaine hydrochloride. In some embodiments, the intranasal formulation comprises about 5-6% lidocaine hydrochloride.
- In some embodiments, the intranasal formulation comprises about 6% lidocaine hydrochloride.
- In some embodiments, the intranasal formulation further comprises a chelator, i.e. a substance that binds primarily di- or tri valent metallic ions (e.g. calcium) that might interfere with the stability or activity of the active ingredient. Chelators are known to those of skill in the art by referring to the recent edition of “Remington's Pharmaceutical Sciences.” A preferred chelator is sodium ethylenediamine tetraacetic acid (sodium EDTA), USP. In some embodiments, the chelator is disodium edetate. The amount of may be from about 0.01% w/v to about 0.1% w/v, for example, 0.02, 0.05, 0.075, and 0.10 w/v.
- In some embodiments, the pH of the intranasal formulation is about 4.5 to 8. In some embodiments, the pH is about 4.8 to 7.5. In some embodiments, the pH is about 7.2.
- In some embodiments, the pH is adjusted by a pharmaceutically acceptable base. In some embodiments, the pharmaceutically acceptable base is sodium hydroxide.
- A pharmaceutically acceptable buffer may be present in order to create optimum pH conditions for both product stability and tolerance (pH range about 4 to about 8; preferably about 6.0 to 7.5). Suitable buffers include without limitation tris(tromethamine) buffer, phosphate buffer, etc. Preferably potassium phosphate NF is used to adjust the pH to 7.2. In some embodiments, the composition comprises up to about 2% of a phosphate buffer, such as potassium phosphate monobasic, potassium phosphate dibasic. In some embodiments, the composition comprises about 0.6 to 0.8% w/v of potassium phosphate monobasic. In some embodiments, the composition comprises about 0.68% w/v of potassium phosphate monobasic.
- In some embodiments, the intranasal formulation is a sprayable liquid.
- In some embodiments, the pharmaceutically acceptable carrier is water.
- In some embodiments, the intranasal formulation comprises:
- (a) about 15% w/v of racemic ketorolac tromethamine,
- (b) about 0.01% w/v to about 0.1% w/v of disodium edetate,
- (c) about 0.68% w/v of potassium phosphate monobasic,
- (d) sodium hydroxide to adjust the pH to 7.2, and
- (e) water to 100% w/v.
- In some embodiments, the intranasal formulation comprises:
- (a) about 15% w/v of racemic ketorolac tromethamine,
- (b) about 5% w/v to about 6% w/v lidocaine hydrochloride,
- (c) about 0.01% w/v to about 0.1% w/v of disodium edetate,
- (d) about 0.68% w/v of potassium phosphate monobasic,
- (e) sodium hydroxide to adjust the pH to 7.2, and
- (f) water to 100% w/v.
- In some embodiments, the intranasal formulation comprises:
- (a) about 30% w/v of racemic ketorolac tromethamine,
- (b) about 0.01% w/v to about 0.1% w/v of disodium edetate,
- (c) about 0.68% w/v of potassium phosphate monobasic,
- (d) sodium hydroxide to adjust the pH to 7.2, and
- (e) water to 100% w/v.
- In some embodiments, the intranasal formulation comprises:
- (a) about 30% w/v of racemic ketorolac tromethamine,
- (b) about 5% w/v to about 6% w/v lidocaine hydrochloride,
- (c) about 0.01% w/v to about 0.1% w/v of disodium edetate,
- (d) about 0.68% w/v of potassium phosphate monobasic,
- (e) sodium hydroxide to adjust the pH to 7.2, and
- (f) water to 100% w/v.
- The intranasal formulation may optionally comprise one or more pharmaceutically acceptable excipients. The preferred diluent for the formulations is water, and other excipients may be added if desired.
- In addition to aqueous, oil or gel diluents, other diluents which may be used in the intranasal formulation comprise solvent systems containing ethyl alcohol, isopropyl alcohol, propylene glycol, polyethylene glycol, mixtures thereof or mixtures of one or more of the foregoing with water.
- Other excipients include chemical enhancers such as absorption promoters. These include fatty acids, bile acid salts and other surfactants, fusidic acid, lysophosphatides, cyclic peptide antibiotics, preservatives, carboxylic acids (ascorbic acid, amino acids), glycyrrhetinic acid, o-acylcarnitine. Preferred promoters are diisopropyladipate, POE(9) lauryl alcohol, sodium glycocholate and lysophosphatidyl choline which proved to be particularly active.
- If present, excipients such as oil, gel, chemical enhancers, including abosorption promoters, etc. should be in an amount that does not adversely affect the homogeneity and sprayability of the solution.
- The intranasal formulation can also contain a compatible preservative that ensures the microbiological stability of the active ingredient. Suitable preservatives include without limitation, methyl paraoxybenzoate (methyl paraben), propyl paraoxybenzoate (propyl paraben), sodium benzoate, benzyl alcohol, and chlorobutanol. In one embodiment, the intranasal ketorolac formulation does not contain a preservative.
- Illustrative formulations may contain the following ingredients and amounts (w/v) in addition to ketorolac, lidocaine and water.
-
Ingredient Broad Range (%) Preferred Range (%) Chelator (1) 0.001-1 0.01-0.1 Preservative (2) 0-2 0-0.25 Absorption promoter (3) 0-10 0-10 Gelling polymer (4) 0-5 0-3 Co-solvent (5) 0-99 0 (1) E.g., sodium EDTA (2) E.g., methyl paraoxybenzoate or propyl paraoxybenzoate or mixtures thereof (3) E.g., sodium glycocholate (4) E.g., sodium CMC (5) E.g., glycerol - The following examples are provided to illustrate certain aspects of the present invention and to aid those of skill in the art in practicing the invention. The examples are in no way to be considered to limit the scope of the invention.
- Headspace oxygen concentrations were measured using a Lighthouse Instruments FMS-760 Headspace Oxygen Analyzer. The measurements were made to assess the performance of a nondestructive measurement method for headspace oxygen analysis.
- Laser absorption spectroscopy is an optical measurement method for rapid and non-invasive headspace gas analysis of containers, such as parenteral containers or containers for intranasal spray. The technique can measure a number of physical parameters within the headspace of the container, including gas concentrations and total headspace pressures.
- Light from a near-infrared semiconductor laser is tuned to match the internal vibrational frequency of the target molecule. The light is passed through the headspace region of a container, scanned in frequency and detected by a photodetector. The amount of light absorbed is proportional to the target molecule concentration.
- The instruments incorporate a high sensitivity detection method known as frequency modulation spectroscopy.
- Oxygen absorbs near infrared light in a band of transitions centered at 0.762 μm. The oxygen A-band is a series of rotational transitions within the 0-0 vibrational band of the X3Σ− g←b1Σ+ g magnetic dipole transition.
- The amount of laser light absorbed by an individual transition in the oxygen A-band is proportional to the oxygen concentration in the headspace of a parenteral or nasal spray container. In general the laser frequency is repeatedly scanned over the absorption feature and successive scans are averaged to improve the signal to noise ratio. The averaged light absorption signal (an example shown in
FIG. 6 ) and the total power are then multiplied by a calibration constant to yield the headspace oxygen concentration. - An instrument calibration constant, k, is determined using a vial filled with a known concentration of oxygen. Oxygen standards are prepared using certified gas mixtures of oxygen and nitrogen. A 20% oxygen/80% nitrogen standard is used for FMS-760 calibration.
- A calibration standard is inserted to the instrument, the system response (signal amplitude, S, and power, P) is measured and a calibration constant is computed.
- The instrument calibration procedure is fully automated and controlled by the instrument computer. Once the user inputs the calibration vial and initiates the calibration routine the instrument begins to record data and using the known concentration computes a calibration constant k,
-
k=(P/S)·Known Concentration [1] - where P is the detected laser power, S is the peak to peak absorption signal (see
FIG. 6 for oxygen example), and Known Concentration is the concentration in the calibration vial. The measured values of P and S are the average of 1000 scans (10 s acquisition time). The system stores the calibration constant and uses it for subsequent sample measurements. - The instrument data acquisition system uses the stored calibration constant to determine the headspace oxygen concentration in a sample. When a sample with an unknown concentration is inserted to an instrument the system measures the absorption signal and laser power and multiplies by the calibration constant to determine the headspace oxygen or water vapor concentration.
-
- where Sm is the sample signal amplitude, Pm is the laser power transmitted through the sample, Pc is the calibration power and Sc is the calibration signal amplitude, % Oxygen in Standard is the known amount of oxygen in the calibration vial.
- Headspace oxygen measurements were performed using a Lighthouse Instruments FMS-760 Headspace Oxygen Analyzer (SN 760-104). The instrument was turned on and allowed to warm up for thirty minutes. Calibration was performed using a 21% oxygen standard. The headspace oxygen concentration in each sample was measured three times.
- A suitable length of a tubing, preferably made of a chemical resistant polymer and preferably free from contamination, is connected to an argon or nitrogen gas tank at one end. The other end of the tubing is inserted in the mouth of a vial having a ketorolac solution and an about 2 mL head space, preferably the tubing does not touch the ketorolac solution inside the vial. Argon or nitrogen is passed through the tubing into the vial for a sufficient amount of time so that the oxygen content in the head space of the vial is less than 10%. The tubing is removed from the vial and the vial is capped with a nasal spray system and stored at room temperature.
- Vials were processed using a conventional oxygen reduction device having a tube with purging holes. Other conditions are the same as described in Example 4 below. The oxygen content of the following five sets of glass vials were tested using the above described protocol of Example 1. The individual results were recorded and averaged and mean concentration and standard deviation were computed. The results of the samples tested are summarized below.
- Set 1: Five 4 mL Clear Glass Vials Containing a 2 mL Fill of Solution with Nitrogen Overlay
- The individual headspace oxygen measurements of the five samples varied from between 17.8% to 20.5%, and the average headspace oxygen concentrations of the each of the five samples varied between 18.3% and 20.2%, with a mean of 19.0% and a standard deviation of 0.80%.
- Set 2: Five 4 mL Clear Glass Vials Containing a 2 mL Fill of Solution without Nitrogen Overlay
- The individual headspace oxygen measurements of the five samples varied from between 20.2% to 21.7%, and the average headspace oxygen concentrations of each of the five samples varied between 20.6% and 21.1%, with a mean of 20.8% and a standard deviation of 0.20%.
- Set 3: Five 4 mL Clear Glass Vials Containing a 2 mL Fill of Solution with Nitrogen Overlay
- Set 3 is a repeat of
Set 1, except that in Set 3 the samples were collected after stopping the capper (simulated line stoppage) for 5 minutes and resuming the capping operation. - The individual headspace oxygen measurements of the five samples varied from between 18.2% to 22.0%, and the average headspace oxygen concentrations of each of the five samples varied between 18.7% and 21.4%, with a mean of 19.5% and a standard deviation of 1.11%.
- Set 4: Five Empty 4 mL Clear Glass Vials with Nitrogen Overlay
- The individual headspace oxygen measurements of the five samples varied from between 20.5% to 21.9%, and the average headspace oxygen concentrations of each of the five samples varied between 18.4% and 21.8%, with a mean of 19.9% and a standard deviation of 1.46%.
- Set 5: Five Empty 4 mL Clear Glass Vials without Nitrogen Overlay
- The individual headspace oxygen measurements of the five samples varied from between 18.1% to 21.7%, and the average headspace oxygen concentrations of each of the five samples varied between 21.1% and 21.4%, with a mean of 21.3% and a standard deviation of 0.12%.
- This experiment was conducted to determine optimal nitrogen flow at capping rates of 150 and 210 vials per minute utilizing an improved oxygen reduction device of this invention. Further engineering changes within the skill in the art can be applied to generate commercial or manufacture devices.
- The experiment was conducted using 20 mm Hi-Recovery vials (4 mL) and snap-on metering pump. The vials were filled with about 1.8 mL of injection quality water (WFI) while purged with nitrogen having varying flow rates. The experiment was repeated with a similar oxygen reduction device having GMP quality. Twenty vials from each fill speed and flow rate combination were sampled and tested. Result summaries are shown in the following tables 1 and 2.
-
TABLE 1 150 Vials per Minute - Results in % O2 (v/v) 0 L/min 20 L/min 40 L/min 60 L/min 80 L/min Average* 20.49 9.53 6.89 6.69 6.78 Minimum** 19.83 8.49 6.10 5.25 5.42 Maximum*** 21.17 12.45 9.52 9.22 10.27 -
TABLE 2 210 Vials per Minute - Results in % O2 (v/v) 0 L/min 20 L/min 40 L/min 60 L/min 80 L/min Average* 20.60 11.03 9.23 7.49 8.14 Minimum** 19.99 8.01 6.99 6.29 6.66 Maximum*** 21.57 13.66 19.29 13.42 17.03 *“Average” indicates the average O2 content in the tested vials for the respective group. **“Minimum” indicates the O2 content of the vial with the lowest O2 content in the respective group. ***“Maximum” indicates the O2 content of the vial with the highest O2 content in the respective group. - The data show all vials prepared using the 150 vials per minute rate had an oxygen content of less than 13% and all vials prepared with flow rates at 40 and 60 L/min had an oxygen content of below the 10%.
- The data show that the capping rate is one of the critical parameters in ensuring that the head space of the vials maintains an oxygen concentration of 10% v/v or less. The results indicate that oxygen contents for the vials run at 150 vials per minute were generally lower than the same settings at 210 vials per minute. It is contemplated that capping speeds would directly affect the amount of retention time each vial has under the oxygen reduction device bar nozzles. In addition, at the high machine speed (210 vials per minute), frequent pauses were observed as the pump bowl was not supplying pumps at the same rate. This may have caused the high oxygen contents in some of the vials prepared at a rate of 210 vials per minute. It is anticipated that adjusted operation of the pump bowl would reduce the frequency and duration of the pauses, which would result in tighter oxygen level results. Another solution is to reject vials after machine stoppage.
- Residual oxygen contents for 80 L/min at both speeds were slightly higher than those observed at the 60 L/min flow. As flow rate gets higher, the volume that can be displaced is higher, but the flow also grows more turbulent, possibly entraining ambient air with the purge air.
- It is to be understood that while the invention has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.
Claims (10)
Priority Applications (2)
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US13/791,780 US20130186391A1 (en) | 2009-03-13 | 2013-03-08 | Device for intranasal administration of ketorolac |
US15/449,295 US20170173277A1 (en) | 2009-03-13 | 2017-03-03 | Device for intranasal administration |
Applications Claiming Priority (3)
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US12/404,250 US8277781B2 (en) | 2009-03-13 | 2009-03-13 | Device for intranasal administration |
US12/722,137 US8551454B2 (en) | 2009-03-13 | 2010-03-11 | Device for intranasal administration |
US13/791,780 US20130186391A1 (en) | 2009-03-13 | 2013-03-08 | Device for intranasal administration of ketorolac |
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US12/722,137 Division US8551454B2 (en) | 2009-03-13 | 2010-03-11 | Device for intranasal administration |
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US15/449,295 Continuation US20170173277A1 (en) | 2009-03-13 | 2017-03-03 | Device for intranasal administration |
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US13/791,780 Abandoned US20130186391A1 (en) | 2009-03-13 | 2013-03-08 | Device for intranasal administration of ketorolac |
US15/449,295 Abandoned US20170173277A1 (en) | 2009-03-13 | 2017-03-03 | Device for intranasal administration |
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US11053037B2 (en) * | 2017-10-06 | 2021-07-06 | Hikma Pharmaceuticals Usa Inc. | System and method for purging oxygen from medical vials |
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US9068694B2 (en) * | 2010-09-22 | 2015-06-30 | Philip J. Gordon Consultants, Inc. | Method of controlling by-products of vitamin C degradation and improving package integrity shelf life |
USD995753S1 (en) * | 2021-02-16 | 2023-08-15 | Joanne M. Tobiasz-Dey | Nasal spray device |
USD970353S1 (en) * | 2022-01-27 | 2022-11-22 | Huang Huang | Oil bottle with brush |
USD980084S1 (en) * | 2022-05-31 | 2023-03-07 | Xiuxia Jiang | Bottle |
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US8551454B2 (en) | 2013-10-08 |
US20100233024A1 (en) | 2010-09-16 |
US20170173277A1 (en) | 2017-06-22 |
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