EP0839043A2 - Compositions pharmaceutiques contenant du sulfate de calcium - Google Patents

Compositions pharmaceutiques contenant du sulfate de calcium

Info

Publication number
EP0839043A2
EP0839043A2 EP96917844A EP96917844A EP0839043A2 EP 0839043 A2 EP0839043 A2 EP 0839043A2 EP 96917844 A EP96917844 A EP 96917844A EP 96917844 A EP96917844 A EP 96917844A EP 0839043 A2 EP0839043 A2 EP 0839043A2
Authority
EP
European Patent Office
Prior art keywords
calcium sulfate
medicament
calcium
compound
substance
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96917844A
Other languages
German (de)
English (en)
Inventor
Sohail Malik
Rolland F. Hebert
Min Yee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biofrontiers Inc
Original Assignee
Biofrontiers Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/449,949 external-priority patent/US5683725A/en
Application filed by Biofrontiers Inc filed Critical Biofrontiers Inc
Publication of EP0839043A2 publication Critical patent/EP0839043A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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

  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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 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 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.
  • 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 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 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.
  • 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 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.
  • 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.
  • 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 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)

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.
EP96917844A 1995-05-25 1996-05-28 Compositions pharmaceutiques contenant du sulfate de calcium Withdrawn EP0839043A2 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US45026195A 1995-05-25 1995-05-25
US449949 1995-05-25
US08/449,949 US5683725A (en) 1995-05-25 1995-05-25 Modulation of substance P by compounds containing calcium sulfate and methods relating thereto
US450261 1995-05-25
US52924495A 1995-09-15 1995-09-15
US529244 1995-09-15
PCT/US1996/007874 WO1996037207A2 (fr) 1995-05-25 1996-05-28 Compositions pharmaceutiques contenant du sulfate de calcium

Publications (1)

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EP0839043A2 true EP0839043A2 (fr) 1998-05-06

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EP96917844A Withdrawn EP0839043A2 (fr) 1995-05-25 1996-05-28 Compositions pharmaceutiques contenant du sulfate de calcium

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EP (1) EP0839043A2 (fr)
AU (1) AU6025296A (fr)
WO (1) WO1996037207A2 (fr)

Families Citing this family (4)

* 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
AU735760B2 (en) * 1997-04-24 2001-07-12 Merck Sharp & Dohme Limited Use of a 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
GB9816897D0 (en) * 1998-08-04 1998-09-30 Merck Sharp & Dohme Therapeutic use

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4689223A (en) * 1986-04-24 1987-08-25 T & R Chemicals, Inc. Method of treating the symptoms of the common cold
US4735802A (en) * 1986-05-05 1988-04-05 Le Bich N Topical dermatological composition and method of treatment
AU1936788A (en) * 1987-06-01 1989-01-04 Allergan, Inc. Preservative free ophthalmic ointments
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
JPH0899848A (ja) * 1994-10-03 1996-04-16 Yoshinori Akiyama 歯槽膿漏治療剤

Non-Patent Citations (1)

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Title
See references of WO9637207A3 *

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WO1996037207A3 (fr) 1997-02-27
AU6025296A (en) 1996-12-11
WO1996037207A2 (fr) 1996-11-28

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