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WO2000030630A1 - Combinaison a base d'inhibiteur de guanylate cyclase et d'anesthesique local tenant lieu d'analgesique - Google Patents

Combinaison a base d'inhibiteur de guanylate cyclase et d'anesthesique local tenant lieu d'analgesique Download PDF

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Publication number
WO2000030630A1
WO2000030630A1 PCT/US1999/027498 US9927498W WO0030630A1 WO 2000030630 A1 WO2000030630 A1 WO 2000030630A1 US 9927498 W US9927498 W US 9927498W WO 0030630 A1 WO0030630 A1 WO 0030630A1
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Prior art keywords
methylene blue
guanylate cyclase
topical anesthetic
cyclase inhibitor
redox dye
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PCT/US1999/027498
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English (en)
Inventor
Zhi-Tao Xia
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LINDEN BIOTECHNOLOGY Inc
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LINDEN BIOTECHNOLOGY Inc
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Priority to AU18243/00A priority Critical patent/AU1824300A/en
Publication of WO2000030630A1 publication Critical patent/WO2000030630A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • 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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to the field of compounds and treatments for the relief of pain, especially the treatment of postoperative pain and the pain resulting from incisions and wounds.
  • the pain from the incision or wound of a surgical procedure is a serious side effect.
  • the recovery time from the operation may be affected in part by the degree of the postoperative pain.
  • the postoperative pain may be so severe that the subject who was operated on may require bed rest for a week or longer.
  • a patient may decide to forgo the operation altogether solely because the postoperative pain is known to be so severe.
  • a specific example of a surgical procedure where the pain is known to be extremely severe is the case of anal surgery, such as a hemorrhoidectomy.
  • the pain is so severe that just changing the wound dressing is an agonizing experience.
  • the pain associated with anal surgery is so renown that many people who are candidates for anal surgery opt for nonsurgical treatment because of the associated pain and discomfort.
  • Hemorrhoids are dilated veins around the anal opening. They are a consequence of prolonged constipation, or occasionally, diarrhea. They most commonly occur at three main points equidistant around the circumference of the anus. Uncomplicated hemorrhoids are seldom painful.
  • the main symptom is bleeding and in first degree hemorrhoids, which never appear at the anus, bleeding at the end of defecation is the only symptom.
  • Second degree hemorrhoids protrude beyond the anus as an uncomfortable swelling, but return spontaneously.
  • Third degree hemorrhoids remain outside the anus and frequently require surgery.
  • a hemorrhoidectomy or the surgical operation to remove hemorrhoids, the hemorrhoids are tied and then excised. After the hemorrhoids have been excised, possible complications are bleeding, or anal stricture which is a narrowing of the anus.
  • the surgical wound is quite painful, and pain medication for the alleviation of this side effect is the rule not the exception.
  • the present invention fulfills this and other needs.
  • the present invention provides a safe and effective compound and therapy for treating and relieving the pain associated with cuts, abrasions, incisions, and wounds.
  • the compound may be used to relieve the postoperative pain from surgical incisions and wounds.
  • anal surgery such as a hemorrhoidectomy
  • the pain is known to be extremely severe, and the compound and therapy of the present invention is used to relieve this pain and discomfort.
  • the present invention is also applicable to other operations, procedures, and conditions where pain is a side effect.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a guanyl ate cyclase inhibitor; a topical anesthetic; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is preferably used to treat pain from surgical wounds.
  • the guanylate cyclase inhibitor is methylene blue, leuko methylene blue, 6- anilinoquinoline-5,8-quinone, N-methylhydroxylamine, hydroxylamine, ethacrynic acid, retinol or mixtures thereof.
  • the topical anesthetics include, but are not limited to, lidocaine, procaine and bupivacaine.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: a redox dye; a topical anesthetic; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is preferably used to treat pain from surgical wounds.
  • the redox dye includes, but is not limited to, methylene blue, toluidine blue, neutral red, tetrazolium salts, chloranil and dichlorophenolindophenol.
  • topical anesthetic include, but are not limited to, lidocaine, procaine and bupivacaine.
  • the present invention relates to a method of treating a mammalian wound comprising: administering to a mammal a therapeutically acceptable amount of a guanylate cyclase inhibitor; and a pharmaceutically acceptable carrier.
  • the guanylate cyclase inhibitor is methylene blue, leuko methylene blue, 6-anilinoquinoline- 5,8-quinone, N-methylhydroxylamine, hydroxylamine, ethacrynic acid or retinol.
  • the method further comprises applying or administering a topical anesthetic as a combination therapy with the guanylate cyclase inhibitor.
  • the present invention relates to a method of treating a mammalian wound, comprising administering to a mammal a therapeutically acceptable amount of a redox dye and a pharmaceutically acceptable carrier.
  • the method further comprises administering a topical anesthetic.
  • Other methods of the present invention include a method of relieving pain from a wound in a mammal, comprising administering to the mammal a therapeutically acceptable amount of a guanylate cyclase inhibitor; and a pharmaceutically acceptable carrier.
  • the present invention provides another method of relieving pain from a wound in a mammal, comprising administering to the mammal a therapeutically acceptable amount of a redox dye and a pharmaceutically acceptable carrier.
  • a still further aspect of the present invention is the use of a compound including a first substance having properties like methylene blue and a second substance having properties like lidocaine to treat pain associated with incisions or wounds. Further, these incisions or wounds may result from surgical procedures. Still further, the compounds with the first and second substances is used to treat postoperative pain resulting from anal surgery. The compound with first and second substances is used to treat and relieve pain associated with toothache, circumcision, or Caesarean section operations. In a specific embodiment, the first substance is about one percent in solution and the second substance is about two percent in solution. The compound with first and second substances is applied topically, transdermally, or interdermally.
  • the compound of the present invention may be applied to the site of the cut, abrasion, incision, or wound.
  • the compound may be applied topically, transdermally, or subdermally.
  • the compound of the present invention may be injected at the site of the incision area. The depth of the injection depends on the incision or cut, and there may be multiple injections to ensure the entire incision area is treated. This single treatment may be effective to relieve pain from the surgical incisions, and further treatment with the compound is not needed.
  • other pain relief drugs such as oral or injected painkillers (e.g., Dolantin or Demerol) are not required.
  • the compound of the present invention may be applied as needed to suit the specific application.
  • the present invention relates to a kit comprising: a guanylate cyclase inhibitor or a redox dye; a topical anesthetic; and instructions for use.
  • the present invention also relates to apparatuses and techniques for effectively and hygienically dispersing the compounds of the present invention.
  • the compound may be supplied in disposable syringes, individually wrapped one-time use applicators and sponges, and individually wrapped bandages, among others. It is also important that the compound of the present invention be distributed to provide for a relatively long shelf life to ensure the compound is effective at the time of use.
  • Figure 2 illustrates the chemical formulae of some redox dyes of this invention.
  • guanylate cyclase inhibitor refers to a compound which inhibits the guanylate cyclase induced formation of the second messenger, cyclic GMP. Methylene blue is a preferred guanylate cyclase inhibitor.
  • redox dye refers to compounds which indicate by color change that either a chemical reduction or chemical oxidation has taken place. Methylene blue is a preferred redox dye.
  • Topical refers to a particular spot which can be in, or on any part of a mammal including, but not limited to, the epidermis, any other dermis or other body tissue.
  • Topical administration means the direct contact of the anesthetic, redox dye or guanylate cyclase inhibitor with tissue, such as a skin or membrane.
  • the term "therapeutically effective amount” refers to the amount of active ingredient sufficient to produce the necessary effect.
  • the active ingredient can be a guanylate cyclase inhibitor or a redox dye if reversible nerve inhibition is desirable.
  • the active ingredient can also be a local anesthetic if topical anesthesia is desired.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a guanylate cyclase inhibitor; a topical anesthetic; and a pharmaceutically acceptable carrier.
  • Guanylate cyclase inhibitors refer to compounds which inhibit guanylate cyclase induced formation of cyclic GMP.
  • guanylate cyclase inhibitors suitable for use in the present invention include, but are not limited to, methylene blue, leuko methylene blue, 6-anilinoquinoline-5,8-quinone, N-methylhydroxylamine, hydroxylamine, ethacrynic acid and retinol.
  • Nitric acid increases cyclic GMP synthesis by activating the soluble heme- containing form of guanylate cyclase.
  • Nitric acid is one product of a reaction catalyzed by nitric oxide synthetase that uses arginine as its substrate (see, Deutsch et al, Neuropsychopharmacology, 15:37-43 (1996)).
  • Local anesthetics generally are esters or amides of benzoic acid derivatives, administered either as the free base or the acid addition salt.
  • the anesthetic agents of this invention are those known, or of a type known, in the art.
  • Examples of local or topical anesthetics of this invention include, but are not limited to, lidocaine, prilocaine mepivacaine, bupivacaine, dibucaine and etdiocaine.
  • Other suitable anesthetics include, but are not limited to, procaine, tetracaine, propoxycaine, chloroprocaine, benzocaine, cocaine, hexylcaine, piperocaine, oxyprocaine, and proparacaine.
  • anesthetics include, but are not limited to, cyclomethycaine, dimethisoquin, ketocaffine, diperodon, dyclonine, and pramoxine, all of which are typically administered in the form of the acid addition hydrochloride or sulfate salts.
  • the salts of the foregoing anesthetics are also useful in the present invention.
  • Such salts include, but are not limited to, a dyclonine salt, a prilocaine salt, a tetracaine salt, a bupivacaine salt, a mepivacaine salt, a lidocaine salt, a procaine salt, an etidocaine salt, and a dibucaine salt.
  • the guanylate cyclase inhibitor is methylene blue and the topical anesthetic is lidocaine.
  • the pharmaceutical composition is preferably used to treat pain from a surgical wound.
  • methylene blue is a phenothiazine derivative and has been used as a biological stain and is known as a guanylate cyclase inhibitor (see, Huang et al, Eur. J Pharmacol, 205:209-294 (1991)).
  • the methylene blue used for medicinal purposes has the molecular formula
  • Methylene blue is known to be an antidote for cyanide and nitrate poisoning.
  • Methylene blue also known as methylthionine chloride, is a member of the class of compounds known as redox dyes.
  • redox dyes include, but are not limited to, toluidine blue, neutral red, leuko methylene blue, tetrazolium. salts, chloranil, and dichlorophenolindophenol (see, Figure 2).
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: a redox dye; a topical anesthetic; and a pharmaceutically acceptable carrier.
  • Suitable redox dyes include, but are not limited to, methylene blue, toluidine blue, neutral red, tetrazolium salts, chloranil and dichlorophenolindophenol.
  • the pharmaceutical composition is preferably used to treat pain from a wound.
  • methylene blue used for medicinal purposes has the molecular formula C ⁇ 6 H 18 N 3 SCl*3H 2 O
  • other forms of methylene blue and derivatives thereof are also suitable for use in the present invention. These include, but are not limited to, methylene blue having various hydrate amounts, methylene blue with various counter ions (e.g., bromide, fluoride, iodide, and others), and methylene blue derivatives wherein the exocyclic ring nitrogen atoms are mono or disubstituted with -C 6 alkyl.
  • alkyl includes, but is not limited to, branched or unbranched hydrocarbon chains, such as, methyl, ethyl, r ⁇ -propyl, w ⁇ -propyl,
  • methylene blue has a high affinity for components of the nervous system, and in particular the nerve endings.
  • the administration of methylene blue to a mammal, such as a human being reversibly inhibits the nerve ending, impairing their function.
  • the reversible inhibition of the nerve endings results in inactivity of the nerves or impairment of the nerve function with concomitant pain relief.
  • the administration of the local anesthetic reduces or eliminates the pain of the temporary nerve inhibition.
  • the body repairs the nerve impairment in about three weeks to a month.
  • the dosage of the composition used in accordance with the invention varies depending on the composition and the condition being treated.
  • the age, weight, and clinical condition of the recipient patient; and the experience and judgment of the clinician or practitioner administering the therapy are among the factors affecting the selected dosage.
  • Other factors include the route of administration to the patient, the patient's medical history, the severity of the disease process, and the potency of the particular compound.
  • the dose should be sufficient to ameliorate symptoms or signs of the disease treated without producing unacceptable toxicity to the patient.
  • the dosage is administered once and preferably only once, but more or less frequent dosing can be recommended by the clinician.
  • the single dose can be administered over a period of time.
  • multiple sub-effective doses can be administered until cumulatively the effective dose is reached.
  • the effective amount of the active ingredient is that amount which provides either subjective relief of symptoms or an objectively identifiable improvement as noted by the clinician or other qualified observer.
  • compositions described in this invention can be used to treat a variety of disorders including pain relief of surgical wounds, anal itching, neurodermatitis, pain relief from the wound caused by a hemorrhoidectomy, dermatological damage, skin lesions, anal fissures and for the reversible inhibition of nerve endings.
  • the pain relieving abilities of the compositions of the present invention are effective for all surgical wounds and incisions. These surgical operations include those which treat disease, injury, deformities, microsurgery, and various other conditions which require surgical treatment.
  • other areas where the compositions of the present invention are effective include, but are not limited to, toothaches, such as tooth extraction, circumcision, and Caesarean section.
  • the present invention relates to a method of treating a mammalian wound. The method comprising: administering to a mammal a therapeutically acceptable amount of a guanylate cyclase inhibitor and a pharmaceutically acceptable carrier.
  • the method further comprises administering a topical anesthetic, such as lidocaine.
  • the topical anesthetic is used to soothe the sensation caused by the action of the guanylate cyclase inhibitor.
  • the guanylate cyclase inhibitor is methylene blue, but other guanylate cyclase inhibitors can be used.
  • the present invention relates to a method of treating a mammalian wound.
  • the method comprising: administering to a mammal a therapeutically acceptable amount of a redox dye and a pharmaceutically acceptable carrier.
  • the method further comprises administering a topical anesthetic.
  • the present invention relates to a method of relieving pain from a surgical wound or incision in a mammal.
  • the method comprising: administering to a mammal a therapeutically acceptable amount of a guanylate cyclase inhibitor and a pharmaceutically acceptable carrier.
  • the method further comprises administering a topical anesthetic, such as lidocaine.
  • the topical anesthetic is used to soothe the sensation caused by the action of the guanylate cyclase inhibitor.
  • the guanylate cyclase is methylene blue.
  • the present invention relates to a method of relieving pain from a surgical wound in a mammal.
  • the method comprising: administering to the mammal a therapeutically acceptable amount of a redox dye and a pharmaceutically acceptable carrier.
  • the method further comprises administering a topical anesthetic, such as lidocaine.
  • the redox dye is methylene blue.
  • the guanylate cyclase inhibitor or redox dye such as methylene blue
  • the administration of methylene blue to a mammal, such as a human being reversibly inhibit the nerve function.
  • the reversible inhibition of the nerve endings results in inactivity of the nerves with concomitant pain relief.
  • the administration of the local anesthetic either simultaneously or sequentially, reduces or eliminates the pain of the temporary nerve inhibition.
  • the body repairs the nerve inhibition in about three weeks to a month.
  • the present invention relates to reversible inhibition of the nerve endings in a mammal.
  • the method comprising: administering to a mammal a guanylate cyclase inhibitor, or a redox dye in a therapeutically effective amount sufficient to reversibly inhibit the nerve and alleviate pain.
  • the method further comprises administering a topical anesthetic, such as lidocaine.
  • the guanylate cyclase inhibitor or redox dye is methylene blue.
  • the present invention relates to a method of relieving pain from a wound in a mammal.
  • the method comprising: reversibly inhibiting the nerve endings.
  • the reversible inhibition is cause by administering to a mammal a guanylate cyclase inhibitor, or a redox dye in a therapeutically effective amount sufficient to reversibly inhibit the nerve and thereby alleviate pain.
  • the method further comprises administering a topical anesthetic, such as lidocaine.
  • the guanylate cyclase inhibitor or redox dye is methylene blue.
  • the combination therapy of the guanylate cyclase inhibitor, or a redox dye and the topical anesthetic can be done sequentially or concomitantly. If done sequentially, a preferred embodiment comprises administering the topical anesthetic first, followed by the guanylate cyclase inhibitor, or a redox dye.
  • the present invention relates to a kit.
  • the kit comprises a guanylate cyclase inhibitor; a topical anesthetic; and instmctions for use.
  • the guanylate cyclase inhibitors suitable for use in the kits of this invention include, but are not limited to, methylene blue, leuko methylene blue, 6-anilinoquinoline-5,8-quinone, N-methylhydroxylamine, hydroxylamine, ethacrynic acid, and retinol. More preferably, the guanylate cyclase is methylene blue.
  • the kit according to the present invention further comprises a topical anesthetic including, but not limited to, lidocaine, procaine and bupivacaine.
  • a topical anesthetic including, but not limited to, lidocaine, procaine and bupivacaine.
  • the topical anesthetic is lidocaine.
  • kits of this invention comprise a redox dye; a topical anesthetic; and instmctions for use.
  • the kits of this invention are compartmentalized kits.
  • a compartmentalized kit of this invention has a first container providing an active ingredient, such as a guanylate cyclase inhibitor or a redox dye; a second container providing an aqueous solution of a topical anesthetic, such as lidocaine; and instmctions for use.
  • the kit contains hypodermic needles and syringes for use.
  • guanylate cyclase inhibitors or redox dyes of this invention can be formulated in a variety of carriers and delivery systems. Means of preparation, formulation and administration are known to those of skill. See generally, Remington's Pharmaceutical Science 15th ed., Mack Publishing Co., Easton,
  • a therapeutically effective concentration of the active ingredient is placed in water, an oil, resin, biopolymer, or other suitable delivery device as is known in the art.
  • the amount of the guanylate cyclase inhibitor or redox dye to be administered and the composition's concentration in depot formulations depends upon the vehicle or device selected, the clinical condition of the patient, the side effects, and the stability of the composition mi the formulation.
  • the physician employs the appropriate preparation containing the appropriate concentration of the guanylate cyclase inhibitor or redox dye and selects the amount of formulation administered, depending upon clinical experience with the patient in question or with similar patients.
  • the compositions can include, depending on the formulation desired, pharmaceutically acceptable nontoxic carriers, or diluents which include vehicles commonly used to form pharmaceutical compositions for animal or human administration.
  • the diluent is selected so as not to unduly affect the biological activity of the combination.
  • examples of diluents which are especially useful for injectable formulations are water, the various saline solutions, Ringer's solution, dextrose solution, and Hank's solution.
  • the pharma ceutical composition or formulation may include additives such as other carriers; adjuvants; or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.
  • excipients can be included in the formulation.
  • examples include co-solvents, surfactants, oils, humectants, emollients, preservatives, stabilizers, and antioxidants.
  • Any pharmacologically acceptable buffer may be used, e.g., Tris or phosphate buffers.
  • Effective amounts of diluents, additives and excipients are those amounts which are effective to obtain a pharmaceutically acceptable formulation in terms of solubility, biological activity, and others.
  • a composition of the invention includes a guanylate cyclase inhibitor or redox dye, a topical anesthetic, both of which can be formulated with a conventional, pharmaceutically acceptable carrier or vehicles for parenteral or topical administration.
  • Formulations can also include small amounts of adjuvants such as buffers and preservatives to maintain isotonicity, physiological, and pH stability. Means of preparation, formulation and administration are known to those of skill. See generally, Remington's Pharmaceutical Science 15th ed., Mack Publishing Co., Easton, Pa. (1980).
  • compositions of this invention are typically administered to human patients parenterally or topically, or both.
  • the compositions are administered in unit dosage forms suitable for single administration of precise dosage amounts.
  • long-acting depot compositions are administered subcutaneously or intra-muscularly as precise unit doses with each dose lasting weeks to a month.
  • one dose of the therapeutically effective amount parenterally administered cutaneous, subcutaneously, or intramuscularly will be effective.
  • compositions can be formulated into preparations by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and, if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, and preservatives.
  • the compositions of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, physiological saline buffer, or distilled water.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the therapeutic compound i.e., the guanylate cyclase inhibitor or the redox dye
  • the concentration is from about one milligram per milliliter to about twenty milligrams per milliliter or about one milligram per milliliter to about five milligrams per milliliter. Most preferably, the concentration is about one milligram per milliliter. Concentrations below one milligram per milliliter may be necessary in some cases depending on the solubility and potency of the active ingredient selected for use.
  • the formulation which is sterile, is suitable for various parenteral routes including dermal, intradermal, subdermal, intramuscular, cutaneous, and subcutaneous.
  • the topical anesthetic solution such as lidocaine hydrochloride, is used in about a one percent solution to about a twenty percent solution, more preferably about a one percent solution to about a ten percent solution, and most preferably about a two percent solution to about a five percent solution.
  • the guanylate cyclase inhibitor or redox dye such as methylene blue solution, is about a one percent solution to about a twenty percent solution, more preferably about a one percent solution to about a ten percent solution and most preferably about a one percent solution to about a five percent solution.
  • the ratio of lidocaine hydrochloride solution to methylene blue solution depends in part on the weight percentages used. If for example, a two percent lidocaine hydrochloride solution is used, and a one percent methylene chloride solution is used, a ratio of about eighteen-to-one to about one-to-nine can be used, more preferably, a ratio of about ten-to-one to about one-to-five can be used, and most preferably, a ratio of eight-to-one to about one-to-two is used.
  • the compositions of this invention can also be delivered topically.
  • a therapeutically effective concentration of a guanylate cyclase inhibitors or redox dye is placed in a dermatological vehicle as is known in the art.
  • the amount of the therapeutic guanylate cyclase inhibitor or redox dye to be administered and the compound's concentration in the topical formulations depend upon the vehicle selected, the clinical condition of the patient, the side effects and the stability of the composition in the formulation.
  • the physician employs the appropriate preparation containing the appropriate concentration of the guanylate cyclase inhibitor or redox dye and selects the amount of formulation administered, depending upon clinical experience with the patient in question or with similar patients.
  • the concentration of the therapeutic compound for topical formulations ranges from about one milligram per milliliter to about one hundred milligrams per milliliter, more preferably, from about one milligram per milliliter to about fifty milligrams per milliliter and, more preferably from about two milligrams per milliliter to about twenty milligrams per milliliter. Most preferably, a concentration of about two milligrams per milliliter is employed.
  • Solid dispersions of the therapeutic compound as well as solubilized preparations can be used. Thus, the precise concentration is subject to modest experimental manipulation in order to optimize the therapeutic response.
  • Suitable vehicles include oil-in-water or water-in-oil emulsions using mineral oils, petrolatum and the like as well as gels such as hydrogels.
  • the therapeutic composition is optionally administered topically by the use of a transdermal therapeutic system (see, Barry, Dermatological Formulations, (1983) p. 181 and literature cited therein).
  • a preferred way to practice the invention is to apply the guanylate cyclase inhibitor or redox dye, together with the topical anesthetic, in a cream, lotion, ointment, or oil based carrier, directly to the skin lesions.
  • the therapeutic composition is alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the composition.
  • a nonaqueous (e.g., fluorocarbon propellent) suspension can be used.
  • Sonic nebulizers are preferred because they minimize exposing the therapeutic compound to shear, which can result in degradation of the composition.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of the therapeutic composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (T weens, Pluronics, or polyethylene glycol); innocuous proteins such as semm albumin, sorbitan esters, oleic acid, lecithin; amino acids such as glycine; buffers; salts; sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • compositions of the present invention are present on a patch, such as a transdermal patch, a dressing, a bandage, a gauze, a membrane or some other carrier which will allow the delivery system to stay adhered to the site of interest.
  • the site of interest can be a surgical wound, an anal fissure, a hemorrhoid, a lesion, a surgical incision or some other area wherein pain relief is desired.
  • the composition is in direct contact with the site of interest.
  • This delivery system optionally contains an adhesive which attaches and preferably strongly attaches to the site of interest.
  • the patch or bandage will be affixed to the site of interest with additional adhesive, such as surgical tape or wound dressing tape.
  • the present invention provides a wound dressing comprising a sterile bandage including an effective amount of a guanylate cyclase inhibitor or a redox dye and a topical anesthetic sufficient to alleviate pain.
  • a guanylate cyclase inhibitor or a redox dye and topical anesthetics have been described above.
  • the guanylate cyclase inhibitor or redox dye is methylene blue and the topical anesthetic is lidocaine.
  • the material for bandage manufacture is well known to those of skill in the art.
  • Suitable bandage materials include, but are not limited to, nontoxic polymers, particularly those types used to carry dmgs for transdermal delivery, natural or synthetic elastomers, polyisobutylene, styrene, butadiene, acrylic acid polyacrylates, cellulose and cellulose derivatives and polymers typically used for bandages and wound dressings.
  • compositions of the present invention are useful for coating medical devices.
  • medical devices include, but are not limited to, catheters, needles, sutures, clips, staples and other instruments wherein a mammal is subject to pain during insertion of the device or instrument.
  • compositions of the present invention are useful for coating medical devices which are implanted for use. These devices include, but are not limited to, insulin pumps, dialysis needles and transfusion needles.
  • This example illustrates a clinical trial and therapy using a composition of the present invention.
  • Participants A total of 5000 subjects were selected for this trial. Each individual had a clinically established case of third degree hemorrhoids. Subjects were male or female, between the age of 20 years to 65 years, with various body weights, and no diagnosed complications. The 5000 subjects represented a cross section of the population. All subjects underwent hemorrhoidectomies. All subjects were of Chinese descent. Physical parameters such as body weight, body mass index, height, medications, and diet were measured and recorded for each subject.
  • the subjects were initially screened and randomly assigned into one of two groups.
  • Group I consisted of those taking the traditional pain relief medication only.
  • Group II were those using the compositions as set forth herein as well as in some instances other pain relief medication.
  • the composition of the present invention was provided to each subject in at least one dose and in some instances multiple subeffective doses, which cumulatively equaled the effective dose.
  • the total dosage of four-to-one lidocaine (two percent) methylene blue (two percent) was provided to each subject.
  • compositions of the present invention were generally administered when the patients were in an unconscious or semiconscious state, after the hemorrhoidectomy was performed. The administration was typically performed right after surgery.
  • composition was injected with an effective dose, or alternatively, multiple injections with subeffective doses that cumulatively equaled an effective dose into the area where the patient felt pain.
  • Table 1 and Table 2 summarizes the study, with Table 1 containing the data from participants who were administered the compositions of the present invention. Table 2 contains the data from participants taking traditional medication.
  • compositions of this invention lasted over twenty days and the local nerve endings were completely restored in about thirty days. No side effects were observed in any of the cases.
  • compositions of the present invention can return to their usual activities with minimal or no discomfort on the second day after surgery. For most patients, hospitalization is usually unnecessary.
  • the compositions of this invention also make it possible to perform hemorrhoidectomies on older and weaker patients. It makes the surgical therapy a much more easy experience for patients.
  • a patient having anal fissures is selected for therapy using the present invention.
  • a composition of methylene blue and lidocaine is prepared in a cream vehicle at a concentration of one percent to five percent (weight/volume), typically two and a half percent and is applied to the affected skin. After the first day of treatment, no pain is associated with the anal fissure.
  • Example 3 This example illustrates a formulation of the composition.
  • the formulation known as composition 1 had the following specification: one milliliter of two percent methylene blue (ten milligrams); four milliliters of two percent lidocaine; five milliliters of distilled water.

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Abstract

L'invention concerne une thérapie sûre et efficace pour le traitement de la douleur liée aux incisions chirurgicales, aux blessures, aux coupures et aux abrasions. L'invention concerne également une composition pharmaceutique renfermant une combinaison à base d'inhibiteur de guanylate cyclase et d'anesthésique local ou une combinaison à base de colorant redox et d'anesthésique local. Ce type de composé et le traitement susmentionné peuvent être utilisés pour supprimer ou atténuer la douleur résultant des procédures chirurgicales, en particulier dans le cas de la chirurgie anale.
PCT/US1999/027498 1998-11-23 1999-11-18 Combinaison a base d'inhibiteur de guanylate cyclase et d'anesthesique local tenant lieu d'analgesique Ceased WO2000030630A1 (fr)

Priority Applications (1)

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AU18243/00A AU1824300A (en) 1998-11-23 1999-11-18 Combination products of a guanylate cyclase inhibitor and a local anesthetic forpain relief

Applications Claiming Priority (2)

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US19818998A 1998-11-23 1998-11-23
US09/198,189 1998-11-23

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EP1669064A1 (fr) * 2004-12-10 2006-06-14 Bionics Pharma Gmbh Composition et méthode d'une thérapie topique de la néurodermite
WO2006096913A1 (fr) 2005-03-15 2006-09-21 Animal Ethics Pty Ltd Une composition anesthesique locale
WO2007008119A1 (fr) * 2005-07-12 2007-01-18 El Fatih Osman Hassan Utilisation du ketoprofene pour le traitement des hemorroides
WO2007003435A3 (fr) * 2005-07-06 2007-04-26 Bayer Healthcare Ag Utilisation d'activateurs de la guanylate cyclase soluble pour favoriser la guerison de blessures
US7407953B2 (en) 2004-09-20 2008-08-05 Photopharmica Limited Wound healing
US7928141B2 (en) * 2005-07-12 2011-04-19 Fuchao Li Synergistic compositions and methods for enhancing potency and/or for prolonging the duration of action of anesthetics
AU2007221941B2 (en) * 2005-03-15 2012-08-23 Animal Ethics Pty Ltd A topical anaesthetic composition
WO2020210889A1 (fr) * 2019-04-18 2020-10-22 Hexsel, Doris Maria Composition d'encre pour marquage de tissu organique avec anesthésiant, et son procédé d'application

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005026741A3 (fr) * 2003-09-08 2005-08-18 Us Gov Health & Human Serv Agonistes et antagonistes non peptidiques d'adrenomedulline et peptide de liberation gastrique
AU2004273057B2 (en) * 2003-09-08 2010-05-27 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Non-peptide agonists and antagonists of adrenomedullin and gastrin releasing peptide
AU2004273057C1 (en) * 2003-09-08 2011-06-30 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Non-peptide agonists and antagonists of adrenomedullin and gastrin releasing peptide
US7407953B2 (en) 2004-09-20 2008-08-05 Photopharmica Limited Wound healing
EP1669064A1 (fr) * 2004-12-10 2006-06-14 Bionics Pharma Gmbh Composition et méthode d'une thérapie topique de la néurodermite
AU2007221941B2 (en) * 2005-03-15 2012-08-23 Animal Ethics Pty Ltd A topical anaesthetic composition
WO2006096913A1 (fr) 2005-03-15 2006-09-21 Animal Ethics Pty Ltd Une composition anesthesique locale
US9592318B2 (en) 2005-03-15 2017-03-14 Animal Ethics Pty Ltd Topical analgesic composition
US8960128B2 (en) 2005-03-15 2015-02-24 Animal Ethics Pty Ltd Topical anesthetic composition
US8822416B2 (en) 2005-03-15 2014-09-02 Animal Ethics Pty Ltd. Topical analgesic composition
WO2007003435A3 (fr) * 2005-07-06 2007-04-26 Bayer Healthcare Ag Utilisation d'activateurs de la guanylate cyclase soluble pour favoriser la guerison de blessures
EP2301547A1 (fr) * 2005-07-06 2011-03-30 Bayer Schering Pharma AG Utilisation d'activateurs de le guanylate cyclase pour favoriser la guérison des blessures
KR101243519B1 (ko) * 2005-07-12 2013-03-20 푸차오 리 국부 마취약의 마취시간 지연제
US7928141B2 (en) * 2005-07-12 2011-04-19 Fuchao Li Synergistic compositions and methods for enhancing potency and/or for prolonging the duration of action of anesthetics
WO2007008119A1 (fr) * 2005-07-12 2007-01-18 El Fatih Osman Hassan Utilisation du ketoprofene pour le traitement des hemorroides
WO2020210889A1 (fr) * 2019-04-18 2020-10-22 Hexsel, Doris Maria Composition d'encre pour marquage de tissu organique avec anesthésiant, et son procédé d'application

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