CA2405238A1 - Single-dose antihistamine/decongestant formulations for treating rhinitis - Google Patents
Single-dose antihistamine/decongestant formulations for treating rhinitis Download PDFInfo
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- CA2405238A1 CA2405238A1 CA002405238A CA2405238A CA2405238A1 CA 2405238 A1 CA2405238 A1 CA 2405238A1 CA 002405238 A CA002405238 A CA 002405238A CA 2405238 A CA2405238 A CA 2405238A CA 2405238 A1 CA2405238 A1 CA 2405238A1
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- decongestant
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- antihistamine
- oral dosage
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- 239000000739 antihistaminic agent Substances 0.000 title claims abstract description 57
- 230000001387 anti-histamine Effects 0.000 title claims abstract description 45
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 206010039083 rhinitis Diseases 0.000 title claims abstract description 26
- 239000000850 decongestant Substances 0.000 title claims description 54
- 239000000203 mixture Substances 0.000 title claims description 27
- 238000009472 formulation Methods 0.000 title claims description 26
- 230000000694 effects Effects 0.000 claims description 24
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 19
- 229960003908 pseudoephedrine Drugs 0.000 claims description 15
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical group CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 claims description 15
- 230000004936 stimulating effect Effects 0.000 claims description 14
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 claims description 11
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical group C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 claims description 11
- 229960000395 phenylpropanolamine Drugs 0.000 claims description 11
- 229960003088 loratadine Drugs 0.000 claims description 8
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical group C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 claims description 8
- 229960003592 fexofenadine Drugs 0.000 claims description 7
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 claims description 5
- 229960001803 cetirizine Drugs 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 230000037406 food intake Effects 0.000 claims description 3
- 239000006186 oral dosage form Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000001624 sedative effect Effects 0.000 abstract description 20
- 208000024891 symptom Diseases 0.000 abstract description 11
- 239000000133 nasal decongestant Substances 0.000 abstract description 5
- 229940125715 antihistaminic agent Drugs 0.000 description 17
- 230000000638 stimulation Effects 0.000 description 17
- 229940124581 decongestants Drugs 0.000 description 16
- 239000003814 drug Substances 0.000 description 15
- 229940079593 drug Drugs 0.000 description 14
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 10
- 238000002483 medication Methods 0.000 description 10
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 6
- 206010022437 insomnia Diseases 0.000 description 6
- 229960001340 histamine Drugs 0.000 description 5
- 206010039897 Sedation Diseases 0.000 description 4
- 230000003111 delayed effect Effects 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 description 4
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 description 4
- 230000036280 sedation Effects 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 206010022998 Irritability Diseases 0.000 description 3
- 238000013265 extended release Methods 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 description 2
- 102000000543 Histamine Receptors Human genes 0.000 description 2
- 108010002059 Histamine Receptors Proteins 0.000 description 2
- 206010028735 Nasal congestion Diseases 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960002146 guaifenesin Drugs 0.000 description 2
- 206010025482 malaise Diseases 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 206010041232 sneezing Diseases 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 230000002618 waking effect Effects 0.000 description 2
- QFDDBBKJOGTVNI-PVTQAGNOSA-N 2-[4-[1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]piperidin-1-yl]butyl]phenyl]-2-methylpropanoic acid;(1s,2s)-2-(methylamino)-1-phenylpropan-1-ol;dihydrochloride Chemical compound Cl.Cl.CN[C@@H](C)[C@@H](O)C1=CC=CC=C1.C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 QFDDBBKJOGTVNI-PVTQAGNOSA-N 0.000 description 1
- 206010052437 Nasal discomfort Diseases 0.000 description 1
- 206010029216 Nervousness Diseases 0.000 description 1
- 206010062519 Poor quality sleep Diseases 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- 208000036071 Rhinorrhea Diseases 0.000 description 1
- 206010039101 Rhinorrhoea Diseases 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- KBYGOCNIUHCOLP-MNIONDOCSA-N ethyl 4-(8-chloro-5,6-dihydrobenzo[1,2]cyclohepta[2,4-b]pyridin-11-ylidene)piperidine-1-carboxylate;(1s,2s)-2-(methylamino)-1-phenylpropan-1-ol;sulfuric acid Chemical compound OS(O)(=O)=O.CN[C@@H](C)[C@@H](O)C1=CC=CC=C1.C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 KBYGOCNIUHCOLP-MNIONDOCSA-N 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An oral once-per-day single dosage unit for treating the symptoms of rhiniti s formulated with a nasal decongestant having a duration of action of not more than about sixteen hours and antihistamine. Preferably, the antihistamine is non-sedating.
Description
SINGLE-DOSE ANTIHISTAMiNE/DECONGESTANT FORMULATIONS
FOR TREATING RHINITIS
BACKGROUND OF THE INVENTION
1. Field of the Invention The present invention relates to treatments for rhinitis, more particularly, to combinations of decongestant and non-sedating antihistamine that avoid stimulation when stimulation is not desired.
2. Description of the Prior Art Rhinitis refers to an inflammatory disorder of the nasal passages. The symptoms of rhinitis typically consist of sneezing, rhinorrhea, nasal congestion, ~5 and increased nasal secretions. Failure of treatment of rhinitis may lead to other disorders that include infection of the sinuses, ears, and lower respiratory tract.
Two types of oral medication are commonly used to treat the symptoms of rhinitis, decongestants and antihistamines. Decongestants and antihistamines differ in their mechanisms of action, therapeutic effects, and side effects. It is common 2o practice to combine both of these medications to bring about more complete symptom relief of rhinitis than with either entity alone.
Decongestants commonly used to treat rhinitis include the adrenaline-like agents pseudoephedrine and phenylpropanolamine. These agents act to constrict vessels in the nasal mucus membranes and thereby decrease tissue 25 swelling and nasal congestion. Decongestants are found to be better than antihistamines for restoring the patency of congested nasal airways. Like adrenaline, nasal decongestants are stimulatory and produce side effects that may be tolerated while the user is awake, and may even be considered desirable to counter fatigue that is known to accompany other symptoms of rhinitis.
3o Decongestants, however, may produce nervousness, restlessness, and insomnia if taken when sleep is desired. This can be a source of confusion for individuals, who mistakenly attribute their inability to sleep to the malaise that may accompany other rhinitis symptoms, rather than to the decongestant medication.
Histamine is a mediator released from cells that line the walls of the nasal mucous membranes (mast cells). When released, histamine binds to local histamine receptors causing sneezing, nasal itching, swelling of the nasal membranes, and increased nasal secretions. Antihistamines relieve these effects, albeit by a different mechanism than decongestants. Antihistamines block the binding of histamines to the histamine receptors by preemptively binding to the receptors. Consequently they are effective only if given prior to histamine release since once histamine is released and binds to the receptors, it is too late. Although individuals typically take antihistamines after symptoms occur, it is more desirable to dose antihistamines so as to effect therapeutic availability in anticipation of histamine release. Antihistamines are generally sedating. However, newer antihistamines with no or little sedation have been developed in the last twenty years.
Combining decongestants and antihistamines utilizes both mechanistic approaches, and has been shown to offer more complete relief of rhinitis symptoms than therapy with either component alone. Consequently, many 2o products have been formulated so that their dosage units contain both. The incorporation of decongestant and sedating antihistamine into a single dosage unit attempts a balance between the stimulating and sedating side effects of these components.
However, individuals are known to vary in their susceptibility to these side effects. Consequently, some individuals experience stimulation and insomnia when taking these combinations at night. More recently, formulations have been commercialized which incorporate a decongestant and a non-sedating antihistamine into a single dosage unit for the purpose of avoiding daytime sedation. Such combinations might be expected to provoke a greater incidence of nighttime irritability and insomnia because the stimulating side effecfis of decongestant are not attenuated by concomitant sedation by antihistamine.
Indeed, a 25% incidence of insomnia has been disclosed among users of a commercialized combination of the non-sedating antihistamine terfenadine and the decongestant pseudoephedrine. Examples of such formulations include:
SELDANE-D Extended-Release Tablets which contains 60 mg tertenadine (non-sedating antihistamine) and 120 mg pseudoephedrine hydrochloride (stimulating decongestant), and which is recommended to be taken every 12 hours (adults and children over 12 years of age).
ALLEGRA-D contains 60 mg fexofenadine (non-sedating antihistamine) and 120 mg pseudoephedrine hydrochloride (stimulating decongestant), and which is recommended to be taken every 12 hours (adults and children over 12 years of age).
CLARITIN-D~ 24-HOUR Extended-Release Tablets which contains 10 mg loratidine (non-sedating antihistamine) and 240 mg pseudoephedrine hydrochloride (stimulating decongestant), and which is recommended to be taken every 24 hours (adults and children over 12 years of age).
2o These and all currently marketed single entity combinations, which are formulated with decongestant and non-sedating antihistamine, fail to address the problem of nighttime irritability and insomnia, a problem that is increased by combining non-sedating, rather than sedating antihistamine. Note is made of prior art which is directed toward reducing the side effects of antihistamines and 2s decongestants. U.S. Patent No. 4,295,567, issued to Knudsen, teaches a regimen for employing separate day and night dosage units for the purpose of avoiding daytime sedation from sedating antihistamines. This patent does not anticipate the advent of non-sedating antihistamine and overlooks the side effect of nighttime stimulation from decongestants. A regimen, commercialized as SYN-~TM' also employs separate day and night dosage units. SYN-RXTM contains a daytime formulation of 600 mg guaifenesin, which is non-stimulating, and 60 mg pseudoephedrine, which is stimulating, and a nighttime formulation of 600 mg of guaifenesin alone. SYN-RXTM does not contain an antihistamine. In failing to contain any medication that would be effective for the symptoms of rhinitis at night, SYN-RXT"" does not constitute a treatment for rhinitis. The use of multi-dosage unit regimens of such prior art is less convenient for a user than a single dose, once-per-day formulation, and more complex to follow, adding the potential for a user to confuse dosage units.
~o Individuals with rhinitis utilize antihistamines and decongestants together many of millions of times a year. Professional as well as consumer confusion is widely encountered with the use of these medications together, and unnecessarily negative consequences occur both by self-selection and prescription. In particular, individuals treated with decongestants at night not only ~5 risk insomnia, but also daytime irritability, fatigue, and malaise from lack of rest.
It is known that these side effects are sometimes mistakenly ascribed to rhinitis rather than to the medication causing them. There is a present need for formulations which circumvent this confusion and which avoid nighttime stimulation.
SUMMARY OF THE INVENTION
It is an object of the present invention to simplify the combined use of antihistamine and nasal decongestant medications for a user for the purpose of enhancing the convenience of utilizing these medications, reducing error in taking these medications, and reducing the side effects of these medications. Another object is to formulate antihistamines and decongestants together for the treatment of rhinitis so as to avoid stimulation at night. Yet another object is to provide a formulation for a user which incorporates antihistamines and decongestants together as a single dosage unit for the treatment of rhinitis in a manner so as not 3o to cause stimulation at night and which can be taken once per day. A
further object is to provide a user with a single dosage unit that provides an operational combination of decongestant and antihistamine during the day and antihistamine without decongestant at night.
The single dosage unit of the present invention for treating the symptoms of rhinitis is expertly formulated with a combination of medications, including a nasal decongestant, antihistamine, and optionally, other medications, such as an analgesic. The dosage unit is for oral ingestion. The dosage unit preferably contains a non-sedating antihistamine, such as loratidine, cetirizine, or fexofenadine. Examples of decongestants include pseudoephedrine and phenylpropanolamine.
Other objects of the present invention will become apparent in light of the following detailed description of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The single dosage unit of the present invention for treating the symptoms of rhinitis contains a combination of medications that include nasal decongestants and antihistamines. The dosage units may be in the form of tablets, pills, capsules, caplets, or other recognized oral form of medication. The dosage unit may be formulated to contain sedating or, preferably, non-sedating antihistamine.
The components are formulated so as to produce the pharmacokinetic and 2o therapeutic characteristics desired. The devising of such formulations requires pharmaceutical expertise and requires understanding of the actions, side effects, and pharmacokinetics of antihistamines, decongestants, components which affect the bioavailability of the medications, and other formulated components.
The terms "day" and "night" used herein are intended to be synonymous 25 with the period of wakefulness, when stimulation might be acceptable, and the period of sleeping, when stimulation would be undesired, respectively. Such times vary in accordance with the schedule of individuals.
Examples of the preferred single dosage units of the present invention include:
3o Example 1. A single dosage unit consisting of 120 mg pseudoephedrine, a stimulating decongestant, prepared so as to be released over a 10-12 hour time, and 10 mg loratidine, a non-sedating antihistamine, formulated so as to be released immediately. When taken at the start of the day (a time anticipating a desire to be awake for 12 to 16 hours), this dosage unit provides immediate dosing with loratidine, which is known to exert an antihistaminic effect 1 to hours after dosing, reach a maximum at 8 to 12 hours, and last in excess of 24 hours.
This dosage unit preferably provides immediate and delayed action of pseudoephedrine so as to exert an effect during daytime hours, when the stimulation of pseudoephedrine is best tolerated, but not at night. Once released, pseudoephedrine has a 4 to 6 hour half-life, considerably shorter than that of loratidine. The comparatively short decongestant effect of pseudoephedrine may be prolonged by release over time so as to achieve efficacy through the waking hours, but not during the time when stimulation is undesired. One such time-release method involves the additional formulation of cellulose ether base ~5 materials such as hydroxypropyl methylcellulose to bond to the therapeutic agent and delay its bioavailability. Such time-release methods may be utilized to delay the bioavailability of all or only a portion of the ingested dose, and for varying lengths of time.
The antihistamine and decongestant components of this formulation are 2o similar to that of CLARITIN-D 24-HOUR Extended-Release Tablets which contains 10 mg loratidine (antihistamine) and 240 mg pseudoephedrine hydrochloride (decongestant), and which is recommended to be taken every 24 hours in adults. The present invention formulation differs, however, in that it contains a lesser dose of pseudoephedrine, and that it limits the duration of 25 action of pseudoephedrine to the daytime hours, thus avoiding the stimulation of pseudoephedrine at night.
Example 2. A single dosage unit consisting of 75 mg phenylpropanolamine, a stimulating decongestant, prepared so as to be released over a 10-hour time period, and 10 mg cetirizine, a non-sedating antihistamine, 3o prepared so as to be released immediately. When taken at the start of the day, this formulation provides immediate dosing with cetirizine, which is known to exert an antihistaminic effect within one hour after dosing and to persist for at least 22 hours. This formulation also preferably provides immediate and delayed action of phenylpropanolamine over a period not to exceed 16 hours after administration so as to exert effect during daytime hours, when stimulation is best tolerated, but exerts no effect at night. Like pseudoephedrine, the comparatively short half-life and decongestant effect of phenylpropanolamine, is prolonged in this formulation by incorporating a prolonged release of phenylpropanolamine over time so as to achieve efficacy through the waking hours, but not so long as to provide phenylpropanolamine activity during the time when stimulation is undesired.
Example 3. A single dosage unit consisting of 75 mg phenylpropanolamine, a stimulating decongestant prepared so as to be released over a 10-hour time period, and 120 mg of fexofenadine, a non-sedating antihistamine, prepared so as to be active over a 24-hour period.
Fexofenadine, when given alone, exhibits antihistaminic effect within one hour, achieves a maximum effect at 12 hours, and still has a visible effect at 24 hours. This formulation preferably provides immediate and delayed activity of fexofenadine over a 24-hour span. This formulation also preferably provides immediate and delayed action of phenylpropanolamine over a period not in excess of 16 hours after administration so as to exert an effect during daytime hours, when 2o stimulation is best tolerated, but not so long as to provide an effect during the time when stimulation is undesired, as at night.
In addition to antihistamines and decongestants, additional therapeutic ingredients for the treatment of rhinitis may be formulated if desired. For example, analgesics such as salicylates and acetaminophen may be considered for inclusion in such dosage units and are within the scope of this invention.
These examples do not constitute an exhaustive list of potential combinations, and variations and modifications may be made by those of ordinary skill in the art. Those of skill in the art may also recognize modifications to these presently disclosed embodiments. One such modification might involve a time-3o release of decongestant over periods other than those exemplified, but not so as to allow stimulation at night. These variations and modifications are meant to be covered by the spirit and scope of the present claims.
Thus it has been shown and described antihistamine/decongestant formulations for treating rhinitis that satisfies the objects set forth above.
Since certain changes may be made in the present disclosure without departing from the scope of the present invention, it is intended that all matter described in the foregoing specification be interpreted as illustrative and not in a limiting sense.
FOR TREATING RHINITIS
BACKGROUND OF THE INVENTION
1. Field of the Invention The present invention relates to treatments for rhinitis, more particularly, to combinations of decongestant and non-sedating antihistamine that avoid stimulation when stimulation is not desired.
2. Description of the Prior Art Rhinitis refers to an inflammatory disorder of the nasal passages. The symptoms of rhinitis typically consist of sneezing, rhinorrhea, nasal congestion, ~5 and increased nasal secretions. Failure of treatment of rhinitis may lead to other disorders that include infection of the sinuses, ears, and lower respiratory tract.
Two types of oral medication are commonly used to treat the symptoms of rhinitis, decongestants and antihistamines. Decongestants and antihistamines differ in their mechanisms of action, therapeutic effects, and side effects. It is common 2o practice to combine both of these medications to bring about more complete symptom relief of rhinitis than with either entity alone.
Decongestants commonly used to treat rhinitis include the adrenaline-like agents pseudoephedrine and phenylpropanolamine. These agents act to constrict vessels in the nasal mucus membranes and thereby decrease tissue 25 swelling and nasal congestion. Decongestants are found to be better than antihistamines for restoring the patency of congested nasal airways. Like adrenaline, nasal decongestants are stimulatory and produce side effects that may be tolerated while the user is awake, and may even be considered desirable to counter fatigue that is known to accompany other symptoms of rhinitis.
3o Decongestants, however, may produce nervousness, restlessness, and insomnia if taken when sleep is desired. This can be a source of confusion for individuals, who mistakenly attribute their inability to sleep to the malaise that may accompany other rhinitis symptoms, rather than to the decongestant medication.
Histamine is a mediator released from cells that line the walls of the nasal mucous membranes (mast cells). When released, histamine binds to local histamine receptors causing sneezing, nasal itching, swelling of the nasal membranes, and increased nasal secretions. Antihistamines relieve these effects, albeit by a different mechanism than decongestants. Antihistamines block the binding of histamines to the histamine receptors by preemptively binding to the receptors. Consequently they are effective only if given prior to histamine release since once histamine is released and binds to the receptors, it is too late. Although individuals typically take antihistamines after symptoms occur, it is more desirable to dose antihistamines so as to effect therapeutic availability in anticipation of histamine release. Antihistamines are generally sedating. However, newer antihistamines with no or little sedation have been developed in the last twenty years.
Combining decongestants and antihistamines utilizes both mechanistic approaches, and has been shown to offer more complete relief of rhinitis symptoms than therapy with either component alone. Consequently, many 2o products have been formulated so that their dosage units contain both. The incorporation of decongestant and sedating antihistamine into a single dosage unit attempts a balance between the stimulating and sedating side effects of these components.
However, individuals are known to vary in their susceptibility to these side effects. Consequently, some individuals experience stimulation and insomnia when taking these combinations at night. More recently, formulations have been commercialized which incorporate a decongestant and a non-sedating antihistamine into a single dosage unit for the purpose of avoiding daytime sedation. Such combinations might be expected to provoke a greater incidence of nighttime irritability and insomnia because the stimulating side effecfis of decongestant are not attenuated by concomitant sedation by antihistamine.
Indeed, a 25% incidence of insomnia has been disclosed among users of a commercialized combination of the non-sedating antihistamine terfenadine and the decongestant pseudoephedrine. Examples of such formulations include:
SELDANE-D Extended-Release Tablets which contains 60 mg tertenadine (non-sedating antihistamine) and 120 mg pseudoephedrine hydrochloride (stimulating decongestant), and which is recommended to be taken every 12 hours (adults and children over 12 years of age).
ALLEGRA-D contains 60 mg fexofenadine (non-sedating antihistamine) and 120 mg pseudoephedrine hydrochloride (stimulating decongestant), and which is recommended to be taken every 12 hours (adults and children over 12 years of age).
CLARITIN-D~ 24-HOUR Extended-Release Tablets which contains 10 mg loratidine (non-sedating antihistamine) and 240 mg pseudoephedrine hydrochloride (stimulating decongestant), and which is recommended to be taken every 24 hours (adults and children over 12 years of age).
2o These and all currently marketed single entity combinations, which are formulated with decongestant and non-sedating antihistamine, fail to address the problem of nighttime irritability and insomnia, a problem that is increased by combining non-sedating, rather than sedating antihistamine. Note is made of prior art which is directed toward reducing the side effects of antihistamines and 2s decongestants. U.S. Patent No. 4,295,567, issued to Knudsen, teaches a regimen for employing separate day and night dosage units for the purpose of avoiding daytime sedation from sedating antihistamines. This patent does not anticipate the advent of non-sedating antihistamine and overlooks the side effect of nighttime stimulation from decongestants. A regimen, commercialized as SYN-~TM' also employs separate day and night dosage units. SYN-RXTM contains a daytime formulation of 600 mg guaifenesin, which is non-stimulating, and 60 mg pseudoephedrine, which is stimulating, and a nighttime formulation of 600 mg of guaifenesin alone. SYN-RXTM does not contain an antihistamine. In failing to contain any medication that would be effective for the symptoms of rhinitis at night, SYN-RXT"" does not constitute a treatment for rhinitis. The use of multi-dosage unit regimens of such prior art is less convenient for a user than a single dose, once-per-day formulation, and more complex to follow, adding the potential for a user to confuse dosage units.
~o Individuals with rhinitis utilize antihistamines and decongestants together many of millions of times a year. Professional as well as consumer confusion is widely encountered with the use of these medications together, and unnecessarily negative consequences occur both by self-selection and prescription. In particular, individuals treated with decongestants at night not only ~5 risk insomnia, but also daytime irritability, fatigue, and malaise from lack of rest.
It is known that these side effects are sometimes mistakenly ascribed to rhinitis rather than to the medication causing them. There is a present need for formulations which circumvent this confusion and which avoid nighttime stimulation.
SUMMARY OF THE INVENTION
It is an object of the present invention to simplify the combined use of antihistamine and nasal decongestant medications for a user for the purpose of enhancing the convenience of utilizing these medications, reducing error in taking these medications, and reducing the side effects of these medications. Another object is to formulate antihistamines and decongestants together for the treatment of rhinitis so as to avoid stimulation at night. Yet another object is to provide a formulation for a user which incorporates antihistamines and decongestants together as a single dosage unit for the treatment of rhinitis in a manner so as not 3o to cause stimulation at night and which can be taken once per day. A
further object is to provide a user with a single dosage unit that provides an operational combination of decongestant and antihistamine during the day and antihistamine without decongestant at night.
The single dosage unit of the present invention for treating the symptoms of rhinitis is expertly formulated with a combination of medications, including a nasal decongestant, antihistamine, and optionally, other medications, such as an analgesic. The dosage unit is for oral ingestion. The dosage unit preferably contains a non-sedating antihistamine, such as loratidine, cetirizine, or fexofenadine. Examples of decongestants include pseudoephedrine and phenylpropanolamine.
Other objects of the present invention will become apparent in light of the following detailed description of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The single dosage unit of the present invention for treating the symptoms of rhinitis contains a combination of medications that include nasal decongestants and antihistamines. The dosage units may be in the form of tablets, pills, capsules, caplets, or other recognized oral form of medication. The dosage unit may be formulated to contain sedating or, preferably, non-sedating antihistamine.
The components are formulated so as to produce the pharmacokinetic and 2o therapeutic characteristics desired. The devising of such formulations requires pharmaceutical expertise and requires understanding of the actions, side effects, and pharmacokinetics of antihistamines, decongestants, components which affect the bioavailability of the medications, and other formulated components.
The terms "day" and "night" used herein are intended to be synonymous 25 with the period of wakefulness, when stimulation might be acceptable, and the period of sleeping, when stimulation would be undesired, respectively. Such times vary in accordance with the schedule of individuals.
Examples of the preferred single dosage units of the present invention include:
3o Example 1. A single dosage unit consisting of 120 mg pseudoephedrine, a stimulating decongestant, prepared so as to be released over a 10-12 hour time, and 10 mg loratidine, a non-sedating antihistamine, formulated so as to be released immediately. When taken at the start of the day (a time anticipating a desire to be awake for 12 to 16 hours), this dosage unit provides immediate dosing with loratidine, which is known to exert an antihistaminic effect 1 to hours after dosing, reach a maximum at 8 to 12 hours, and last in excess of 24 hours.
This dosage unit preferably provides immediate and delayed action of pseudoephedrine so as to exert an effect during daytime hours, when the stimulation of pseudoephedrine is best tolerated, but not at night. Once released, pseudoephedrine has a 4 to 6 hour half-life, considerably shorter than that of loratidine. The comparatively short decongestant effect of pseudoephedrine may be prolonged by release over time so as to achieve efficacy through the waking hours, but not during the time when stimulation is undesired. One such time-release method involves the additional formulation of cellulose ether base ~5 materials such as hydroxypropyl methylcellulose to bond to the therapeutic agent and delay its bioavailability. Such time-release methods may be utilized to delay the bioavailability of all or only a portion of the ingested dose, and for varying lengths of time.
The antihistamine and decongestant components of this formulation are 2o similar to that of CLARITIN-D 24-HOUR Extended-Release Tablets which contains 10 mg loratidine (antihistamine) and 240 mg pseudoephedrine hydrochloride (decongestant), and which is recommended to be taken every 24 hours in adults. The present invention formulation differs, however, in that it contains a lesser dose of pseudoephedrine, and that it limits the duration of 25 action of pseudoephedrine to the daytime hours, thus avoiding the stimulation of pseudoephedrine at night.
Example 2. A single dosage unit consisting of 75 mg phenylpropanolamine, a stimulating decongestant, prepared so as to be released over a 10-hour time period, and 10 mg cetirizine, a non-sedating antihistamine, 3o prepared so as to be released immediately. When taken at the start of the day, this formulation provides immediate dosing with cetirizine, which is known to exert an antihistaminic effect within one hour after dosing and to persist for at least 22 hours. This formulation also preferably provides immediate and delayed action of phenylpropanolamine over a period not to exceed 16 hours after administration so as to exert effect during daytime hours, when stimulation is best tolerated, but exerts no effect at night. Like pseudoephedrine, the comparatively short half-life and decongestant effect of phenylpropanolamine, is prolonged in this formulation by incorporating a prolonged release of phenylpropanolamine over time so as to achieve efficacy through the waking hours, but not so long as to provide phenylpropanolamine activity during the time when stimulation is undesired.
Example 3. A single dosage unit consisting of 75 mg phenylpropanolamine, a stimulating decongestant prepared so as to be released over a 10-hour time period, and 120 mg of fexofenadine, a non-sedating antihistamine, prepared so as to be active over a 24-hour period.
Fexofenadine, when given alone, exhibits antihistaminic effect within one hour, achieves a maximum effect at 12 hours, and still has a visible effect at 24 hours. This formulation preferably provides immediate and delayed activity of fexofenadine over a 24-hour span. This formulation also preferably provides immediate and delayed action of phenylpropanolamine over a period not in excess of 16 hours after administration so as to exert an effect during daytime hours, when 2o stimulation is best tolerated, but not so long as to provide an effect during the time when stimulation is undesired, as at night.
In addition to antihistamines and decongestants, additional therapeutic ingredients for the treatment of rhinitis may be formulated if desired. For example, analgesics such as salicylates and acetaminophen may be considered for inclusion in such dosage units and are within the scope of this invention.
These examples do not constitute an exhaustive list of potential combinations, and variations and modifications may be made by those of ordinary skill in the art. Those of skill in the art may also recognize modifications to these presently disclosed embodiments. One such modification might involve a time-3o release of decongestant over periods other than those exemplified, but not so as to allow stimulation at night. These variations and modifications are meant to be covered by the spirit and scope of the present claims.
Thus it has been shown and described antihistamine/decongestant formulations for treating rhinitis that satisfies the objects set forth above.
Since certain changes may be made in the present disclosure without departing from the scope of the present invention, it is intended that all matter described in the foregoing specification be interpreted as illustrative and not in a limiting sense.
Claims (20)
1. An oral dosage unit comprising:
an antihistamine in an amount and formulation to exhibit anthhistaminic activity in a human for greater than 22 hours; and (b) a decongestant in an amount and formulation to exhibit stimulatory activity in a human for less than 16 hours.
an antihistamine in an amount and formulation to exhibit anthhistaminic activity in a human for greater than 22 hours; and (b) a decongestant in an amount and formulation to exhibit stimulatory activity in a human for less than 16 hours.
2. An oral dosage unit according to claim 1 wherein said decongestant is in an amount and formulation to exhibit decongestant activity in a human for less than 16 hours.
3. The dosage unit according to claim 1 or 2 wherein the duration of action of said decongestant formulation is from about 10 hours to about 16 hours.
4. An oral dosage unit according to claim 1, 2 or 3 wherein said decongestant is pseudoephedrine.
5. An oral dosage unit according to claim 4 wherein said pseudoephedrine is present in an amount of 30 to 120 mg.
6. An oral dosage unit according to claim 1, 2 or 3 wherein said decongestant is phenylpropanolamine.
7. An oral dosage unit according to claim 6 wherein said phenylpropanolamine is present in an amount of 75 mg.
8. An oral dosage unit according to claim 1 or 2 wherein said antihistamine is loratidine or cetirizine.
9. An oral dosage unit according to claim 8 wherein said loratidine is present in an amount of 10 mg to 40 mg.
10. An oral dosage unit according to claim 8 wherein said cetirizine is present in an amount of 5 mg to 10 mg.
11. An oral dosage unit according to claim 1 or 2 wherein said antihistamine is fexofenadine.
12. An oral dosage unit according to claim 11 wherein said fexofenadine is present in an amount of 120 mg.
13. The dosage unit according to claim 1, 2 or 3 wherein said decongestant formulation is immediately released upon ingestion.
14. The dosage unit according to claim 1, 2 or 3 wherein said decongestant formulation is time-released.
15. The dosage unit according to claim 1 wherein said antihistamine formulation is immediately released upon ingestion.
16. The dosage unit according to claim 1 wherein said antihistamine formulation is time-released.
17. A kit for treating rhinitis in a human comprising:
(a) an oral dosage form containing an amount of an antihistamine to exhibit antihistaminic activity in a human for greater than 22 hours;
(b) an oral dosage form containing an amount of a decongestant to exhibit stimulatory activity in a human for less than 16 hours; and (c) instructions to administer the antihistamine and decongestant at the start of the day.
(a) an oral dosage form containing an amount of an antihistamine to exhibit antihistaminic activity in a human for greater than 22 hours;
(b) an oral dosage form containing an amount of a decongestant to exhibit stimulatory activity in a human for less than 16 hours; and (c) instructions to administer the antihistamine and decongestant at the start of the day.
18. A kit according to claim 17 wherein the antihistamine and the decongestant are combined in a single oral dosage unit.
19. A method of providing treatment for rhinitis in a human comprising:
(a) formulating an amount of an antihistamine to exhibit antihistaminic activity in a human for greater than 22 hours;
(b) formulating an amount of a decongestant to exhibit stimulatory activity in a human for less than 16 hours;
(c) combining the antihistamine and the decongestant is a single oral dosage unit; and (d) providing instructions to administer the oral dosage unit at the start of the day.
(a) formulating an amount of an antihistamine to exhibit antihistaminic activity in a human for greater than 22 hours;
(b) formulating an amount of a decongestant to exhibit stimulatory activity in a human for less than 16 hours;
(c) combining the antihistamine and the decongestant is a single oral dosage unit; and (d) providing instructions to administer the oral dosage unit at the start of the day.
20. A method of making a single oral dosage unit for treating rhinitis, said method comprising the steps of:
(a) formulating a quantity of decongestant to have a duration of action not more than about 16 hours in a human;
(b) formulating a quantity of antihistamine to have a duration of action greater than about 22 hours in a human; and (c) combining said formulated quantity of decongestant and said formulated quantity of antihistamine into a single oral dosage unit.
(a) formulating a quantity of decongestant to have a duration of action not more than about 16 hours in a human;
(b) formulating a quantity of antihistamine to have a duration of action greater than about 22 hours in a human; and (c) combining said formulated quantity of decongestant and said formulated quantity of antihistamine into a single oral dosage unit.
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| PCT/US2000/010328 WO2001078782A1 (en) | 2000-04-14 | 2000-04-14 | Single-dose antihistamine/decongestant formulations for treating rhinitis |
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| CA2405238C CA2405238C (en) | 2014-03-18 |
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| AU (2) | AU4248400A (en) |
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| JP2004026810A (en) * | 2002-05-07 | 2004-01-29 | Rohto Pharmaceut Co Ltd | Composition for rhinitis |
| JP4320217B2 (en) * | 2002-07-10 | 2009-08-26 | 剤盛堂薬品株式会社 | Oral preparation for rhinitis |
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| US4990535A (en) * | 1989-05-03 | 1991-02-05 | Schering Corporation | Pharmaceutical composition comprising loratadine, ibuprofen and pseudoephedrine |
| US5314697A (en) * | 1992-10-23 | 1994-05-24 | Schering Corporation | Stable extended release oral dosage composition comprising loratadine and pseudoephedrine |
| HUP9904075A3 (en) * | 1996-10-31 | 2002-02-28 | Schering Corp | Composition, for the treatment of asthma,containing loratadine and a decongestant |
| EP0903151A1 (en) * | 1997-09-22 | 1999-03-24 | ASTA Medica Aktiengesellschaft | Use of combinations comprising non-sedating antihistamines and alpha-adrenergic drugs for the topical treatment of rhinitis/conjunctivitis and cold, cold-like and/or flu symptoms |
| US6132758A (en) * | 1998-06-01 | 2000-10-17 | Schering Corporation | Stabilized antihistamine syrup |
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- 2000-04-14 CA CA2405238A patent/CA2405238C/en not_active Expired - Lifetime
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| AU2000242484B2 (en) | 2006-02-09 |
| EP1276502A1 (en) | 2003-01-22 |
| WO2001078782A1 (en) | 2001-10-25 |
| JP5592042B2 (en) | 2014-09-17 |
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