WO1996037207A2 - Compositions pharmaceutiques contenant du sulfate de calcium - Google Patents

Compositions pharmaceutiques contenant du sulfate de calcium Download PDF

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Publication number
WO1996037207A2
WO1996037207A2 PCT/US1996/007874 US9607874W WO9637207A2 WO 1996037207 A2 WO1996037207 A2 WO 1996037207A2 US 9607874 W US9607874 W US 9607874W WO 9637207 A2 WO9637207 A2 WO 9637207A2
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Prior art keywords
calcium sulfate
medicament
calcium
compound
substance
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PCT/US1996/007874
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English (en)
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WO1996037207A3 (fr
Inventor
Sohail Malik
Rolland F. Hebert
Min Yee
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Biofrontiers, Inc.
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Priority claimed from US08/449,949 external-priority patent/US5683725A/en
Application filed by Biofrontiers, Inc. filed Critical Biofrontiers, Inc.
Priority to AU60252/96A priority Critical patent/AU6025296A/en
Priority to EP96917844A priority patent/EP0839043A2/fr
Publication of WO1996037207A2 publication Critical patent/WO1996037207A2/fr
Publication of WO1996037207A3 publication Critical patent/WO1996037207A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay

Definitions

  • the present invention relates generally to compositions and methods for modulating substance P by compounds containing calcium sulfate, particularly syngenite, g ⁇ rgeyite and gypsum, and more specifically, to the synthesis of such compounds as well as their use to prevent and/or treat conditions associated with substance P such as gingivitis or periodontitis.
  • Substance P along with neurokinin A and neurokinin B, are members of the tachykinin family of mammalian regulatory peptides (Dockray, Gut Peptides: Biochemistry and Physiology, Walsh and Dockray, editors, Raven Press, Ltd, New York, NY, pp. 401-422, 1994).
  • substance P was the first of the gut neuropeptides to be discovered (von Euler and Gaddum, J. Physiol. 72:74-87, 1931).
  • substance P was isolated and sequenced from bovine hypothalamus, and determined to be an undecapeptide (Chang and Leeman, J. Biol. Chem.
  • NK1, NK2 and NK3 multiple receptor subtypes (i.e., NK1, NK2 and NK3) for the various tachykinin neuropeptides have been cloned and sequenced, with substance P being considered the natural ligand for receptors of the NK1 subtype (Dockray, pp. 408-409).
  • Substance P is stored in the secretory granules of substance P immunoreactive nerves, which are afferent, small diameter, unmyelinated polymodal, C-type fibers with dual functions. Upon orthodromic stimulation by noxious stimuli, substance P is released from the spinal tract for central transmission of nociceptive information.
  • a secondary function involves release of substance P and other neuropeptides from collateral nerve terminals and peripheral tissue following antidromic noxious stimulation, resulting in "neurogenic inflammation".
  • substance P has been implicated as a neurogenic promoter o various inflammatory processes, including asthma, rhinitis, conjunctivitis, and inflammation of the skin and mucosa (see Bartold et al., J. Periodontol 55:1113-21, 1994).
  • Substance P has also been found to be a potent vasodilator and increases vascular permeability, and has pro-inflammatory effects on neutrophils, macrophages, mast cells, lymphocytes, and endothelial cells (Bartold et al.).
  • substance P immunoreactive nerves In addition to the central and peripheral nervous system, substance P immunoreactive nerves, and thus substance P itself, have been found in a variety of different mammalian tissues, including smooth muscles of the arteries and veins, pulmonary, urinary and gastrointestinal tracts, basal ganglia, substantia nigra, striatonigral pathways, hypothalamus, retina, hair follicles, gingival tissues, prostate gland, and even in spermatozoa.
  • substance P is nearly ubiquitous in mammalian tissues. This wide distribution is believed to be due, at least in part, to the association of substance P (either directly or indirectly) with numerous processes and/or conditions, including neurogenic inflammation (Barnes, J. Asthma 29: 165-180, 1992; Ohkubo, Archs. Oral Biol. 55:151-158, 1993), pain (Cui et al., Annals of NY. Acad. Sci. 552:488-489, 1991), allergy (Nieber et al., Int Arch. Allergy Appl. Immunol. 94:334- 338, 1991), asthma (Nadel, Allergy Proc.
  • Periodont disease is generally used to describe disorders of the periodontium, ranging from the relatively benign form of gingivitis confined to the marginal tissues, to more aggressive forms such as rapidly progressive periodontitis, in which the disease process leads to loss of connective tissue attachment to the root surfaces, loss of alveolar support, and impaired function of the dentition (see generally Armitage, Periodontology 2000 7:39-53, 1995).
  • Gingivitis affects approximately 80% of all people in the United States by the age of 15. It is characterized by redness, gingival bleeding, swelling, gingival sensitivity and tenderness (Johnson et al., J. Periodontol 57:141-150, 1986; Loe et al., J. Periodontol 36:177-187, 1965; Suzuki, Dent. Clin. North. Am. 52:195-216, 1988). There are several types of gingivitis, the most common being chronic or long-standing plaque-induced gingivitis (Tanner et al., Clinical Infectious Diseases 76:304-309, 1993). A gummy film that coats the surface of the teeth, plaque results from the metabolic processes of normal mouth micro-organisms.
  • gingivitis can lead to periodontitis, which is characterized in a loss of alveolar support to the teeth, resulting in bone erosion and loose teeth. Periodontitis is the major cause of tooth loss in adults in the United States, and it is estimated that 50% of adults in the United States over the age of 45 are afflicted with periodontitis.
  • 4,963,346 to Amer is directed to the use of phytosterols (namely sitosterol, campersterol and stigmasterol) for the treatment or prevention of dental plaque, calculus and gingivitis;
  • U.S. Patent No. 3,914,406 to Yankell is directed to use of amine fluorides for preventing and treating gingivitis by administering the same to the oral cavity;
  • U.S. Patent No. 4,160,821 to Sipos is directed to the use of glycerin solution of zinc salt (especially zinc chloride) for the treatment o gingivitis;
  • U.S. Patent No. 5,281,410 to Lukacovic et al. is directed to the use o stannous compounds for reducing plaque and gingivitis;
  • U.S. Patent No. 5,300,289 to Garlich et al. is directed to the use of phytic acid compositions for controlling dental calculus, dental plaque, gingivitis, periodontitis and oral maloder; and U.S. Patent No. 5,298,237 to Fine is directed to gel compositions containing ascorbic acid and copper sulfate for the prevention or treatment of gingivitis, periodontitis and plaque.
  • plaque is considered essential for the development of gingivitis and periodontitis, its presence, even in large amounts, does not necessarily lead to gingivitis, or to progression of gingivitis to the more severe periodontitis. This has led many investigators to postulate the involvement of other factors, including mental, physical and biological stress. Stress has been correlated to severity of periodontal disease in humans, associated with changes in bone in stressed laboratory animals, and changes in the cellular and fibrous components of the periodontium (Bartold et al., p. 1113).
  • such agents would have utility in preventing and/or treating pain, neurogenic inflammation, headaches, migraine, neurological disorders, respiratory disorders, blood pressure, hematopoiesis, allergies, asthma, arthritis, irritable bowel syndrome, hemorrhoids, anal fissures, ulcerative colitis, Crohn's disease, proctitis, benign prostatic hypertrophy (BPH), cystitis, skin disorders, CNS disorders (such as Parkinson's disease, MS and Alzheimer's disease), as well as infertility, emesis, cough, bronchitis, osteoporosis, ulcers, fever and obesity.
  • an ideal agent would have the ability to resist peptidases, and have the ability to enter the CNS (Lembeck, __M «. N Y. Acad. Sci. 632:490-493, 1991).
  • the present invention discloses compounds which modulate substance P, and methods for the use thereof.
  • such compounds contain calcium sulfate, and are hereinafter referred to as "calcium sulfate compounds”.
  • Preferred calcium sulfate compounds of this invention include, but are not limited to, syngenite, g ⁇ rgeyite and gypsum.
  • the calcium sulfate compounds of the present invention have utility as substance P modulating agents, as well as in the prevention and/or treatment of a wide variety of conditions associated with substance P.
  • a calcium sulfate compound of this invention is administered to a warm-blooded animal in need thereof to modulate substance P.
  • a calcium sulfate compound is administered to a warm-blooded animal in need thereof to prevent and/or treat a condition associated with substance P.
  • a calcium sulfate compound is administered to the oral cavity of a warm-blooded animal to prevent and/or inhibit periodontal disease, such as gingivitis and/or periodontitis.
  • a calcium sulfate compound is administered to a warm-blooded animal to prevent and/or treat pain, neurogenic inflammation, headaches, migraines, neurological disorders, respiratory disorders, blood pressure, hematopoiesis, allergies, asthma, arthritis, irritable bowel syndrome, hemorrhoids, anal fissures, ulcerative colitis, Crohn's disease, proctitis, benign prostatic hypertrophy, cystitis, skin disorders, and CNS disorders (such as Parkinson's disease, multiple sclerosis and Alzheimer's disease), as well as infertility, emesis, cough, bronchitis, osteoporosis, ulcers, fever and obesity.
  • Figure 1A is an IR spectrum
  • Figure IB presents an X-ray powder diffraction analysis, of syngenite made according to this invention.
  • Figure 2A is an IR spectrum
  • Figure 2B presents an X-ray powder diffraction analysis, of g ⁇ rgeyite made according to this invention. Detailed Description of the Invention
  • this invention is generally directed to compounds containing calcium sulfate (referred to herein as "calcium sulfate compounds").
  • calcium sulfate compounds modulate substance P, and therefor have utility as modulating agents of substance P, as well as in the prevention and/or treatment of a wide variety of conditions associated with substance P in warm-blooded animals, including humans, and in the manufacture of medicaments for use in the prevention and/or treatment of such conditions.
  • condition includes diseases, injuries, disorders, indications and/or afflictions which are associated with substance P.
  • Conditions "associated with substance P” are those conditions which result, either directly or indirectly, from release of substance P and/or abnormally high levels of substance P.
  • the term “treat” or “treatment” means that the symptoms associated with one or more conditions associated with substance P are alleviated or reduced in severity or frequency, and the term “prevent” means that subsequent occurrence of such symptoms are avoided or that the frequency between such occurrences is prolonged.
  • modulate substance P means that substance P is regulated, adjusted, or adapted to a desired degree. For example, modulation of substance P may involve the prevention, inhibition or antagonization of substance P release, or that substance P, once released, is bound complexed, impaired, scavenged or otherwise removed or affected as a causative agent of the condition.
  • a calcium sulfate compound of this invention contains, at a minimum, calcium sulfate (CaSO_ ⁇ .) as a component thereof.
  • Calcium sulfate may be present in the compound in a non-hydrated or hydrated form (or mixture thereof). It should be understood that reference herein to "components" of the calcium sulfate compound include associated, disassociated, ionic, neutral, elemental, salt, hydrated and other forms or mixtures thereof.
  • calcium sulfate may be present within the compound in an associated form as a neutral or ionic species; as part of a larger complex; or in a disassociated form in which calcium and sulfate are present as distinct, non-complexed neutral or ionic species.
  • the calcium sulfate compound is selected from calcium sulfate dihydrate or "gypsum" (CaSO_ ⁇ .-2H2 ⁇ ), calcium sulfate hemihydrate (CaS ⁇ 4- 1 2 H2 ⁇ ) and anhydrous calcium sulfate (CaSO4).
  • Anhydrous calcium sulfate, as well as its hemihydrate and dihydrate forms, are commercially available from a variety of sources (e.g., J.T. Baker Inc., Phillipsburg, Pennsylvania; Sigma Chemical Co., St. Louis, Missouri; Aldrich Chemical Co., Milwaukee, Wisconsin).
  • calcium sulfate dihydrate may be obtained from natural sources, such as gypsum rock, which may then be calcined to the hemihydrate or anhydrous form.
  • the above forms of calcium sulfate may also be synthesized from various chemical processes, including production as a by-product of citric acid manufacturing techniques, with appropriate calcination or hydration to yield the desired form.
  • the calcium sulfate compound is selected from calcium thiosulfate (CaS 2 O 3 ) and calcium sulfite (CaSO 3 ). Both compounds are commercially available from a variety of sources.
  • calcium sulfate is complexed with one or more sulfate-containing components having a constituent selected from potassium, magnesium, aluminum, sodium, lithium, silicon, chlorine, cobalt, strontium, chromium, zinc, copper, iron, tin, nickel and manganese.
  • Preferred sulfate-containing components include K2SO4, MgSO A_2(SO4)3, Na2SO4, L_2SO4, Cr2(SO4)3, MnSO4, FeSO4, Fe2(SO4)3, C0SO4, NiSO CuSO ZnSO BaSO SnSO4 and SrSO4.
  • the sulfate-containing component is potassium sulfate (K2SO4)
  • the calcium sulfate compound is a calcium sulfate and potassium sulfate complex (CaS ⁇ 4 * I_2S ⁇ 4)
  • the calcium sulfate compound is syngenite (CaSO4 __2SO4-H2O) or g ⁇ rgeyite (5CaSO4*K2SO4-H2O). Syngenite and g ⁇ rgeyite are naturally occurring intermediate phases of potassium sulfate, calcium sulfate and water (i.e., K.2SO4-CaSO4-H2O).
  • Syngenite occurs sparingly as a volcanic product and in salt deposits of oceanic origin. It is also found as crusts on lava in Heleakala crater (Maui, Hawaii), as well as being present in natural deposits in Italy, Germany, Tru, Australia and China.
  • g ⁇ rgeyite occurs in Ischle salt deposits in Austria, in the Q Basin, Hubei province, China (Mayrhofer, Am. Min. 5 :403, 1954). Both syngenite and g ⁇ rgeyite have been described in a variety of mineralogical references (see Encyclopedia of Minerals, W.L.
  • Syngenite and g ⁇ rgeyite can be collected or synthesized by methods known to those skilled in this field.
  • syngenite and g ⁇ rgeyite can be collected from mineral deposits, and syngenite can be synthesized as disclosed in PCT Publication No. WO 94/09798.
  • Synthetic routes for syngenite also include those disclosed in U.S. Patent No. 4,554,139 to Worthington et al.; Calistru et al., Bulgarian Patent No. 88,488 (Chem. Abstracts 106:31984k, 1986); Yunusova et al., Izu. Akad. Nauk Kirg. SSR, Khim-Tekhnol. Biol.
  • syngenite and g ⁇ rgeyite are disclosed.
  • highly pure syngenite can be manufactured in high yield by mixing potassium chloride and potassium sulfate with calcium chloride. More specifically, potassium chloride and potassium sulfate are dissolved in water at a molar ratio of potassium sulfate to potassium chloride ranging from 10:1 to 1:25, and preferably 1:1 to 1:6. This can be achieved at a temperature ranging from 20°-80°C, and preferably from 25°-45°C, with constant stirring.
  • Calcium chloride is then added, preferably pre-dissolved in water, to the stirring potassium chloride/potassium sulfate solution to yield a molar ratio of calcium chloride to potassium sulfate ranging from 10:1 to 1:25 (preferably ranging from 1:1 to 1:8), and a molar ratio of calcium chloride to potassium chloride ranging from 10:1 to 1:25 (preferably ranging from 1 :1 to 1:9).
  • the resulting solution yields syngenite as vitreous white precipitate.
  • the precipitate may then be filtered and washed with either a combination of ethanol/water (1 :4) solution and then with water, or simply washed with water (preferably cold) to yield syngenite in excess of 90% purity.
  • potassium sulfate and potassium chloride are dissolved in water at a molar ratio ranging from 3:1 to 1:3 with constant stirring, and at a temperature ranging from 20°-80°C (preferably 25°-45°C).
  • Calcium chloride is then added, preferably pre-dissolved in water, to the above stirring solution at a calcium chloride to potassium sulfate molar ratio ranging from 3:1 to 1:3 with constant stirring at a temperature ranging from 20°-80°C (preferably ranging from 25°-45°C).
  • additional potassium chloride is then added.
  • the molar ratio of the previously added potassium chloride to the additional potassium chloride ranges from 3:1 to 1:3.
  • the resulting solution yields syngenite as vitreous white precipitate.
  • the precipitate may then be filtered and washed with water (preferably cold) to yield syngenite at a purity in excess of 90%.
  • a relatively fast and efficient method for the synthesis of g ⁇ rgeyite is disclosed.
  • a calcium sulfate-containing compound and potassium sulfate are dissolved in water at a molar ratio ranging from
  • the calcium sulfate-containing compound may be calcium sulfate dihydrate, calcium sulfate hemihydrate or anhydrous calcium sulfate, or may be syngenite.
  • g ⁇ rgeyite forms as a precipitate which may be removed from the solution by filtration. The precipitate may then be washed either with a combination of ethanol/water (1:5) solution and then with water, or simply washed with water
  • the calcium sulfate compounds of this invention have been found to modulate substance P, and are relatively stable due to their resistance to degradation by, for example, peptidases.
  • substance P is an undecapeptide and a member of the tachykinin class of neuropeptides.
  • Substance P is found in secretory granules of sensory neurons which are designated as substance P immunoreactive (SP- IR) nerves.
  • SP- IR substance P immunoreactive
  • the primary function of the SP-IR nerves are for nociceptive information which, upon stimulation by noxious stimuli, release substance P and thereby mediate pain perception.
  • release of substance P and other neuropeptides from collateral nerve terminals and peripheral tissues result in neurogenic inflammation.
  • the calcium sulfate compounds of this invention can be used to inhibit neurogenic inflammation by modulating substance P.
  • the calcium sulfate compounds of this invention may be used to prevent and/or treat a variety of conditions associated with substance P.
  • SP-IR nerves and thus substance P itself, are found in many different tissues, including the central and peripheral nervous system, smooth muscles of the arteries and veins, pulmonary, urinary and gastrointestinal tracts, basal ganglia, substantia nigra, striatonigral pathways, hypothalamus, retina, gingival tissues, prostate gland and even in spermatozoa. Due to its nearly ubiquitous distribution in mammalian tissue, substance P is believed to be associated with a variety of conditions.
  • substance P In addition to its involvement in pain mediation and promotion of neurogenic inflammation, substance P is associated with periodontal disease, headaches and migraines, emesis, vomiting and nausea, cough (of both viral and bacterial origin), chronic bronchitis, immune system stimulation and regulation, hematopoieses, neurological disorders, respiratory disorders, allergies, fertility, female reproductive cycle control and regulation of spermatogenesis in males, obesity, osteoporosis/bone regulation, spasmodic conditions, ulcers, blood pressure regulation, stress response conditions, irritable bowel syndrome, hemorrhoids, anal fissures, and BPH/prostate conditions. Accordingly, the calcium sulfate compounds of this invention are believed effective in preventing and/or treating the above conditions due to their ability to modulate substance P.
  • the calcium sulfate compounds of the present invention may be utilized for pharmaceutical, prophylactic and/or cosmetic purposes, and are administered to a warm-blooded animal in an effective amount to achieve a desired result.
  • an effective amount is a quantity sufficient to treat the symptoms of a condition and/or the underlying condition itself.
  • An effective amount in the context of prophylactic administration means an amount sufficient to avoid or delay the onset of a condition and/or its symptoms.
  • an effective amount with regard to cosmetic administration is an amount sufficient to achieve the desired cosmetic result.
  • the calcium sulfate compounds of the present invention are administered to a warm-blooded animal as a pharmaceutical, prophylactic or cosmetic composition containing at least one calcium sulfate compound in combination with at least one pharmaceutically, prophylactically or cosmetically acceptable carrier or diluent.
  • a pharmaceutical, prophylactic or cosmetic composition typically contain a calcium sulfate compound or compounds in an amount ranging from 0.01% to 85%, typically from about 0.05% to 50% and preferably from about 0.1% to 20% by weight of the composition.
  • such compositions contain a calcium sulfate compound (or compounds) in an amount less than 5%, typically from about 0.001 to 3%, and preferably from about 0.02% to 1% by weight of the composition.
  • the calcium sulfate compound is present in the composition at a concentration not exceeding its saturation point (at room or physiological temperature) in the carrier or diluent.
  • Administration may be accomplished by systemic or topical application, with the preferred mode dependent upon the type and location of the conditions to be treated. Frequency of administration may vary, and is typically accomplished by daily administration.
  • Suitable modes of administration include (but are not limited to) enteral administration (such as oral, sublingual, rectal and vaginal) and parenteral administration (such as intravenous, intramuscular and subcutaneous), as well as other routes such as inhalation, topical, transdermal and intrathecal.
  • enteral administration such as oral, sublingual, rectal and vaginal
  • parenteral administration such as intravenous, intramuscular and subcutaneous
  • other routes such as inhalation, topical, transdermal and intrathecal.
  • Systemic administration may be achieved, for example, by injection (e.g., intramuscular, intravenous, subcutaneous or intradermal) or oral delivery of the composition to the warm-blooded animal.
  • Suitable carriers and diluents for injection are known to those skilled in the art, and generally are in the form of an aqueous solutions containing appropriate buffers and preservatives.
  • Oral delivery is generally accomplished by formulating the composition in a liquid or solid form, such as a tablet or capsule, by known formulation techniques.
  • Topical administration may be accomplished, for example, by formulating the composition as solution, cream, gel, ointment, powder, paste, gum or lozenge using techniques known to those skilled in the formulation field.
  • topical administration includes delivery of the composition to mucosal tissue of the mouth, nose and throat by, for example, spray or mist application, as well as to the vagina and rectum by, for example, suppository application.
  • a composition containing one or more calcium sulfate compounds is formulated for topical administration to the oral cavity of a warm-blooded animal.
  • the composition is administered topically to the oral cavity, held therein for a period of time, and then largely expectorated (rather than swallowed).
  • Such compositions include toothpastes, tooth gels, tooth powders, mouthwashes, mouth sprays, propylaxyis pastes, dental treatment solutions, oral gels, lozenges, chewing gums, dental floss, controlled-releases drug delivery systems for placement in the periodontal pocket, and the like.
  • Components of topical, oral compositions are those that are generally suitable for administration to the oral cavity, and are compatible with the calcium sulfate compounds of this invention.
  • “compatible” means that the components of the composition are capable of being commingled with one another, in a manner such that there is no interaction which would substantially reduce the efficacy of the composition under normal use.
  • Such components are well known in the art, and include (but are not limited to) anticarries agents, antiplaque agents, anticalculas agents, dental abrasives, surfactants, flavoring agents, sweetening agents, binders, humectants, thickening agents, buffering agents, preservatives, coloring agents, pigments, alcohol (e.g., ethanol) and water.
  • the calcium sulfate compound is administered in the form of a composition
  • the calcium sulfate compound can be used as the sole ingredient, or combined with other minor components.
  • a calcium sulfate compound may be the sole compound (i.e., 100% by weight), or may be the major component (i.e., in excess of 50%) or may be the principle component (e.g., in excess of 90% or 95% by weight).
  • the calcium sulfate compound may be formulated such that it is present in the composition in an amount in excess of 50% by weight, or in excess of 90% or 95% by weight, and up to and including 100% by weight.
  • a composition of this invention may be administered to an animal in need thereof to modulate substance P.
  • the composition is administered to the oral cavity for the prevention and/or treatment of a periodontal disease, such as gingivitis or periodontitis. This may be accomplished by contacting the soft tissue afflicted with gingivitis or periodontitis for about 15 seconds, preferably from about 20 seconds to 10 minutes, and more preferably from about 30 seconds to 1 minute. The composition may then be expectorated from the oral cavity.
  • the frequency of such administration is preferably from about once per week to about four times per day, and more preferably once or twice per day.
  • compositions of the present invention are believed to function with regard to the prevention and/or treatment of periodontal disease by modulating substance P and by controlling the temperature of gingival tissues.
  • Temperature as a periodontal diagnostic tool has recently been reported (Kung et al., J. Clin. Periodontology 77:557-563, 1990; Isogai et al, J. Periodontology 55:710-712, 1994). It is believed that release of substance P within the tissues of the oral cavity increases the temperature of gingival tissues. Such a temperature elevation provides a more favorable environment for microbial growth, which results in the onset or worsening of gingivitis and or periodontitis (see Hoffajee et al., J. Clin. Periodontology 19:417-422, 15
  • compositions of this invention administered to the oral cavity results in substance P modulation and a lowering of gingival tissues temperature which, in turn, leads to less favorable conditions for bacterial growth.
  • the ability of the calcium sulfate compounds of this invention to modulate substance P may be assayed by known techniques, such as those disclosed by Mizrahi et al. (Eur. J. Pharmacol. P7:139-140, 1983) and Holzer et al. (Eur. J. Pharmacol. 91:83-88, 1983).
  • PanLabs Test Number 3-0580 screen the ability of compounds to function as substance P antagonists by determining the ability of the compound to inhibit substance P-induced contractions of guinea pig ileum (see Example 6 herein below).
  • Substance P plays a role in the release of various immunomodulatory cytokines produced by macrophages, such as tumor necrosis factor (TNF) and interleukin 1 (IL-1). Such cytokines induce release of prostaglandin E2 (PGE2) which plays a major role in the pathogenesis of bone and cartilage destruction in inflammatory diseases.
  • PGE2 prostaglandin E2
  • Utility of the calcium sulfate compounds of this invention as immunomodulatory agents may be assayed by a number of commercially available techniques, including the techniques disclosed by Maloff et al. (Clin. Chim. Ada. 181:73-78, 1989). Representative assays include, for example, PanLabs Test Numbers 4-0140 and 4-0120 which screen agents for the ability to inhibit (or promote) PGE2 release from cells exposed to TNF and IL-1, respectively.
  • the ability of the calcium sulfate compounds of this invention to bind to the neurokinin NKj receptor may be determined by the procedure of Lee et al. (Mol. Pharmacol. 25:563-569, 1983). In this assay, submaxillary glands are obtained from male guinea pigs and a membrane fraction prepared by standard techniques. The membrane preparation is then incubated with labeled substance P, and non-specific binding is estimated in the presence of the test compound. The membranes are then filtered and washed, and the filters are counted to determine bound, labeled substance P.
  • Fever is a defense mechanism which is regulated in the central nervous system and, more specifically, in the preoptic area of the anterior hypothalamus. This area has been known to play an important regulatory role in body temperature (Blatteis et al., Ann. ofNYAcad. Sci. 741:162-173, 1994). It is also known that substance P containing nerve cell terminals are present in the preoptic area of the anterior hypothalamus (Gallagher, Brain Research Bull. 20: 199-207, 1992). In a guinea pig model of fever, IN injection of an exogenous pyrogen increased colonic temperature as measured using thermocouples. Substance P antagonist microinjected intrapreoptically attenuated the fevers showing that substance P inhibition results in reduced febrile response.
  • the calcium sulfate compounds of this invention have activity in decreasing the febrile response in mammals.
  • sensory neuropeptides including substance P, neurokinin A and calcitonin-gene-related peptide may be one of the mechanisms of migraine pathogenesis (Buzzi et al., Br. J. Pharmacol. PP:202-206, 1990). Moussaoiu et al. (European Journal of Pharmacology 238:421-424, 1993) suggest that selective ⁇ K1 receptor antagonists could be greatly effective in humans for the treatment of 17
  • Capsaicin a substance P inhibitor
  • the calcium sulfate compounds of this invention are useful in the treatment of migraine headaches, particularly via intranasal administration.
  • thermogenesis is thought to be the primary reason for obesity, although other mechanisms also play a role (Williams et al., Clinical Sci. 50:419-426, 1991).
  • the hypothalamus is an important organ for control of food intake and thermogenesis. It contains over 50 putative neurotransmitters, among these substance P (Morely, Endocrine Rev. 5:257-287, 1987). High concentrations of substance P have been found in the ventro-medial hypothalamus which is the satiety center in mammalian species (Iverson, Br. Med. Bull. 55:277-282, 1982). Baroncenelli et al.
  • the calcium sulfate compounds of this invention may be used as weight loss agents modifying plasma substance P levels.
  • Vomiting and nausea occur in a wide variety of disorders such as peptic ulcer disease, peritonitis, acute systemic infections with fever, elevated intracranial pressure, morning sickness of early pregnancy, myocardial infarction and as a side effect of many drugs, ingested chemicals and anesthesia.
  • Patients undergoing chemotherapy and radiation therapy for cancer also experience vomiting as a side effect
  • the nucleus tractus solitarius is the region in the brain where gastric vagal afferen fibers terminate, and this area is innervated by substance P-containing fibers (Otuska Physiology Review 73:229, 1993). It has been suggested that substance P which i released by cytotoxic agents may induce emesis.
  • substance P is a emetic (Andrews et al., Trends Pharmacol. Sci. 9:334, 1988). Consequently, th calcium sulfate compounds of this invention are expected to attenuate emesis.
  • ferret model of induced emesis is commonly used to test antiemetic drug (Tattersall, European J. of Pharmacol. 250.R5-R6, 1993; Knox et al., Brain Researc Bull. 57:477-484, 1993).
  • Substance P is a neuropeptide known to cause coughing (Kohrogi Journal of Clinical Investigation 52:2063-2068, 1988).
  • substance P i known to activate the cough reflex and capsaicin has been used as a provocative agen to test the sensitivity of the cough reflex (Morice et al., Lancet n:l 116-1118, 1987) Karlsson (Thorax 45:396-400, 1993) suggests that there is a role for substance sensitive nerves in chronic, non-productive cough and sneezing.
  • Yoshihara et al regulatory Peptides 45:238-240, 1993
  • have reported that plasma substance P level were higher in a pertussis group during the coughing stage than during the recover stage or in the control group.
  • the plasma substance level decreased simultaneously with a decreasing number of coughing attacks.
  • the calcium sulfate compounds of this invention may be used in the prevention and o treatment of coughs of various etiologies.
  • Substance P immune reactive fibers have been localized in the anterio pituitary in the rat (Battmann et al., J Endocrinol. 750:160-175, 1991) and in human (Wormald et al., J Clin. Endocrinol. Matab. 5P:612-615, 1989).
  • Substance P receptor are present in ovaries (Wuttke, Human Reproduction 5(Suppl. 2): 141 -146, 1993) and i mouse and human testes (Chiwakta et al., Endocrinology 725:2441-2448, 1991).
  • substance P may also be involved in the regulation of midcycle L surges, and may be an important peptide in the regulation of reproductive events. It i also known that substance P is present in lactotrophs and gonadotropes in the ra anterior pituitary (Morel et al., Neuroendocrinology 55:86-92, 1982). The presence of substance P in these organs is apparently essential for reproduction. In addition, substance P may also play a role in the midcycle LH surge. Thus, the calcium sulfate compounds of this invention may be used to treat conditions of mammalian reproduction.
  • Substance P neurons are found in afferent sensory branches of the trigeminal nerve which innervates the walls of the submucosal glands and blood vessels and the epithelium of the human nasal mucosa (Lundberg, Am. Rev. Respir. Dis. 757):S16-S23, 1987). Chaen et al. (Ann. Otol. Rhinol. Laryngol. 702:16-21, 1993) reported that substance P is actively secreted into the nose and may play an important role in nasal mucosa allergy reactions. Substance P is also reported to act as a mast cell secretagogue (Repke et al., FEBS Letters 221(2):236-240, 1987).
  • the calcium sulfate compounds of this invention may be used to treat allergic reactions such as allergic rhinitis, as well as other conditions in which there is nasal obstruction and or abnormal mucus secretions, such as the common cold and acute and chronic bronchitis.
  • Example 1 illustrates the synthesis of syngenite and g ⁇ rgeyite by various techniques
  • Example 2 illustrates the preparation and use of a mouth rinse containing syngenite or g ⁇ rgeyite
  • Examples 3-4 illustrate use of the mouth rinse of Example 2 to treat periodontal disease
  • Example 5 illustrates use of a mouth rinse containing gypsum to prevent periodontal disease
  • Example 6 illustrates modulation of substance P by syngenite, g ⁇ rgeyite and gypsum
  • Example 7 illustrates the non-toxic nature of syngenite.
  • Source of Chemicals Chemicals utilized in the following examples may be purchased from a number of suppliers, including Sigma Chemical Co., St. Louis, Missouri; Aldrich Chemical Co., Milwaukee, Wisconsin; and J.T. Baker, Inc., Phillipsburg, Pennsylvania.
  • Syngenite can be synthesized by mixing potassium chloride and potassium sulfate with calcium chloride.
  • a mouth rinse was prepared by mixing 0.3% w/v syngenite or g ⁇ rgeyite (as prepared by the procedures of Examples 1A and IB, respectively) in drinking water.
  • the mouth rinse was used without further modification in Examples 3 and 4.
  • Patients were instructed to use the mouth rinse twice (2x) per day after brushing their teeth (i.e., morning and evening). After brushing, the patients placed approximately 10 ml of mouth rinse in their mouth and "swished" for 1-2 minutes, and then expectorated the solution from their mouth. The patients were further instructed not to immediately rinse their mouth with water after swishing.
  • Example 2 In the following case studies, the administration procedures set forth in Example 2 were followed by the patients.
  • Case Study 1 A male patient in his early forties had a recent history of mild gingival inflammation and bleeding. The patient used the mouth rinse of Example 2 containing syngenite. After a few days of treatment, the bleeding was remarkably reduced and, after one week of treatment, gingival symptoms were completely gone. Treatment was then discontinued and the gingival symptoms have not recurred for five months post- treatment.
  • the patient used the mouth rinse of Example 2 containing syngenite for three months. After the first month of treatment, the gingival swelling, redness, sensitivity and bleeding were reduced. At the end of the second and third months of treatment, bleeding had ceased, and sensitivity was less than experienced at the end of the first month of treatment.
  • a male patient in his fifties has a history of severe periodontal disease.
  • the patent begins use of a mouth rinse containing g ⁇ rgeyite as set forth in Example 2. After one month of treatment, the symptoms associated with the periodontal disease, such as gum bleeding, has significantly reduced.
  • a male patient in his fifties has a past history of reoccurring periodontal disease.
  • a mouth rinse containing 0.2% w/v gypsum is used by the patient according to the procedures set forth in Example 2. Reoccurrence of periodontal disease, and the symptoms associated therewith, do not reoccur after four months of use.
  • This example illustrates the ability of representative calcium sulfate compounds of this invention to modulate substance P by functioning as substance P antagonists.
  • Activity was measured by the procedures disclosed by Mizrahi et al. (Eur. J. Pharmacol. P7:139-140, 1983) and Holzer et al., (Eur. J. Pharmacol. 91:83-88, 1983). Specifically, isolated guinea pig ileum, bathed in physiological salt solution containing atropine (4.5 ⁇ M), diphenhydramaine (3.4 ⁇ M), and indomethacin (2.8 ⁇ M) at 37°C was used. The ability of a test compounds to inhibit substance P-induced contractions of the illeum indicates antagonist activity. The results of this experiment are presented in Table 1.
  • This example illustrates the non-toxic nature of a representative calcium sulfate compound of this invention (i. e. , syngenite).

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Abstract

L'invention concerne des compositions et des procédés pour moduler la substance P et prévenir et/ou traiter les états associés à la substance P. Dans un mode de réalisation, on décrit des compositions et des procédés pour prévenir et/ou traiter une parodonpathie, telle que la gingivite et la parodontite. Les compositions selon l'invention comprennent un composé de sulfate de calcium associé à un porteur ou un diluent pharmaceutiquement acceptable. Des composés de sulfate de calcium représentatifs comprennent la syngénite et la görgeyite. L'invention traite également de procédés de fabrication de la syngénite et de la görgeyite.
PCT/US1996/007874 1995-05-25 1996-05-28 Compositions pharmaceutiques contenant du sulfate de calcium WO1996037207A2 (fr)

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AU60252/96A AU6025296A (en) 1995-05-25 1996-05-28 Pharmaceutical compositions containing calcium sulfate
EP96917844A EP0839043A2 (fr) 1995-05-25 1996-05-28 Compositions pharmaceutiques contenant du sulfate de calcium

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US45026195A 1995-05-25 1995-05-25
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US08/449,949 US5683725A (en) 1995-05-25 1995-05-25 Modulation of substance P by compounds containing calcium sulfate and methods relating thereto
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US52924495A 1995-09-15 1995-09-15
US08/529,244 1995-09-15

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Cited By (4)

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WO1998047514A1 (fr) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Utilisation d'un antagoniste du recepteur nk-1 et d'un inhibiteur selectif de reabsorption de la serotonine (ssri) dans le traitement de l'obesite
WO1998047513A1 (fr) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Utilisation des antagonistes du recepteur de nk-1 dans le traitement des troubles alimentaires
WO2000007598A1 (fr) * 1998-08-04 2000-02-17 Merck Sharp & Dohme Limited Utilisation d'un antagoniste du recepteur nk-1 pour traiter ou prevenir la resorption osseuse anormale
US6267962B1 (en) 1990-12-21 2001-07-31 C-P Technology Limited Partnership Compositions and methods of treatment using peat derivatives

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US4735802A (en) * 1986-05-05 1988-04-05 Le Bich N Topical dermatological composition and method of treatment
WO1988009665A1 (fr) * 1987-06-01 1988-12-15 Allergan, Inc. Pommades ophtalmiques sans conservateurs
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US4735802A (en) * 1986-05-05 1988-04-05 Le Bich N Topical dermatological composition and method of treatment
WO1988009665A1 (fr) * 1987-06-01 1988-12-15 Allergan, Inc. Pommades ophtalmiques sans conservateurs
US4915936A (en) * 1988-10-31 1990-04-10 United States Gypsum Company Dental hygiene composition for reducing periodontal disease
WO1994009798A1 (fr) * 1992-10-29 1994-05-11 C-P Technology Limited Partnership Melanges ou complexes contenant du calcium et du sulfate
WO1995005752A1 (fr) * 1993-08-24 1995-03-02 Kappa Pharmaceuticals Limited Absorption reduite d'acides gras

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6267962B1 (en) 1990-12-21 2001-07-31 C-P Technology Limited Partnership Compositions and methods of treatment using peat derivatives
WO1998047514A1 (fr) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Utilisation d'un antagoniste du recepteur nk-1 et d'un inhibiteur selectif de reabsorption de la serotonine (ssri) dans le traitement de l'obesite
WO1998047513A1 (fr) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Utilisation des antagonistes du recepteur de nk-1 dans le traitement des troubles alimentaires
US6162805A (en) * 1997-04-24 2000-12-19 Merck Sharp & Dohme Limited Use of an NK-1 receptor antagonist and an SSRI for treating obesity
AU744261B2 (en) * 1997-04-24 2002-02-21 Merck Sharp & Dohme Limited Use of NK-1 receptor antagonists for treating eating disorders
WO2000007598A1 (fr) * 1998-08-04 2000-02-17 Merck Sharp & Dohme Limited Utilisation d'un antagoniste du recepteur nk-1 pour traiter ou prevenir la resorption osseuse anormale

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