Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2002-06-17
2003-01-21
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S443000, C424S486000, C514S817000, C514S818000
Reexamination Certificate
active
06509028
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods and compositions for treating the pain associated with mucosal damage, such as inflamation, abrasions, ulcerations, lesions, incisions, and trauma.
BACKGROUND OF THE INVENTION
The term mucous membrane refers to the moist linings of the buccal cavity, nasal cavity, gastrointestinal tract, respiratory tract, conjunctiva, vagina, colon, urinary bladder, and urethra (Forstner et al., 1973
J. Cell. Sci.
12:585; Peppas et al., 1985
J. Control. Release
2:257; Lehr et al., 1992
J. Control Release
18:249; Spiro, 1970
Ann. Rev. Biochem.
39:599; Lebat-Robert et al., 1979
Path. Biol.
24:241). The normally smooth, moist, and pink buccal mucosa is very sensitive and inflamation or ulceration (oral mucositis) causes severe pain. Dental surgery, such as root canal and tooth extraction can also severely damage the buccal mucosa causing severe pain. Moreover, oral mucositis and dental surgery can induce secondary conditions, such as weight loss and dehydration from reluctance to eat or drink, infection (bacterial, fungal, and viral), fever, nausea, and diarrhea.
Oral mucositis has a variety of causes, for example, bacterial infections, such as streptococci; viral infections, such as herpes simplex virus; fungal infections; side effects of systemic diseases; vitamin deficiency; iron deficiency; cheek biting; mouth breathing; jagged teeth; orthodontic appliances; ill-fitting dentures; excessive use of alcohol or tobacco; thermally-hot foods; spicy foods; and as a side effect of medication. Severely-painful oral mucositis is a symptom endured by almost all chemotherapy patients. Mucositis symptoms peak 7 to 10 days following chemotherapy, and gradually recede over the following two weeks. For a discussion of the causes and symptoms of mucositis, see
The Merck Manuel, Fifteenth Edition,
Merck Sharp & Dohme Research Laboratories, Rahway, N.J., (1987) pp. 2322-2320.
Topical application of local anesthetics can provide some relief of oral-mucositis and dental-surgery pain but absorption through the mucous membranes occurs rapidly, and pharmaceuticals applied to the mucous membrane for their local effect sometimes cause systemic toxicity (
Goodman and Gilman's The Pharmacological Basis of Therapeutics
9th ed. J. G. Harman and L. E. Limird Eds., McGraw-Hill New York 1996 p. 8) especially with the higher doses required for adequate pain relief. Systemic absorption is even more likely when the mucous membrane is ulcerated or inflamed. Thus, with traditional anesthetic compositions for mucositis, e.g., 2 percent lidocaine oral rinse or 5% lidocaine ointment, systemic toxicity limits the dosage and so adequate pain relief is difficult to achieve. Other less toxic pain relieving compositions, such as rinses comprising hydrogen peroxide and sodium bicarbonate are less effective at reducing pain. An additional problem with oral rinses is, that following application, the action of swallowing and saliva reduces the concentration of active agent on the affected area, thus oral rinses comprising local anesthetics have a low duration of activity.
In summation, a long-lasting, non-toxic anesthetic composition effective for amelioration of the severe pain induced by mucosal damage, such as mucositis and dental surgery, is needed.
SUMMARY OF THE INVENTION
In one aspect, the invention provides compositions and methods that provide long-lasting local anesthesia and effective pain relief. The compositions of the invention can be topically applied to the affected area, for example, via a dose-metered applicator adapted for spraying or adapted for use with a cannula. When topically applied, the compositions of the invention provide a powerful local-anesthetizing effect, in spite of low anesthetic concentration. Hence, the compositions of the invention provide significant pain relief with low systemic absorption and, therefore, low systemic toxicity. The compositions of the invention, in addition to the ability to remain on the affected area for extended periods, hydrate and soothe.
In one embodiment, the compositions of the invention can be topically applied directly to the affected area to alleviate pain in a subject on any area of a subject's body.
In another embodiment, the compositions of the invention are useful for topical application to a subject's mucous membrane, to induce a long-lasting local-anesthetic effect, thereby relieving pain from mucositis, such as mucosal inflamation, abrasions, ulcerations, and lesions, without significant systemic absorption.
In yet another embodiment, the compositions of the invention are useful for topical application to the site of dental surgery, such as root-canal or tooth-extraction surgery, to induce a long-lasting local-anesthetic effect, thereby relieving the surgical pain, without significant systemic absorption.
In one more embodiment, the invention relates to compositions comprising a mucoadhesive, a local anesthetic or a pharmaceutically-acceptable salt thereof, and an opioid or a pharmaceutically-acceptable salt thereof. In a preferred embodiment, the compositions contain water and are sterile. In a more preferred embodiment, the compositions of the invention, further comprise a chelating agent and a preservative.
In another embodiment, the invention relates to a container adapted for topical application and containing a pharmaceutically-acceptable composition comprising a mucoadhesive, a local anesthetic or a pharmaceutically-acceptable salt thereof, and an opioid or a pharmaceutically-acceptable salt thereof. Preferably, the container is adapted for dose-metered application, such as a dose-metered pump for use with a spray applicator or cannula.
In still another embodiment, the invention relates to a method of inducing local anesthesia in a subject's mucosal membrane by topically applying a pharmaceutically-acceptable composition comprising a local anesthetic or a pharmaceutically-acceptable salt thereof and an opioid or a pharmaceutically-acceptable salt thereof to the subject's mucosal membrane. Preferably, the composition is applied to an area within the subject's buccal or nasal cavity. Preferably, the composition further comprises a mucoadhesive.
In yet another embodiment, the invention relates to a method of inducing local anesthesia in a subject by topically applying a composition comprising a mucoadhesive, a local anesthetic or a pharmaceutically-acceptable salt thereof, and an opioid or a pharmaceutically-acceptable salt thereof to a subject. Preferably, the composition is applied to a mucosal surface of the subject, for example, an area within the subject's buccal or nasal cavity.
These and other features, aspects, and advantages of the invention will become better understood with reference to the following detailed description, examples, and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The phrase “pharmaceutically-acceptable salt(s),” as used herein includes but is not limited to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically-acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, sulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
Compounds included in the present compositio
Koleng John J.
Kolesnikov Yuri A.
Pasternak Gavril W.
Williams Robert O.
Zhang Feng
EpiCept Corporation
Fubara Blessing
Page Thurman K.
Pennie & Edmonds LLP
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