US20120053563A1 - Non-sedating antihistamine injection formulations and methods of use thereof - Google Patents
Non-sedating antihistamine injection formulations and methods of use thereof Download PDFInfo
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- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P37/08—Antiallergic agents
Definitions
- Acute allergic reaction including anaphylaxis is a systemic, immediate hypersensitivity reaction caused by exposure to a specific antigen.
- the immune system activates immunoglobulin E (IgE), which reacts with effector cells (mast cells and basophils). These cells, in turn, release histamine, serotonin, leukotrienes, and prostaglandins, and induce a range of signs and symptoms, such as facial flushing, urticaria (hives), edema, pruritus, broncho-constriction, cough, cardiac arrhythmias, hypotension, nausea, vomiting, and diarrhea. Cutaneous manifestations are most common, with urticaria and angioedema present in 88% or more of patients experiencing acute allergic reactions.
- Swelling in the airway is the most life-threatening symptom, commonly causing dyspnea, wheezing, stridor, and upper airway obstruction from severe edema.
- Cardiovascular symptoms include dizziness, hypotension, and syncope related to third-spacing of intravascular fluid.
- Common gastrointestinal manifestations include nausea, vomiting, abdominal pains or cramps, and diarrhea.
- Acute allergic reactions occur in all age groups. Food allergies are more common in the young, whereas more drug reactions occur in adults, possibly due to greater exposure to medications, including narcotics, aspirin/NSAIDs, antibiotics, IV contrast media, anesthesia, muscle relaxants, etc. Although prior exposure is essential for the development of true anaphylaxis, reactions occur even when no documented prior exposure exists. Thus, patients may react to a first exposure to an antibiotic or insect sting. Elderly persons have the greatest risk of mortality from acute allergic reactions due to the presence of preexisting disease.
- Emergency treatment includes airway protection, alpha-agonists, antihistamines, steroids, and beta agonists.
- Medications currently used in the treatment of acute allergic reactions include epinephrine, diphenhydramine injection, corticosteroids, albuterol, and glucagon.
- Epinephrine is the first-line drug to be given to a patient having an acute allergic reaction.
- An alpha-receptor agonist, epinephrine reverses hypotension. It also has beta-receptor activity, which dilates the airways, increases the force of myocardial contraction, and suppresses histamine and leukotriene release, reducing inflammatory responses.
- Diphenhydramine injection is the second-line drug to be given to a patient having an acute allergic reaction as an adjunct therapy to epinephrine for the relief of peripheral symptoms such as pruritus, engioedema, hives, erythema, etc.
- a method of treating anaphylaxis or an acute allergic reaction comprises administering to an individual in need thereof an effective amount of an injectable composition comprising a non-sedating (also termed as 2 nd or 3 rd generation) H1 antihistamine wherein the H1 antihistamine comprises cetirizine, loratadine, levocetirizine, desloratadine, or fexofenadine.
- a non-sedating also termed as 2 nd or 3 rd generation
- H1 antihistamine comprises cetirizine, loratadine, levocetirizine, desloratadine, or fexofenadine.
- the 90% confidence limits of a ratio of a logarithmic transformed geometric mean of AUC 0-INF for the injectable formulation as described above to a logarithmic transformed geometric mean of AUC 0-INF for a reference oral product of the non-sedating H1 antihistamine are 0.80 to 1.25; and/or wherein the 90% confidence limits of a ratio of a logarithmic transformed geometric mean of AUC 0-t for the injectable formulation to a logarithmic transformed geometric mean of AUC 0-t for the reference oral product of the non-sedating H1 antihistamine are 0.80 to 1.25.
- the injectable formulation of the non-sedating antihistamine as described above has a 90% confidence interval around the difference in the reduction of at least one symptom of anaphylaxis or an acute allergic reaction to a reference injectable product, such as diphenhydramine injection, for the per protocol evaluable population, within about ⁇ 30.00 to about +30.00, wherein the symptom is pruritus severity, pruritus duration, erythema, angioedema, number of urticaria areas, number of erythema areas, and/or wheezing.
- the injectable formulation of the non-sedating antihistamine as described above is statistically superior (p ⁇ 0.05) to a placebo in the reduction of at least one symptom of anaphylaxis or an acute allergic reaction, wherein the symptom is pruritus severity, pruritus duration, erythema, angioedema, urticaria areas, erythema areas, and/or wheezing.
- an automatic injector designed to allow a user to self-administer a pre-measured dose of a non-sedating antihistamine composition subcutaneously or intramuscularly, comprises a housing comprising a chamber for the non-sedating antihistamine composition and a dispensing assembly in communication with the chamber, wherein the non-sedating antihistamine composition comprises an non-sedating antihistamine and a pH adjusting agent and has a pH of 3 to 9, wherein the non-sedating antihistamine comprises cetirizine, loratadine, levocetirizine, desloratadine, or fexofenadine.
- a kit comprises the automatic injector comprising a non-sedating antihistamine composition as described above and a second automatic injector comprising a second housing comprising a second chamber for an epinephrine composition and a second dispensing assembly in communication with the second chamber.
- Acute allergic reaction including anaphylaxis is an acute multi-system severe type I hypersensitivity reaction. Pseudoanaphylaxis does not involve an allergic reaction, but is due to direct mast cell degranulation. Both anaphylaxis and pseudoanaphylaxis result in an anaphylactoid reaction and treatment for both conditions is similar.
- the term anaphylaxis as used herein refers to both conditions unless otherwise specified. Clinical signs and symptoms of acute allergic reaction are given in Table 1:
- Non-sedating antihistamines to be used, for example, in the hospital or acute care settings.
- an antigen interacts with and cross-links surface IgE antibodies on mast cells and basophils.
- IgE antibodies surface IgE antibodies on mast cells and basophils.
- histamine receptor sites, histamine-1 (H 1 ), and histamine-2 (H 2 ) have a role in acute allergic reactions/anaphylaxis.
- H 1 receptors Acting on H 1 receptors, histamine produces pruritus, vasodilation, hypotension, flushing, headache, tachycardia, bronchoconstriction, and increased vascular permeability.
- Histamine causes increased stomach acid production, nausea, and flushing.
- Symptoms of acute allergic reactions include pruritus, erythema, angioedema, urticaria, urticaria areas, erythema areas, wheezing, and etc.
- Exemplary patient populations for study include patients coming to emergency rooms or allergy clinics, patients with food allergies (peanuts, other nuts, sea food, etc), patients with exercise induced allergies, patients allergic to insects stings, patients with poison Ivy induced allergies, etc. Additional patients include those already in the hospital experiencing drug induced allergies to: antibiotics, IV contrast media, anesthesia, aspirin/NSAIDs, opioids, chemotherapy agents, muscle relaxants, latex gloves, blood materials, etc.
- a clinical endpoint bioequivalence study to compare the efficacy of a non-sedating antihistamine or second or third generation antihistamine injection to diphenhydramine injection is performed.
- the efficacy of a non-sedating antihistamine or second or third generation antihistamine injection is compared to placebo.
- Pruritus is a condition involving localized or general itching that is a common and distressing symptom in a variety of diseases, especially in an allergic reaction. Although usually occurring in the skin, pruritus can also occur in non-cutaneous sites such as mucous membranes. Erythema is redness of the skin, caused by congestion of the capillaries in the lower layers of the skin.
- the primary efficacy end points are the difference between the treatment disclosed herein and the treatment of placebo in the mean change from the baseline of the average of the pruritus severity score and the erythema severity score.
- the study will be designed to give a 90% power to detect a 0.5 unit mean difference for the primary efficacy endpoint at a two-sided alpha-level of 0.05.
- duration of pruritus as an efficacy end point that can be measured. Duration of pruritus is categorized as follows: 3 if >6 hours/24 hr, 2 if 1 to 6 hours/24 hr, 1 if less than 1 hour/24 hr, and 0 if no pruritus. The study will be designed to give a 90% power to detect a 0.5 unit mean reduction for the primary efficacy endpoint at a two-sided alpha-level of 0.05.
- Angioedema is an uncomfortable and disfiguring type of temporary swelling especially in the lips and other parts of the mouth and throat, the eyelids, the genitals, and the hand and feet. Angioedema is life-threatening if swelling in your mouth or throat makes it difficult for you to breathe. Less often the sheer amount of swelling means that so much fluid has moved out of the blood circulation that blood pressure drops dangerously.
- Wheezing is a high-pitched whistling sound produced by air flowing through narrowed breathing tubes, especially the smaller ones deep in the lung.
- Exemplary clinical studies include a randomized, double-blind, active and placebo-controlled trial of about 300 patients over the age of 12 with acute allergic syndromes. About 100 patients will be randomly assigned to each of the 3 treatments including a non-sedating antihistamine injection as disclosed herein, a diphenhydramine injection, or a placebo injection, all via intravenous, intramuscular or subcutaneous administration. Patients will be recruited at multiple centers, from emergency departments at urban hospitals and allergy clinics throughout the country. The primary endpoints will be the reduction of pruritus severity score, pruritus duration, erythema, angioedema, wheezing, number of urticaria areas, and/or number of erythema areas, at 2-4 hours after protocol treatment. Symptom scores will be also assessed at baseline.
- ED real-life emergency department
- Patients over the age of 12 will be considered for recruitment from the ED if they have the following syndromes after an ingested food or ingested, inhaled, or injected drug, after in contact with latex or bee stings: acute urticaria (score 1 and above), acute angioedema (score 1 and above), wheezing (score 1 and above), and acute pruritic rash (score 1 and above).
- These manifestations should have been present for no greater than 12 hours from the time of alleged allergen exposure.
- Pregnant patients will be excluded.
- recruited patients will be randomly assigned to treatment with either 10 mg of cetirizine injection (the test product group, i.e. product of present disclosure), diphenhydramine 50 mg injection (the comparator or active control group) or placebo injection (placebo control group)
- Each treatment designation will be blinded based on the randomization code.
- the physician who is unaware of the treatment content will administer the contents by means of intravenous (or intramuscular, or subcutaneous, depending on protocol requirement) injection to the subject.
- Supplemental medications such as epinephrine, corticosteroids, bronchodilators, and additional doses of antihistamine may be administered at the discretion of the study physicians as a rescue procedure.
- Patients may also receive supplemental oxygen and intravenous fluids at the discretion of the study physicians as a rescue procedure.
- Patients will have heart rate, blood pressure, physical findings, side effects, and symptoms assessed at baseline, 1 hour, 2 hours and 4 hours relative to experimental treatment. Baseline temperatures will be also recorded.
- Clinical recording will include the presence and extent or severity scores of urticaria and erythema, angioedema, wheezing, pruritus, number of urticaria areas, number of erythema areas, abdominal distention or tenderness, and abdominal hyperactive bowel sounds. Historical features, physical findings (including heart rates, blood pressure, and respiratory rates), and treatments will be recorded on a study-specific data input form. The extent of involvement with urticaria and erythema will be assessed by using a check-off cartoon of body areas (similar to that used to assess burn area extent) printed on the data input sheet. Symptom scores will be assessed at baseline, 1 hour, and 2, or 4 hours by using a preprinted form with none (score 0), mild (score 1), moderate (score 2), and severe (score 3) check-off categories.
- the primary variables of interest will be resolution or reduction of urticaria, angioedema, erythema, pruritus, wheezing, number of urticaria areas, and number of erythema areas. Changes in heart rates, respiratory rates, blood pressure, and symptoms will also be examined. The final disposition of the patient will be noted (admission, discharge, or leaving against medical advice). The study will be approved by the institutional review board, and informed written consent will be obtained from all patients.
- Statistical assessment will be using bivariate 2 analysis and analysis of variance or covariance (ANCOVA), multivariate logistic regression. Covariates will be included in some multivariate models. Analyses will be performed by using the SAS software. Certain statistical values are expressed with 90% confidence intervals (CIs).
- the above clinical trials may be split into two separate studies.
- One study will be an active controlled study comparing the invention injectable product with diphenhydramine injection.
- the other will be a placebo controlled study comparing the invention injectable product with a placebo.
- Prompt treatment with antihistamines is highly recommended to alleviate the symptoms of acute allergic reactions.
- Antihistamines are helpful in reducing histamine-mediated vasodilation and secondary edema.
- Commonly used drugs such as diphenhydramine injection provide H 1 blockade.
- Diphenhydramine reduces vasodilation in small blood vessels in the nose, eyes, and airways and provide some anticholinergic effects toward drying secretions.
- Diphenhydramine (1 to 2 mg/kg, up to a maximum of 50 mg, given IV or IM) is the drug of choice when treating acute allergic reactions.
- Concomitant administration of an H 2 agonist such as ranitidine (1 mg/kg IV) or cimetidine (4 mg/kg IV) is also of value to provide antihistaminic effect.
- the only antihistamine injection existing on the market is diphenhydramine injection, a first generation antihistamine, with known side effects of cardio toxicity (QT prolongation), severe sedation, anti-cholinergic effect, potential of drug/drug interaction, and short acting which requires 3-4 doses a day.
- Cardio toxicity presents a huge safety concern, and the sedation side effect causes significantly inconvenience and discomfort for patients.
- the sedating side effect presents a safety concern when patients have to drive home themselves after being discharged from the emergency room.
- the sedating side effect also interferes with neurological exams for patients who are in need such exams in the hospital. Patients with allergic reactions to opioids are treated with diphenhydramine injections. This causes a dangerous additive effect in sedation.
- Diphenhydramine's QT prolongation is potentially life threatening and could lead to hospital admission.
- QT prolongation is worsened by drug/drug interaction.
- diphenhydramine injection is frequently used as a preventive measure to desensitize antibiotics (antibiotics have a high incidence for drug induced allergic shock).
- ICUs patients are normally on multiple medications, and the potential drug/drug interaction and liver enzyme P450 inhibition leading to cardiac arrest due to QT prolongation is extremely dangerous.
- Diphenhydramine injection is commonly used together with blood transfusion to prevent allergic reactions to blood or plasma. Clearly sedation is unwanted. Diphenhydramine injection is often used to treat anesthesia induced allergies in the operating room. It takes longer for patients to awake from the anesthesia when diphenhydramine injection is co-used.
- the present disclosure includes injectable formulations of second and third generation antihistamines, or non-sedating antihistamines, via intravenous, intramuscular, or subcutaneous administration to provide an immediate onset of action.
- second and third generation antihistamines are commercially available as oral dosage forms as shown in the following table.
- Additional non-sedating antihistamines include des-diphenhydramine, epinastine, azelastine, Acrivastine, Ebastine, carbastine, levocarbastine, Mizolastine, and Rupatadine.
- Parenteral injectable formulations may be in unit dose form in ampoules, small volume parenteral (SVP) vials, large volume parenterals (SVP), pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
- the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
- oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, buffering, emulsifying or suspending, stabilizing and/or dispersing agents.
- the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
- Parenteral injectable formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9.5), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
- excipients such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9.5)
- a suitable vehicle such as sterile, pyrogen-free water.
- the injectable compositions contain a solution of one or more non-sedating antihistamines in an aqueous solvent combined with a buffer or pH adjusting agents having a pH of 3 to 9.
- the composition optionally contains at least one isotonicity agent.
- a water-insoluble inert gas may be carefully bubbled through the aqueous solvent to remove oxygen from the medium.
- the compositions contain at least one preservative and/or at least one solubility enhancing agent and/or at least one stabilizing agent.
- the non-sedating H1 antihistamine is cetirizine or a salt thereof.
- the quantity of cetirizine or salt thereof in the injection formulation is 1-100 mg per milliliter of liquid, preferably 1.5-50 mg, more preferably 2-25 mg per milliliter of liquid.
- the non-sedating H1 antihistamines is fexofenadine or a salt thereof.
- the quantity of fexofenadine or salt thereof in the injection formulation is 1-200 mg per milliliter of liquid, preferably 1.5-180 mg, preferably 2-90 mg, more preferably 2.5-70 mg per milliliter of liquid.
- the injectable composition optionally comprises at least one H2 antihistamine, specifically ranitidine and cimetidine, more specifically ranitidine.
- Concomitant administration of an H2 agonist such as ranitidine (1 mg/kg IV) or cimetidine (4 mg/kg IV) may be of value to provide antihistaminic effect.
- An automatic injector or auto-injector is a device designed to allow a user to self-administer a pre-measured dose of a medicament composition subcutaneously or intramuscularly, usually in an emergency situation.
- a typical auto-injector has a housing, inside of which is a cartridge.
- the cartridge has one or several chambers containing medicament compositions or components thereof and is in communication with a dispensing assembly such as needle assembly.
- the cartridge can hold either a pre-mixed liquid medicament or a solid medicament and a liquid that are mixed prior to injection.
- the housing carries an actuation assembly with a stored energy source, for example, a compressed spring.
- Activation of the actuation assembly causes a sequence of movements, whereby the needle extends from the auto-injector into the user so that the medicament compound is then forced through the needle and into the user. After delivery of the dose of medicament into the injection site, the needle remains in an extended position or in a hidden position.
- the auto-injector is of the type designed to carry plural components of the medicament composition in separate, sealed compartments, structure may be included that forces the components to mix when the actuation assembly is activated.
- Autoinjectors for antihistamine administration do not exist. Advantages of the use of auto-injectors to dispense non-sedating (second and third generation) antihistamines for the treatment of severe allergic reactions include availability for emergency treatment, precise dosing, portability, readiness for use, rapid intramuscular or subcutaneous administration, administration through clothing and protective wear, and rapid self-administration. The advantages of this invention also include its non-cardiotoxicity (no QT prolongation), and non-sedating. Unlike the current highly sedating diphenhydramine injections, the non-sedating feature of this invention allows patients to be alert enough to drive to the hospital or emergency care facility after they self administer the non-sedating antihistamine injection via an auto injector.
- a kit comprises the automatic injector comprising a non-sedating antihistamine composition as described above, and a second automatic injector comprising a second housing comprising a second chamber for an epinephrine composition and a second dispensing assembly in communication with the second chamber.
- an injectable second or third generation antihistamine (non-sedating antihistamine) formulation comprising administering to an individual in need thereof an effective amount of an injectable composition comprising a second or third generation antihistamine (or non-sedating antihistamine).
- the antihistamine is not diphenhydramine.
- the non-sedating antihistamine is selected from cetirizine, loratadine, levocetirizine, desloratadine, and fexofenadine, des-diphenhydramine, epinastine, azelastine, Acrivastine, Ebastine, carbastine, levocarbastine, Mizolastine, and Rupatadine.
- the injectable formulation further comprises at least one H2 receptor antagonist, such as ranitidine or cimetidine.
- the injectable formulation further comprises epinephrine.
- the injectable formulation further comprises at least one steroid, such as methylprednisolone or prednisolone.
- disclosed herein are methods of treating an acute allergic reaction comprising administering to an individual in need thereof an effective amount of an injectable composition comprising a second or third generation antihistamine (or non-sedating antihistamine), wherein the injectable composition is bioequivalent to an oral formulation of the 2 nd or 3 rd generation antihistamine.
- Non-sedating Dosage range of injectable Antihistamine Oral product formulation Cetirizine 10 mg tablet about 2 mg to about 10 mg 10 mg chewable tablet 10 mg capsule 5 mg tablet 5 mg/5 mL syrup
- Loratadine 10 mg tablet about 1 mg to about 10 mg 10 mg capsule 5 mg tablet 5 mg chewable tablet 0.5 mg/mL syrup 1 mg/mL suspension 1 mg/mL syrup
- Fexofenadine 180 mg tablet/capsule about 5 mg to about 60 mg tablet 180 mg 30 mg tablet 30 mg/5 mL suspension
- Levocetirizine 5 mg tablet about 1 mg to about 5 mg 2.5 mg tablet 2.5 mg/5 mL syrup Desloratadine 5 mg tablet about 1 mg to about 5 mg 2.5 mg/5 mL syrup
- the term equivalent to an oral product means that the 90% confidence limits of a ratio of a logarithmic transformed geometric mean of AUC 0-INF and/or AUC 0-t for the injectable formulation to a logarithmic transformed geometric mean of AUC 0-INF and/or AUC 0-t for the reference oral product are about 0.80 to about 1.25, specifically 0.80 to 1.25.
- AUC is the area under the curve of a graph of the measured concentration of an active agent (typically plasma concentration) vs. time, measured from one time point to another time point.
- AUC 0-t is the area under the curve of plasma concentration versus time from time 0 to time t, the last blood draw time point.
- the AUC 0- ⁇ or AUC 0-INF is the calculated area under the curve of plasma concentration versus time from time 0 to time infinity by extrapolation.
- the AUC 0-INF and/or AUC 0-t are given in Table 2.
- the AUC INF and/or AUC 0-t for the injectable formulation and the reference oral dosage form are given determined in a reference-controlled study.
- disclosed herein are methods of treating an acute allergic reaction including anaphylaxis comprising administering to an individual in need thereof an effective amount of an injectable composition comprising a second or third generation antihistamine (or non-sedating antihistamine), wherein the injectable composition is therapeutically equivalent to a reference diphenhydramine injectable formulation.
- the reference diphenydramine injectable formulation is a 50 mg/mL solution, and the dose is about 12.5-150 mg dose.
- Diphenhydramine injection is commercially available from Pfizer as Benadryl® Injection. Many generic versions of diphenhydramine injections are also available on the market. Therapeutic equivalence can be determined in a reference-controlled study using a diphenydramine injectable formulation as the reference.
- therapeutically equivalent to a reference diphenydramine injectable formulation means that the test formulation has a 90% confidence interval around the difference in the reduction of at least one symptom of an acute allergic reaction including anaphylaxis of the test drug to the reference drug, for the per protocol evaluable population, within about ⁇ 30.00 to about +30.00.
- the symptoms of anaphylaxis or an acute allergic reaction are, pruritus severity, pruritus duration, erythema, angioedema and/or wheezing reduction, and urticaria areas or erythema areas.
- a placebo is an inactive pill, liquid, or powder that has no treatment value.
- experimental treatments are often compared with placebos to assess the treatment's effectiveness.
- a placebo-controlled study is a method of investigation of drugs in which an inactive substance (the placebo) is given to one group of participants, while the drug being tested is given to another group. The results obtained in the two groups are then compared to see if the investigational treatment is more effective in treating the condition.
- therapeutically effective compared to placebo means that the treatment of this invention is statistically superior (p ⁇ 0.05) to a placebo in the reduction of at least one symptom of anaphylaxis or an acute allergic reaction, wherein the symptom is pruritus severity, pruritus duration, erythema, angioedema, urticaria areas, erythema areas, and/or wheezing.
- the methods described herein optionally further comprise administering a second active agent as well as the second or third generation antihistamine.
- the second active agent is an H2 receptor antagonist, such as ranitidine or cimetidine.
- the second active agent is epinephrine.
- the second active agent comprises at least one steroid, such as methylprednisolone or prednisolone.
- the methods disclosed herein further comprise administering a second active agent comprising ranitidine, cimetidine, epinephrine, methylprednisolone, prednisolone, or a combination thereof.
- non-sedating antihistamines represent the 2 nd and/or 3 rd generation antihistamines that are truly non-sedating and that are less-sedating than diphenhydramine.
- antihistamine can also be expressed as “antagonist of the H1 receptor” or “H1 antihistamine”.
- the term “Therapeutic equivalence” can also be expressed as “clinical equivalence”, “clinically bioequivalent”, or “clinical endpoint bioequivalence”.
- Acute allergic reaction means an allergic condition of the immediate type, severe allergies/anaphylaxis, or severe allergic reaction such as allergic reactions to blood or plasma, to food, to medications, or to other allergy inducing materials.
Abstract
Described herein are automatic injectors suitable for administration of a non-sedating antihistamine, and methods of using the automatic injectors. A specific non-sedating antihistamine is cetirizine. The automatic injectors are useful in treating acute urticaria or angioedema associated with an acute allergic reaction including anaphylaxis.
Description
- This application is a divisional of U.S. patent application Ser. No. 12/704,089, filed Feb. 11, 2010, which is a nonprovisional of U.S. Provisional Application Ser. Nos. 61/248,441 filed Oct. 3, 2009 and 61/222,951 filed Jul. 3, 2009, all which are hereby incorporated by reference in their entirety.
- Acute allergic reaction including anaphylaxis, is a systemic, immediate hypersensitivity reaction caused by exposure to a specific antigen. The immune system activates immunoglobulin E (IgE), which reacts with effector cells (mast cells and basophils). These cells, in turn, release histamine, serotonin, leukotrienes, and prostaglandins, and induce a range of signs and symptoms, such as facial flushing, urticaria (hives), edema, pruritus, broncho-constriction, cough, cardiac arrhythmias, hypotension, nausea, vomiting, and diarrhea. Cutaneous manifestations are most common, with urticaria and angioedema present in 88% or more of patients experiencing acute allergic reactions. Swelling in the airway is the most life-threatening symptom, commonly causing dyspnea, wheezing, stridor, and upper airway obstruction from severe edema. Cardiovascular symptoms include dizziness, hypotension, and syncope related to third-spacing of intravascular fluid. Common gastrointestinal manifestations include nausea, vomiting, abdominal pains or cramps, and diarrhea. Although symptoms vary between acute allergy patients, onset generally occurs seconds to minutes after exposure to an antigen and requires prompt treatment.
- The true incidence of acute allergic reactions including anaphylaxis is unknown, partly because of the lack of a precise definition of the syndrome. Some clinicians reserve the term anaphylaxis for the full-blown syndrome, while others use it to describe milder cases. Fatal anaphylaxis is relatively rare; milder forms occur much more frequently. The frequency of acute allergic reaction is increasing, and this has been attributed to the increased number of potential allergens to which people are exposed, such as increased varieties of food and medications. A recent review concluded that the lifetime prevalence of acute allergic reactions including anaphylaxis is ˜5% of the population with higher prevalence in developed countries than developing countries.
- Approximately 1 in 5000 exposures to a parenteral dose of a penicillin or cephalosporin antibiotic causes anaphylaxis. More than 100 deaths per year are reported in the United States due to antibiotic induced allergies. Fewer than 100 fatal reactions to Hymenoptera stings are reported each year in the United States but this is considered to be an underestimate. One to 2% of people receiving IV radiocontrast experience some sort of reaction. The majority of these reactions are minor, and fatalities are rare. Low molecular weight contrast causes fewer and less severe reactions. Narcotics also induce acute allergic reactions.
- Acute allergic reactions occur in all age groups. Food allergies are more common in the young, whereas more drug reactions occur in adults, possibly due to greater exposure to medications, including narcotics, aspirin/NSAIDs, antibiotics, IV contrast media, anesthesia, muscle relaxants, etc. Although prior exposure is essential for the development of true anaphylaxis, reactions occur even when no documented prior exposure exists. Thus, patients may react to a first exposure to an antibiotic or insect sting. Elderly persons have the greatest risk of mortality from acute allergic reactions due to the presence of preexisting disease.
- Emergency treatment includes airway protection, alpha-agonists, antihistamines, steroids, and beta agonists. Medications currently used in the treatment of acute allergic reactions include epinephrine, diphenhydramine injection, corticosteroids, albuterol, and glucagon. Epinephrine is the first-line drug to be given to a patient having an acute allergic reaction. An alpha-receptor agonist, epinephrine reverses hypotension. It also has beta-receptor activity, which dilates the airways, increases the force of myocardial contraction, and suppresses histamine and leukotriene release, reducing inflammatory responses. Diphenhydramine injection is the second-line drug to be given to a patient having an acute allergic reaction as an adjunct therapy to epinephrine for the relief of peripheral symptoms such as pruritus, engioedema, hives, erythema, etc.
- What is needed are additional treatments for severe allergic reactions including anaphylaxis.
- In one aspect, a method of treating anaphylaxis or an acute allergic reaction comprises administering to an individual in need thereof an effective amount of an injectable composition comprising a non-sedating (also termed as 2nd or 3rd generation) H1 antihistamine wherein the H1 antihistamine comprises cetirizine, loratadine, levocetirizine, desloratadine, or fexofenadine.
- In another aspect, the 90% confidence limits of a ratio of a logarithmic transformed geometric mean of AUC0-INF for the injectable formulation as described above to a logarithmic transformed geometric mean of AUC0-INF for a reference oral product of the non-sedating H1 antihistamine are 0.80 to 1.25; and/or wherein the 90% confidence limits of a ratio of a logarithmic transformed geometric mean of AUC0-t for the injectable formulation to a logarithmic transformed geometric mean of AUC0-t for the reference oral product of the non-sedating H1 antihistamine are 0.80 to 1.25.
- In yet another aspect, the injectable formulation of the non-sedating antihistamine as described above has a 90% confidence interval around the difference in the reduction of at least one symptom of anaphylaxis or an acute allergic reaction to a reference injectable product, such as diphenhydramine injection, for the per protocol evaluable population, within about −30.00 to about +30.00, wherein the symptom is pruritus severity, pruritus duration, erythema, angioedema, number of urticaria areas, number of erythema areas, and/or wheezing.
- In another aspect, the injectable formulation of the non-sedating antihistamine as described above is statistically superior (p<0.05) to a placebo in the reduction of at least one symptom of anaphylaxis or an acute allergic reaction, wherein the symptom is pruritus severity, pruritus duration, erythema, angioedema, urticaria areas, erythema areas, and/or wheezing.
- In another aspect, an automatic injector designed to allow a user to self-administer a pre-measured dose of a non-sedating antihistamine composition subcutaneously or intramuscularly, comprises a housing comprising a chamber for the non-sedating antihistamine composition and a dispensing assembly in communication with the chamber, wherein the non-sedating antihistamine composition comprises an non-sedating antihistamine and a pH adjusting agent and has a pH of 3 to 9, wherein the non-sedating antihistamine comprises cetirizine, loratadine, levocetirizine, desloratadine, or fexofenadine.
- In yet another aspect, a kit comprises the automatic injector comprising a non-sedating antihistamine composition as described above and a second automatic injector comprising a second housing comprising a second chamber for an epinephrine composition and a second dispensing assembly in communication with the second chamber.
- Acute allergic reaction including anaphylaxis is an acute multi-system severe type I hypersensitivity reaction. Pseudoanaphylaxis does not involve an allergic reaction, but is due to direct mast cell degranulation. Both anaphylaxis and pseudoanaphylaxis result in an anaphylactoid reaction and treatment for both conditions is similar. The term anaphylaxis as used herein refers to both conditions unless otherwise specified. Clinical signs and symptoms of acute allergic reaction are given in Table 1:
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TABLE 1 Clinical signs and symptoms of acute allergic reactions including anaphylaxis Cutaneous/subcutaneous/mucosal tissue Flushing, pruritus, hives (urticaria), angioedema, morbilliform rash, pilor erection Pruritus of lips, tongue, and palate; edema of lips, tongue, and uvula Periorbital pruritus, erythema and edema, conjunctival erythema, tearing Respiratory Laryngeal: pruritus and tightness in the throat, dysphagia, dysphonia and hoarseness, dry staccato cough, stridor, sensation of pruritus in the external auditory canals Lung: shortness of breath, dyspnea, chest tightness, deep cough and wheezing/bronchospasm (decreased peak expiratory flow) Nose: pruritus, congestion, rhinorrhea, sneezing Cardiovascular Hypotension Feeling of faintness (near-syncope), syncope, altered mental status Chest pain, dysrhythmia Gastrointestinal Nausea, crampy abdominal pain, vomiting (stringy mucus), diarrhea Other Uterine contractions in women, and aura of doom - Disclosed herein are injection formulations of non-sedating antihistamines to be used, for example, in the hospital or acute care settings. In allergic reactions, an antigen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast-cell-antibody-antigen complex is formed, a complicated series of events occurs that eventually leads to mast cell degranulation and the release of histamine and other chemical mediators from the mast cell or basophil. After its release, histamine can react with local or widespread tissues through histamine receptors. Histamine receptor sites, histamine-1 (H1), and histamine-2 (H2) have a role in acute allergic reactions/anaphylaxis. Acting on H1 receptors, histamine produces pruritus, vasodilation, hypotension, flushing, headache, tachycardia, bronchoconstriction, and increased vascular permeability. Targeting H2-receptor sites, histamine causes increased stomach acid production, nausea, and flushing.
- Symptoms of acute allergic reactions include pruritus, erythema, angioedema, urticaria, urticaria areas, erythema areas, wheezing, and etc. Exemplary patient populations for study include patients coming to emergency rooms or allergy clinics, patients with food allergies (peanuts, other nuts, sea food, etc), patients with exercise induced allergies, patients allergic to insects stings, patients with poison Ivy induced allergies, etc. Additional patients include those already in the hospital experiencing drug induced allergies to: antibiotics, IV contrast media, anesthesia, aspirin/NSAIDs, opioids, chemotherapy agents, muscle relaxants, latex gloves, blood materials, etc.
- In one aspect, a clinical endpoint bioequivalence study to compare the efficacy of a non-sedating antihistamine or second or third generation antihistamine injection to diphenhydramine injection is performed. In another embodiment, the efficacy of a non-sedating antihistamine or second or third generation antihistamine injection is compared to placebo.
- Pruritus is a condition involving localized or general itching that is a common and distressing symptom in a variety of diseases, especially in an allergic reaction. Although usually occurring in the skin, pruritus can also occur in non-cutaneous sites such as mucous membranes. Erythema is redness of the skin, caused by congestion of the capillaries in the lower layers of the skin. The primary efficacy endpoints included the pruritus severity score and the erythema severity score (scored on a 0=absent, 1=mild, 2=moderate, to 3=severe scale, at 0.5 increments), and the reduction of the scores following treatment. For clinical trials, patients with “score 1-3” (mild to severe) will be recruited.
- The primary efficacy end points are the difference between the treatment disclosed herein and the treatment of placebo in the mean change from the baseline of the average of the pruritus severity score and the erythema severity score. The study will be designed to give a 90% power to detect a 0.5 unit mean difference for the primary efficacy endpoint at a two-sided alpha-level of 0.05.
- In addition, the duration of pruritus as an efficacy end point that can be measured. Duration of pruritus is categorized as follows: 3 if >6 hours/24 hr, 2 if 1 to 6 hours/24 hr, 1 if less than 1 hour/24 hr, and 0 if no pruritus. The study will be designed to give a 90% power to detect a 0.5 unit mean reduction for the primary efficacy endpoint at a two-sided alpha-level of 0.05.
- Angioedema is an uncomfortable and disfiguring type of temporary swelling especially in the lips and other parts of the mouth and throat, the eyelids, the genitals, and the hand and feet. Angioedema is life-threatening if swelling in your mouth or throat makes it difficult for you to breathe. Less often the sheer amount of swelling means that so much fluid has moved out of the blood circulation that blood pressure drops dangerously. The primary efficacy endpoints for angioedema include the angioedema severity score (scored on a 0=absent, 1=mild, 2=moderate, to 3=severe scale, at 0.5 increments), and the reduction of the score following treatment.
- Wheezing is a high-pitched whistling sound produced by air flowing through narrowed breathing tubes, especially the smaller ones deep in the lung. The primary efficacy endpoints include the wheezing severity score (scored on a 0=absent, 1=mild, 2=moderate, to 3=severe scale, at 0.5 increments), and the reduction of the score following treatment.
- Exemplary clinical studies include a randomized, double-blind, active and placebo-controlled trial of about 300 patients over the age of 12 with acute allergic syndromes. About 100 patients will be randomly assigned to each of the 3 treatments including a non-sedating antihistamine injection as disclosed herein, a diphenhydramine injection, or a placebo injection, all via intravenous, intramuscular or subcutaneous administration. Patients will be recruited at multiple centers, from emergency departments at urban hospitals and allergy clinics throughout the country. The primary endpoints will be the reduction of pruritus severity score, pruritus duration, erythema, angioedema, wheezing, number of urticaria areas, and/or number of erythema areas, at 2-4 hours after protocol treatment. Symptom scores will be also assessed at baseline.
- A broad definition of allergic syndromes to approximate real-life emergency department (ED) approaches will be used to assess the patients with various symptoms and signs. Patients over the age of 12 will be considered for recruitment from the ED if they have the following syndromes after an ingested food or ingested, inhaled, or injected drug, after in contact with latex or bee stings: acute urticaria (score 1 and above), acute angioedema (score 1 and above), wheezing (score 1 and above), and acute pruritic rash (score 1 and above). These manifestations should have been present for no greater than 12 hours from the time of alleged allergen exposure. Pregnant patients will be excluded. Recruited patients will be randomly assigned to treatment with either 10 mg of cetirizine injection (the test product group, i.e. product of present disclosure), diphenhydramine 50 mg injection (the comparator or active control group) or placebo injection (placebo control group)
- Each treatment designation will be blinded based on the randomization code. The physician who is unaware of the treatment content will administer the contents by means of intravenous (or intramuscular, or subcutaneous, depending on protocol requirement) injection to the subject. Supplemental medications, such as epinephrine, corticosteroids, bronchodilators, and additional doses of antihistamine may be administered at the discretion of the study physicians as a rescue procedure. Patients may also receive supplemental oxygen and intravenous fluids at the discretion of the study physicians as a rescue procedure. Patients will have heart rate, blood pressure, physical findings, side effects, and symptoms assessed at baseline, 1 hour, 2 hours and 4 hours relative to experimental treatment. Baseline temperatures will be also recorded. Clinical recording will include the presence and extent or severity scores of urticaria and erythema, angioedema, wheezing, pruritus, number of urticaria areas, number of erythema areas, abdominal distention or tenderness, and abdominal hyperactive bowel sounds. Historical features, physical findings (including heart rates, blood pressure, and respiratory rates), and treatments will be recorded on a study-specific data input form. The extent of involvement with urticaria and erythema will be assessed by using a check-off cartoon of body areas (similar to that used to assess burn area extent) printed on the data input sheet. Symptom scores will be assessed at baseline, 1 hour, and 2, or 4 hours by using a preprinted form with none (score 0), mild (score 1), moderate (score 2), and severe (score 3) check-off categories.
- The primary variables of interest will be resolution or reduction of urticaria, angioedema, erythema, pruritus, wheezing, number of urticaria areas, and number of erythema areas. Changes in heart rates, respiratory rates, blood pressure, and symptoms will also be examined. The final disposition of the patient will be noted (admission, discharge, or leaving against medical advice). The study will be approved by the institutional review board, and informed written consent will be obtained from all patients.
- Statistical assessment will be using bivariate 2 analysis and analysis of variance or covariance (ANCOVA), multivariate logistic regression. Covariates will be included in some multivariate models. Analyses will be performed by using the SAS software. Certain statistical values are expressed with 90% confidence intervals (CIs).
- The above clinical trials may be split into two separate studies. One study will be an active controlled study comparing the invention injectable product with diphenhydramine injection. The other will be a placebo controlled study comparing the invention injectable product with a placebo.
- In addition, pediatric studies will be conducted on patients younger than the age of 12 with similar study design and lower drug dosage.
- Prompt treatment with antihistamines is highly recommended to alleviate the symptoms of acute allergic reactions. Antihistamines are helpful in reducing histamine-mediated vasodilation and secondary edema. Commonly used drugs such as diphenhydramine injection provide H1 blockade. Diphenhydramine reduces vasodilation in small blood vessels in the nose, eyes, and airways and provide some anticholinergic effects toward drying secretions. Diphenhydramine (1 to 2 mg/kg, up to a maximum of 50 mg, given IV or IM) is the drug of choice when treating acute allergic reactions. Concomitant administration of an H2 agonist such as ranitidine (1 mg/kg IV) or cimetidine (4 mg/kg IV) is also of value to provide antihistaminic effect.
- Currently, the only antihistamine injection existing on the market is diphenhydramine injection, a first generation antihistamine, with known side effects of cardio toxicity (QT prolongation), severe sedation, anti-cholinergic effect, potential of drug/drug interaction, and short acting which requires 3-4 doses a day. Cardio toxicity presents a huge safety concern, and the sedation side effect causes significantly inconvenience and discomfort for patients. The sedating side effect presents a safety concern when patients have to drive home themselves after being discharged from the emergency room. The sedating side effect also interferes with neurological exams for patients who are in need such exams in the hospital. Patients with allergic reactions to opioids are treated with diphenhydramine injections. This causes a dangerous additive effect in sedation. Diphenhydramine's QT prolongation is potentially life threatening and could lead to hospital admission. Sometimes severe allergic patients come to the ER and already took a few diphenhydramine tablets. ER doctors then put the patients on injection diphenhydramine as a standard procedure. This accumulated diphenhydramine concentration could cause cardiac arrest leading to hospital admission. QT prolongation is worsened by drug/drug interaction. In ICUs, diphenhydramine injection is frequently used as a preventive measure to desensitize antibiotics (antibiotics have a high incidence for drug induced allergic shock). In ICUs, patients are normally on multiple medications, and the potential drug/drug interaction and liver enzyme P450 inhibition leading to cardiac arrest due to QT prolongation is extremely dangerous. Diphenhydramine injection is commonly used together with blood transfusion to prevent allergic reactions to blood or plasma. Clearly sedation is unwanted. Diphenhydramine injection is often used to treat anesthesia induced allergies in the operating room. It takes longer for patients to awake from the anesthesia when diphenhydramine injection is co-used.
- Therefore there is a great advantage and unmet medical need for a non-sedating antihistamine injection with longer duration of action, and without QT prolongation.
- In one embodiment, the present disclosure includes injectable formulations of second and third generation antihistamines, or non-sedating antihistamines, via intravenous, intramuscular, or subcutaneous administration to provide an immediate onset of action. Such second and third generation antihistamines are commercially available as oral dosage forms as shown in the following table.
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TABLE 2 Second and third generation antihistamines Currently marketed dosage form Second generation antihistamines cetirizine 10 mg tablet, once daily for adults over 6 5 mg chewable, once daily for children under 6 AUC0-24 = about 4023 ng · hr/mL for adult dose of 10 mg; (range: about 2500 to about 5500 ng · hr/mL) AUC0-INF = about 4638 ng · hr/mL, for adult dose of 10 mg; (range: about 3000 to about 6200 ng · hr/mL) loratidine 10 mg tablet every 12 hours for adults over 6 5 mg chewable every 12 hours for children 2-6 AUC0-24 = about 7.36 ng · hr/mL (fasting) AUC0-INF = about 7.90 ng · hr/mL (fasting) AUC0-24 = about 10.3 ng · hr/mL (fed) AUC0-INF = about 11.1 ng · hr/mL (fed) Third generation antihistamines fexofenadine 60 mg tablet twice daily or 180 mg tablet once daily for adults over 12 30 mg tablet once daily for children 6-11 AUC0-inf (60 mg) = about 958 ng · hr/mL AUC0-inf (180 mg) = about 3397 ng · hr/mL AUC0-INF (240 mg) = about 6571 ng · hr/mL levocetirizine 5 mg tablet, once daily for adults over 12 2.5 mg tablet once daily for children 6-11 1.25 mg (½ teaspoon oral solution) once daily for children 6 months to 5 years AUC0-24 = about 3469 ng · hr/mL; (range: about 1500 to about 5000 ng · hr/mL) AUC0-INF = about 3998 ng · hr/mL; (range: about 2000 to about 5500 ng · hr/mL) desloratadine 5 mg tablet once daily for adults over 12 1 teaspoonful (2.5 mg in 5 mL) once daily for children 6 to 11 ½ teaspoonful (1.25 mg in 2.5 mL) once daily for children 12 months to 5 years AUCss = about 56.9 ng·hr/mL AUC0-24 (single dose) = about 34.2 ng · hr/mL AUC(single dose)0-inf = about 35.6 ng/hr/mL - Additional non-sedating antihistamines include des-diphenhydramine, epinastine, azelastine, Acrivastine, Ebastine, carbastine, levocarbastine, Mizolastine, and Rupatadine.
- Parenteral injectable formulations may be in unit dose form in ampoules, small volume parenteral (SVP) vials, large volume parenterals (SVP), pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, buffering, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
- Parenteral injectable formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9.5), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
- In one embodiment, the injectable compositions contain a solution of one or more non-sedating antihistamines in an aqueous solvent combined with a buffer or pH adjusting agents having a pH of 3 to 9. The composition optionally contains at least one isotonicity agent. A water-insoluble inert gas may be carefully bubbled through the aqueous solvent to remove oxygen from the medium. Optionally the compositions contain at least one preservative and/or at least one solubility enhancing agent and/or at least one stabilizing agent.
- In one embodiment, the non-sedating H1 antihistamine is cetirizine or a salt thereof. In another embodiment, the quantity of cetirizine or salt thereof in the injection formulation is 1-100 mg per milliliter of liquid, preferably 1.5-50 mg, more preferably 2-25 mg per milliliter of liquid.
- In another embodiment, the non-sedating H1 antihistamines is fexofenadine or a salt thereof. In yet another embodiment, the quantity of fexofenadine or salt thereof in the injection formulation is 1-200 mg per milliliter of liquid, preferably 1.5-180 mg, preferably 2-90 mg, more preferably 2.5-70 mg per milliliter of liquid.
- In another embodiment, the injectable composition optionally comprises at least one H2 antihistamine, specifically ranitidine and cimetidine, more specifically ranitidine. Concomitant administration of an H2 agonist such as ranitidine (1 mg/kg IV) or cimetidine (4 mg/kg IV) may be of value to provide antihistaminic effect.
- Due to the fast onset of acute allergic reactions including anaphylaxis, often patients do not have sufficient time to reach medical care facilities for treatment. In this life and death situation, it is important that patients administer medications to themselves immediately. Accordingly, there is a need in the art to develop injectable formulations and optionally self operated and ready to use auto injector products, needle or needleless, providing a rapid delivery of the injectable non-sedating antihistamine formulation.
- An automatic injector or auto-injector is a device designed to allow a user to self-administer a pre-measured dose of a medicament composition subcutaneously or intramuscularly, usually in an emergency situation. A typical auto-injector has a housing, inside of which is a cartridge. The cartridge has one or several chambers containing medicament compositions or components thereof and is in communication with a dispensing assembly such as needle assembly. The cartridge can hold either a pre-mixed liquid medicament or a solid medicament and a liquid that are mixed prior to injection. The housing carries an actuation assembly with a stored energy source, for example, a compressed spring. Activation of the actuation assembly causes a sequence of movements, whereby the needle extends from the auto-injector into the user so that the medicament compound is then forced through the needle and into the user. After delivery of the dose of medicament into the injection site, the needle remains in an extended position or in a hidden position. If the auto-injector is of the type designed to carry plural components of the medicament composition in separate, sealed compartments, structure may be included that forces the components to mix when the actuation assembly is activated.
- Autoinjectors for antihistamine administration do not exist. Advantages of the use of auto-injectors to dispense non-sedating (second and third generation) antihistamines for the treatment of severe allergic reactions include availability for emergency treatment, precise dosing, portability, readiness for use, rapid intramuscular or subcutaneous administration, administration through clothing and protective wear, and rapid self-administration. The advantages of this invention also include its non-cardiotoxicity (no QT prolongation), and non-sedating. Unlike the current highly sedating diphenhydramine injections, the non-sedating feature of this invention allows patients to be alert enough to drive to the hospital or emergency care facility after they self administer the non-sedating antihistamine injection via an auto injector.
- In another embodiment, a kit comprises the automatic injector comprising a non-sedating antihistamine composition as described above, and a second automatic injector comprising a second housing comprising a second chamber for an epinephrine composition and a second dispensing assembly in communication with the second chamber.
- In one embodiment, disclosed herein is an injectable second or third generation antihistamine (non-sedating antihistamine) formulation. Also disclosed are methods of treating an acute allergic reaction comprising administering to an individual in need thereof an effective amount of an injectable composition comprising a second or third generation antihistamine (or non-sedating antihistamine). In specific embodiments, the antihistamine is not diphenhydramine. In other embodiments, the non-sedating antihistamine is selected from cetirizine, loratadine, levocetirizine, desloratadine, and fexofenadine, des-diphenhydramine, epinastine, azelastine, Acrivastine, Ebastine, carbastine, levocarbastine, Mizolastine, and Rupatadine.
- In one embodiment, the injectable formulation further comprises at least one H2 receptor antagonist, such as ranitidine or cimetidine. In another embodiment, the injectable formulation further comprises epinephrine. In yet another embodiment, the injectable formulation further comprises at least one steroid, such as methylprednisolone or prednisolone.
- In one embodiment, disclosed herein are methods of treating an acute allergic reaction comprising administering to an individual in need thereof an effective amount of an injectable composition comprising a second or third generation antihistamine (or non-sedating antihistamine), wherein the injectable composition is bioequivalent to an oral formulation of the 2nd or 3rd generation antihistamine.
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Non-sedating Dosage range of injectable Antihistamine Oral product formulation Cetirizine 10 mg tablet about 2 mg to about 10 mg 10 mg chewable tablet 10 mg capsule 5 mg tablet 5 mg/5 mL syrup Loratadine 10 mg tablet about 1 mg to about 10 mg 10 mg capsule 5 mg tablet 5 mg chewable tablet 0.5 mg/mL syrup 1 mg/mL suspension 1 mg/mL syrup Fexofenadine 180 mg tablet/capsule about 5 mg to about 60 mg tablet 180 mg 30 mg tablet 30 mg/5 mL suspension Levocetirizine 5 mg tablet about 1 mg to about 5 mg 2.5 mg tablet 2.5 mg/5 mL syrup Desloratadine 5 mg tablet about 1 mg to about 5 mg 2.5 mg/5 mL syrup - As used herein, the term equivalent to an oral product means that the 90% confidence limits of a ratio of a logarithmic transformed geometric mean of AUC0-INF and/or AUC0-t for the injectable formulation to a logarithmic transformed geometric mean of AUC0-INF and/or AUC0-t for the reference oral product are about 0.80 to about 1.25, specifically 0.80 to 1.25. “AUC” is the area under the curve of a graph of the measured concentration of an active agent (typically plasma concentration) vs. time, measured from one time point to another time point. For example AUC0-t is the area under the curve of plasma concentration versus time from time 0 to time t, the last blood draw time point. The AUC0-∞ or AUC0-INF is the calculated area under the curve of plasma concentration versus time from time 0 to time infinity by extrapolation. In one embodiment, the AUC0-INF and/or AUC0-t are given in Table 2. In another embodiment, the AUCINF and/or AUC0-t for the injectable formulation and the reference oral dosage form are given determined in a reference-controlled study.
- In one embodiment, disclosed herein are methods of treating an acute allergic reaction including anaphylaxis comprising administering to an individual in need thereof an effective amount of an injectable composition comprising a second or third generation antihistamine (or non-sedating antihistamine), wherein the injectable composition is therapeutically equivalent to a reference diphenhydramine injectable formulation. In one embodiment, the reference diphenydramine injectable formulation is a 50 mg/mL solution, and the dose is about 12.5-150 mg dose. Diphenhydramine injection is commercially available from Pfizer as Benadryl® Injection. Many generic versions of diphenhydramine injections are also available on the market. Therapeutic equivalence can be determined in a reference-controlled study using a diphenydramine injectable formulation as the reference.
- As used herein, therapeutically equivalent to a reference diphenydramine injectable formulation means that the test formulation has a 90% confidence interval around the difference in the reduction of at least one symptom of an acute allergic reaction including anaphylaxis of the test drug to the reference drug, for the per protocol evaluable population, within about −30.00 to about +30.00. In specific embodiments, the symptoms of anaphylaxis or an acute allergic reaction are, pruritus severity, pruritus duration, erythema, angioedema and/or wheezing reduction, and urticaria areas or erythema areas.
- Predicted results for clinical equivalence are presented in Table 3:
-
On Treatment Difference 90% CI Treatment N Baseline adjusted mean from Placebo (−30.00, +30.00) Pruritus severity score reduction Cetirizine 10 mg About About 2.80 About 1.70 +0.05 About (−3.00, 8.00) injection 100 Diphenhydramine About About 2.75 About 1.65 50 mg injection 100 Pruritus duration reduction Cetirizine 10 mg About About 1.00 hr −0.50 hr About (−8.50, 3.50) injection 100 Diphenhydramine About About 1.50 hr 50 mg injection 100 Erythema Reduction Cetirizine 10 mg About About 2.50 About 1.0 0.00 About (−10.00, injection 100 10.00) Diphenhydramine About About 2.55 About 1.0 50 mg injection 100 Angioedema Reduction Cetirizine 10 mg About About 2.50 About 1.0 −0.25 About (−10.00, injection 100 8.00) Diphenhydramine About About 2.45 About 1.25 50 mg injection 100 Wheezing reduction Cetirizine 10 mg About About 2.45 About 1.40 +0.40 About (−0.20, injection 100 15.00) Diphenhydramine About About 2.55 About 1.00 50 mg injection 100 Number of urticaria areas Cetirizine 10 mg About About 4.2 About 1.0 −0.20 About (−10.00, injection 100 8.00) Diphenhydramine About About 4.0 About 1.20 50 mg injection 100 Number of erythema areas Cetirizine 10 mg About About 7.0 About 1.0 −1.0 About (−15.00, injection 100 10.00) Diphenhydramine About About 7.2 About 2.0 50 mg injection 100 - Expected results for effectiveness comparing to placebo are presented in Table 4:
-
On Treatment Difference Treatment N Baseline adjusted mean from Placebo P-value Pruritus severity score reduction Cetirizine 10 mg About 100 About 2.80 About 1.80 −0.70 <0.05 injection Placebo injection About 100 About 2.75 About 2.50 Pruritus duration reduction Cetirizine 10 mg About 100 About 1.50 hr −2.5 hr <0.05 injection Placebo injection About 100 About 4.00 hr Erythema Reduction Cetirizine 10 mg About 100 About 2.50 About 1.0 −1.15 <0.05 injection Placebo injection About 100 About 2.55 About 2.15 Angioedema Reduction Cetirizine 10 mg About 100 About 2.50 About 1.0 −1.25 <0.05 injection Placebo injection About 100 About 2.45 About 2.25 Wheezing reduction Cetirizine 10 mg About 100 About 2.45 About 1.40 −0.75 <0.05 injection Placebo injection About 100 About 2.55 About 2.15 Number of urticaria areas Cetirizine 10 mg About 100 About 4.2 About 1.0 −2.8 <0.05 injection Placebo injection About 100 About 4.0 About 3.8 Number of erythema areas Cetirizine 10 mg About 100 About 6.0 About 1.0 −4.0 <0.05 injection Placebo injection About 100 About 6.2 About 5.0 - In one embodiment, disclosed herein are methods of treating an acute allergic reaction including anaphylaxis comprising administering to an individual in need thereof an effective amount of an injectable composition comprising a second or third generation antihistamine, the non-sedating antihistamine, wherein the injectable composition is therapeutically effective compared to placebo. As used herein, a placebo is an inactive pill, liquid, or powder that has no treatment value. In clinical trials, experimental treatments are often compared with placebos to assess the treatment's effectiveness. A placebo-controlled study is a method of investigation of drugs in which an inactive substance (the placebo) is given to one group of participants, while the drug being tested is given to another group. The results obtained in the two groups are then compared to see if the investigational treatment is more effective in treating the condition.
- As used herein, therapeutically effective compared to placebo means that the treatment of this invention is statistically superior (p<0.05) to a placebo in the reduction of at least one symptom of anaphylaxis or an acute allergic reaction, wherein the symptom is pruritus severity, pruritus duration, erythema, angioedema, urticaria areas, erythema areas, and/or wheezing.
- The methods described herein optionally further comprise administering a second active agent as well as the second or third generation antihistamine. In one embodiment, the second active agent is an H2 receptor antagonist, such as ranitidine or cimetidine. In another embodiment, the second active agent is epinephrine. In yet another embodiment, the second active agent comprises at least one steroid, such as methylprednisolone or prednisolone. In one embodiment, the methods disclosed herein further comprise administering a second active agent comprising ranitidine, cimetidine, epinephrine, methylprednisolone, prednisolone, or a combination thereof.
- The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and/or.” The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to”). Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. The endpoints of all ranges directed to the same component or property are inclusive and independently combinable.
- The term “non-sedating antihistamines” represent the 2nd and/or 3rd generation antihistamines that are truly non-sedating and that are less-sedating than diphenhydramine.
- The term “antihistamine” can also be expressed as “antagonist of the H1 receptor” or “H1 antihistamine”.
- The term “Therapeutic equivalence” can also be expressed as “clinical equivalence”, “clinically bioequivalent”, or “clinical endpoint bioequivalence”.
- The term “equivalent” can also be expressed as “bioequivalent”.
- “Acute allergic reaction” means an allergic condition of the immediate type, severe allergies/anaphylaxis, or severe allergic reaction such as allergic reactions to blood or plasma, to food, to medications, or to other allergy inducing materials.
- Embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments would become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
Claims (8)
1. A method of treating acute urticaria or angioedema associated with an acute allergic reaction including anaphylaxis in an individual in need thereof, comprising
self-administering from an automatic injector a pre-measured dose of a non-sedating antihistamine composition subcutaneously or intramuscularly,
wherein the non-sedating antihistamine composition comprises a non-sedating antihistamine and a pH adjusting agent and has a pH of 3 to 9, wherein the non-sedating antihistamine comprises cetirizine or a salt thereof,
wherein the automatic injector comprises a housing comprising a chamber for the non-sedating antihistamine composition and a dispensing assembly in communication with the chamber.
2. The method of claim 1 , wherein the non-sedating antihistamine composition further comprises ranitidine, cimetidine, epinephrine, methylprednisolone, prednisolone, or a combination thereof.
3. The method of claim 1 , further comprising self-administering from a second automatic injector an epinephrine composition, wherein the second automatic injector comprises a second housing comprising a second chamber for the epinephrine composition and a second dispensing assembly in communication with the second chamber.
4. The method of claim 1 , wherein treating is in an emergency situation.
5. The method of claim 1 , wherein self-administering the non-sedating antihistamine from the automatic injector is non-cardiotoxic and non-sedating.
6. An automatic injector for self-administration of a pre-measured dose of a non-sedating antihistamine composition subcutaneously or intramuscularly, comprising
a housing comprising a chamber for the non-sedating antihistamine composition and a dispensing assembly in communication with the chamber,
wherein the non-sedating antihistamine composition comprises a non-sedating antihistamine and a pH adjusting agent and has a pH of 3 to 9, wherein the non-sedating antihistamine comprises cetirizine or a salt thereof.
7. The automatic injector of claim 6 , wherein the non-sedating antihistamine composition further comprises ranitidine, cimetidine, epinephrine, methylprednisolone, prednisolone, or a combination thereof.
8. A kit comprising the automatic injector comprising a non-sedating antihistamine composition of claim 6 , and a second automatic injector comprising a second housing comprising a second chamber for an epinephrine composition and a second dispensing assembly in communication with the second chamber.
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Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110004164A1 (en) * | 2009-07-03 | 2011-01-06 | Jie Du | Non-sedating antihistamine injection formulations and methods of use thereof |
US8513259B2 (en) | 2009-07-03 | 2013-08-20 | Jdp Therapeutics, Inc. | Non-sedating antihistamine injection formulations and methods of use thereof |
US8945063B2 (en) | 2009-03-20 | 2015-02-03 | Antares Pharma, Inc. | Hazardous agent injection system |
US9144648B2 (en) | 2006-05-03 | 2015-09-29 | Antares Pharma, Inc. | Injector with adjustable dosing |
US9180259B2 (en) | 2005-01-24 | 2015-11-10 | Antares Pharma, Inc. | Prefilled syringe jet injector |
US20150352102A1 (en) * | 2013-03-13 | 2015-12-10 | Inflammatory Response Research, Inc. | Use of levocetirizine and montelukast in the treatment of anaphylaxis |
US9220660B2 (en) | 2011-07-15 | 2015-12-29 | Antares Pharma, Inc. | Liquid-transfer adapter beveled spike |
US9333309B2 (en) | 2002-02-11 | 2016-05-10 | Antares Pharma, Inc. | Intradermal injector |
US9364611B2 (en) | 2012-05-07 | 2016-06-14 | Antares Pharma, Inc. | Needle assisted jet injection device having reduced trigger force |
US9393367B2 (en) | 2013-03-12 | 2016-07-19 | Antares Pharma, Inc. | Prefilled syringes and kits thereof |
US9446195B2 (en) | 2011-07-15 | 2016-09-20 | Antares Pharma, Inc. | Injection device with cammed ram assembly |
US9486583B2 (en) | 2012-03-06 | 2016-11-08 | Antares Pharma, Inc. | Prefilled syringe with breakaway force feature |
US9561333B2 (en) | 2008-08-05 | 2017-02-07 | Antares Pharma, Inc. | Multiple dosage injector |
US9707354B2 (en) | 2013-03-11 | 2017-07-18 | Antares Pharma, Inc. | Multiple dosage injector with rack and pinion dosage system |
US9744302B2 (en) | 2013-02-11 | 2017-08-29 | Antares Pharma, Inc. | Needle assisted jet injection device having reduced trigger force |
US9808582B2 (en) | 2006-05-03 | 2017-11-07 | Antares Pharma, Inc. | Two-stage reconstituting injector |
US9867949B2 (en) | 2008-03-10 | 2018-01-16 | Antares Pharma, Inc. | Injector safety device |
US9925183B2 (en) | 2014-09-15 | 2018-03-27 | Inflammatory Response Research, Inc. | Levocetirizine and montelukast in the treatment of inflammation mediated conditions |
US9937166B2 (en) | 2013-03-13 | 2018-04-10 | Inflammatory Response Research, Inc. | Use of levocetirizine and montelukast in the treatment of traumatic injury |
US9950125B2 (en) | 2012-04-06 | 2018-04-24 | Antares Pharma, Inc. | Needle assisted jet injection administration of testosterone compositions |
US10201537B2 (en) | 2013-03-13 | 2019-02-12 | IRR, Inc. | Use of levocetirizine and montelukast in the treatment of autoimmune disorders |
US10206919B2 (en) | 2013-03-13 | 2019-02-19 | IRR, Inc. | Use of levocetirizine and montelukast in the treatment of vasculitis |
US10537568B2 (en) | 2010-06-16 | 2020-01-21 | IRR, Inc. | Use of levocetirizine and montelukast to ameliorate inflammation following radiation exposure |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9789071B2 (en) | 2012-06-27 | 2017-10-17 | G2B Pharma, Inc. | Intranasal formulation of epinephrine for the treatment of anaphylaxis |
US9717726B2 (en) | 2013-03-14 | 2017-08-01 | Maregade Rx, LLC | Product and method for treating diarrhea |
US9585867B2 (en) | 2015-08-06 | 2017-03-07 | Charles Everett Ankner | Cannabinod formulation for the sedation of a human or animal |
CN107961214B (en) * | 2016-10-18 | 2021-08-24 | 北京科信必成医药科技发展有限公司 | Cetirizine injection |
CN107961215B (en) * | 2016-10-20 | 2021-08-24 | 北京科信必成医药科技发展有限公司 | Levocetirizine injection |
ES2953520T3 (en) | 2016-12-23 | 2023-11-14 | Maregade Rx Llc | Low dose product and method for the treatment of diarrhea |
WO2019182745A1 (en) | 2018-03-19 | 2019-09-26 | Bryn Pharma, LLC | Epinephrine spray formulations |
US11253513B2 (en) | 2019-10-07 | 2022-02-22 | Jdp Therapeutics Llc | Dosing regimen for injectable cetirizine |
US11617716B2 (en) | 2021-06-10 | 2023-04-04 | Belhaven BioPharma Inc. | Dry powder formulations of epinephrine and associated methods |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4031893A (en) * | 1976-05-14 | 1977-06-28 | Survival Technology, Inc. | Hypodermic injection device having means for varying the medicament capacity thereof |
Family Cites Families (112)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4117141A (en) | 1977-02-18 | 1978-09-26 | Dov Michaeli | Method of inhibiting flea-bite allergy |
FI75816C (en) | 1981-02-06 | 1988-08-08 | Ucb Sa | Process for the preparation of therapeutically active 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid or its amide |
US4434237A (en) | 1982-03-31 | 1984-02-28 | Dinarello Charles A | Human leukocytic pyrogen test for the detection of exogenous fever-producing substances |
US4826689A (en) | 1984-05-21 | 1989-05-02 | University Of Rochester | Method for making uniformly sized particles from water-insoluble organic compounds |
US5093360A (en) | 1989-04-07 | 1992-03-03 | Yu Ruey J | Retinal, derivatives and their therapeutic use |
US5276044A (en) | 1991-08-14 | 1994-01-04 | Allergan, Inc. | Leukotriene receptor antagonist and antihistamine complex pharmaceutical compositions |
CA2145413A1 (en) * | 1992-09-24 | 1994-03-31 | Nancy M. Gray | Methods and compositions for treating allergic disorders using optically pure (+) cetirizine |
EP0950412A3 (en) | 1992-09-24 | 2001-05-16 | Sepracor, Inc. | Compositions for treating allergic disorders using (-) cetirizine |
KR100329887B1 (en) | 1992-11-02 | 2002-11-02 | 시오노기세이야쿠가부시키가이샤 | (E) -Method for preparing alkoxyimino- and hydroxyimino-acetamide compounds and intermediates for preparation thereof |
TW401300B (en) | 1992-12-25 | 2000-08-11 | Senju Pharma Co | Antiallergic composition for ophthalmic or nasal use |
US20020048596A1 (en) | 1994-12-30 | 2002-04-25 | Gregor Cevc | Preparation for the transport of an active substance across barriers |
FR2732221B1 (en) | 1995-03-28 | 1997-04-25 | Oreal | USE OF A CGRP ANTAGONIST TO TREAT CUTANEOUS REDNESS OF NEUROGENIC ORIGIN AND COMPOSITION OBTAINED |
US7833543B2 (en) | 1995-06-07 | 2010-11-16 | Durect Corporation | High viscosity liquid controlled delivery system and medical or surgical device |
EP0811374A1 (en) | 1996-05-29 | 1997-12-10 | Pfizer Inc. | Combination dosage form comprising cetirizine and pseudoephedrine |
IL127691A0 (en) | 1996-06-28 | 1999-10-28 | Oxigene Inc | Useful formulations of acid addition salt drugs |
JP2002514194A (en) | 1996-11-19 | 2002-05-14 | ザ スキーペンズ アイ リサーチ インスティテュート インコーポレイテッド | Topical use of IL-1RA in rejection of corneal transplantation or eye disease |
US6451815B1 (en) | 1997-08-14 | 2002-09-17 | Aventis Pharmaceuticals Inc. | Method of enhancing bioavailability of fexofenadine and its derivatives |
US20020164374A1 (en) | 1997-10-29 | 2002-11-07 | John Jackson | Polymeric systems for drug delivery and uses thereof |
IN188720B (en) * | 1997-11-06 | 2002-11-02 | Panacea Biotec Ltd | |
US6660301B1 (en) | 1998-03-06 | 2003-12-09 | Biosphere Medical, Inc. | Injectable microspheres for dermal augmentation and tissue bulking |
US6384038B1 (en) | 1998-04-14 | 2002-05-07 | Sepracor Inc. | Methods and compositions using cetirizine in combination with leukotriene inhibitors or decongestants |
US6239119B1 (en) | 1998-04-27 | 2001-05-29 | Medimmune Oncology, Inc. | Topical administration of amifostine and related compounds |
US20050158408A1 (en) | 1998-07-24 | 2005-07-21 | Yoo Seo H. | Dried forms of aqueous solubilized bile acid dosage formulation: preparation and uses thereof |
US7303768B2 (en) | 1998-07-24 | 2007-12-04 | Seo Hong Yoo | Preparation of aqueous clear solution dosage forms with bile acids |
IT1303671B1 (en) | 1998-07-28 | 2001-02-23 | Nicox Sa | SALTS OF NITRIC ACID WITH ACTIVE DRUGS IN THE TREATMENT OF DISEASES OF THE RESPIRATORY SYSTEM |
US6432961B1 (en) | 1998-08-18 | 2002-08-13 | Ucb S.A. | Method for preventing the onset of asthma |
TW581675B (en) | 1998-08-18 | 2004-04-01 | Ucb Sa | A pharmaceutical composition for use in preventing the onset of asthma in a patient |
BR9804993A (en) | 1998-11-10 | 2000-06-06 | Panacea Biotec Ltd | Antiallergic and anti-inflammatory composition |
CH693625A5 (en) | 1999-02-18 | 2003-11-28 | Inpharma Sa | Pharmaceutical compositions containing compounds of promoter activity of absorption of active ingredients. |
US20040185145A1 (en) | 1999-07-22 | 2004-09-23 | Ehrman Richard A. | Food product and related method |
NZ518052A (en) | 1999-09-28 | 2005-04-29 | Panacea Biotec Ltd | Controlled release compositions comprising nimesulide (4-nitro-2-phenoxymethanesulfonanilide) for a once-a-day oral dosage to treat diseases such as arthritis |
US6720001B2 (en) | 1999-10-18 | 2004-04-13 | Lipocine, Inc. | Emulsion compositions for polyfunctional active ingredients |
US6458384B2 (en) | 2000-02-23 | 2002-10-01 | Impetus Ag | Pharmaceutical with predetermined activity profile |
US7338657B2 (en) | 2001-03-15 | 2008-03-04 | Biosphere Medical, Inc. | Injectable microspheres for tissue construction |
US7217770B2 (en) | 2000-05-17 | 2007-05-15 | Samyang Corporation | Stable polymeric micelle-type drug composition and method for the preparation thereof |
US6258814B1 (en) | 2000-10-13 | 2001-07-10 | Schering Corporation | Method of using cetirizine and pharmaceutical compositions containing the same for inducing sleep |
AU2002256967A1 (en) * | 2000-10-30 | 2002-09-12 | Schering Corporation | Treating or reducing the risk of cardiovascular disease |
WO2002047689A2 (en) | 2000-12-15 | 2002-06-20 | Ucb, S.A. | Use of cetirizine or efletirizine for preventing urticaria |
JP4074427B2 (en) | 2000-12-18 | 2008-04-09 | 株式会社栃木臨床病理研究所 | Preventive or therapeutic agent for endometriosis |
PT1353668E (en) | 2001-01-25 | 2008-06-30 | Bristol Myers Squibb Co | Processes for the preparation of pharmaceutical preparations containing epothilone analogues for the treatment of cancer |
US20030068375A1 (en) | 2001-08-06 | 2003-04-10 | Curtis Wright | Pharmaceutical formulation containing gelling agent |
US20030144336A1 (en) | 2001-08-27 | 2003-07-31 | Pfizer Inc. | Method of selecting nonsedating H1-antagonists |
US20030134811A1 (en) | 2001-10-09 | 2003-07-17 | John Jackson | Methods and compositions comprising hydroxyapatite useful for the administration of therapeutic agents |
US20030134810A1 (en) | 2001-10-09 | 2003-07-17 | Chris Springate | Methods and compositions comprising biocompatible materials useful for the administration of therapeutic agents |
US6824786B2 (en) | 2001-11-27 | 2004-11-30 | Ruey J. Yu | Compositions comprising phenyl-glycine derivatives |
CA2471948A1 (en) | 2002-01-03 | 2003-07-17 | Smithkline Beecham Corporation | Novel pharmaceutical dosage forms and method for producing same |
JP2003212773A (en) | 2002-01-04 | 2003-07-30 | Oramon Arzneimittel Gmbh | Topical medicine composition of cetirizine and loratadine |
US7115563B2 (en) | 2002-05-29 | 2006-10-03 | Insignion Holding Limited | Composition and its therapeutic use |
CA2487712A1 (en) | 2002-06-28 | 2004-01-08 | Nastech Pharmaceutical Company Inc. | Compositions and methods for modulating physiology of epithelial junctional adhesion molecules for enhanced mucosal delivery of therapeutic compounds |
ATE386526T1 (en) | 2002-07-02 | 2008-03-15 | Ucb Farchim Sa | DIARYLMETHYLPIPERAZINES AS PROPHYLACTIC OR THERAPEUTIC AGENTS AGAINST VIRAL MYOCARDITIS |
US8729036B2 (en) | 2002-08-07 | 2014-05-20 | University Of Massachusetts | Compositions for RNA interference and methods of use thereof |
AU2003287526A1 (en) | 2002-11-06 | 2004-06-03 | Protein-stabilized liposomal formulations of pharmaceutical agents | |
CA2506965A1 (en) | 2002-12-03 | 2004-06-17 | Ucb Farchim S.A. | Use of levocetirizine for the treatment of persistent allergic rhinitis |
US7871607B2 (en) | 2003-03-05 | 2011-01-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases |
AU2004218354B2 (en) | 2003-03-05 | 2009-10-01 | Halozyme, Inc. | Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof |
US20090123367A1 (en) | 2003-03-05 | 2009-05-14 | Delfmems | Soluble Glycosaminoglycanases and Methods of Preparing and Using Soluble Glycosaminoglycanases |
US20060104968A1 (en) | 2003-03-05 | 2006-05-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases |
US20060063827A1 (en) | 2004-09-23 | 2006-03-23 | Yu Ruey J | Systemic administration of therapeutic amino acids and N-acetylamino acids |
SE0300831D0 (en) | 2003-03-26 | 2003-03-26 | Pharmacia Ab | New formulations and use therof |
ZA200507877B (en) | 2003-03-31 | 2007-01-31 | Titan Pharmaceuticals Inc | Implantable polymeric device for sustained release of dopamine agonist |
KR101208291B1 (en) | 2003-04-04 | 2012-12-05 | 노파르티스 아게 | High concentration antibody and protein formulations |
CA2522007A1 (en) | 2003-04-11 | 2004-10-28 | Medimmune, Inc. | Methods of preventing or treating respiratory conditions |
US20040228831A1 (en) | 2003-05-15 | 2004-11-18 | Belinka Benjamin A. | Polymeric conjugates for tissue activated drug delivery |
US7589233B2 (en) | 2003-07-29 | 2009-09-15 | Signature R&D Holdings, Llc | L-Threonine derivatives of high therapeutic index |
US8173840B2 (en) | 2003-07-29 | 2012-05-08 | Signature R&D Holdings, Llc | Compounds with high therapeutic index |
US20050032173A1 (en) | 2003-08-05 | 2005-02-10 | Mauricio Rojas | Fusion proteins with a membrane translocating sequence and methods of using same to inhibit an immune response |
US20050031713A1 (en) | 2003-08-06 | 2005-02-10 | Elliot Ehrich | Methods for administering active agents to CYP3A4 sensitive patients |
US20070020196A1 (en) | 2003-12-31 | 2007-01-25 | Pipkin James D | Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid prepared from a unit dose suspension |
US20050192290A1 (en) | 2004-01-13 | 2005-09-01 | Isaac Melamed | Treatment of behavioral disorders |
US20050208134A1 (en) | 2004-02-25 | 2005-09-22 | Shlomo Magdassi | Biocompatible polymeric beads and use thereof |
US20050255154A1 (en) | 2004-05-11 | 2005-11-17 | Lena Pereswetoff-Morath | Method and composition for treating rhinitis |
US20050282879A1 (en) | 2004-06-17 | 2005-12-22 | Foad Salehani | Methods and composition for treatment of migraine and symptoms thereof |
DE602004022523D1 (en) | 2004-07-02 | 2009-09-24 | Novagali Pharma Sa | Use of emulsions for intra- and periocular injection |
US20070213660A1 (en) | 2004-10-29 | 2007-09-13 | Mark Richards | Fibrin sealant delivery device including pressure monitoring, and method and kits thereof |
US8357147B2 (en) | 2005-08-17 | 2013-01-22 | Spinal Restoration, Inc. | Method for repairing intervertebral discs |
US20090054994A1 (en) | 2007-08-21 | 2009-02-26 | James Rogan | Methods and kits for prophylactically reinforcing degenerated spinal discs and facet joints near a surgically treated spinal section |
US20070286881A1 (en) | 2005-07-14 | 2007-12-13 | Brian Burkinshsw | Method, composition and kit for treating degenerated disc disease and discogenic pain |
US8403923B2 (en) | 2004-10-29 | 2013-03-26 | Spinal Restoration, Inc. | Injection of fibrin sealant in the absence of corticosteroids in spinal applications |
US8419722B2 (en) | 2004-10-29 | 2013-04-16 | Spinal Restoration, Inc. | Apparatus and method for injection of fibrin sealant in spinal applications |
US8206448B2 (en) | 2004-10-29 | 2012-06-26 | Spinal Restoration, Inc. | Injection of fibrin sealant using reconstituted components in spinal applications |
US9132116B2 (en) | 2004-08-02 | 2015-09-15 | Willowcroft Pharm Inc. | Mast cell stabilizers to prevent or treat laminitis |
WO2006037047A2 (en) | 2004-09-27 | 2006-04-06 | Bridge Pharma, Inc. | The r-isomer of 2-{2-[n-(2-indanyl)-n-phenylamino]ethyl}piperidine and other dermal anesthetic agents |
US7718674B2 (en) | 2004-09-27 | 2010-05-18 | Bridge Pharma, Inc. | Methods of relieving neuropathic pain with the S-isomer of 2-{2[N-(2-indanyl)-N-phenylamino]ethyl}piperidine |
AU2005294382A1 (en) | 2004-10-04 | 2006-04-20 | Qlt Usa, Inc. | Ocular delivery of polymeric delivery formulations |
US20060079846A1 (en) | 2004-10-08 | 2006-04-13 | Alton Williams | Hypodermic syringes with multiple needles and methods of calming psychiatric patients using such |
JP2008517938A (en) * | 2004-10-25 | 2008-05-29 | シェーリング コーポレイション | M1 receptor antagonist and / or M3 receptor antagonist in combination with other active agents to treat respiratory disorders |
CN101119713A (en) | 2004-11-24 | 2008-02-06 | 阿尔高克斯制药公司 | Capsaicinoid gel formulation and uses thereof |
US20060211754A1 (en) | 2005-03-16 | 2006-09-21 | Yu Ruey J | Compositions comprising N-propanoyl derivatives of amino acids, aminocarbohydrates and derivatives thereof |
US20060216363A1 (en) | 2005-03-28 | 2006-09-28 | Liu Su Y | Novel herbal composition |
EP2397034A1 (en) | 2005-07-14 | 2011-12-21 | Lithera, Inc. | Sustained Release Enhanced Lipolytic Formulation for Regional Adipose Tissue Treatment |
JP5155883B2 (en) | 2006-01-25 | 2013-03-06 | ターロ ファーマシューティカルズ ノース アメリカ インコーポレイテッド | Antihistamine composition and use thereof |
TW200744568A (en) * | 2006-02-28 | 2007-12-16 | Verus Pharmaceuticals Inc | Epinephrine dosing regimens |
TW200744697A (en) | 2006-02-28 | 2007-12-16 | Verus Pharmaceuticals Inc | Shock absorber for an automatic injector |
CA2645080A1 (en) | 2006-03-07 | 2007-09-13 | Novavax,Inc. | Nanoemulsions of poorly soluble pharmaceutical active ingredients and methods of making the same |
JP2010502723A (en) | 2006-09-11 | 2010-01-28 | ボーシュ アンド ローム インコーポレイティド | Compositions and methods for treating, controlling, reducing, ameliorating or preventing allergies |
US20080066739A1 (en) | 2006-09-20 | 2008-03-20 | Lemahieu Edward | Methods and systems of delivering medication via inhalation |
FR2906140B1 (en) | 2006-09-22 | 2008-12-05 | Philippe Perovitch | GALENIC FORM FOR TRANSMUCOSUS ADMINISTRATION OF ACTIVE INGREDIENTS |
US20080145405A1 (en) | 2006-12-15 | 2008-06-19 | Kunzler Jay F | Drug delivery devices |
US8476243B2 (en) | 2006-12-29 | 2013-07-02 | Transderm, Inc. | Methods and compositions for treating keratin hyperproliferative disorders |
CN103554263B (en) | 2007-03-22 | 2016-09-28 | 健泰科生物技术公司 | Apoptotic anti-IgE antibodies in conjunction with the IgE that film combines |
US20080294261A1 (en) | 2007-05-24 | 2008-11-27 | Kevin Pauza | Method for treating herniated discs |
CA2695127A1 (en) | 2007-07-30 | 2009-02-05 | Immuneregen Biosciences, Inc. | Methods of treating blood cell depletion |
GB0719518D0 (en) | 2007-10-05 | 2007-11-14 | Therapeutics Ltd E | Therapy |
EP2067469A1 (en) | 2007-11-06 | 2009-06-10 | Teva Pharmaceutical Industries Ltd. | Chewable formulations |
US7875001B2 (en) | 2008-02-25 | 2011-01-25 | Americo Michael Minotti | Multi medication nasal spray device and method |
US8080562B2 (en) | 2008-04-15 | 2011-12-20 | Sarcode Bioscience Inc. | Crystalline pharmaceutical and methods of preparation and use thereof |
ATE532505T1 (en) | 2008-04-18 | 2011-11-15 | Novaliq Gmbh | INHALATIVE AND INSTILLATIVE USE OF SEMIFLUORINATED ALKANES AS ACTIVE CARRIERS IN THE INTRAPULMONAL AREA |
US7883488B2 (en) | 2008-06-16 | 2011-02-08 | Shantha Totada R | Transdermal local anesthetic patch with injection port |
US7883487B2 (en) | 2008-06-16 | 2011-02-08 | Shantha Totada R | Transdermal local anesthetic patch with injection port |
US8080550B2 (en) | 2008-08-01 | 2011-12-20 | Alpha Synergy Development, Inc. | Anesthetic compositions and methods of use |
US8263581B2 (en) | 2009-07-03 | 2012-09-11 | Jdp Therapeutics, Inc. | Non-sedating antihistamine injection formulations and methods of use thereof |
US8513259B2 (en) | 2009-07-03 | 2013-08-20 | Jdp Therapeutics, Inc. | Non-sedating antihistamine injection formulations and methods of use thereof |
-
2010
- 2010-02-11 US US12/704,089 patent/US8263581B2/en active Active
- 2010-07-02 ES ES10794820.0T patent/ES2616703T3/en active Active
- 2010-07-02 EP EP10794820.0A patent/EP2477634B1/en active Active
- 2010-07-02 WO PCT/US2010/040925 patent/WO2011003074A1/en active Application Filing
- 2010-07-02 CA CA2803987A patent/CA2803987C/en active Active
- 2010-07-02 AU AU2010266103A patent/AU2010266103B2/en active Active
- 2010-07-02 US US12/829,857 patent/US8314083B2/en active Active
-
2011
- 2011-11-08 US US13/291,514 patent/US20120053563A1/en not_active Abandoned
-
2012
- 2012-07-27 US US13/559,954 patent/US9119771B2/en active Active
- 2012-10-04 US US13/644,290 patent/US9180090B2/en active Active
-
2013
- 2013-07-12 US US13/940,747 patent/US9161902B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4031893A (en) * | 1976-05-14 | 1977-06-28 | Survival Technology, Inc. | Hypodermic injection device having means for varying the medicament capacity thereof |
Non-Patent Citations (1)
Title |
---|
Dux et al (Brit J Pharmacol 137:874-880, 2002) * |
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EP2477634A1 (en) | 2012-07-25 |
US20110003781A1 (en) | 2011-01-06 |
ES2616703T3 (en) | 2017-06-14 |
US9119771B2 (en) | 2015-09-01 |
EP2477634B1 (en) | 2016-11-30 |
US8314083B2 (en) | 2012-11-20 |
WO2011003074A1 (en) | 2011-01-06 |
US8263581B2 (en) | 2012-09-11 |
AU2010266103B2 (en) | 2016-04-14 |
US9180090B2 (en) | 2015-11-10 |
US20130296829A1 (en) | 2013-11-07 |
AU2010266103A1 (en) | 2012-02-16 |
CA2803987A1 (en) | 2011-01-06 |
US20110004164A1 (en) | 2011-01-06 |
EP2477634A4 (en) | 2013-01-02 |
CA2803987C (en) | 2017-11-28 |
US20120289489A1 (en) | 2012-11-15 |
US20130030010A1 (en) | 2013-01-31 |
US9161902B2 (en) | 2015-10-20 |
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