Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-29
2004-06-01
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S345000, C544S318000
Reexamination Certificate
active
06743801
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention generally relates to therapeutic compositions formulated for topical delivery to the surfaces of the human lips, mouth, and the anorectal area. This invention more particularly relates to a class of chemicals that activate receptors on sensory nerve endings at or near the entrance and exit of the human gastrointestinal tract and therapeutic use of these chemicals for pain and inflammation. The particularly preferred embodiment compositions are formulated as an ointment, cream, paste, aerosol or suppository and comprise “icilin”, a 1,2,3,6-tetrahydropyrimidine-2-one compound.
2. Description of Related Art
Background on Icilin. 1,2,3,6-Tetrahydropyrimidine-2-one compounds were described in U.S. Pat. No. 3,821,221(inventors C. Podesva and J.M. Do Nascimentoet al, Jun. 28, 1974). These compounds were thought to have depressant and/or stimulant effects on the central nervous system. In 1972, an abstract described a compound in this series called AG-3-5 (1[2-hydroxyphenyl]
4-[3
-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one). This prototype elicited a syndrome of “wet dog shake behavior” in rats and monkeys accompanied by hyperthermia, hyperactivity and ptosis. Wei (Chemical stimulants of shaking behavior. Journal of Pharmacy and Pharmacology 28: 722-724, 1976) provided the first detailed report of the actions of AG-3-5 in animals and noted that shaking behavior similar to those of a dog when wet could be evoked in various laboratory animals such as the rat, mouse, cat, dog, gerbils, guinea pigs and hamsters.
Subsequently, Wei (Pharmacological aspects of shaking behavior produced by AG-3-5, TRH, and morphine withdrawal. Federation Proceedings 40: 1491-1496, 1981) reported that 0.1 mg of AG-3-5, dissolved in propylene glycol, applied to the dorsum of the tongue elicited prickling sensations of cold and ingestion of 6 mg mixed in orange juice, on one occasion out of three, produced sensations of coolness on the cheeks and on the inner surfaces of the arms and legs. It was hypothesized that AG-3-5 may produce specific activation of receptors for cold, and that stimulation of these receptors accounted for the shaking seen in laboratory animals. In a subsequent publication (E. T. Wei and D. A. Seid. AG-3-5: A chemical producing sensations of cold. Journal of Pharmacy and Pharmacology 35: 110-112, 1983) the effects of AG-3-5 on shaking behavior in the rat were compared to those of menthol and AG-3-5 was shown to be 400 times more potent than menthol on a molar basis on this behavioral endpoint. AG-3-5 was less toxic than menthol, as measured by the oral median lethal dose in rats. AG-3-5 was named icilin because of its cold-producing properties.
Recently, two independent groups simultaneously cloned a biological macromolecule (called a receptor) from trigeminal sensory neurons of the rat. These receptors belong to the transient receptor potential (TRP) family of ion channels and responded to cold temperature and to menthol. Using a sample provided by Wei, McKemy et al. (Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416: 52-58, 2002) showed that icilin was about 200 times more potent than menthol in eliciting ion channel current changes in the cloned and transfected TRP(M8) receptor. The ion permeability changes elicited in transfected cells were more robust with icilin than those elicited by menthol, and the presence of extracellular calcium was required for activity. Menthol currents did not require extracellular calcium.
The chemical structure of icilin bears little similarity to that of menthol; the former chemical being a pyrimidine-2-one attached to two phenyl rings, and the latter a cyclohexanol derivative. Activation of the TRP(M8) receptor on the neuronal membrane may lead to depolarization of the sensory nerve ending and send action potentials towards the spinal cord and brain that are eventually recognized as psychic signals of skin stimulation.
Background on Pain and Inflammation of the Oral and Anal Areas.
The mouth is the entrance to the gastrointestinal tract and the anus is the exit. At the point of entrance and exit, the surfaces change from thicker skin to thinner skin, and then to mucous membrane. The border between the skin and mucous membrane is called a mucocutaneous junction. The anatomy of the lips illustrates this transition. The lips present three surfaces and a core. The external surface is thin skin with hair follicles, sebaceous glands, and sweat glands. The second surface is the transition zone or vermilion border; it has no hair follicles or sweat glands and is the external border of the lips. The lips have a pinkish red color due to underlying rich blood capillary network and its forms a transition from keratinized to nonkeratinized epithelium. The inner surface of the lips and mouth is nonkeratinized stratified squamous epithelium and the underlying tissue contains numerous small mucous glands and mucoserous salivary (labial) glands. The central core of the lips is composed of striated muscle embedded in elastic fibroconnective tissue.
The perineum is the skin between the anus and the genitalia and has the typical keratinized epithelium of normal skin. The anatomy of the anus is similar in histology to the lips. The anal epithelium (skin) extends about 1.5 cm inside from the anal verge (external edge) and transits from keratinized to nonkeratinized epithelium at the dentate line, the part that demarcates the anus from the rectum. The rectal surface is a mucous membrane and is not keratinized.
The skin epithelia of the lips and anus and surrounding tissues are densely innervated with sensory nerve fibers and these afferent (A delta and C) fibers code for pain and temperature signals. When the lips or anus, or the tissues surrounding, are injured, the subsequent inflammation stimulates the somatosensory nerve endings and the result is pain and sometimes itch. By contrast, the visceral sensory nerve endings that innervate the mucous membrane of the inner lips, mouth, and rectum do not transmit discrete, localized signals of pain, but are sensitive to stretch. Stimulation of rectal nerve endings produces a sense of distension, an urge to have a bowel movement, flatulence, and, if the stimulation is excessive, rectal pain and discomforts.
Inflammatory Conditions of the Lips and Mouth. The skin and mucosa of the lips are demarcated by the vermilion border. The mucosa seen on viewing the face is keratinized and dry; the mucosa of the inner aspect of the lips is nonkeratinized and moist. Branches of the 5th cranial nerve (trigeminal) innervate these tissues. Non-specific disorders can cause inflammation around the mouth and lips. These include immunological disorders, such as pemphigus, pemphigoid, lichen planus; infections, such as venereally transmitted warts (condyloma cuminatum) and herpes simplex; metaplasia, such as dyskeratosis; and physical causes, such as lip and mouth surgery, sunlight, and wind. Some common conditions affecting the surface of the mouth and lips are:
Angular Cheilitis—Chelitis is the technical term for inflammation of the lips. Angular cheilitis occurs at the corners of the lips. This lesion is seen as dry, scaly, red skin and there may be a fissure or slit in the mucocutaneous junction, causing severe pain when the mouth is opened wide. Angular cheilitis may be caused by dry weather, too much sunlight, allergic reactions, or excessive salivation. Cheilitis is also seen more frequently in persons who have reduced immune function, viral infections, or persistent yeast infection. Other forms of inflammation of the lips are cracking exfoliative cheilitis, cheilitis glandularis, and cheilitis granulomatosa.
“Cold sores” or herpes labialis, are the result of an infection with a common virus known as herpes simplex. The sores begin as a group of small red bumps that blister. Itching and burning of the area precedes the pr
Raymond Richard L.
Truong Tamthom N.
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