US20070111964A1 - Vitamin B12 nasal spray and method of use - Google Patents

Vitamin B12 nasal spray and method of use Download PDF

Info

Publication number
US20070111964A1
US20070111964A1 US11/506,148 US50614806A US2007111964A1 US 20070111964 A1 US20070111964 A1 US 20070111964A1 US 50614806 A US50614806 A US 50614806A US 2007111964 A1 US2007111964 A1 US 2007111964A1
Authority
US
United States
Prior art keywords
set forth
cobalamin compound
dose
aqueous composition
cobalamin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/506,148
Other languages
English (en)
Inventor
Theodore Feller
Angela Sutterer
Thomas Fleming
Patrick Arnall
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Endo Pharmaceuticals Inc
Fleming and Co Pharmaceuticals
Original Assignee
Fleming and Co Pharmaceuticals
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fleming and Co Pharmaceuticals filed Critical Fleming and Co Pharmaceuticals
Priority to US11/506,148 priority Critical patent/US20070111964A1/en
Publication of US20070111964A1 publication Critical patent/US20070111964A1/en
Priority to US12/618,099 priority patent/US9186374B2/en
Priority to US14/738,417 priority patent/US10251908B2/en
Priority to US14/878,430 priority patent/US10052344B2/en
Assigned to ENDO PHARMACEUTICALS INC. reassignment ENDO PHARMACEUTICALS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ENDO PAR INNOVATION COMPANY, LLC, PAR PHARMACEUTICAL, INC.
Priority to US16/296,876 priority patent/US20190216842A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • 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
    • A61M11/006—Sprayers or atomisers specially adapted for therapeutic purposes operated by applying mechanical pressure to the liquid to be sprayed or atomised
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the present invention relates generally to vitamin B 12 nasal spray compositions and methods of using the same in the treatment of vitamin B 12 deficiency and various disorders that are related to such deficiency.
  • the present invention is directed to treatment methods comprising intranasal administration of a cobalamin composition according to a particular dosing and frequency schedule and to a preservative-free nasal spray composition comprising a cobalamin compound useful in the practice of such treatment methods.
  • Vitamin B 12 is a water soluble vitamin that plays a role in mammalian growth, hematopoiesis, production of epithelial cells, and maintenance of the nervous system. It was first isolated from liver concentrate in 1948 and structurally elucidated in the late 1950's.
  • Cyanocobalamin is a form of vitamin B 12 and is one of the class of B 12 vitamins or cobalamin compounds that includes vitamin B 12a (hydroxocobalamin), vitamin B 12b (aquacobalamin), vitamin B 12c (nitrilocobalamin), methyl B 12 (methylcobalamin) and coenzyme B 12 (5′deoxyadenosine cobalamin).
  • Cyanocobalamin and hydroxocobalamin are the principal members of the class and the most widely employed in compositions used to treat vitamin B 12 deficiency and disorders that are related to this deficiency. Such disorders include anemias (most commonly pernicious anemia) and diphyllobothrium latum (fish tapeworm) infestation of the intestine, a disorder with symptomology that mimics pernicious anemia.
  • vitamin B 12 Several routes of administration of vitamin B 12 are known. Among these are parenterally, including intramuscular and subcutaneous injection, orally as a component of a tablet or solution, and nasally, as a component of a nasal spray or gel. Although the minimum daily dietary requirement of vitamin B 12 is approximately 0.1 ⁇ g for a healthy human, therapeutic administration of vitamin B 12 is typically in significantly larger doses. For example, the prescribed initial therapeutic dose is generally from about 100 ⁇ g to about 1000 ⁇ g, and is most often administered by intramuscular injection. Subsequent vitamin B 12 maintenance therapy may be by injection or by oral administration of a cobalamin composition. Use of vitamin B 12 injections for maintenance therapy has obvious disadvantages, including the inconvenience and pain associated with the injection that typically must be administered by medical personnel. Orally administered cobalamin compositions may fail to be adequately absorbed in the patient, particularly in those in which secretion or utilization of intrinsic factor is inadequate.
  • Intranasal administration of cobalamin compositions for vitamin B 12 maintenance therapy offers advantages over these alternative routes of administration.
  • such therapy includes relatively infrequent, high dose nasal administration of a cobalamin composition.
  • NASCOBAL nasal spray solution containing 0.5% by weight cyanocobalamin is administered in one nostril once weekly in a dose of 500 ⁇ g (i.e., 500 ⁇ g cyanocobalamin per 0.1 mL actuation of the spray bottle pump).
  • vitamin B 12 nasal compositions Although maintenance therapy with vitamin B 12 nasal compositions has proven generally effective, those undergoing such therapy may experience some irritation of the nasal mucosa and discomfort due, in part, to the high dosage of the cobalamin compound typically administered as well as preservatives and other additives often present in these compositions. Moreover, effective vitamin B 12 maintenance therapy would be enhanced if more stable or even blood serum levels of vitamin B 12 could be attained through intranasal administration of a cobalamin composition. Accordingly, a need persists for improvements in vitamin B 12 nasal compositions and methods of nasal administration of such compositions in the treatment of vitamin B 12 deficiency and various vitamin B 12 deficiency-mediated disorders.
  • the present invention is directed to a method for maintaining vitamin B 12 blood serum levels in a mammals, the method comprising nasally administering to the mammal at least once every three days an aqueous composition comprising a cobalamin compound in an amount sufficient to deliver a dose of no more than about 150 ⁇ g of the cobalamin compound to the mammal.
  • the present invention is further directed to a method for maintaining normal hematologic status in a pernicious anemia patient following intramuscular vitamin B 12 injection therapy, the method comprising nasally administering to said patient at least once every three days an aqueous composition comprising a cobalamin compound in an amount sufficient to deliver a dose of no more than about 150 ⁇ g of the cobalamin compound to the patient.
  • the present invention is further directed to a composition for nasal administration of a cobalamin compound, the composition comprising an aqueous solution containing a cobalamin compound and a pharmaceutically acceptable buffer, the composition having a pH of at least about 6.5.
  • the present invention is further directed to a composition for nasal administration of a cobalamin compound, the composition comprising an aqueous solution containing a cobalamin compound and a pharmaceutically acceptable buffer and being free of preservatives.
  • FIG. 1 depicts the mean serum vitamin B 12 levels and 95% confidence interval for all six visits in the study conducted in the Example.
  • the present invention is based in part on the observation that conventional intranasal administration of cobalamin compositions may lead to irritation of the nasal membranes or mucosa. Irritation may be caused or exacerbated by the relatively high dose of cobalamin compound typically administered and/or preservatives and other additives commonly contained in these compositions. This irritation, compounded by infrequent, high dose administration of conventional intranasal cobalamin compositions (e.g., anywhere from once a week to as rarely as once a month), can lead to patient noncompliance and variable blood serum vitamin B 12 levels and ultimately to inconsistent or ineffective treatment of vitamin B 12 deficiency-mediated disorders.
  • the present invention is directed to methods for maintaining vitamin B 12 blood serum levels in a mammal comprising more frequent intranasal administration of a cobalamin composition and at lower dosages than previously recognized as effective in the treatment of such disorders.
  • the present invention further provides compositions containing a cobalamin compound useful in the practice of the treatment methods disclosed herein, while minimizing the risk of irritation of the nasal mucosa and patient noncompliance with the prescribed treatment regimen.
  • the treatment methods disclosed herein are generally applicable for maintenance of vitamin B 12 blood serum levels in a patient in need of vitamin B 12 therapy.
  • a patient may be suffering from a vitamin B 12 deficiency, a disorder resulting from such a deficiency, or a disorder mimicking the symptomology of such a deficiency.
  • disorders resulting from or mimicking a vitamin B 12 deficiency include, for example, anemia, including pernicious anemia; nerve degeneration, typically as a result of degradation or lack of myelin; and infestation by intestinal parasites or bacteria such as diphyllobothrium latum (fish tapeworm) that absorb large quantities of vitamin B 12 in the host.
  • vitamin B 12 malabsorption phenomena such as that resulting from inadequate secretion and/or utilization of intrinsic factor (e.g., due to HIV infection, AIDS, Crohn's disease, tropical and nontropical sprue, extensive neoplasia, subtotal or total gastrectomy, etc.); maintenance of vitamin B 12 in excess of normal dietary requirements due to pregnancy, renal disease, thyrotoxicosis, hemolytic anemia, hemorrhage, etc; and patients having elevated serum homocysteine, cystathionine, methylmalonic acid and/or 2-methylcitric acid levels.
  • the present invention is directed particularly to the treatment of humans in need of vitamin B 12 therapy.
  • the methods disclosed herein are generally applicable to the treatment of mammals including, for example, domesticated house pets, such as dogs and cats, as well as farm animals, such as cattle, pigs, horses, sheep and goats.
  • the treatment methods of the present invention comprise more frequent and lower dose intranasal administration of a composition containing a cobalamin compound. It has been discovered that more frequent and lower dose intranasal administration of a cobalamin composition offers several advantages over conventional intranasal vitamin B 12 maintenance therapy, including reduced risk of irritation of the nasal mucosa and more stable or even vitamin B 12 blood serum levels (i.e., smaller peak to trough variances) by more closely mimicking the typical mammalian dietary intake of vitamin B 12 . Moreover, it is believed that patient compliance is improved by treatment regimens including more frequent administration of the cobalamin composition.
  • compositions used in the practice of the methods disclosed herein include, for example, aqueous solutions of the cobalamin compound along with various optional components such as isotonicity agents, buffering agents, humectants, surfactants and preservatives.
  • the treatment method for maintaining vitamin B 12 blood serum levels in a mammal in accordance with the present invention comprises nasally administering to the mammal an aqueous composition comprising a cobalamin compound at least once every three days, preferably at least once every two days.
  • the frequency of administration may vary during the treatment period.
  • the composition may be administered every day during an initial portion (e.g., the first week or first two weeks) of the treatment period (e.g., daily during an initial “loading” period to increase vitamin B 12 blood serum levels), and then at less frequent intervals during the remainder of the treatment period.
  • administration preferably occurs at regular intervals throughout the treatment period.
  • the treatment method of the present invention comprises daily intranasal administration (i.e., one or more administrations per day), and especially once daily, intranasal administration of the cobalamin composition during the treatment period.
  • the dose of the cobalamin compound delivered to the patient with each administration will vary generally with the frequency of administration (a higher dose being utilized with longer intervals between administrations), as well as with the needs of the patient and the type of disorder being treated, as would be apparent to those skilled in the art, but is generally lower than the dosing conventionally employed.
  • the dose of the cobalamin compound delivered to the patient with each administration is no more than about 150 ⁇ g, preferably no more than about 125 ⁇ g, more preferably no more than about 100 ⁇ g, and still more preferably no more than about 75 ⁇ g of the cobalamin compound, and is at least 5 ⁇ g, preferably at least about 10 ⁇ g of the cobalamin compound.
  • the daily dose of the cobalamin compound delivered to the patient is preferably from about 5 ⁇ g to about 100 ⁇ g, more preferably from about 20 ⁇ g to about 80 ⁇ g, still more preferably from about 30 ⁇ g to about 70 ⁇ g and even more preferably from about 40 ⁇ g to about 60 ⁇ g.
  • the dose of the cobalamin compound delivered to the patient with each administration is usually no more than about 80 ⁇ g.
  • the dose of the cobalamin compound delivered to the patient with each administration is preferably from about 5 ⁇ g to about 80 ⁇ g, more preferably from about 10 ⁇ g to about 60 ⁇ g, more preferably from about 15 ⁇ g to about 50 ⁇ g, more preferably from about 20 ⁇ g to about 50 ⁇ g, more preferably from about 30 ⁇ g to about 50 ⁇ g, still more preferably from about 40 ⁇ g to about 50 ⁇ g and even more preferably from about 45 ⁇ g to about 50 ⁇ g.
  • the dose of the cobalamin compound delivered to the patient per administration may be about 10 ⁇ g, about 15 ⁇ g, about 20 ⁇ g, about 25 ⁇ g, about 30 ⁇ g, about 35 ⁇ g, about 40 ⁇ g, about 45 ⁇ g, or about 50 ⁇ g.
  • the dose of the cobalamin compound delivered to the patient with each administration is from about 5 ⁇ g to about 45 ⁇ g, preferably from about 10 ⁇ g to about 45 ⁇ g, more preferably from about 15 ⁇ g to about 45 ⁇ g, more preferably from about 20 ⁇ g to about 45 ⁇ g, still more preferably from about 30 ⁇ g to about 45 ⁇ g, and even more preferably from about 40 ⁇ g to about 45 ⁇ g.
  • each administration may comprise one or a plurality of applications or sprays of the cobalamin composition delivered to the nasal mucosa of the patient through one or both nostrils, the number of applications or sprays being dependent upon the concentration of the cobalamin compound in the composition, the quantity of the composition delivered per spray, and the desired dose per administration as readily determined by one skilled in the art.
  • the cobalamin composition is preferably dispensed from a spray bottle including a pump (e.g., a manually actuated pump) capable of delivering a metered spray of the cobalamin composition of predetermined volume (typically about 0.1 mL).
  • a daily dose of 50 ⁇ g of a cobalamin compound may be administered in a single administration comprising one or more applications or metered sprays containing a total of 50 ⁇ g of cobalamin compound (e.g., a single administration comprising two applications or metered sprays, one in each nostril and each containing 25 ⁇ g of cobalamin compound) or in multiple administrations (e.g., four administrations at six hour intervals, each administration comprising one or more applications or metered sprays, in one or both nostrils, each administration containing a total of 12.5 ⁇ g of cobalamin compound).
  • a single administration comprising two applications or metered sprays, one in each nostril and each containing 25 ⁇ g of cobalamin compound
  • multiple administrations e.g., four administrations at six hour intervals, each administration comprising one or more applications or metered sprays, in one or both nostrils, each administration containing a total of 12.5 ⁇ g of cobalamin compound.
  • the weekly dose of the cobalamin compound received by the patient will generally not be in excess of about 1000 ⁇ g, more preferably about 800 ⁇ g, still more preferably about 600 ⁇ g, even more preferably about 500 ⁇ g, still more preferably about 450 ⁇ g, even more preferably about 400 ⁇ g, and most preferably not in excess of about 350 ⁇ g of the cobalamin compound. Accordingly, in one embodiment, the patient may receive a weekly dosage of from about 50 ⁇ g to about 500 ⁇ g of the cobalamin compound. In another embodiment, the patient may receive a weekly dosage of from about 100 ⁇ g to about 450 ⁇ g of the cobalamin compound.
  • the patient may receive a weekly dosage of from about 150 ⁇ g to about 400 ⁇ g of the cobalamin compound. In still another embodiment, the patient may receive a weekly dosage of from about 200 ⁇ g to about 400 ⁇ g of the cobalamin compound. In yet another embodiment, the patient may receive a weekly dosage of from about 250 ⁇ g to about 350 ⁇ g of the cobalamin compound. In still another embodiment, the patient may receive a weekly dosage of from about 300 ⁇ g to about 350 ⁇ g of the cobalamin compound. In a particularly preferred embodiment, the patient may receive a weekly dosage of about 350 ⁇ g of the cobalamin compound, delivered by once daily nasal administration of 50 ⁇ g of a cobalamin compound.
  • a further aspect of the present invention is a composition comprising a cobalamin compound that may be used in a regimen to treat vitamin B 12 deficiency and deficiency related disorders.
  • the composition may be used in previously known regimens of treatment for vitamin B 12 deficiency, but preferably is used in the practice of the treatment regimen of the present invention described above.
  • a composition of the present invention generally comprises an aqueous solution containing a cobalamin compound.
  • the aqueous solution is preferably isotonic.
  • the cobalamin may be any of a number of known cobalamin compounds, including for example, cyanocobalamin, hydroxocobalamin (vitamin B 12a ), hydroxocobalamin HCl, sulfate, acetate and other hydroxocobalamin salts, aquacobalamin (vitamin B 12b ), nitrilocobalamin (vitamin B 12c ), methylcobalamin (methyl B 12 ), 5′-deoxyadenosine cobalamin (coenzyme B 12 ), pharmaceutically acceptable salts thereof, chemically modified equivalents thereof, and mixtures thereof.
  • cobalamin The selection of the specific form of cobalamin to be used in the composition depends upon a number of factors known to those of skill in the art, including, for example, the composition in which the cobalamin compound is to be mixed or dissolved, the amount or concentration of cobalamin compound desired in the composition, the solubility of the cobalamin compound and the pH of the composition.
  • the cobalamin compound is cyanocobalamin USP.
  • the cobalamin compound is hydroxocobalamin.
  • the concentration of the cobalamin compound in the composition can vary depending upon a number of factors known to those skilled in the art, including, for example, the composition in which the cobalamin compound is to be mixed or dissolved, the solubility of the cobalamin compound, the pH of the composition, the means by which the cobalamin composition is delivered to the nasal mucosa (e.g., using compressed gas or a propellant), the volume of the spray dispensed per application and the desired dosage to be delivered to the patient.
  • the cobalamin compound may be present in the composition in a concentration of no more than about 20 weight percent (% w/w), for example, from about 0.0001% w/w to about 20% w/w, preferably from about 0.01% w/w to about 10% w/w, more preferably from about 0.02% w/w to about 1% w/w, still more preferably from about 0.02% w/w to about 0.04% w/w and most preferably about 0.025% w/w.
  • % w/w weight percent
  • the isotonicity of the composition may generally be achieved and maintained using sodium chloride or another pharmaceutically acceptable isotonicity agent, such as, for example, dextrose, boric acid, sodium tartrate, other organic or inorganic solutes and mixtures thereof.
  • the isotonicity agent is typically present in the composition in a concentration sufficient to cause the osmolarity of the composition to be from about 280 mOsmols to about 290 mOsmols ⁇ 50 mOsmols.
  • Sodium chloride is generally preferred, particularly if a buffer containing sodium ions is used in the composition, and is typically present in an amount that is physiologically equivalent to the tonicity of the nasal membranes.
  • the cobalamin composition of the present invention may further include a pharmaceutically acceptable buffer in order to maintain the desired pH.
  • suitable buffers used to adjust and maintain the pH of the composition include acetate, citrate, prolamine, phosphate, carbonate, phthalate, borate, or other pharmaceutically acceptable buffers and mixtures thereof.
  • the buffer comprises sodium phosphate.
  • the pH of the composition is maintained generally to be compatible with the fluids of the nasal membrane in order to minimize irritation.
  • the composition may be maintained at a pH from about 3 to about 11.
  • the composition may be maintained at a pH from about 3 to about 6.5, preferably from about 4 to about 6.5, more preferably from about 5 to about 6.5, still more preferably from about 6 to about 6.5, and most preferably about 6.5.
  • the composition may be maintained at a pH greater than 6.5, preferably from about 6.5 to about 11, more preferably from about 7 to about 10, still more preferably from about 7 to about 9, even more preferably from about 7 to about 7.7, even more preferably about 7.2, and most preferably about 7.7.
  • the concentration of the buffer in the composition will depend upon the selection of the buffer and the desired pH.
  • the present composition may also contain various pharmaceutically acceptable additives such as tolerance enhancers (sometimes more specifically referred to as humectants), absorption enhancers (sometimes also referred to as surfactants), preservatives, viscosity modifying agents (e.g., thickening agents), osmolarity adjusters, complexing agents, stabilizers, solubilizers, or any combination thereof.
  • tolerance enhancers sometimes more specifically referred to as humectants
  • absorption enhancers sometimes also referred to as surfactants
  • preservatives e.g., viscosity modifying agents (e.g., thickening agents), osmolarity adjusters, complexing agents, stabilizers, solubilizers, or any combination thereof.
  • a tolerance enhancer may be used in order to inhibit drying of the nasal membrane or mucosa.
  • a tolerance enhancer may also serve the purpose of inhibiting or relieving irritation of the nasal membranes.
  • suitable tolerance enhancers include, for example, humectants such as sorbitol, propylene glycol, glycerol, glycerin, hyaluronan, aloe, mineral oil, vegetable oil, soothing agents, membrane conditioners, sweeteners, and mixtures thereof.
  • the selection and concentration of a tolerance enhancer may depend on a number of factors, including, for example, the type and concentration of cobalamin compound being used in the composition. When used, the concentration of the tolerance enhancer in the composition will typically be in amounts from about 0.01% w/w to about 20% w/w.
  • a surfactant or absorption enhancer may also be used in the composition in order to enhance the absorption of the cobalamin compound across the nasal membrane.
  • Suitable absorption enhancers include non-ionic, anionic and cationic surfactants. Any of a number of well-known surfactants may be used, including, for example, polyoxyethylene derivatives of fatty acids, partial esters of sorbitol anhydrides, sodium lauryl sulfate, sodium salicylate, oleic acid, lecithin, dehydrated alcohol, Tween (e.g., Tween 20, Tween 40, Tween 60, Tween 80 and the like), Span (e.g., Span 20, Span 40, Span 80 and the like), polyoxyl 40 stearate, polyoxy ethylene 50 stearate, edetate disodium, propylene glycol, glycerol monooleate, fusieates, bile salts, octoxynol and combinations thereof.
  • the concentration of the surfactant in the composition will typically be from about 0.1% w/w to about 50% w/w.
  • concentrations of sodium salicylate, sodium lauryl sulfate and edetate disodium may be from about 0.01% to about 5% w/w of the composition.
  • Concentrations of polyoxyl 40 stearate, lecithin, dehydrated alcohol can be from about 0.1% to about 10% w/w of the composition.
  • Concentrations of oleic acid can be from about 0.01% to about 5% w/w of the composition.
  • Concentrations of propylene glycol and Tween 20 can be from about 0.1% to about 25% w/w of the composition.
  • a pharmaceutically acceptable thickening agent may also be used in the composition in order to modify the viscosity of the composition.
  • Numerous pharmaceutically acceptable thickening agents are well-known and include, for example, methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.
  • the concentration of the thickening agent will depend upon the agent selected and the viscosity desired. Such agent may be present in the composition at a concentration of from about 0.1% w/w to about 20% w/w.
  • a preservative may also be employed to increase the shelf-life of the composition.
  • a number of well-known and pharmaceutically acceptable preservatives may be used in the present composition, including, for example, parabens, thimerosal, chlorobutanol, benzalkonium chloride, or benzyl alcohol and combinations thereof.
  • Other ingredients which extend shelf life can be added such as for example, antioxidants.
  • antioxidants include sodium metabisulfite, potassium metabisulfite, ascorbyl palmitate and other pharmaceutically acceptable antioxidants.
  • the antioxidant will be present in the composition in a concentration of from about 0.01% w/w to about 5% w/w.
  • Benzyl alcohol and benzalkonium chloride are preferred preservatives.
  • a suitable concentration of preservative will depend on a number of factors, including, for example, the particular preservative selected, the intended shelf-life of the composition, and the results of preservative effectiveness and minimum preservative studies. When used, the concentration of the preservative in the composition will typically be from about 0.001% w/w to about 5% w/w, preferably from about 0.01% w/w to about 1% w/w and more preferably from about 0.02% w/w to about 0.4% w/w.
  • the cobalamin composition comprises sodium chloride, 0.649% w/w (0.11M); sodium phosphate, monobasic, anhydrous, 0.19% w/w (0.016M); benzyl alcohol, NF, 0.366% w/w (0.034M); sodium hydroxide, NF, 0.04% w/w (0.010M); benzalkonium chloride, 50%, NF, 0.02% w/w; cyanocobalamin, USP, 0.025% w/w (0.00018M); in purified water, USP, 98.71% w/w.
  • the cobalamin composition may be formulated to be a sterile, preservative-free composition. While preservatives may extend the shelf life of a composition, they may also cause or exacerbate irritation to the nasal membranes. Furthermore, because of the frequency with which the composition of the present invention is preferably administered, a bottle of typical volume for storing and dispensing the composition will likely be emptied by the patient before the occurrence of the degradation, spoilage, or bacterial growth that a preservative is meant to prevent.
  • the cobalamin composition is preservative-free and comprises sodium chloride, 0.649% w/w (0.11M); sodium phosphate, monobasic, anhydrous, 0.19% w/w (0.016M); sodium hydroxide, NF, 0.04% w/w (0.10M); cyanocobalamin, USP, 0.025% w/w (0.00018M); in purified water, USP, 99.096% w/w.
  • composition may be prepared by methods known to those of skill in the art, including by combining or mixing the components according to generally accepted procedures.
  • the selected components may be simply mixed in a blender or other standard mixing machine to produce a concentrated composition which is then adjusted to the final concentration by the addition of water.
  • Suitable containers and metering valves for dispensing the cobalamin composition according to the methods of the invention are available commercially and are known to those of skill in the art.
  • the container and valve system used to deliver the cobalamin composition may incorporate any of the conventional aerosol formation techniques.
  • a low boiling liquid hydrocarbon such as, for example, butane, isobutane, propane, and other low boiling hydrocarbons in either pure or mixed forms
  • halohydrocarbon fluorocarbons (such as, for example, FC-152A), chlorofluorocarbons (such as Freon or Freon like fluorocarbons, such as, for example, CFC-11, CFC-12 and CFC-114), and hydrofluorocarbons, also referred to as hydrofluoroalkanes (such as, for example, HFA-134a and HFA-227) are vaporized to exert a pressure and force the composition through the metering valve.
  • the cobalamin composition is stored for administration in a container or bottle including a pump and metering valve adapted for delivery of a metered spray of the composition and designed to inhibit or prevent degradation or spoilage of and bacterial growth in the composition contained therein.
  • a container or bottle including a pump and metering valve adapted for delivery of a metered spray of the composition and designed to inhibit or prevent degradation or spoilage of and bacterial growth in the composition contained therein.
  • Examples of such a container are the spray pump bottles produced by and available from Pfeiffer (Advanced Preservative Free System) and from Valois (VPY).
  • the study comprised twenty-five subjects, ages 18-85, with a history of documented vitamin B 12 deficiency who had previously been receiving maintenance intramuscular (IM) injections of B 12 .
  • the purpose of this study was to determine whether as an alternative to IM injections, one daily administration of a 0.025% by weight cobalamin composition is sufficient to sustain an efficacious level of B 12 in place of IM therapy and, thereby, maintain a serum B 12 level within the therapeutic range of greater than about 200 ng/L.
  • an aqueous isotonic composition containing a cobalamin compound was provided to the subjects to allow them to dose themselves at home with one daily intranasal (IN) administration comprising two puffs or sprays of B 12 (cobalamin).
  • IN intranasal
  • B 12 cobalamin
  • Subjects with chronic B 12 deficiencies were treated with intramuscular (IM) injections every 4-8 weeks.
  • IM intramuscular
  • the primary efficacy endpoint is the average of the vitamin B 12 levels from Visits 3, 4, 5 and 6 relative to the B 12 levels at Visit 1.
  • the ratio of each post baseline value to baseline was calculated, and the repeated measures model was used to calculate the means of the ratios at each visit.
  • the estimate statement (statement 1) provided an estimate of the average of the ratios across visits 3, 4, 5 and 6 and the confidence interval around that average.
  • Visit 1 and Visit 2 will not correspond to the same relative week.
  • the following schedule describes the actual times:
  • Visit #1 (V1)—Midpoint between IM injections (anywhere from 2 to 4 weeks post IM therapy).
  • Visit #2 (V2)—Termination of IM therapy (anywhere from 4 to 8 weeks post IM therapy). This is the point at which the next IM injection would have been given, but for the fact that the study participants began intranasal therapy instead.
  • the average (standard deviation) age of the 25 subjects was 59.8 (15.5) years, ranging from 28.0 to 82.6 years. Seventeen (68.0%) of the subjects were female. Twenty-one (84.0%) were Caucasian and four (16.0%) were African American. The general pattern was an initial decline from Visit #1 to Visit #2 and a steady increase in the last four visits (Visits #3-#6), although there were exceptions.
  • the mean B 12 value, range, and standard deviation at each visit are summarized in Table 2, and the means and their 95% confidence intervals are also shown in FIG. 1 .

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Otolaryngology (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pulmonology (AREA)
  • Mechanical Engineering (AREA)
  • Diabetes (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US11/506,148 2005-08-17 2006-08-17 Vitamin B12 nasal spray and method of use Abandoned US20070111964A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US11/506,148 US20070111964A1 (en) 2005-08-17 2006-08-17 Vitamin B12 nasal spray and method of use
US12/618,099 US9186374B2 (en) 2005-08-17 2009-11-13 Vitamin B12 nasal spray and method of use
US14/738,417 US10251908B2 (en) 2005-08-17 2015-06-12 Vitamin B12 nasal spray and method of use
US14/878,430 US10052344B2 (en) 2005-08-17 2015-10-08 Vitamin B12 nasal spray and method of use
US16/296,876 US20190216842A1 (en) 2005-08-17 2019-03-08 Vitamin b12 nasal spray and method of use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US70920005P 2005-08-17 2005-08-17
US11/506,148 US20070111964A1 (en) 2005-08-17 2006-08-17 Vitamin B12 nasal spray and method of use

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/618,099 Continuation US9186374B2 (en) 2005-08-17 2009-11-13 Vitamin B12 nasal spray and method of use

Publications (1)

Publication Number Publication Date
US20070111964A1 true US20070111964A1 (en) 2007-05-17

Family

ID=37758389

Family Applications (5)

Application Number Title Priority Date Filing Date
US11/506,148 Abandoned US20070111964A1 (en) 2005-08-17 2006-08-17 Vitamin B12 nasal spray and method of use
US12/618,099 Active 2028-04-07 US9186374B2 (en) 2005-08-17 2009-11-13 Vitamin B12 nasal spray and method of use
US14/738,417 Active US10251908B2 (en) 2005-08-17 2015-06-12 Vitamin B12 nasal spray and method of use
US14/878,430 Active US10052344B2 (en) 2005-08-17 2015-10-08 Vitamin B12 nasal spray and method of use
US16/296,876 Abandoned US20190216842A1 (en) 2005-08-17 2019-03-08 Vitamin b12 nasal spray and method of use

Family Applications After (4)

Application Number Title Priority Date Filing Date
US12/618,099 Active 2028-04-07 US9186374B2 (en) 2005-08-17 2009-11-13 Vitamin B12 nasal spray and method of use
US14/738,417 Active US10251908B2 (en) 2005-08-17 2015-06-12 Vitamin B12 nasal spray and method of use
US14/878,430 Active US10052344B2 (en) 2005-08-17 2015-10-08 Vitamin B12 nasal spray and method of use
US16/296,876 Abandoned US20190216842A1 (en) 2005-08-17 2019-03-08 Vitamin b12 nasal spray and method of use

Country Status (3)

Country Link
US (5) US20070111964A1 (fr)
JP (1) JP2009504767A (fr)
WO (1) WO2007022345A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120015880A1 (en) * 2008-12-22 2012-01-19 Seymour Fein Intranasal desmopressin administration
US20150320787A1 (en) * 2006-05-30 2015-11-12 Orahealth Corp. Cobalamin compositions and methods for treating or preventing mucositis
US9539302B2 (en) 2009-06-18 2017-01-10 Allergan, Inc. Safe desmopressin administration
CN111671912A (zh) * 2020-06-22 2020-09-18 上海上药第一生化药业有限公司 含腺苷钴胺的组合物、冻干粉及其制备方法、注射用药物

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7404489B1 (en) 2003-03-04 2008-07-29 Qol Medical, Llc Cyanocobalamin low viscosity aqueous formulations for intranasal delivery
US20070111964A1 (en) 2005-08-17 2007-05-17 Fleming And Company, Pharmaceuticals Vitamin B12 nasal spray and method of use
CN101600729A (zh) * 2006-06-23 2009-12-09 帕尔医疗公司 用于鼻内递送的氰钴胺低粘度水性制剂
ES2686299T3 (es) * 2010-10-29 2018-10-17 Troikaa Pharmaceuticals Ltd Composiciones nasales de vitamina B12
NL2010550C2 (en) 2012-11-30 2014-06-04 Klaas Alouis Riepma An intranasal pharmaceutical composition containing vitamin b12.
JP5797227B2 (ja) * 2013-05-21 2015-10-21 パル ファーマシューティカル， インコーポレーテッド 鼻内送達用シアノコバラミン低粘度水性製剤
ITUB20153950A1 (it) * 2015-09-28 2017-03-28 Tred Srl Dispositivo nasale in grado di attivare il riflesso rino-palatale per l'igienizzazione rinofaringea
DK3698791T3 (da) * 2017-02-02 2024-01-15 Otolanum Ag Intranasal sammensætning, der omfatter betahistin
EP3589269B1 (fr) * 2017-03-02 2021-04-07 Dutch Renewable Energy B.V. Administration intranasale de substances physiologiquement actives
CN112969450B (zh) 2018-09-20 2023-05-30 阿卡蒂亚药品公司 卡贝缩宫素药物产品及用于制备其的方法
WO2020061414A1 (fr) 2018-09-20 2020-03-26 Levo Therapeutics, Inc. Formulations intranasales stables de carbétocine

Citations (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2703303A (en) * 1950-02-25 1955-03-01 Merck & Co Inc Production of l. l. d-active substances by streptomyces
US2703302A (en) * 1952-12-08 1955-03-01 Merck & Co Inc Vitamin b12-active composition and process of preparing same
US2746796A (en) * 1953-08-05 1956-05-22 Pharma Craft Corp Metering valve aerosol bottle
US2914222A (en) * 1957-05-20 1959-11-24 Meshberg Philip Aerosol package
US2951017A (en) * 1957-06-27 1960-08-30 Distillers Co Yeast Ltd Cobalamin producing fermentation process
US3000793A (en) * 1957-01-22 1961-09-19 Merck & Co Inc Production of cobalamins
US3018225A (en) * 1959-03-09 1962-01-23 Merck & Co Inc Production of vitamin b12
US3057851A (en) * 1959-04-13 1962-10-09 Armour Pharma Process for preparing vitamin b12
US3120509A (en) * 1959-12-16 1964-02-04 Hoffmann La Roche Process for the manufacture of vitamins of the group b
US3282781A (en) * 1960-11-25 1966-11-01 Merck & Co Inc Inhalant compositions
US3548057A (en) * 1969-04-29 1970-12-15 Merck & Co Inc Topical administration of vitamin b12
US3577537A (en) * 1970-03-09 1971-05-04 Merck & Co Inc Topical administration of vitamin b-12
US3584115A (en) * 1968-05-31 1971-06-08 Arthur Ira Gebhart Method of applying visible aerosol compositions
US3957966A (en) * 1972-05-19 1976-05-18 Gaf Corporation Stabilized vitamin food coatings
US4174295A (en) * 1976-08-13 1979-11-13 Montedison S.P.A. Aerosol propellant compositions
US4269835A (en) * 1979-12-13 1981-05-26 Whittle Barry J Nasal composition for relieving nasal distress
US4525341A (en) * 1984-04-09 1985-06-25 Mayor Pharmaceutical Laboratories, Inc. Method of administering vitamins
US4624965A (en) * 1984-11-15 1986-11-25 Nastech Pharmaceutical Co., Inc. Novel method of administering anti-nausea and anti-emetic pharmaceutical agents and novel dosage forms containing same
US4724231A (en) * 1985-04-16 1988-02-09 Nastech Pharmaceutical, Inc. Nasel compositions containing vitamin B12
US4727231A (en) * 1985-10-01 1988-02-23 Doryokuro Kakunenryo Kaihatsu Jigyodan Method and apparatus for denitration of nitrate solution by microwave heating
US4749700A (en) * 1984-10-23 1988-06-07 Nastech Pharmaceutical Co, Inc. Novel methods of administering antihistamines, antinausea and antiemetic pharmaceutical agents and novel dosage forms containing same
US5112804A (en) * 1987-04-01 1992-05-12 Temple University Of The Commonwealth System Of Higher Education Pharmaceutical composition and method of intranasal administration
US5508282A (en) * 1993-05-17 1996-04-16 Jeffrey Tulin-Silver Composition and method for treating acute or chronic rhinosinusitis
US5797390A (en) * 1996-03-06 1998-08-25 Mcsoley; Thomas E. Nasal inhaler having a directed spray pattern
US5801161A (en) * 1993-12-20 1998-09-01 Merkus; Franciscus W. H. M. Pharmaceutical composition for the intranasal administration of hydroxocobalamin
US5840278A (en) * 1997-02-20 1998-11-24 Coleman; Thomas Nasal spray having a mineral vitamin component, a mineral component and aloe vera
US5925625A (en) * 1994-05-13 1999-07-20 Merkus; Franciscus W. H. M. Pharmaceutical composition for the intranasal administration of hydroxocobalamin
US6004560A (en) * 1998-11-16 1999-12-21 Hsu; Wu-Ching Nasal spray (drop) for treating fever/cold, and its preparation
US6017963A (en) * 1995-11-14 2000-01-25 Euro-Celtique, S.A. Formulation for intranasal administration
US6080783A (en) * 1998-09-01 2000-06-27 Gum Tech International, Inc. Method and composition for delivering zinc to the nasal membrane
US6103218A (en) * 1997-04-23 2000-08-15 Brucker; Donald Therapeutic nasal spray administered composition containing feverfew
US6180663B1 (en) * 1999-12-03 2001-01-30 Stanley Lang Therapeutic nasal inhalant
US6248363B1 (en) * 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US6255294B1 (en) * 1998-12-28 2001-07-03 Allergy Limited Cyanocobalamin (vitamin B12) treatment in allergic disease
US6297244B1 (en) * 1997-10-20 2001-10-02 Dainippon Pharmaceutical Co., Ltd. Stable drug composition
US6333044B1 (en) * 1991-07-22 2001-12-25 Recordati, S.A. Chemical And Pharmaceutical Company Therapeutic compositions for intranasal administration which include KETOROLAC®
US6428805B1 (en) * 1998-08-26 2002-08-06 Teijin Limited Powdery nasal compositions
US6528496B1 (en) * 1992-12-29 2003-03-04 Allen Robert H Compositions treating, preventing or reducing elevated metabolic levels
US20030059440A1 (en) * 1998-09-01 2003-03-27 Tim Clarot Composition and method for moisturizing nasal tissue
US20030144198A1 (en) * 2001-09-28 2003-07-31 Collins Douglas A. Coadministration of transport protein with conjugated cobalamin to deliver agents
US20030225044A1 (en) * 2002-06-03 2003-12-04 Bachman Stephen E. Method to increase serum levels of vitamins in animals including humans
US6660293B2 (en) * 2001-06-29 2003-12-09 Everett Laboratories, Inc. Compositions and methods for prophylactic and therapeutic supplementation of nutrition in subjects
US20040057907A1 (en) * 2002-09-23 2004-03-25 Leonard Mackles Dri-nasal sprays
US20040219107A1 (en) * 2002-09-16 2004-11-04 Tim Clarot System for delivering a composition to the nasal membrane and method of using same
US20050019411A1 (en) * 2001-10-18 2005-01-27 Paolo Colombo Powder for nasal administration of drugs
US6881423B2 (en) * 1996-02-27 2005-04-19 Teijin Limited Powdery composition for nasal administration
US20050226906A1 (en) * 2004-04-08 2005-10-13 Micro Nutrient, Llc Nutrient system for individualized responsive dosing regimens
US20050226907A1 (en) * 2004-04-08 2005-10-13 Moneymaker Ricky D Pharmanutrient composition(s) and system(s) for individualized, responsive dosing regimens
US20050232981A1 (en) * 2004-04-15 2005-10-20 Ben-Sasson Shmuel A Compositions capable of facilitating penetration across a biological barrier

Family Cites Families (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3120508A (en) 1959-08-20 1964-02-04 Hoechst Ag Process for the manufacture of waterinsoluble azo-dyestuffs
US3547138A (en) 1968-09-19 1970-12-15 Gen Electric Fluidic high to low frequency converter circuit
US3957968A (en) 1973-08-20 1976-05-18 Colgate-Palmolive Company Dentifrices containing flat flakes of alpha-alumina
IT1164227B (it) 1983-05-13 1987-04-08 Angeli Inst Spa Composizione farmaceutica atta alla somministrazione nasale di sali quaternari d'ammonio ed attivita' anticolinergica
DE3323389A1 (de) 1983-06-29 1985-01-10 B. Braun Melsungen Ag, 3508 Melsungen Auf schleimhaeute des mundes, der nase und/oder des rachens wirkende arzneimittel auf der basis von heparin und tensiden
US4523341A (en) 1983-12-12 1985-06-18 Queen Carl J Bathing cabinet with transporter cart
DE3682862D1 (de) 1985-04-16 1992-01-23 Nastech Pharm Co Aerosolmittel zur nasenverstaeubung von vitamin b 12.
US4782047A (en) 1986-05-22 1988-11-01 Syntex Pharmaceuticals International Ltd. Aqueous steroid formulations for nasal administration
US4959176A (en) 1988-04-29 1990-09-25 Beckman Instruments, Inc. High resolution non corrosive amino acid analysis buffer solutions
JPH03129153A (ja) 1989-10-12 1991-06-03 Kiyomi Okamoto 無段変速装置
US5277311A (en) 1991-12-20 1994-01-11 Smiths Industries Medical Systems, Inc. Needle assembly holder with rotatable safety sheath member and method of effecting proper alignment of a cannula using such needle assembly holder
JPH05170663A (ja) 1991-12-20 1993-07-09 Mitsubishi Kasei Corp カルシトニン点鼻用医薬組成物
US5825625A (en) 1996-05-20 1998-10-20 Hewlett-Packard Company Heat conductive substrate mounted in PC board for transferring heat from IC to heat sink
AU724728B2 (en) 1997-07-03 2000-09-28 Pfizer Inc. Pharmaceutical compositions containing eletriptan hemisulphate and caffeine
US6406730B1 (en) 1998-12-01 2002-06-18 Carl E. Banyard Process for producing low acid food products
FR2787029A1 (fr) 1998-12-09 2000-06-16 Biovector Therapeutics Utilisation dans une composition pharmaceutique pour l'administration par voie nasale de vitamine b12 pour la delivrance d'agents actifs au systeme nerveux central
WO2001013322A1 (fr) 1999-08-17 2001-02-22 Image Therm Engineering Systeme d'analyse et de caracterisation des donnees d'un nuage d'aerosol
EP1210580B1 (fr) 1999-08-17 2009-08-05 Proveris Scientific Corporation Procede d'acquisition de donnees de pulverisation
WO2002024165A2 (fr) 2000-09-20 2002-03-28 Nycomed Pharma As Preparation d'emulsions et de concentres de ces dernieres
US6745760B2 (en) 2001-05-15 2004-06-08 Trudell Medical International Medicament applicator
DK1506464T3 (da) 2001-06-21 2010-05-03 Proveris Scient Corp Præcist positionsstyret aktiveringssystem
JP4164730B2 (ja) 2001-07-30 2008-10-15 東洋紡績株式会社 選択分離膜
US20060074034A1 (en) 2001-09-17 2006-04-06 Collins Douglas A Cobalamin mediated delivery of nucleic acids, analogs and derivatives thereof
US6911434B2 (en) 2002-02-04 2005-06-28 Corixa Corporation Prophylactic and therapeutic treatment of infectious and other diseases with immunoeffector compounds
US20040034042A1 (en) * 2002-08-14 2004-02-19 Masao Tsuji Preservative composition
US20040109826A1 (en) 2002-12-06 2004-06-10 Dey, L.P. Stabilized albuterol compositions and method of preparation thereof
US6685421B1 (en) 2003-01-02 2004-02-03 Charles N. Reeves Hitch-mounted lift assembly
DE10300719A1 (de) 2003-01-11 2004-07-22 Basf Ag Verbessertes Verfahren zur Herstellung von Vitamin B12
US7404489B1 (en) * 2003-03-04 2008-07-29 Qol Medical, Llc Cyanocobalamin low viscosity aqueous formulations for intranasal delivery
WO2005004895A2 (fr) 2003-06-09 2005-01-20 Nastech Pharmaceutical Company Inc. Compositions et procedes d'une meilleure administration d'hormone de croissance par voie muqueuse
JP2005016262A (ja) 2003-06-27 2005-01-20 Kyocera Corp 太陽電池モジュール取付構造体
US20060127320A1 (en) 2004-05-10 2006-06-15 Nastech Pharmaceutical Company Inc. Method of delivering parathyroid hormone to a human
US20060046969A1 (en) 2004-08-25 2006-03-02 Aegis Therapeutics Llc Antibacterial compositions for drug administration
US20070111964A1 (en) 2005-08-17 2007-05-17 Fleming And Company, Pharmaceuticals Vitamin B12 nasal spray and method of use

Patent Citations (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2703303A (en) * 1950-02-25 1955-03-01 Merck & Co Inc Production of l. l. d-active substances by streptomyces
US2703302A (en) * 1952-12-08 1955-03-01 Merck & Co Inc Vitamin b12-active composition and process of preparing same
US2746796A (en) * 1953-08-05 1956-05-22 Pharma Craft Corp Metering valve aerosol bottle
US3000793A (en) * 1957-01-22 1961-09-19 Merck & Co Inc Production of cobalamins
US2914222A (en) * 1957-05-20 1959-11-24 Meshberg Philip Aerosol package
US2951017A (en) * 1957-06-27 1960-08-30 Distillers Co Yeast Ltd Cobalamin producing fermentation process
US3018225A (en) * 1959-03-09 1962-01-23 Merck & Co Inc Production of vitamin b12
US3057851A (en) * 1959-04-13 1962-10-09 Armour Pharma Process for preparing vitamin b12
US3120509A (en) * 1959-12-16 1964-02-04 Hoffmann La Roche Process for the manufacture of vitamins of the group b
US3282781A (en) * 1960-11-25 1966-11-01 Merck & Co Inc Inhalant compositions
US3584115A (en) * 1968-05-31 1971-06-08 Arthur Ira Gebhart Method of applying visible aerosol compositions
US3548057A (en) * 1969-04-29 1970-12-15 Merck & Co Inc Topical administration of vitamin b12
US3577537A (en) * 1970-03-09 1971-05-04 Merck & Co Inc Topical administration of vitamin b-12
US3957966A (en) * 1972-05-19 1976-05-18 Gaf Corporation Stabilized vitamin food coatings
US4174295A (en) * 1976-08-13 1979-11-13 Montedison S.P.A. Aerosol propellant compositions
US4269835A (en) * 1979-12-13 1981-05-26 Whittle Barry J Nasal composition for relieving nasal distress
US4525341A (en) * 1984-04-09 1985-06-25 Mayor Pharmaceutical Laboratories, Inc. Method of administering vitamins
US4749700A (en) * 1984-10-23 1988-06-07 Nastech Pharmaceutical Co, Inc. Novel methods of administering antihistamines, antinausea and antiemetic pharmaceutical agents and novel dosage forms containing same
US4624965A (en) * 1984-11-15 1986-11-25 Nastech Pharmaceutical Co., Inc. Novel method of administering anti-nausea and anti-emetic pharmaceutical agents and novel dosage forms containing same
US4724231A (en) * 1985-04-16 1988-02-09 Nastech Pharmaceutical, Inc. Nasel compositions containing vitamin B12
US4727231A (en) * 1985-10-01 1988-02-23 Doryokuro Kakunenryo Kaihatsu Jigyodan Method and apparatus for denitration of nitrate solution by microwave heating
US5112804A (en) * 1987-04-01 1992-05-12 Temple University Of The Commonwealth System Of Higher Education Pharmaceutical composition and method of intranasal administration
US6333044B1 (en) * 1991-07-22 2001-12-25 Recordati, S.A. Chemical And Pharmaceutical Company Therapeutic compositions for intranasal administration which include KETOROLAC®
US6528496B1 (en) * 1992-12-29 2003-03-04 Allen Robert H Compositions treating, preventing or reducing elevated metabolic levels
US5508282A (en) * 1993-05-17 1996-04-16 Jeffrey Tulin-Silver Composition and method for treating acute or chronic rhinosinusitis
US5508282C1 (en) * 1993-05-17 2001-01-23 Tulin Silver Jeffrey Composition and method for treating acute or chronic rhinosinusitis
US5801161A (en) * 1993-12-20 1998-09-01 Merkus; Franciscus W. H. M. Pharmaceutical composition for the intranasal administration of hydroxocobalamin
US5925625A (en) * 1994-05-13 1999-07-20 Merkus; Franciscus W. H. M. Pharmaceutical composition for the intranasal administration of hydroxocobalamin
US6017963A (en) * 1995-11-14 2000-01-25 Euro-Celtique, S.A. Formulation for intranasal administration
US6881423B2 (en) * 1996-02-27 2005-04-19 Teijin Limited Powdery composition for nasal administration
US5797390A (en) * 1996-03-06 1998-08-25 Mcsoley; Thomas E. Nasal inhaler having a directed spray pattern
US5840278A (en) * 1997-02-20 1998-11-24 Coleman; Thomas Nasal spray having a mineral vitamin component, a mineral component and aloe vera
US6103218A (en) * 1997-04-23 2000-08-15 Brucker; Donald Therapeutic nasal spray administered composition containing feverfew
US6297244B1 (en) * 1997-10-20 2001-10-02 Dainippon Pharmaceutical Co., Ltd. Stable drug composition
US6428805B1 (en) * 1998-08-26 2002-08-06 Teijin Limited Powdery nasal compositions
US20030059440A1 (en) * 1998-09-01 2003-03-27 Tim Clarot Composition and method for moisturizing nasal tissue
US20050180924A1 (en) * 1998-09-01 2005-08-18 Tim Clarot Composition and method for moisturizing nasal tissue
US6673835B1 (en) * 1998-09-01 2004-01-06 Zicam Llc Method and composition for delivering zinc to the nasal membrane
US6080783A (en) * 1998-09-01 2000-06-27 Gum Tech International, Inc. Method and composition for delivering zinc to the nasal membrane
US6004560A (en) * 1998-11-16 1999-12-21 Hsu; Wu-Ching Nasal spray (drop) for treating fever/cold, and its preparation
US6255294B1 (en) * 1998-12-28 2001-07-03 Allergy Limited Cyanocobalamin (vitamin B12) treatment in allergic disease
US6248363B1 (en) * 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US6180663B1 (en) * 1999-12-03 2001-01-30 Stanley Lang Therapeutic nasal inhalant
US6660293B2 (en) * 2001-06-29 2003-12-09 Everett Laboratories, Inc. Compositions and methods for prophylactic and therapeutic supplementation of nutrition in subjects
US20030144198A1 (en) * 2001-09-28 2003-07-31 Collins Douglas A. Coadministration of transport protein with conjugated cobalamin to deliver agents
US20050019411A1 (en) * 2001-10-18 2005-01-27 Paolo Colombo Powder for nasal administration of drugs
US20030225044A1 (en) * 2002-06-03 2003-12-04 Bachman Stephen E. Method to increase serum levels of vitamins in animals including humans
US20040219107A1 (en) * 2002-09-16 2004-11-04 Tim Clarot System for delivering a composition to the nasal membrane and method of using same
US20040057907A1 (en) * 2002-09-23 2004-03-25 Leonard Mackles Dri-nasal sprays
US20050226906A1 (en) * 2004-04-08 2005-10-13 Micro Nutrient, Llc Nutrient system for individualized responsive dosing regimens
US20050226907A1 (en) * 2004-04-08 2005-10-13 Moneymaker Ricky D Pharmanutrient composition(s) and system(s) for individualized, responsive dosing regimens
US20050232981A1 (en) * 2004-04-15 2005-10-20 Ben-Sasson Shmuel A Compositions capable of facilitating penetration across a biological barrier

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150320787A1 (en) * 2006-05-30 2015-11-12 Orahealth Corp. Cobalamin compositions and methods for treating or preventing mucositis
US20120015880A1 (en) * 2008-12-22 2012-01-19 Seymour Fein Intranasal desmopressin administration
US9539302B2 (en) 2009-06-18 2017-01-10 Allergan, Inc. Safe desmopressin administration
US11419914B2 (en) 2009-06-18 2022-08-23 Serenity Pharmaceuticals Llc Safe desmopressin administration
CN111671912A (zh) * 2020-06-22 2020-09-18 上海上药第一生化药业有限公司 含腺苷钴胺的组合物、冻干粉及其制备方法、注射用药物

Also Published As

Publication number Publication date
US9186374B2 (en) 2015-11-17
US20190216842A1 (en) 2019-07-18
US10251908B2 (en) 2019-04-09
US20150272876A1 (en) 2015-10-01
WO2007022345A2 (fr) 2007-02-22
US20100210580A1 (en) 2010-08-19
WO2007022345A3 (fr) 2009-04-30
US20160022726A1 (en) 2016-01-28
US10052344B2 (en) 2018-08-21
JP2009504767A (ja) 2009-02-05

Similar Documents

Publication Publication Date Title
US10052344B2 (en) Vitamin B12 nasal spray and method of use
US6702997B2 (en) Albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma
US20080031959A1 (en) Anti-migraine oral spray formulations and methods
JP2003221335A (ja) 慢性閉塞性肺疾患の症状を緩和するためのアルブテロールおよびイプラトロピウム吸入溶液、システム、キットおよび方法
JPS62500789A (ja) ビタミンｂ↓１↓２含有経鼻組成物
CA1317881C (fr) Compositions en aerosol pour l'administration de la vitamine b__ par voie nasale
CA2897432A1 (fr) Compositions de dnj parenterales stables
US9415007B2 (en) Cyanocobalamin low viscosity aqueous formulations for intranasal delivery
CA2656823C (fr) Formulations aqueuses de faible viscosite de cyanocobalamine pour administration intra-nasale
US7229636B1 (en) Cyanocobalamin low viscosity aqueous formulations for intranasal delivery
CN116472033A (zh) 用于经鼻施用的钴胺素化合物的药物组合物
Feller et al. Vitamin B 12 nasal spray and method of use
US20130338200A1 (en) Pharmaceutical dosage forms of tizanidine and administration routes thereof
JP6097787B2 (ja) 鼻内送達用シアノコバラミン低粘度水性製剤
AU2014202415B2 (en) Cyanocobalamin low viscosity aqueous formulations for intranasal delivery
CA2863377C (fr) Formulations aqueuses de faible viscosite de cyanocobalamine pour administration intra-nasale
RU2021121189A (ru) Композиции, устройства и способы для лечения расстройств передозировки и связанных с вознаграждением
JP2013227319A (ja) 鼻内送達用シアノコバラミン低粘度水性製剤

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: ENDO PHARMACEUTICALS INC., PENNSYLVANIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PAR PHARMACEUTICAL, INC.;ENDO PAR INNOVATION COMPANY, LLC;REEL/FRAME:043118/0747

Effective date: 20170726